“Adoptive T-Cell” Immunotherapy Shows Activity Against Advanced Ovarian Cancer in Phase I Study

In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania School of Medicine show that a two-step personalized immunotherapy treatment — a dendritic cell vaccine using the patient’s own tumor followed by adoptive T cell therapy — triggers anti-tumor immune responses in advanced ovarian cancer patients.

Most ovarian cancer patients are diagnosed with late stage disease that is unresponsive to existing therapies. In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania School of Medicine show that a two-step personalized immunotherapy treatment — a dendritic cell vaccine using the patients’ own tumor followed by adoptive T cell therapy — triggers anti-tumor immune responses in these type of patients. Four of the six patients treated in the phase I trial responded to the therapy, the investigators report this month in OncoImmunology.

“What we proved in this study is that this is a safe treatment strategy,” says co-first author Lana Kandalaft, PharmD, MTR, Ph.D., research assistant professor of Obstetrics and Gynecology and director of clinical development in the Ovarian Cancer Research Center. “It is a walk in the park for patients, especially compared to standard chemotherapies and surgical treatments for ovarian cancer – literally, some patients left the clinic and went for a walk in a nearby park after their treatment.”

The findings follow research by the study’s senior author, George Coukos, M.D., Ph.D., director of the Ovarian Cancer Research Center at Penn, who showed in 2003 that women whose ovarian tumors were infiltrated by healthy immune cells, called T cells, tended to live longer than women whose tumors were devoid of T cells. That observation and other subsequent ones suggest the patient’s immune system is trying to fight off the disease but can’t quite muster the strength to beat it. Therefore, investigators have been trying to find ways using patients’ own tumor cells to boost the immune system’s power.

Adoptive T-Cell Therapy Approach

In the first segment of the study, the University of Pennsylvania researchers prepared an individualized dendritic cell vaccine for each ovarian cancer patient. (Photo Credit: Penn Medicine)

In the current study, Coukos, Kandalaft, co-first author Daniel J. Powell Jr., PhD, research assistant professor of Pathology and Laboratory Medicine, and colleagues treated six women with advanced ovarian cancer in a two-staged immunotherapy protocol in which they utilized a dendritic cell vaccine created from tissue in the patients’ own tumor, which was stored at time of surgery. All of these women’s cancers had progressed on standard of care chemotherapy.

In the first segment of the study, the team prepared an individualized dendritic cell vaccine for each patient. They harvested dendritic cells from each patient using apheresis, the same process volunteers go through when they donate platelets or other blood products such as those collected for stem cell transplants. Kandalaft and colleagues then exposed each patient’s dendritic cells to tumor extract produced from the woman’s ovarian cancer tumor, which teaches the dendritic cells who the enemy is. After this priming, the investigators vaccinated each patient with her own dendritic cells and gave them a combination chemotherapy regimen consisting of bevacizumab (Avastin) and  metronomic cyclophosphamide. Because dendritic cells are like the generals of the immune system, they then induce other immune cells to take up the fight.

Of the six advanced ovarian cancer patients who received the dendritic cell vaccine, four patients developed an anti-tumor immune response, indicating that the approach was working. One of those patients had no measurable disease at study entry because all of it had been successfully removed during surgery. She remains in remission today, 42 months following vaccine treatment. The remaining three who had an immune response to the vaccine still had residual disease and went on to the second segment of treatment.

In the second segment of the study, T cells were harvested from the ovarian cancer patients, grown in the laboratory, thereby expanding their numbers exponentially, and then were reintroduced into each patient after she underwent a lymphodepleting chemotherapy regimen. (Photo Credit: Penn Medicine)

In the second segment of the study, the team harvested T cells from each of the three women mentioned above. Using a technique developed at Penn, the researchers grew the cells in the laboratory, expanding their numbers exponentially, and then reintroduced them into each patient after she underwent a lymphodepleting chemotherapy regimen. Because the T cells had already been trained by the dendritic cell vaccine to attack the tumor cells, the adoptive T cell transfer amplifies the anti-tumor immune response.

Two of the women showed a restored immune response after the T cell transfer. One of the women continued to have stable disease, whereas the other had a complete response to the therapy.

The researchers say it is too early to say whether this type of therapy will be effective in a large number of ovarian cancer patients, but the early results are promising. First, and foremost, she notes, the two-step approach appears safe and well tolerated by the patients. Additionally, the team saw a correlation in both treatment steps between immune responses and clinical benefit, suggesting that it is, in fact, the immune response that is holding the disease in check.

With these encouraging results in hand, the team has opened a larger trial (UPCC-19809 & UPCC-26810; clinical trial protocols listed below) in which they have already enrolled about 25 women and aim for up to 30 more. The new protocol uses an improved vaccine platform and an optimized adoptive T cell transfer protocol. The prinicipal investigator of this study is Janos Tanyi, MD, PhD.

“Large clinical trials have shown that intensifying chemotherapy doesn’t improve outcomes for women with advanced ovarian cancer,” Coukos says. “So we need to explore other avenues. We think the combinatorial approach of both immune and chemotherapy is the way to go.”

Other co-authors from Penn include Cheryl L. Chiang, Janos Tanyi, Sarah Kim, Kathy Montone, Rosemarie Mick, Bruce L. Levine, Drew A. Torigian, and Carl H. June. Co-author Marnix Bosch is from Northwest Biotherapeutics in Bethesda, Maryland.

This study was supported by National Cancer Institute Ovarian SPORE grant P01-CA83638, National Institution of Health R01FD003520-02, and the Ovarian Cancer Immunotherapy Initiative. 

___________________________

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

____________________________

Sources:

Kandalaft L, Powell D, Chiang C, et. al. Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer. OncoImmunology 2013; 2:e22664; http://dx.doi.org.

Two-Step Immunotherapy Attacks Advanced Ovarian Cancer, Penn Medicine Researchers Report, Penn Medicine, Press Release, January 31, 2013.

Closed Clinical Trial Protocols (two study segments discussed above):

Study Segment One: A Phase I Clinical Trial of Autologous Dendritic Cell Vaccine Loaded With Autologous Tumor Cell Lysate for Recurrent Ovarian or Primary Peritoneal Cancer; ClinicalTrials.gov Identifier: NCT00683241; UPCC ID: 11807.

Study Segment Two: A Phase-I/II Randomized Trial of Maintenance Vaccination Combined With Metronomic Cyclophosphamide w/wo Adoptive Transfer of CD3/CD28-CoStimulated T-Cells for Recurrent Ovarian or Primary Peritoneal Cancer Previously Vaccinated DCVax-L; ClinicalTrials.gov Identifier: NCT00603460; UPCC ID: 10808

Open Clinical Trial Protocols (enrolling new patients, as of this writing):

A Pilot Clinical Trial of Dendritic Cell Vaccine Loaded With Autologous Tumor for Recurrent Ovarian, Primary Peritoneal or Fallopian Tube Cancer;  ClinicalTrials.gov ID: NCT01132014;  UPCC ID: 19809. [currently recruiting patients]

A Phase-1 Trial of Adoptive Transfer of Vaccine-Primed CD3/CD28-Costimulated Autologous T-Cells Combined With Vaccine Boost and Bevacizumab for Recurrent Ovarian Fallopian Tube or Primary Peritoneal Cancer Previously Vaccinated With Autologous Tumor Vaccine; ClinicalTrials.gov ID: NCT01312376;  UPCC ID: 26810. [currently recruiting patients]

Related Libby’s H*O*P*E* Articles:

Gene Transfer Therapy Destroys Tumors in Chronic Lymphocytic Leukemia Patients; Holds Promise For Ovarian Cancer, by Paul Cacciatore, August 11, 2011.

Penn’s Genetically Modified T Cells Create Antitumor Effect In Mice With Folate Positive Ovarian Cancer; Clinical Trial Pending, by Paul Cacciatore, August 17, 2011.

ENMD-2076 Monotherapy Demonstrates Anti-Cancer Activity in Recurrent, Platinum-Resistant Ovarian Clear Cell Carcinoma

An Aurora A/angiogenic kinase inhibitor named “ENMD-2076” demonstrated anti-cancer activity in recurrent, platinum-resistant epithelial ovarian cancer patients, including three patients with a difficult-to-treat subtype of the disease referred to as “clear cell carcinoma.”

An Aurora A/angiogenic kinase inhibitor named “ENMD-2076” demonstrated anti-cancer activity in recurrent, platinum-resistant epithelial ovarian cancer patients, including three patients with a difficult-to-treat subtype of the disease referred to as “clear cell carcinoma.” The trial drug results were reported in connection with a phase II clinical trial testing of ENMD-2076. The findings associated with ENMD-2076 were published in the January 2013 edition of the European Journal of Cancer.

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers.

The phase II trial was an open-label, single-arm Phase II study of single agent ENMD-2076 taken daily (orally). The study enrolled 64 patients, and the progression-free survival (PFS) rate at 6 months was 22%, with a median time-to-progression of 3.6 months. The median number of prior treatment regimens per patient was two. The most common adverse events were fatigue, hypertension and diarrhea, with the most significant events being hypertension and fatigue. Unfortunately, none of the markers of mitotic index or angiogenesis evaluated in the archival tissue samples obtained were predictive of greater benefit or resistance to ENMD-2076 treatment.

Based on the foregoing results, the clinical investigators concluded that ENMD-2076 possesses anti-cancer activity in recurrent, platinum-resistant ovarian cancer, and they observed  toxicities were similar to other protein kinase inhibitors. The clinical investigators also noted that additional studies with ENMD-2076 are warranted, especially in combination with active chemotherapeutic agents in platinum-resistant patients. The investigators added that further work to determine appropriate biomarkers for ENMD-2076 should be incorporated into new clinical studies.

The co-authors of the article include clinical investigators from the Memorial Sloan-Kettering Cancer Center, Indiana University Simon Cancer Center, University of Colorado, and University of Chicago in the U.S., as well as the Princess Margaret Hospital and Campbell Family Institute for Cancer Research in Toronto, Canada.

Ursula A. Matulonis, M.D., Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute

Lead study author Dr. Ursula A. Matulonis, who is the medical director of Gynecologic Oncology at the Dana-Farber Cancer Institute, commented on the publication as follows:

“Epithelial ovarian cancer represents the 4th leading cause of cancer deaths among women in the United States. There is unmet medical needs to develop new drugs with fewer side effects and/or better efficacy to improve the quality and duration of life of the patients, especially those whose cancer is resistant to platinum treatment.

ENMD-2076 is a novel small molecule kinase inhibitor with unique combination of mechanisms of action that involve inhibition of several pathways key to tumor growth and survival including angiogenesis, proliferation, and the cell cycle. Based on pre-clinical and Phase 1 clinical studies of ENMD-2076, we believed that the drug candidate may play a role in fitting some of the unmet medical needs. This Phase 2 trial further demonstrates the anti-cancer activity of ENMD-2076 in yet a difficult to treat patient population of platinum-resistant ovarian cancer with tolerable side effects.”

Notably, Dr. Matulonis also commented on the anti-cancer activity of ENMD-2076 in three ovarian clear cell carcinoma patients as follows:

“ENMD-2076 also showed anti-cancer activities in patients with clear cell carcinoma [CCC], a histological subtype considered as chemo-resistant. Two of three [CCC] patients recruited had longer PFS than the median with one patient in stable disease for over two years. As recent reports suggest VEGF is frequently expressed in clear cell cancers, this subtype might be particularly responsive to therapies that incorporate VEGF inhibition. Further clinical evaluations of ENMD-2076 may therefore be warranted in this patient subset either as a single agent or in combinations.” [emphasis added]

Ken Ren, Ph.D., EntreMed’s Chief Executive Officer, further commented:

“We are very pleased and honored to have this Phase 2 trial data published in such an esteemed journal. This is a further endorsement of the global medical and science community on the clinical and scientific value of ENMD-2076 in ovarian cancer treatment. We truly believe that ENMD-2076 may potentially offer unique and competitive advantages for unmet medical needs in such difficult to treat oncology indications including platinum-resistant and/or clear cell ovarian cancer in improving the patients’ quality and duration of life. We are committed to the global clinical development of ENMD-2076 for cancer patients who might benefit from its therapy. With the support of clinical investigators like Dr. Matulonis, their commitment and dedication, and the support from our long term shareholders, we are confident that we can achieve our goal.”

About EntreMed

EntreMed, Inc. is a clinical-stage pharmaceutical company employing a drug development strategy primarily in the United States and China to develop targeted therapeutics for the global market. Its lead compound, ENMD-2076, a selective angiogenic kinase inhibitor, has completed several Phase 1 studies in solid tumors, multiple myeloma, and leukemia, and is currently completing a multi-center Phase 2 study in ovarian cancer. EntreMed, Inc. recently initiated a dual-institutional Phase 2 study of ENMD-2076 in triple-negative breast cancer. Additional information about EntreMed is available on the Company’s web site at www.entremed.com.

About ENMD-2076

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers. ENMD-2076 has shown promising activity in Phase 1 clinical trials in solid tumor cancers, leukemia, and multiple myeloma. ENMD-2076 is currently completing a Phase 2 trial for ovarian cancer. EntreMed, Inc. recently initiated a dual-institutional Phase 2 study of ENMD-2076 in triple-negative breast cancer.

ENMD-2076 received orphan drug designation from the United States Food and Drug Administration (FDA) for the treatment of ovarian cancer, multiple myeloma and acute myeloid leukemia (AML). In the United States, the Orphan Drug Act is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 people in this country. Orphan drug designation provides seven years of market exclusivity that begins once ENMD-2076 receives FDA marketing approval. It also provides certain financial incentives that can help support the development of ENMD-2076.

Citation:

Matulonis UA, Lee J, Lasonde B, et. al. ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer. Eur J Cancer. 2013 Jan;49(1):121-31.doi:10.1016/j.ejca.2012.07.020. PubMed PMID: 22921155.

Additional Source:

Dana-Farber Cancer Institute’s Ursula A. Matulonis, M.D. Article on EntreMed’s ENMD-2076 Published in the European Journal of Cancer, EntreMed, Inc. Press Release, Sept. 6, 2012.

ENMD-2076 Phase II Ovarian Cancer Clinical Trial Protocol Summary:

A Phase 2 Study of Oral ENMD-2076 Administered to Patients With Platinum Resistant Ovarian Cancer, ClinicalTrials.gov Identifier: NCT01104675 (study ongoing, but not recruiting patients).

PARP Inhibitor Olaparib Has Activity in High-Grade Serous Ovarian Cancer Without Inherited BRCA1 or BRCA2 Gene Mutations

Researchers affiliated with the British Columbia Cancer Agency reported Phase 2 clinical study results indicating that advanced ovarian cancer, with and without germline (inherited) BRCA 1 or BRCA 2 gene mutations, responded to treatment with the PARP inhibitor olaparib. The Phase 2 study results were published online in the August 21 edition of The Lancet Oncology.

Karen A. Gelmon, M.D., Lead Study Author, Medical Oncologist, and Head of the Investigational Drug Program, Experimental Therapeutics, Department of Medical Oncology, British Columbia Cancer Agency

Researchers affiliated with the British Columbia Cancer Agency reported results from a Phase 2 clinical study indicating that advanced ovarian cancer, with and without germline (inherited) BRCA 1 or BRCA 2 gene mutations, responded to treatment with the PARP (poly(ADP-ribose) polymerase ) inhibitor olaparib (a/k/a AZD2281).[1] The Phase 2 study results were published online in the August 21 edition of the Lancet Oncology.

Preliminary findings from this study were reported at the 2011 American Society of Clinical Oncology annual meeting, which was held in Chicago earlier this year. [2]

The Phase 2 study results indicate that approximately 41% of women with BRCA1 or BRCA 2-mutated ovarian cancer had objective responses to the targeted agent, along with 24% of patients with non-BRCA gene mutated ovarian cancer. The findings suggest that the PARP inhibitor olaparib might have broad applicability in ovarian cancer.

Unfortunately, the drug olaparib failed to produce any objective responses in patients with non-BRCA gene mutated, triple negative breast cancer. Triple negative breast cancer is a difficult to treat subtype of the disease that lacks three of the cellular “receptors” known to fuel most breast cancers: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2).

Background

Olaparib is a small-molecule, potent oral PARP inhibitor. Olaparib targets PARP, an enzyme essential for repair of single-strand DNA breaks. Preclinical evidence showed that the drug olaparib had activity against tumors with homologous recombination (HR) DNA repair defects, such as those caused by BRCA 1 or BRCA 2 gene mutations.

Germline (inherited) BRCA 1 or BRCA 2 gene mutations confer a high risk of breast and ovarian cancers, and tumors arising from the mutations have aggressive tendencies, such as triple-negative breast cancer. PARP inhibition has already demonstrated activity in cancers with germline mutations. Accordingly, the goal of the Canadian researchers was to assess the safety and tolerability of this drug in patients with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer, which did not possess BRCA1 or BRCA2 mutations.

Past study reporting associated with olaparib over the past twelve months has been somewhat mixed. Data reported at the 2010 European Society of Medical Oncology annual congress showed no significant effect of olaparib on progression-free survival (PFS) in women with advanced BRCA gene-mutated ovarian cancer. [3] In contrast, data presented at the 2011 American Society of Clinical Oncology meeting showed almost a doubling of PFS with olaparib among women with relapsed, platinum-sensitive ovarian cancer. [4]

Olaparib Phase 2 Study Design

The olaparib Phase 2 study enrolled women into 4 cohorts or trial arms. The two stage trial design included:

• BRCA 1 or BRCA 2 gene mutation negative (or unknown mutation status) patients with high-grade serous, undifferentiated, fallopian-tube, or primary peritoneal cancer (Arm A) or triple-negative breast cancer (Arm B); and

• Two reference groups with recurrent ovarian cancer (Arm C) or breast cancer (Arm D) who possessed BRCA 1 or BRCA 2 gene mutations.

All patients had tumor biopsies taken prior to treatment, after 2 cycles of treatment, and at disease progression to assess PARP inhibitor activity, loss of heterozygosity, gene mutational changes, BRCA 1 or BRCA 2 gene expression, and other markers of response. Computed tomography (CT)/magnetic ressonance imaging (MRI) assessments were performed prior to treatment and at every 2 treatment cycles. The patients were treated with single agent olaparib (400 mg twice a day) on a continuous basis in 4 week cycles.

Researchers at six centers in Canada enrolled 91 patients in this Phase 2, open-label, nonrandomized trial (ClinicalTrials.gov ID: NCT00679783). [5] Eligible patients had advanced metastatic or recurrent breast cancer, or advanced ovarian cancer.

The study population consisted of 65 patients with ovarian cancer and 26 patients with breast cancer. All of the breast cancer patients and 64 ovarian cancer patients received at least one dose of olaparib (400 mg twice a day) and were included in the final study analysis.

The ovarian cancer cohort consisted of 17 patients with BRCA gene mutations and 47 patients without BRCA gene mutations. The breast cancer cohort consisted of 10 patients with BRCA gene mutations and 16 patients without BRCA gene mutations.

The researchers reported that 58 patients with ovarian cancer had the serous subtype (13 patients with BRCA gene mutations, 45 patients without BRCA gene mutations). In the breast cancer cohort, 21 patients had triple-negative disease, including five patients with BRCA gene mutations.

The primary endpoint of the Phase 2 study was objective response, as determined by RECIST (Response Evaluation Criteria In Solid Tumors) criteria.

Olaparib Phase 2 Study Results

None of the breast cancer patients had objective responses, and the disease control rate (proportion of patients with complete response, partial response, or stable disease) at eight weeks was 38% (10 of 26 patients).

In the ovarian cancer cohort, seven of 17 (41%) patients with BRCA gene mutations, and 11 of 46 (24%) patients without BRCA gene mutations, experienced objective responses. The overall disease control rate was 66% (42 of 64), including benefit in 76% (11 of 17) of BRCA-negative patients and 62% (29 of 47) of the BRCA-positive subgroup.

The researchers reported: “Although responses were seen in both platinum-sensitive and platinum-resistant populations, our post hoc analysis reported activity mostly in patients with platinum-sensitive disease.” As a precaution, the researchers noted that their findings should be interpreted conservatively because of the small study sample size.

Among the ovarian cancer patients, there were thirteen premature discontinuations, without confirmed radiological disease progression. Six patients dropped out of the Phase 2 olaparib study. Of those patients, three women dropped out because of worsening disease, and three more women dropped out because of adverse events. One patient in the breast cancer group discontinued early because of an adverse event.

The most common adverse events in ovarian and breast cancer patients were fatigue (58 patients), nausea (58), vomiting (34), and decreased appetite (30).

“To our knowledge, this study is the first to show that olaparib monotherapy has activity in women with pretreated high-grade serous ovarian cancer without germline BRCA1 or BRCA2 mutations,” said Karen A. Gelmon, M.D., lead study author, medical oncologist, and head of the Investigational Drug Program, Experimental Therapeutics, within the department of medical oncology of the British Columbia Cancer Agency, along with her co-authors. Dr. Gelmon is also a professor of  medicine at the University of British Columbia.

“New treatments targeting DNA repair mechanisms seem to provide new hope for treatment of ovarian cancer,” the Canadian researchers added. “Subsequent reports of this study assessing tumor biopsies might identify which patients obtain most clinical benefit from olaparib.”

Expert Commentary

Melinda Telli, M.D., Assistant Professor, Stanford School of Medicine, Stanford University

The study findings by Gelmon et al. were accompanied by a commentary which was written by Melinda L. Telli, M.D., assistant professor, Stanford School of Medicine. [6] In that commentary, Dr. Telli states:

… Their [Gelson et al.] study is noteworthy in that it shows, for the first time, activity of a PARP inhibitor as monotherapy in women with advanced high-grade serous ovarian cancer who do not have a germline BRCA1 or BRCA2 mutation. This finding not only suggests new therapeutic possibilities for women with this aggressive type of ovarian cancer, but also importantly confirms the hypothesis that subpopulations of patients with common sporadic tumors can be targeted effectively with PARP inhibitor therapy. An additional important negative finding of this study was the absence of objective responses to single-agent olaparib in women with sporadic triple-negative breast cancer, although the numbers were small and patients heavily pretreated. With new therapies come new challenges, and the clinical development of PARP inhibitors has certainly encountered many obstacles. Thus, to see the potential of these drugs realized is particularly satisfying. This important finding of activity in high-grade serous ovarian cancer marks a new beginning to what will hopefully be a long and fruitful future for PARP inhibitors as they make their move beyond BRCA.

Another expert expressed excitement about the future potential of olaparib. Stephanie V. Blank, M.D., an assistant professor in clinical gynecologic oncology at NYU School of Medicine, said:

It is extremely exciting that an agent as promising as olaparib can be effective in a broader group of women than had been expected. The next challenge will lie in getting our hands on the drug, which at present is only available for patients on clinical trials.

Study Relationship Disclosures

The study was supported by AstraZeneca. Gelmon and several co-authors disclosed relationships with AstraZeneca. The co-authors included AstraZeneca employees. Dr. Telli reported no relevant disclosures.

Libby’s H*O*P*E* Commentary

We would like to extend our congratulations to Dr. Gelmon, as well as her co-investigators, many of whom are critical team members of  the Ovarian Cancer Research Program of British Columbia (OvCaRe). On September 8, 2010, we reported on the OvCaRe team finding of prevalent ARID1A gene mutations in endometriosis-associated, epithelial ovarian cancers (i.e., clear cell and endometrioid). [7]

The findings reported by Gelmon et al. will take on critical importance if it is eventually proven that PARP inhibitors could benefit up to 50% of high-grade serous ovarian cancer patients who possess germline (inherited) or somatic (lifetime acquired) mutations in the BRCA 1 or BRCA 2 gene, or other alternations in the HR DNA repair pathway, as suggested by past preclinical study findings, [8] including those recently reported by The Cancer Genome Atlas. [9]

References

1/ Gelmon KA, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase II, multicenter, open-label, nonrandomized study. Lancet Oncol 2011; 12: 852-861. [Abstract]

2/Gelmon KA, et al. Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. J Clin Oncol 28:15s, 2010 (suppl; abstr 3002) [2011 American Society of Clinical Oncology Annual Meeting, Abstract 3002]

3/Kaye S, et al Phase II study of the oral PARP inhibitor olaparib (AZD2281) versus liposomal doxorubicin in ovarian cancer patients with BRCA1 and/or BRCA2 mutations. Annals of Oncology 2010 21(8)8): viii304–viii313, 2010 doi:10.1093/annonc/mdq526 [2010 European Society of Medical Oncology Annual Meeting, Abstract 9710, Adobe Reader PDF Document].

4/Ledermann JA, et al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). J Clin Oncol 29: 2011 (suppl; abstr 5003) [2011 American Society of Clinical Oncology Annual Meeting, Abstract 5003]

5/Phase II, Open Label, Non-Randomized Study of AZD2281 in the Treatment of Patients With Known BRCA or Recurrent High Grade Serous/ Undifferentiated Tubo-Ovarian Carcinoma and in Known BRCA or Triple Negative Breast Cancer to Determine Response Rate and Correlative Markers of Response, ClinicalTrials.gov ID: NCT00679783.

6/Telli ML. PARP inhibitors in cancer: Moving beyond BRCA. Lancet Oncol 2011; 12: 827-828. [Full Text]

7/British Columbian Researchers Make Groundbreaking Genetic Discovery In Endometriosis-Associated Ovarian Cancers, by Paul Cacciatore, Libby’s H*O*P*E*™, September 8, 2010.

8/New Assay Test Predicts That 50% of Ovarian Cancers Will Respond To In Vitro PARP Inhibition, by Paul Cacciatore, Libby’s H*O*P*E*™, November 11, 2010.

9/In-Depth Review: The Cancer Genome Atlas Reports On Landmark Analysis of High-Grade Serous Ovarian Cancer, by Paul Cacciatore, Libby’s H*O*P*E*™, August 5, 2011.

Additional Sources:

• PARP Inhibitor Active in Non-BRCA Ovarian Cancer, by Charles Bankhead, Staff Writer, MedPage Today, August 21, 2011.

• Trial Drug Shows Preliminary Promise Against Ovarian Cancer, Doctor’s Lounge, August 21, 2011.

PARP Inhibitor Clinical Trial Information

• A list of open PARP inhibitor ovarian cancer clinical trials.

• A list of open PARP inhibitor solid tumor clinical trials.

Related Libby’s H*O*P*E* Posts

• Inherited Mutations in RAD51D Gene Confer Susceptibility to Ovarian Cancer, August 7, 2011.

• In-Depth Review: The Cancer Genome Atlas Reports On Landmark Analysis of High-Grade Serous Ovarian Cancer, August 5, 2011.

• ASCO 2011: Maintenance Therapy With PARP Inhibitors Could Play Important Role in Treatment of Recurrent Ovarian Cancer, May 19, 2011.

• PARP Inhibitor MK-4827 Shows Anti-Tumor Activity in First Human Clinical Study, November 17, 2010.

• New Assay Test Predicts That 50% of Ovarian Cancers Will Respond To In Vitro PARP Inhibition, November 11, 2010.

• PARP Inhibitor Olaparib Benefits Women With Inherited Ovarian Cancer Based Upon Platinum Drug Sensitivity, April 23, 2010.

Related WORD of HOPE Ovarian Cancer Podcast

• 10 Exciting Ovarian Cancer Research Topics from 2010 — PARP Inhibitors & BRCA Gene-Mutated Ovarian Cancer (Topic #2 of 10), Episode #2, WORD of HOPE Ovarian Cancer Podcast, April 11, 2011.

2011 ASCO: Exelixis Reports Expanded Cabozantinib (XL184) Phase II Data For Advanced Ovarian Cancer; Six Deaths Reported

Exelixis, Inc. reported expanded Phase 2 study data with respect to cabozantinib (XL184) use in advanced ovarian cancer patients at the recent 2011 American Society of Clinical Oncology Annual Meeting. The overall solid tumor Phase 2 safety and tolerability data reference six deaths, including two ovarian cancer patients.

Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Departments of Internal Medicine & Obstetrics and Gynecology, University of Michigan

Exelixis, Inc. reported expanded Phase 2 study data with respect to cabozantinib (XL184) use in advanced ovarian cancer patients at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting . The overall solid tumor Phase 2 safety and tolerability data refers to six deaths, including two ovarian cancer patients.

On May 19, 2011, we reported promising cabozantinib phase 2 solid tumor (including ovarian) data, which was presented at an ASCO press briefing held in advance of the 2011 ASCO Annual Meeting. As noted in our May 19 article, cabozantinib demonstrated excellent activity against several solid tumors, including ovarian cancer. In addition, we reported that cabozantinib showed promising activity in ovarian cancer patients independent of prior response to platinum drug-based therapies.

Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Departments of Internal Medicine & Obstetrics and Gynecology, University of Michigan, presented the expanded cabozantinib Phase 2 data relating to use of the drug in advanced ovarian cancer patients, on June 4 at the 2011 ASCO Annual Meeting.

Ovarian Cancer Patient Population & Overall Response Rate

(Image Source: Exelixis, Inc.)

The cabozantinib trial is an ongoing phase 2 adaptive randomized discontinuation trial. As of the February 11, 2011 cut-off date, accrual in the cabozantinib study cohort was complete at 70 patients.

The 70 patients enrolled in the ovarian cancer cohort received oral cabozantinib (100 mg) daily over a 12 week “Lead-in Stage.” These patients had a minimum follow-up of at least 12 weeks and were thus evaluable for safety and the primary efficacy endpoint of response per RECIST (Response Evaluation Criteria in Solid Tumors).

Patient tumor response was assessed every 6 weeks. Receipt of cabozantinib treatment beyond the 12 week open label Lead-in Stage was based upon patient response: (1) patients with a partial response (PR) or complete response (CR) continued taking cabozantinib, (2) patients with stable disease (SD) were randomized to the cabozantinib treatment arm or the placebo treatment arm (collectively referred to as the “Blinded Randomized Stage”), and (iii) patients with progressive disease (PD) discontinued study treatment. The study primary endpoint was overall response rate (ORR) per RECIST in the Lead-in Stage, and progression free survival (PFS) in the Blinded Randomized Stage. Accrual in any cohort could be halted for high ORR or PD.

Approximately half of the 70 patients enrolled in the cohort were considered platinum drug-refractory/-resistant (49%), defined as a platinum drug-free interval of 6 months or less, and the remainder of patients (51%) had platinum-sensitive disease based on a platinum-free interval greater than 6 months.

The baseline patient tumor histologic characteristics are as follows: serous ovarian cancer (79%), clear cell ovarian cancer (4%), endometrioid ovarian cancer (6%), and other forms of ovarian cancer (11%)

More than half the patients (57%) received 2 or more prior lines of platinum therapy prior to trial enrollment. Some patients also had additional prior lines of therapy with agents such as pegylated liposomal doxorubicin (brand name: Doxil®) or topotecan (brand name: Hycamtin®) (32%), gemcitabine (brand name: Gemzar®) (29%), and VEGF (vascular endothelial growth factor) pathway inhibitors (10%).

Evidence of objective tumor regression was observed in 73% of patients with at least 1 post-baseline medical imaging scan. The best overall response rate per RECIST criteria was 24% (16 PRs and 1 CR). The overall Week-12 disease control rate (DRC = CR + PR + SD) was 53%. The Week-12 DCRs in the platinum drug-refractory, -resistant, and -sensitive groups were 36%, 39%, and 67%, respectively.

Based on an observed high rate of clinical activity, randomization was halted, and randomized patients were unblinded.  At this point, the unblinded randomized patients that were treated with placebo were allowed to “cross-over” to treatment with cabozantinib. Disease stabilization was experienced by some ovarian cancer patients who had progressive disease prior to treatment cross-over.

“These latest results in metastatic ovarian cancer demonstrate the potential broad utility of cabozantinib beyond bone-predominant types of cancers such as castration-resistant prostate cancer. The high rates of durable response with our dual inhibitor of MET and VEGFR2 compare favorably to those of other single-agent targeted therapies and cytotoxic agents in development,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “These results underscore the potential of cabozantinib in metastatic ovarian cancer, and we are in discussions with leading cooperative groups to plan further evaluation of cabozantinib in randomized trials for this indication.”

Activity in Platinum Drug-Sensitive, -Refractory, and -Resistant Disease

Ignace Vergote, M.D., Ph.D., senior author of the cabozantinib (XL184) ASCO presentation & Chairman, Leuven Cancer Institute, University of Leuven, European Union

(Image Source: Exelixis, Inc.)

Two of 11 patients (18%) with platinum refractory disease, defined as a platinum-free interval of <1 month, achieved a confirmed response (1 CR and 1 PR).

In the subset of patients with platinum-resistant disease, defined as a platinum-free interval of 1-6 months, 5 of 23 (22%) achieved a PR.

Ten of 36 patients (28%) with platinum sensitive disease achieved a PR.

A total of 37 patients experienced reductions in the ovarian cancer tumor marker CA-125 (cancer antigen-125), including 8 with decreases greater than 50%. There is no consistent concordance between CA-125 changes and tumor regression. The median duration of response has not yet been reached with 36 weeks of median follow-up.

“The continued activity of cabozantinib in a larger population of ovarian cancer patients is very encouraging, especially with respect to the clinical benefit observed in both platinum-sensitive and platinum-resistant/refractory disease. This activity profile has not been observed with other single-agent TKIs [tyrosine kinase inhibitors], and cabozantinib has the potential to be an important new treatment for ovarian cancer,” said Ignace Vergote, M.D., Ph.D., senior author of the presentation and Chairman of the Leuven Cancer Institute at the University of Leuven, European Union. “The high rate of disease control in platinum-resistant and platinum-refractory disease suggests that cabozantinib may help to address the substantial unmet medical need faced by patients who have sub-optimal responses to platinum-based therapies. I believe that further evaluation will help to define the potential role of cabozantinib in the treatment of ovarian cancer.”

General Safety & Tolerability Data 

Safety data are available for the 70 patients in the Lead-In phase of the cabozantinib study. The most common CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or 4 adverse events (AEs), regardless of causality, were diarrhea (10%), fatigue (9%), palmar-plantar erythrodysesthesia  syndrome (also referred as “hand-foot syndrome”)(7%), vomiting (4%), abdominal pain (3%), hypomagnesemia (3%), and nausea, constipation, rash, increased transaminase, and hypertension (each 1%). At least one dose reduction was reported in 37% of patients. Less frequent important medical events, regardless of causality, were hemorrhage (11% all CTCAE grades, 0% CTCAE grade 3 or 4), venous thrombosis (6% all CTCAE grades, 4% CTCAE grade 3 or 4), and gastrointestinal perforation (6% all CTCAE grades, 0% CTCAE grade 3 or 4).

To access the cabozantinib clinical study data information, please visit www.exelixis.com/sites/default/files/pdf/ASCO_2011-XL184-Ovarian.pdf

Six Deaths Reported (Including Two Ovarian Cancer Patients)

If you examine the Exelixis press release dated June 4 (entitled, Exelixis’ Cabozantinib Demonstrates Encouraging Clinical Activity in Patients with Metastatic Ovarian Cancer — Disease control rate of 53% at week 12, response rate of 24%), which addresses data for cabozantinib use in advanced ovarian cancer patients, pay particular attention to the wording under the heading entitled, “Safety and Tolerability.”  Within the wording set forth under that heading, you will find the following statement: “Two cabozantinib-related grade 5 AEs [adverse events], one enterocutaneous fistula and one intestinal perforation, were reported after the Lead-In phase.” Pursuant to the CTCAE guidelines, a “grade 5 adverse event” is defined as “death related to AE [adverse event].”

We should also note that the two ovarian cancer deaths were summarized briefly in the ASCO presentation regarding cabozantinib use in advanced ovarian cancer.

The reporting of all six deaths is set forth in the Exelixis press release, dated June 5, 2011 (entitled, Exelixis’ Cabozantinib Demonstrates Broad Clinical Activity in Multiple Tumor Types), in similar fashion. Within this release, the sentence provided under the heading “Safety and Tolerability” states: “There were 6 (1%) cabozantinib-related grade 5 [adverse] events, all of which were reported after the Lead-In phase of the trial: respiratory compromise (breast cancer), hemorrhage (NSCLC [non-small cell lung cancer]), enterocutaneous perforation (ovarian cancer), intestinal perforation (ovarian cancer), gastrointestinal hemorrhage (pancreatic cancer), and death (CRPC [castrate resistant prostate cancer]).”

Exelixis Chief Executive Michael Morrissey said the safety statistics are consistent with targeted cancer therapies like cabozantinib that block a pathway used by tumor cells to secure blood vessels.

Cowen & Co analyst Eric Schmidt said the rate of cabozantinib treatment-related deaths — 1 percent — was “no different from what we have seen for every other Phase 1 and 2 trials here at ASCO.”

“While drug safety is of less concern in cancer indications than in others, the apparent morbidities associated with cabo[zantinib] use will confound interpretation of clinical benefit in a trial designed to show anything less than overall survival,” Canaccord analyst George Farmer said in a research note.

In a note to investors, Piper Jaffray analyst Edward Tenthoff said: “The company is exploring lower doses, but the concern is that cabo[zantinib] will not retain the impressive efficacy seen to date.”

Mr. Morrissey said Exelixis plans to move forward with the current daily 100 mg dose of the drug.

Dr. Nicholas J. Vogelzang (Director, Comprehensive Cancer Centers of Nevada) Discusses Mortalities in the Cabozantinib (XL184) Trial

Take Away Message

• Cabozantinib demonstrates promising activity in both platinum drug-sensitive and platinum drug-resistant/-refractory ovarian cancer.
• Week 12 overall disease control rate of 53%.
• Response rates of 18% in platinum-refractory, 22% in platinum-resistant and 28% in platinum-sensitive patients.
• Cabozantinib shows encouraging duration of response.
• After 36 weeks of follow-up, median duration of response not reached.
• Tolerability profile is consistent with that of other tyrosine kinase inhibitors (6 solid tumor patient deaths (1% of all solid tumor pts), including 2 ovarian cancer patients (3% of ovarian cancer pts)).
• Discordant effects observed between CA-125 changes and clinical activity.
• Simultaneous targeting of MET and VEGFR2 with cabozantinib results in robust effects in patients with advanced ovarian cancer.
• Non-randomized expansion cohort is currently accruing in platinum-resistant/-refractory ovarian cancer.

About the MET & VEGFR2 Pathways

To learn more about (i) the role of MET in cancer, (ii) the relationship between the MET and VEGFR pathways, and (iii) the dual inhibition of MET and VEGFR2, visit http://www.metinhibition.com/.

About Cabozantinib (XL184)

Cabozantinib (XL184) is a potent, dual inhibitor of MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumor cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumor types. MET is upregulated in many tumor types, thus facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions (i.e., deprivation of adequate oxygen supply) in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, anti-metastatic and anti-angiogenic effects, including: (i) extensive apoptosis of malignant cells; (ii) decreased tumor invasiveness and metastasis; (iii) decreased tumor and endothelial cell proliferation; (iv) blockade of metastatic bone lesion progression; and (v) disruption of tumor vasculature.

About Exelixis

Exelixis, Inc. is a biotechnology company committed to developing small molecule therapeutics for the treatment of cancer. Exelixis is focusing its resources and development efforts exclusively on cabozantinib, its most advanced solely-owned product candidate, in order to maximize the therapeutic and commercial potential of this compound. Exelixis believes cabozantinib has the potential to be a high-quality, differentiated pharmaceutical product that can make a meaningful difference in the lives of patients. Exelixis has also established a portfolio of other novel compounds that it believes have the potential to address serious unmet medical needs. For more information, please visit the company’s web site at www.exelixis.com

Sources: 

• Buckanovich R.J., Berger R, Sella A, et. al. Activity of cabozantinib (XL184) in advanced ovarian cancer patients (pts): Results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 29: 2011 (suppl; abstr 5008)(2011 ASCO Annual Meeting).

• R. J. Buckanovich, R. Berger, A. Sella, et. al. Activity of Cabozantinib (XL184) in Advanced Ovarian Cancer Patients: Results From a Phase 2 Randomized Discontinuation Trial (RDT), Slide Presentation, Gynecologic Cancer, Oral Abstract Session, 2011 American Society of Clinical Oncology, Saturday June 4, 2011.  [Adobe Reader PDF document]

• A Randomized Discontinuation Study of XL184 in Subjects With Advanced Solid Tumors, Clinical Trial Summary, NCT00940225, http://www.ClinicalTrials.gov.

• Exelixis shrs fall on cancer drug safety concerns, Reuters (U.S. Edition), June 6, 2011.

• Exelixis’ Cabozantinib Demonstrates Encouraging Clinical Activity in Patients with Metastatic Ovarian Cancer — Disease control rate of 53% at week 12, response rate of 24% .Median duration of response not yet reached, Press Release, Exelixis, Inc., June 4, 2011.

• Exelixis’ Cabozantinib Demonstrates Broad Clinical Activity in Multiple Tumor Types — Resolution of metastatic soft tissue, visceral, and bone lesions observed in randomized discontinuation trial, Press Release, Exelixis, Inc., June 5, 2011.

Cabozantinib (XL184) Clinical Trial Information

• A list of open ovarian cancer and solid tumor clinical trials involving cabozantinib.

Related Libby’s H*O*P*E*™ Postings

• ASCO 2011: Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors, May 19, 2011.

• Exelixis Reports Promising Interim Data From Ovarian Cancer Patients Treated With XL184, November 18, 2010.

Related Libby’s H*O*P*E*™ Videos

• Cabozantinib (XL184) : Dual Inhibition of MET & VEGF – Exelixis, Inc., June 10, 2011.

2011 ASCO: Additional Phase III Study Data Support the Potential Role of Avastin in Newly-Diagnosed & Recurrent Ovarian Cancer

Positive results from two bevacizumab (Avastin®) phase III clinical studies were presented at the 2011 American Society of Clinical Oncology Annual Meeting on June 4. The data reported add to the growing body of evidence in support of bevacizumab use to treat recurrent and newly-diagnosed ovarian cancer.

Positive results from two bevacizumab (Avastin®) phase III clinical studies were presented at the 2011 American Society of Clinical Oncology Annual Meeting on June 4. The data reported add to the growing body of evidence in support of bevacizumab use to treat recurrent and newly-diagnosed ovarian cancer.

About Bevacizumab (Avastin®)

A diagram illustrating the role of the VEGF protein in the formation of new blood vessels that support tumor growth. Click on the picture above to view a video regarding the mechanism of action with respect to bevacizumab (Avastin®). (Photo: Genentech)

“Angiogenesis” refers to the process of new blood vessel formation. When tissues need more oxygen, they release molecules that encourage blood vessel growth. Angiogenesis is a normal and vital process in human growth and development, as well as in wound healing. Unfortunately, cancer tumors also utilize this same process to enhance their own blood supply in order to nourish their aberrant growth.

Ovarian cancer is associated with high concentrations of vascular endothelial growth factor (VEGF), a protein associated with tumor growth and spread. Studies have shown a correlation between a high concentration of VEGF and ascites  (excess fluid in the body cavity) development, disease worsening, and a poorer prognosis in women with ovarian cancer.[1-2]

Bevacizumab is a humanized monoclonal antibody designed to specifically bind to the VEGF protein, which plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels through angiogenesis. The drug interferes with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. The tumor blood supply is thought to be critical to a tumor’s ability to grow and spread in the body (metastasize).

Bevacizumab is the first U.S. Food and Drug Administration (FDA) approved therapy designed to inhibit angiogenesis. Although FDA-approved for several forms of cancer, bevacizumab is not yet approved for the treatment of ovarian cancer. Patients treated with bevacizumab may experience side effects. In past clinical trials, some people treated with bevacizumab experienced serious and sometimes fatal side effects, related to gastrointestinal (GI) perforation, surgery and wound healing, and severe bleeding. For more information, review the Avastin BOXED WARNINGS and Additional Important Safety Information.

OCEANS Phase III Clinical Study: Women with Recurrent Platinum Sensitive Ovarian Cancer Experience 78% Response Rate & 52% Reduction In Disease Progression Risk

• About the OCEANS Study

“OCEANS” is a multicenter, randomized, double-blind, placebo-controlled Phase III study in 484 women with platinum drug-sensitive recurrent ovarian, primary peritoneal or fallopian tube cancer.[3] Women in the OCEANS study received no more than one treatment regimen prior to study enrollment.  The OCEANS study randomized enrolled women to one of two clinical study arms:

Arm A: Intravenous carboplatin (area under the curve (AUC) 4; Day 1) + gemcitabine  (1,000 mg/m2; Day 1 & 8; brand name: Gemzar®) + placebo (Day 1) every 21 days x 6 cycles, followed by placebo maintenance every 21 days, until disease progression or unacceptable toxicity occurred.

Arm B: Carboplatin + gemcitabine + bevacizumab (15 mg/kg; Day 1) every 21 days x 6 cycles, followed by single agent bevacizumab maintenance every 21 days, until disease progression or unacceptable toxicity occurred.

The primary endpoint of the OCEANS study was progression free survival. The secondary endpoints of the study included overall survival, objective response, duration of response and safety profile.

• OCEANS Study Data

Carol Aghajanian, M.D. speaks during the Oral Abstract Session: Gynecologic Cancer at the American Society of Clinical Oncology Annual Meeting on Saturday June 4, 2011. (Photo: ASCO/GMG/Silas Crews 2011)

Carol Aghajanian, M.D., chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center, presented the data from the OCEANS study comparing efficacy and safety of chemotherapy and antiangiogenic therapy in platinum drug-sensitive recurrent ovarian cancer.

Two hundred forty-two women were allocated to each study arm and the median follow-up period was 24 months. Patient characteristics were well-matched in the two treatment groups with regard to age (median age ~60), race (~91% white), performance status (~75%, PS = 0), histologic subtype (~80% serous), cytoreductive surgery (~11%), and platinum-free interval (defined as the time between finishing front-line platinum-based therapy and starting second-line chemotherapy) of more than 12 months (~60%). The study stratification variables were platinum-free interval (6 to 12 months vs. more than 12) and cytoreductive surgery for recurrent disease (yes vs. no).

The median number of chemotherapy cycles was six for each group, and a median of 11 cycles of bevacizumab or placebo was given. At least one-third of the patients received more than six cycles of carboplatin and gemcitabine, although slightly more of the placebo-treated group continued chemotherapy beyond six cycles.

Progression-free survival was significantly longer for women given bevacizumab (12.4 months vs. 8.4 months in the placebo-treated group (hazard ratio [HR]: 0.484; 95% confidence interval (CI) [0.388, 0.605]; p < 0.0001). These results were corroborated by the analyses of an independent review committee. Analyses according to platinum-free interval, cytoreductive surgery, age, and baseline performance status indicate a consistent benefit in all subgroups.

Objective response rate increased by 21.1% (p < 0.0001), from 57.4% in the placebo group to 78.5% in the bevacizumab treated group; duration of response increased from a median of 7.4 months to 10.4 months, respectively (HR: 0.534; 95% CI [0.408, 0.698]; p < 0.0001). Overall survival data are still premature, with median survival of 29.9 months in the placebo group and 35.5 months in the bevacizumab treatment group.

Sixty-five percent of the patients in the placebo group were withdrawn from the protocol due to disease progression, compared with only 41% of the treatment group, but 23% of the discontinuations in the bevacizumab group were due to adverse events, compared with only 5% in the placebo group. Much of this increase was due to grade 3 (or worse) adverse events; specifically hypertension and proteinuria associated with bevacizumab therapy. Overall, the safety profile of bevacizumab was consistent with past trials.

• OCEANS Study Commentary

Dr. Aghajanian concluded that the OCEANS study results demonstrate a statistically significant and clinically relevant benefit when bevacizumab is added to carboplatin and gemcitabine. Aghajanian stated that this regimen should be considered a new option for the treatment of recurrent, platinum drug-sensitive ovarian cancer. As expected, the rate of adverse events was higher among patients who received bevacizumab, explained Dr. Aghajanian. “Hypertension and proteinuria were increased, but febrile neutropenia was the same in both arms.” “The safety data are reassuring and consistent with the known bevacizumab side-effect profile, and there were no new safety signals,” said Dr. Aghajanian.

“In advanced ovarian cancer, just as in advanced breast cancer, there is often an opportunity to intervene with different lines of chemotherapy,” said Andrew Seidman, M.D., attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Medical College of Cornell University. “There are many chapters in the story, so to speak,” said Dr. Seidman, who moderated a press briefing held in advance of the presentation. “We want to prolong each and every chapter in the disease, and make the story longer and ultimately improve survival. These trials results are certainly an important step in that direction.”

“Women with recurrent ovarian cancer need new treatment options, and it is therefore an important advance to halve the risk of disease progression in this incurable cancer,” said Hal Barron, M.D., chief medical officer and head of Roche Holdings Global Product Development. “These data add to the growing body of evidence supporting Avastin’s potential role in this disease, which includes two previously presented Phase III clinical trials [Gynecologic Oncology Group (GOG)-218 [4] & ICON7] in women with newly diagnosed ovarian cancer.”

In his discussion of the study, Anil K. Sood, M.D., professor and director of the Blanton-Davis Ovarian Cancer Research Program in the Departments of Gynecologic Oncology and Cancer Biology at the University of Texas M.D. Anderson Cancer Center, suggested that further understanding of the timing and dosing of bevacizumab should be pursued in light of (i) its great financial cost, and (ii) reports that inhibition of angiogenesis in animal models reduces primary cancer tumor growth, but accelerates invasion and metastasis — unintended consequences that might be linked to the failure of bevacizumab to extend overall survival in most clinical trials.

ICON7 Phase III Clinical Study:  Newly-Diagnosed Women with High-Risk Ovarian Cancer Experience 36% Reduction in Risk of Death

Gunnar Kristensen M.D., Ph.D. speaks during the Women's Cancers Press Briefing at the American Society of Clinical Oncology Annual Meeting on June 4, 2011. (Photo: ASCO/GMG/Scott Morgan 2011)

ICON7 was designed to investigate safety and efficacy of adding bevacizumab to standard chemotherapy in women with newly diagnosed ovarian cancer. [5] Gunnar Kristensen, M.D, Ph.D., senior consultant in the Department for Gynecologic Oncology of the Norwegian Radium Hospital located in Oslo, reported the Phase III clinical study results.

• About the ICON7 Study

From December 2006 to February 2009, 1,528 women were randomized from 263 centers in 7 Gynecologic Cancer InterGroups. Eligible women with high-risk early FIGO (Federation of International Gynecology and Obstetrics) stage I or IIa (grade 3 or clear cell histology), capped ≤10%) or advanced (stage IIb-IV) epithelial ovarian, primary peritoneal or fallopian tube cancer were randomizsed (1:1) to one of two study arms:

Arm A: 6 cycles of 3 weekly chemotherapy (carboplatin AUC 5 or 6 and paclitaxel 175mg/m2) alone;  or

Arm B: Same chemotherapy as in Arm A, given concurrently with bevacizumab (7.5mg/kg) for 5 or 6 cycles, followed by continued 3-weekly single-agent bevacizumab maintenance therapy for 12 additional cycles (up to 12 months) or until disease progression (whichever event occurs first).

The baseline patient characteristics were balanced between both study arms: median age (57 years); ECOG Performance Status 0-1 (47%); high-risk early-stage disease (9%); poor prognosis patients (30%); histology (69% serous, 8% endometrioid, 8% clear cell).

• Updated ICON7 Progression Free Survival Data

Data from the ICON7 study were presented for the first time at the 2010 European Society of Medical Oncology (ESMO) Congress. As reported at ESMO, chemotherapy-naïve ovarian cancer patients who received bevacizumab in combination with standard chemotherapy, and then continued with single agent bevacizumab maintenance therapy, experienced approximately 27% improvement (18.3 months versus 16 months) in the likelihood of living longer without the disease worsening (i.e., progression-free survival) compared to those women who received only chemotherapy (hazard ratio = 0.79, p=<0.0010), which corresponds to a 21% reduction in risk of cancer progression or death. The ICON7 data presented at ESMO was based upon mature progression-free survival results.

The updated ICON7 progression-free survival data presented at the ASCO annual meeting were consistent with the data reported last year at ESMO. In the updated analysis, women assigned to the bevacizumab arm experienced longer progression-free survival than those in the control group (19.8 months vs 17.4 months; HR, 0.87; p =.039). “There is a substantial prolongation of time to progression,” said Dr. Kristensen, adding that the gain was 2.4 months.

• ICON7 Overall Survival Data Immature; But Clear Benefit To Women With “Poor Prognosis.” 

At a median follow-up of 28 months, there were fewer deaths among women who received bevacizumab than among those who received standard chemotherapy (178 vs 200). Although this represents a 15% overall reduction in mortality risk, the difference did not reach statistical significance (hazard ratio [HR], 0.85; P = .11). The final analyses for overall survival will be performed when 715 patient deaths have occurred. The current analysis was conducted because an interim analysis with at least 365 deaths was requested by the FDA and the European Medicines Agency for licensing consideration.

Although the overall survival data is not mature, a subgroup analysis of women with a “poor prognosis” (defined as FIGO stage III patients debulked to >1.0cm of visible diease or FIGO stage IV with debulking) was performed. Within this subgroup, there were 79 deaths within the bevacizumab arm and 109 deaths in the control arm. Based on this data, there was a 36% reduction in the risk of death (HR=0.64, 95% CI=0.48 to 0.85, p=0.0022 with p=0.015 for test for interaction (treatment/risk group)) among the poor prognosis subgroup.  This result was statistically significant. “We have previously shown that [the high-risk] group has a greater benefit from bevacizumab than the other patients,” said Dr. Kristensen. “For this group, there is a very clear gain for overall survival.”

• ICON7 Study Commentary

“We conclude that the addition of concurrent and continued bevacizumab for 12 months does improve progression-free survival,” said Dr. Kristensen.  Kristensen also noted that, on the basis of an interim analysis involving approximately 53% of the number of deaths needed for the final analysis, there is an overall trend for improvement in overall survival.

“In this study, we see the ability of antiangiogenic therapy to delay the progression of ovarian cancer, this time in the first-line setting,” said Andrew Seidman, M.D. He added that previous studies have demonstrated the efficacy of bevacizumab in ovarian cancer. “These lend support to a potential role for bevacizumab as the first biologic agent to be used in this disease,” said Seidman, who moderated a press briefing during which study highlights were presented.

There are many strengths in a study like this, in that it addresses questions about the role of anti-VEGF therapies in this setting, said Anil Sood, M.D., who served as a discussant for this paper. “The randomized design is obviously a major strength.”

However, there are potential issues to examine, explained Dr. Sood. “One is the role of bevacizumab in the combination setting, compared with the maintenance setting.”

“How useful is bevacizumab in the combination setting up front? Is the real role for bevacizumab in the maintenance setting following initial chemotherapy,” he asked.

The issue of bevacizumab dosing was also raised by Dr. Sood. “One of the questions is whether higher doses are needed,” he said. “There are data emerging from other studies showing that lower doses are as efficacious, if not more so.”

References:

1/Rudlowski C, Pickart AK, Fuhljahn C, et. al. Prognostic significance of vascular endothelial growth factor expression in ovarian cancer patients: a long-term follow-up. Int J Gynecol Cancer. 2006 Jan-Feb;16 Suppl 1:183-9. PubMed PMID: 16515588.

2/Cooper BC, Ritchie JM, Broghammer CL, et. al. Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer. Clin Cancer Res. 2002 Oct;8(10):3193-7.  PMID: 12374688

3/Aghajanian C, Finkler NJ, Rutherford T, et. al. OCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC). J Clin Oncol 29: 2011 (suppl; abstr LBA5007)[2011 American Society of Clinical Oncology Annual Meeting].

4/ Burger RA, Brady MF, Bookman MA, et. al. Phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): a Gynecologic Oncology Group study [GOG 218 Abstract]. J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1).

5/Kristensen G, Perren T, Qian W., et. al. Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer. J Clin Oncol 29: 2011 (suppl; abstr LBA5006) [2011 American Society of Clinical Oncology Annual Meeting].

Additional Sources & Helpful Information:

• Bevacizumab Benefits Patients With Recurrent Ovarian Cancer, by Roxanne Nelson; American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting, Medscape Today Medical News, June 5, 2011.

• Bevacizumab Plus Chemo Improves Survival in Ovarian Cancer, by Roxanne Nelson; American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting, Medscape Today Medical News, June 5, 2011.

• Bevacizumab Prolongs Progression-free Survival for Women with Platinum-sensitive Recurrent Ovarian Cancer, American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting, ASCO Daily News (Section 6A), June 6, 2011.

• Incorporating Bevacizumab into Ovarian Cancer Treatment: Practical Considerations, by By Alexandra Leary, M.D., and Martin Gore, Ph.D., FRCP, Gynecologic Oncology Category, Educational Book, 2011 American Society of Clinical Oncology Annual Meeting, June 3-7, 2011. [Full Text Adobe Reader PDF document]

Bevacizumab (Avastin®) Clinical Trial Information

• A list of open ovarian cancer clinical trials involving bevacizumab.

• A list of open solid tumor clinical trials involving bevacizumab.

• ICON7 – A Randomised, Two-Arm, Multi-Centre Gynaecologic Cancer InterGroup Trial of Adding Bevacizumab to Standard Chemotherapy (Carboplatin and Paclitaxel) in Patients With Epithelial Ovarian Cancer (NCT00483782), Clinical Trial Protocol Summary, ClinicalTrials.gov.

• A Phase III, Multicenter, Randomized, Blinded, Placebo-Controlled Trial of Carboplatin and Gemcitabine Plus Bevacizumab in Patients With Platinum-Sensitive Recurrent Ovary, Primary Peritoneal, or Fallopian Tube Carcinoma (OCEANS) (NCT00434642), Clinical Trial Protocol Summary, ClinicalTrials.gov.

Related WORD of HOPE Ovarian Cancer Podcast™

• 10 Exciting Ovarian Cancer Research Topics from 2010 — Avastin Phase III Clinical Trials (Topic #1 of 10); Episode #1; WORD of HOPE Ovarian Cancer Podcast™, March 25, 2011.

Related Libby’s H*O*P*E*™ Postings

• 2011 NCCN Conference: New Treatment Options Lead to Steady Progress Against Ovarian Cancer, March 15, 2011.

• Ohio State University Reports That Ovarian Cancer Drug Bevacizumab Is Not Cost-Effective, March 8, 2011.

• Genentech Announces Positive Results of Avastin Phase III Study in Women with Advanced Ovarian Cancer, February 25, 2010.

Related Libby’s H*O*P*E*™ Videos

• To view videos regarding bevacizumab (Avastin®), click here.

2011 ASCO: EC145 Demonstrates 85 Percent Improvement in Progression-Free Survival for Treatment of Platinum Resistant Ovarian Cancer

EC145, in combination with pegylated liposomal doxorubicin (Doxil®/Caelyx®) in patients with platinum-resistant ovarian cancer, met its primary endpoint by showing an 85 percent (2.3 month) improvement in median progression-free survival in the intent-to-treat population, and a 260 percent (4.0 month) improvement in a subset of folate receptor positive patients. The final EC145 phase 2 clinical study data were presented today at the 2011 American Society of Clinical Oncology Annual Meeting.

EC145 delivers a very potent vinca chemotherapy directly to cancer cells by targeting the folate receptor expressed on cancer cells, but not on most normal cells. Approximately 80-90 percent of ovarian and lung cancers express the receptor, as do many other types of cancer. Click on the picture above to view a video regarding EC145's mechanism of action. (Photo: Endocyte, Inc.)

Endocyte, Inc., a biopharmaceutical company developing targeted small molecule drug conjugates (SMDCs) and companion imaging diagnostics for personalized therapy, today announced that the phase 2 PRECEDENT trial, which is investigating the company’s lead drug candidate, EC145, in combination with pegylated liposomal doxorubicin (PLD)(brand name: Doxil®/Caelyx®) in patients with platinum-resistant ovarian cancer, met its primary endpoint by showing: (i) an 85 percent (2.3 month) improvement in median progression-free survival (PFS) in the intent-to-treat population, and (ii) a 260 percent (4.0 month) improvement in a subset of folate receptor positive patients. EC145 in combination with PLD showed limited additional toxicity compared to standard therapy with PLD alone. The most commonly occurring adverse events were neutropenia, small intestine obstruction, and palmar-plantar erythrodysesthesia (or hand-foot syndrome). EC145 is a therapeutic that targets the folate receptor and EC20 is a companion imaging diagnostic used to assess folate receptor presence.

These final PFS data from the PRECEDENT trial were presented today at the 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO), in Chicago, Illinois and are available at http://investor.endocyte.com/events.cfm.

“I am encouraged by these data as EC145 is the first drug candidate to demonstrate a significant improvement in PFS in a randomized trial of patients with platinum-resistant ovarian cancer, a very challenging disease with a high unmet need. Historical data show that for these patients on standard therapy, PFS is approximately three months and overall survival is approximately twelve months. No new drug has been approved in the U.S. for this indication in over a decade,” said Wendel Naumann, M.D., Associate Director of Gynecologic Oncology at Blumenthal Cancer Center, Carolinas Medical Center. “In addition the companion imaging diagnostic, EC20, is designed to identify patients who over-express the targeted receptor and are most likely to respond to EC145. This represents a personalized therapeutic approach that I believe will help oncologists direct patients to the most promising treatment.”

EC145 Phase 2 PRECEDENT Clinical Study Data 

The Phase 2 PRECEDENT trial was an international, multi-center, randomized study of 149 women with platinum-resistant ovarian cancer. Patients were randomized to receive EC145 plus PLD or PLD alone at a standard dose until disease progression or death. The primary endpoint of the study was progression-free survival. Secondary endpoints included response rate and overall survival.

The EC145 phase 2 PRECEDENT trial results are summarized below.

• 85 Percent (2.3 Month) Improvement in Median Progression-Free Survival for All Patients

Patients receiving EC145 in combination with PLD, regardless of folate receptor expression, had a median progression free survival of 5.0 months compared to 2.7 months for patients receiving single agent PLD. The hazard ratio for PFS was 0.626 (p=0.031). The overall response rate was 28 percent in the EC145 combination group versus 16 percent in the PLD-alone group. CA-125 (cancer antigen-125) responses were also more common in patients receiving EC145 in combination with PLD compared to those receiving PLD alone, with response rates (based on CA-125 blood serum measurement) of 38 percent and 19 percent, respectively.

• 260 Percent (4.0 Month) Improvement in Median Progression-Free Survival for Patients Most Positive for Folate Receptor

The study also utilized EC20, an investigational companion imaging diagnostic that is designed to identify patients with folate receptor positive tumors. As expected, in the folate receptor positive patients the improvement in PFS was even greater. In the subpopulation most positive for the folate receptor, PFS increased 4.0 months from 1.5 months to 5.5 months. The hazard ratio for PFS was 0.381 (p=0.018). This represents more than a 60 percent reduction in the risk of progression and provides evidence supporting the mechanism of action through targeting of the folate receptor. The overall response rate was 22 percent in the EC145 combination group versus 7 percent in the PLD alone group. CA-125 responses were also more common in patients receiving EC145 in combination with PLD compared to those receiving PLD alone, 43 percent and 13 percent, respectively.

“We see tremendous potential for continued development of EC145 based on these data that demonstrate, for the first time, a significant improvement in PFS in patients with platinum resistant ovarian cancer,” said Ron Ellis, President and Chief Executive Officer of Endocyte. “We have already advanced EC145 into Phase 3 evaluation with the PROCEED trial, which has a similar design to the PRECEDENT trial, and plan to file for regulatory approval in the European Union based on the PFS data from the PRECEDENT study.”

Plan to File PRECEDENT Data for Conditional Approval in Europe

As a result of Endocyte’s interaction with the European Medicines Agency (EMA), including a meeting with the Scientific Advice Working Party and written advice from the Committee for Medicinal Products for Human Use (CHMP), the Company will prepare marketing applications for both EC145 and EC20. Based on feedback from the CHMP, Endocyte plans to seek conditional marketing authorization for patients with platinum-resistant ovarian cancer who test positive for the folate receptor using the EC20 companion imaging diagnostic.

Phase 3 PROCEED Trial Initiated

Endocyte recently announced the initiation of patient enrollment in the Phase 3 PROCEED trial of EC145, which is structured to replicate the PRECEDENT trial design. The Phase 3 trial is a randomized, double-blinded trial of EC145 in combination with PLD compared to PLD plus placebo. The patient population — those with platinum-resistant ovarian cancer — will be the same as in the PRECEDENT trial, and the primary endpoint will be progression-free survival in patients selected by EC20 as folate-receptor positive. The trial will also be statistically powered for overall survival as a secondary endpoint with projected enrollment in excess of 500 patients. The trial will be conducted in approximately 150 sites in the U.S., Canada, and Europe.  More information regarding the trial is available at www.clinicaltrials.gov.

About EC145

EC145 is a conjugate of the vitamin folate and a super-potent vinca alkaloid. Folate is required for cell division and rapidly dividing cancer cells often over-express folate receptors in order to capture enough folate to support cell division. By attaching a chemotherapy drug to folate through proprietary chemistry, EC145 targets cancer cells while avoiding most normal cells. This targeted approach is designed to provide treatment with super-potent drugs while lowering toxicity compared to standard chemotherapy.

About EC20

EC20 is a folate-targeted molecular imaging agent that is being developed as a non-invasive method to identify tumors that over-express folate receptors. These tumors are the molecular target of Endocyte’s folate-targeted therapeutic compounds such as EC145. To date, EC20 has been administered to over 500 patients and has been found to be well tolerated.

About Endocyte

Endocyte is a biopharmaceutical company developing targeted therapies for the treatment of cancer and inflammatory diseases. Endocyte uses its proprietary technology to create novel small molecule drug conjugates (SMDCs) and companion imaging diagnostics for personalized targeted therapies. The company’s SMDCs actively target receptors that are over-expressed on diseased cells, relative to healthy cells. This targeted approach is designed to enable the treatment of patients with highly active drugs at greater doses, delivered more frequently, and over longer periods of time than would be possible with the untargeted drug alone. The companion imaging diagnostics are designed to identify patients whose disease over-expresses the target of the therapy and who are therefore more likely to benefit from treatment.

Sources:

• Naumann RW, Coleman RL, Burger RA, et. al. PRECEDENT: A randomized phase II trial comparing EC145 and pegylated liposomal doxorubicin (PLD) in combination, versus PLD alone, in subjects with platinum-resistant ovarian cancer. J Clin Oncol 29: 2011 (suppl; abstr 5045).

• EC145 PRECEDENT Trial Results — 2011 American Society of Clinical Oncology Annual Meeting Poster Presentation, June 5, 2011. [Adobe Reader PDF document]

• Endocyte’s EC145 Meets Primary Endpoint in Phase 2 Study, Demonstrating 85 Percent (2.3 month) Improvement in Median Progression-Free Survival for Treatment of Platinum Resistant Ovarian Cancer, Press Release, Endocyte, Inc., June 5, 2011. [Adobe Reader PDF document]

• A Randomized Phase II Trial Comparing EC145 and Pegylated Liposomal Doxorubicin (PLD/Doxil/Caelyx) in Combination, Versus PLD Alone, in Subjects With Platinum-Resistant Ovarian Cancer (“PRECEDENT” Trial)(status: enrollment complete), Clinical Trial Summary, ID#: NCT00722592, http://www.ClinicalTrials.gov.

EC145 PROCEED Clinical Trial Information:

• A Randomized Double-Blind Phase 3 Trial Comparing EC145 and Pegylated Liposomal Doxorubicin (PLD/Doxil®/Caelyx®) in Combination Versus PLD in Participants With Platinum-Resistant Ovarian Cancer (“PROCEED” Trial) (status: recruiting patients), Clinical Trial Summary, ID#: NCT01170650, http://www.ClinicalTrials.gov.

• PROCEED Clinical Trial Website, www.endocyte.com/proceed/

Related Libby’s H*O*P*E* Video:

• Mechanism of Endocyte ‘s EC145 Targeted Therapy, Libby’s H*O*P*E* Video Library, http://www.vodpod.com/libbyshopetm, May 26, 2011.

Related Libby’s H*O*P*E*™ Postings:

• Endocyte’s EC145 Produces Significant Anti-Tumor Activity In Advanced Stage Chemoresistant Ovarian Cancer Patients, October 21, 2009.

• Endocyte Begins Phase II Clinical Trial of EC145 for Treatment of Women with Platinum Resistant Ovarian Cancer, February 20, 2009.

2011 ASCO: EntreMed’s ENMD-2076 Demonstrates Clinical Activity in Recurrent, Platinum-Resistant Ovarian Cancer Patients

EntreMed, Inc. announced that ENMD-2076 demonstrated clinical activity — a six-month progression free survival rate of 19% — when administered as a single agent to platinum drug-resistant recurrent ovarian cancer patients. The announcement is based upon interim phase 2 data presented today at the 2011 American Society of Clinical Oncology Annual Meeting. 

Ursula A. Matulonis, M.D., Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School

EntreMed, Inc., a clinical-stage pharmaceutical company developing therapeutics for the treatment of cancer announced today the presentation of clinical data for its phase 2 study with ENMD-2076 in platinum drug-resistant recurrent ovarian cancer patients. The data were presented by the principal investigator for the study, Dr. Ursula A. Matulonis, medical director of gynecologic oncology at the Dana-Farber Cancer Institute and associate professor of medicine, Harvard Medical School, during a poster discussion session at the American Society of Clinical Oncology (ASCO) Annual Meeting being held June 3 – 7, 2011 in Chicago, Illinois.

The trial was an open-label, single-arm, multicenter study of ENMD-2076 dosed orally as a single agent in patients with platinum-resistant recurrent ovarian, peritoneal or fallopian tubal cancer. The study was conducted at six sites in the United States and Canada and included the Dana-Farber Cancer Institute, Indiana University Melvin & Bren Simon Cancer Center, University of Chicago Medical Center, Memorial Sloan-Kettering Cancer Center, University of Colorado Cancer Center, and Princess Margaret Hospital. Sixty-four patients were enrolled, of which 57 were evaluable at the time of the presentation. The primary endpoint for the study was progression-free survival rate at six months. Secondary end-points include response rate, duration of response, and overall survival.

ENMD-2076 demonstrated clinical activity when administered daily orally as a single agent. Interim data from 57 evaluable patients showed a six-month progression free survival rate of 19 percent. Of the evaluable patients, four patients achieved a partial response and 30 patients achieved stable disease as measured by RECIST v1.1. Median overall survival has not yet been reached. The side effect profile was consistent with activity against ENMD-2076’s molecular targets, in particular, VEGFR2 (vascular endothelial growth factor receptor-2) and Aurora A. Studies to evaluate potential markers of ENMD-2076 in this patient group are ongoing.

Dr. Matulonis commented on the results of the study, “ENMD-2076 has demonstrated impressive anti-cancer activity in platinum-resistant ovarian cancer which is notoriously difficult to treat, and these patients have few options.”

EntreMed’s chief medical officer, Carolyn F. Sidor, M.D., M.B.A., added, “These results are very encouraging as they support further development of ENMD-2076 and also help us clarify its developmental path in ovarian cancer. We are currently designing the next clinical trial in this indication and look forward to opportunities to make ENMD-2076 available to ovarian cancer patients in the future.”

About ENMD-2076

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers. ENMD-2076 has shown promising activity in phase I clinical trials in solid tumor cancers, leukemia, and multiple myeloma. While ENMD-2076 is currently in a phase 2 trial in ovarian cancer, preclinical and clinical activities are ongoing in assessing the compound’s applicability in other forms of cancer.

To view an Adobe Reader PDF copy of the presentation, visit http://www.entremed.com/files/umatulonis_enmd_2076_p2_ovarian.pdf

About EntreMed

EntreMed, Inc. is a clinical-stage pharmaceutical company committed to developing ENMD-2076, a selective angiogenic kinase inhibitor, for the treatment of cancer. ENMD-2076 is currently in a multi-center phase 2 study in ovarian cancer and in several phase 1 studies in solid tumors, multiple myeloma, and leukemia.

Primary Sources:

• Matulonis UA, Tew WP, Matei D, et. al. A phase II study of ENMD-2076 in platinum-resistant ovarian cancer. J Clin Oncol 29: 2011 (suppl; abstr 5021).

• Matulonis UA,  Lee J, Lasonde B, et. al. A Phase 2 Study of ENMD-2076 in Platinum Resistant Ovarian Cancer Poster Board: 10, Location: E450a. [Adobe Reader PDF document]

• EntreMed’s ENMD-2076 Demonstrates Clinical Activity in Recurrent, Platinum-Resistant Ovarian Cancer Patients, Press Release, EntreMed, Inc., June 3, 2011.

• A Phase 2 Study of Oral ENMD-2076 Administered to Patients With Platinum Resistant Ovarian Cancer, Clinical Trial Summary, NCT01104675, http://www.Clinicaltrials.gov.

Secondary Sources:

• Fletcher GC, Brokx RD, Denny TA, et. al. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol Cancer Ther. 2011 Jan;10(1):126-37. Epub 2010 Dec 21. PubMed PMID: 21177375.

• Diamond JR, Bastos BR, Hansen RJ, et. al. Phase I safety, pharmacokinetic, and pharmacodynamic study of ENMD-2076, a novel angiogenic and Aurora kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2011 Feb 15;17(4):849-60. Epub 2010 Dec 3. PubMed PMID: 21131552.

2011 ASCO: Matching Targeted Therapies To Specific Tumor Gene Mutations Key to Personalized Cancer Treatment

Customizing targeted therapies to each tumor’s molecular characteristics, instead of a “one-size-fits-all” approach by tumor type, may be more effective for some types of cancer, according to research presented today at the American Society of Clinical Oncology annual meeting by the M.D. Anderson Cancer Center. In patients with end-stage disease, matched patients achieved a 27% response rate, versus 5% in those unmatched.

Customizing targeted therapies to each tumor’s molecular characteristics, instead of a “one-size-fits-all approach” by tumor type, may be more effective for some types of cancer, according to research conducted by The University of Texas M.D. Anderson Cancer Center.

Apostolia M. Tsimberidou, M.D., Ph.D., Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

M.D. Anderson’s phase I clinical study findings were presented today on the opening press program of the 47th Annual Meeting of the American Society of Clinical Oncology. Apostolia-Maria Tsimberidou, M.D., Ph.D., associate professor in the M.D. Anderson Department of Investigational Cancer Therapeutics, and the principal investigator of the study, presented the data.

Marking the largest scale on which this approach has been examined to date, the study analyzed the results of matching targeted therapies with specific gene mutations in patients. The data indicated that this strategy was associated with higher rates of response, survival and failure-free survival than observed in non-matched patients.

Pairing Patient and Treatment

“This preliminary study strongly suggests that molecular analysis is needed to use the right drug for the right patient. Up to this point, we have treated tumor types, but this study shows we cannot treat all patients with a tumor type the same way. We need to take into consideration a number of factors, and this study suggests that a personalized approach is needed to improve clinical outcomes for patients with cancer,” said Tsimberidou.

The identification of pathways involved in carcinogenesis, metastasis and drug resistance; new technologies enabling tumor molecular analysis; and the discovery of targeted therapies have stimulated research focusing on the use of targeted agents as part of a personalized medicine approach, she said.

“Over the past decades, a personalized medicine approach using Gleevec has changed the way we treat chronic myeloid leukemia, as well as survival rates,” said Razelle Kurzrock, M.D., professor and chair of the M.D. Anderson Department of Investigational Cancer Therapeutics. “We wanted to apply a similar approach to solid tumors.”

“Ultimately, to best match treatments to patients and offer the most therapeutic benefit, assessing a patient’s molecular markers has to become the standard at diagnosis. … 

This study affirms what we in the cancer community have been talking about for a decade – matching drugs to patients. The time is now. The drugs are here. The technology is here, and with our program at M.D. Anderson we can bring the two together in hopes to offer the most personalized care for our patients. …”

–Razelle Kurzrock, M.D., Professor & Chair, Department of Investigational Cancer Therapeutics, University of Texas M.D. Anderson Cancer Center

Research Methods and Results

In the initial analysis, Tsimberidou analyzed 1,144 patients with metastatic or inoperable cancer who underwent testing for molecular aberrations at M.D. Anderson. Their median age was 58, and the median number of prior treatments was four. Of these patients, 460 had one or more gene aberrations, including:

• 10 percent with a PIK3CA mutation;
• 18 percent with a KRAS mutation;
• 8 percent with a NRAS mutation;
• 17 percent with a BRAF mutation;
• 3 percent with an EGFR mutation;
• 2 percent with a CKIT mutation;
• 21 percent with a PTEN loss; and
• 37 percent with a p53 mutation

Patients with gene aberrations were treated on clinical trials with matched targeted agents, when available. Regimens included one or more therapies targeting PIK3CA, mTOR, BRAF, MEK, multikinases, KIT or EGFR. Outcomes of patients with gene aberrations treated with matched therapy were compared with those patients with gene aberrations who were not treated with matched therapy because of issues such as eligibility, study availability; insurance coverage and/or logistical problems with the study calendar.

For the 175 patients with one aberration, the response rate was 27 percent with matched targeted therapy. The response rate was 5 percent in 116 patients when treated with non-matched therapy.

Patients who received matched targeted therapy had median survival of 13.4 months, while median survival for patients treated with unmatched targeted therapy was nine months. Median failure-free survival in patients who received matched targeted therapy was 5.2 months, compared to 2.2 months for patients who received unmatched targeted therapy.

Further Research Needed

These preliminary results merit further investigation and confirmatory, prospective studies are needed, especially because the study was not a randomized study and therefore biases could influence the results.

“M.D. Anderson’s goal is to better understand the biology involved in each patient’s carcinogenesis by testing each tumor for genetic abnormalities driving tumor growth to guide treatment selection. This strategy will lead to the optimization of personalized therapy,” Tsimberidou said.

Another goal is to match targeted therapies to patients earlier in treatment.

“When Gleevec was first introduced, it was tested in patients in blast crisis and the response rate was about 15 percent. In contrast, when tested in the front line setting, and with the introduction of similar but increasingly potent second- and third-generation drugs, patients’ response rate was close to 100 percent, and now their expected survival is 25 years and counting,” said Kurzrock. “Ultimately, to best match treatments to patients and offer the most therapeutic benefit, assessing a patient’s molecular markers has to become the standard at diagnosis.”

About the Phase I Program – The Time is Now

The M.D. Anderson’s Phase I program is the largest of its kind and accounts for the majority – but not all – of the institution’s earliest clinical studies. In 2010, of the 11,000 patients who participated in M.D. Anderson clinical trials, more than 1,150 were enrolled in one of the 120 Phase I trials in the program.

Currently, tumors are tested for up to 12 molecular aberrations, but at the rate technology is rapidly advancing, Kurzrock expects that number to climb to more than 100 in the near future.

Patients treated in the Phase I Program are typically very ill and all other approved therapies have failed them. Yet they are “fighters” who are willing to try anything, including studies not specific to their diagnosis to test the effectiveness of a new drug, drug combination or delivery method, said Kurzrock.

“This study affirms what we in the cancer community have been talking about for a decade – matching drugs to patients,” said Kurzrock. “The time is now. The drugs are here. The technology is here, and with our program at M.D. Anderson we can bring the two together in hopes to offer the most personalized care for our patients.”

In addition to Tsimberidou and Kurzrock, other authors on the all-M.D. Anderson study included N. G. Iskander, David S. Hong, M.D., Jennifer J. Wheler, M.D., Siqing Fu, M.D., Ph.D., Sarina A. Piha-Paul, M.D., Aung Naing, M.D., Gerald Falchook, Filip Janku, M.D., Ph.D., all assistant professors of the Department of Investigational Cancer Therapeutics; Raja Luthra, Ph.D., professor, Department of Hematopathology, Research and Sijin Wen, Ph.D., Division of Quantitative Sciences.

Libby’s H*O*P*E*™ Commentary — Use of Molecular Profiling and Chemosensitivity Testing To Determine Individualized Ovarian Cancer Treatment

It is wonderful that various medical research institutions, including M.D. Anderson, are beginning to match targeted therapies to a patient’s specific molecular tumor characteristics. This approach is generally referred to as “molecular profiling,” and it represents one promising method of matching an individual cancer patient to an effective therapy. As noted in the related Libby’s H*O*P*E*™ postings set forth below, there are several medical and scientific institutions which are pursuing development of molecular profiling for clinical study use. In the most recent related posting listed below, we discuss the molecular profile testing that is commercially available through The Clearity Foundation and Caris Life Sciences.

In the future, it may be helpful to use a form of chemosensitivity testing (e.g., the type of testing provided by Precision Therapeutics, Rational Therapeutics, and the Weisenthal Cancer Group), which is based upon the measurement of actual cancer cell death, as a second method to match a cancer patient to a potential drug or drug combination within the context of a clinical study. In fact, we would like to see a future prospective, randomized ovarian cancer clinical trial in which enrolled women are provided with treatment after assignment to one of three clinical trial arms:  (i) treatment based upon the standard of care (e.g., paclitaxel and carboplatin), (ii) treatment based upon molecular profiling, or (iii) treatment based upon chemosensitivity testing.  This type of study may uncover additional ovarian cancer treatment insights (both molecular and functional) with respect to the most lethal gynecologic cancer, while ultimately helping women with forms of the disease that may not possess a known molecular characteristic that is potentially “targetable” by an existing clinical trial drug or compound.

This combination of “bottom-up” scientific research (i.e., molecular profiling) performed side-by-side with “top-down” research (i.e., chemosensitivity testing) may represent an effective and efficient approach — albeit provocative — for evaluation of optimal personalized ovarian cancer treatment.

It is important to note that Libby’s H*O*P*E*™ and its founder Paul Cacciatore do not receive financial renumeration or benefit of any kind from the companies referred to in the paragraphs above.

About the University of Texas M.D. Anderson Cancer Center

The University of Texas M.D. Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For seven of the past nine years, including 2010, M.D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.

Primary Sources:

• Tsimberidou, AM, Iskander, NG, Hong DS, et. al. Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center Initiative. J Clin Oncol 29: 2011 (suppl; abstr CRA2500).

• Matching targeted therapies to tumor’s specific gene mutations key to personalized cancer treatment, Press Release, University of Texas M. D. Anderson Cancer Center, June 3, 2011.

• Personalized Therapy Benefits Late-Stage Cancer Patients in Clinical Trial, Cancerwise Blog, University of Texas M. D. Anderson Cancer Center, June 3, 2011.

Secondary Sources:

• Stephen B, Wheler JJ, Tsimberidou AM, et. al. Survival of 1,181 patients in a phase I clinic: The University of Texas M. D. Anderson Cancer Center experience. J Clin Oncol 29: 2011 (suppl; abstr 2528).

• El-Osta HE, Falchook GS, Tsimberidou AM, et. al. Clinical characterstics and outcomes of patients with BRAF-mutant advanced cancer in a phase I clinic: The University of Texas M. D. Anderson Cancer Center experience. J Clin Oncol 29: 2011 (suppl; abstr 10535).

• Janku F, Garrido-Laguna I, Wheler JJ, et. al.  Screening for PIK3CA mutations, PTEN loss, and RAS/RAF mutations in early-phase protocols with PI3K/mTOR pathway inhibitors. J Clin Oncol 29: 2011 (suppl; abstr 10507).

• Sun M, Falchook GS, Wheler JJ, et. al.  Association of VEGF single-nucleotide polymorphisms (SNPs) with response and toxicity in patients treated with bevacizumab. J Clin Oncol 29: 2011 (suppl; abstr e13560).

• Fok J, Kurzrock R, Tsimberidou AM, et. al. An umbrella protocol for histology-independent, phase I modular study based on EGFR mutation status: Using erlotinib alone or in combination with cetuximab, bortezomib, or dasatinib to overcome resistance.  J Clin Oncol 29: 2011 (suppl; abstr 2536).

Related Libby’s H*O*P*E* Postings:

• Caris Life Sciences Launches Molecular Profiling Service For Ovarian Cancer Patients, January 14, 2011.

• Dana-Farber Researchers “OncoMap” The Way To Personalized Treatment For Ovarian Cancer, November 16, 2010.

• Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results, August 3, 2010.

• PI3K Pathway: A Potential Ovarian Cancer Therapeutic Target? November 20, 2009.

• Personalized Medicine Helps Breast, Colorectal & Ovarian Cancer Patients Survive, August 20, 2009.

• Massachusetts General Hospital Cancer Center To Genetically Profile All Patient Tumors, March 14, 2009.

ASCO 2011: Genetic Biomarker Predicts Taxane Drug-Induced Neuropathy

A new study has identified the first genetic biomarkers for taxane-induced peripheral neuropathy, a potentially severe complication of taxane chemotherapy that affects nerves in about one-third of patients with cancer receiving such treatment.

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

New study results involving a genetic marker which can predict taxane drug-induced neuropathy were highlighted today in the ASCO press briefing, as summarized below.

Genetic Biomarker Predicts Taxane-Induced Neuropathy

A new study has identified the first genetic biomarkers for taxane drug-induced peripheral neuropathy, a potentially severe complication of taxane chemotherapy that affects nerves in about one-third of patients with cancer receiving such treatment. The finding may eventually lead to a simple blood test to determine whether a patient is at high risk for neuropathy.

Bryan P. Schneider, M.D., Physician & Researcher, Indiana University Melvin & Bren Simon Cancer Center; Associate Director, Indiana Institute for Personalized Medicine

“If these findings can be replicated, this may allow physicians to know prior to recommending therapy whether the patient is at an inordinate risk for developing taxane-induced neuropathy,” said Bryan P. Schneider, M.D., lead author and a physician/researcher at the Indiana University Melvin and Bren Simon Cancer Center and Associate Director for the Indiana Institute for Personalized Medicine. “This may allow for better counseling, use of alternative drugs or schedules, or omission of taxanes in the appropriate settings. These genetic findings might also provide insight into the mechanism of this side effect and help develop drugs to prevent this toxicity altogether.”

Such damage to the nerves can cause pain and numbness and limit the dose of chemotherapy a patient can receive. While only a few factors seem to predict which patients are likely to get peripheral neuropathy, including a history of diabetes and advanced age, genetic variations may explain why some patients are more sensitive to taxane drugs.

The authors conducted a genome wide association study on 2,204 patients enrolled in an Eastern Cooperative Oncology Group breast cancer clinical trial (E5103) in which all patients received taxane-based chemotherapy, namely paclitaxel (Taxol). The study looked for variations in DNA (deoxyribonucleic acid) called single nucleotide polymorphisms, or SNPs (pronounced “snips”), by evaluating more than 1.2 million SNPs in each patient.  A SNP is a DNA sequence variation which occurs when a single nucleotide — A (adenine), T (thymine), C (cytosine), or G (guanine) — in the genome (or other shared sequence) differs between two individuals, or between paired chromosomes located within the nucleus of an individual’s cells.

With a median follow-up of 15 months, the study identified genetic subgroups that were markedly more likely to develop peripheral neuropathy.

Those who carried two normal nucleotides in the RWDD3 gene had a 27 percent chance of experiencing neuropathy; those who carried one normal nucleotide and one SNP had a 40 percent risk; and those who carried two SNPs had a 60 percent risk.

In contrast, those who carried two normal nucleotides in the TECTA gene had a 29 percent chance of experiencing neuropathy; those who carried one normal nucleotide and one SNP had a 32 percent risk; and those who carried two SNPs had a 57 percent risk.

The study also found that older patients and African Americans were much more likely to have peripheral neuropathy, and further analysis of SNPs in these groups is underway.

The authors plan to continue their work in additional trials to validate these findings and to determine whether a different type or schedule of taxane therapy would result in less neuropathy in the more susceptible genetic groups. The authors also are collaborating with neurobiologists to understand why these genetic variations might make the nerves more sensitive to these drugs.

____________________

Sources:

• ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine – Genetic Biomarker Predicts Taxane-Induced Neuropathy, Press Release, American Society of Clinical Oncology, May 18, 2011. [Adobe Reader PDF]

• Schneider BP, Li L, Miller K, et. al. Genetic associations with taxane-induced neuropathy by a genome-wide association study (GWAS) in E5103. J Clin Oncol 29: 2011 (suppl; abstr 1000)(2011 ASCO Annual Meeting).

Resources:

• Genetic Variations Identify Patients Sensitive to Nerve Damage from Chemotherapy, http://www.Cancer.net, May 18, 2011.

ASCO 2011: Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors

Cabozantinib (XL184) demonstrated high rates of disease control in patients with prostate, ovarian and liver cancers. The investigators concluded that cabozantinib exhibits clinical activity in ovarian cancer patients with advanced disease, regardless of prior platinum drug status, as reflected by the high rates of response. 

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

The study results from a phase II clinical trial involving cabozantinib (XL184) were highlighted today in the ASCO press briefing, as summarized below.

Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors, and Can Shrink or Eliminate Bone Metastases 

Cabozantinib (XL184) – an oral inhibitor of MET and VEGFR2 kinases involved in the development and progression of many cancers – showed strong responses in patients with various advanced cancers in a phase II trial. The drug demonstrated particularly high rates of disease control for advanced prostate, ovarian and liver cancers, which are historically resistant to available therapies. The drug also fully or partially eliminated bone metastases in patients with breast and prostate cancers and melanoma.

Michael S. Gordon, M.D., President & Chief Executive Officer, Pinnacle Oncology Hematology.

“Cabozantinib appears to have significant effects on several treatment-resistant tumors, as well as impressive effects on bone metastases. In addition, these effects are associated with rapid improvement in pain, a reduction in opiate narcotic requirements and improvement in anemia,” said lead author Michael S. Gordon, M.D., a medical oncologist at Pinnacle Oncology Hematology located in Scottsdale, Arizona. “The implications of these results are very exciting—it is unusual to find a targeted therapy, absent of a molecular mutation in tumors, that works in bony disease and has this activity.”

To be eligible for the study, patients had to have advanced, progressive solid tumors, with or without bone metastases. Of 398 evaluable patients (of 483 enrolled in the trial), 39 percent had bone metastases at baseline. Patients received cabozantinib over 12 weeks. The trial was designed as a “discontinuation” trial, in which those who had partial responses stayed on the drug; those with stable disease were randomized to cabozantinib or placebo; and patients with progressive disease were removed from the trial. This novel type of clinical trial design more quickly evaluates the disease-stabilizing activity of growth-inhibitory agents like cabozantinib, compared to the traditional model of randomizing all patients to either the experimental arm or placebo.

Among 398 patients evaluable with all types of cancer included in the trial, the collective overall response rate was 9 percent (34 of 398). The highest disease control rates (partial response and stable disease) at week 12 were 76 percent for liver cancer (22 of 29 patients), 71 percent for prostate cancer (71 of 100 patients), and 58 percent for ovarian cancer (32 of 51 patients). [emphasis added].

Of the 51 evaluable ovarian cancer patients noted above, 28 are platinum drug resistant, 17 are platinum drug sensitive, and 6 have unknown status. The median number of systemic treatments prior to trial enrollment was 2. The overall response rate (complete response and partial response based on modified RECIST criteria) for ovarian cancer was 12/51 (24%).  Upon breakdown, the response rate was 5/28 (18%) for platinum drug resistant patients, and 5/17 (29%) for platinum drug sensitive patients. Five additional partial responses await confirmation. After a median follow-up of 4 months (range: 1 to 11 months), the median duration of response and median progression free survival have not been reached. The most common related adverse events ( ≥grade 3) among ovarian cancer patients were hand-foot syndrome (10%), diarrhea (8%) and fatigue (4%). Drug dose reductions and permanent discontinuations for adverse events occurred in 43% and 10% of the ovarian cancer patients, respectively. Based on these findings, the investigators concluded that cabozantinib exhibits clinical activity in ovarian cancer patients with advanced disease, regardless of prior platinum drug status, as reflected by the high rates of response. [emphasis added] Accordingly, randomization in the ovarian cancer cohort was halted & patients unblinded due to the observed high efficacy.

Fifty-nine of 68 patients with bone metastases (including patients with breast and prostate cancers and melanoma) experienced either partial or complete disappearance of the cancer on bone scans, often with significant pain relief and other improved cancer-related symptoms.

The reduction of bone metastases and pain relief was an unexpected finding in this study, Dr. Gordon said. Independent review by radiologists confirmed that bone metastases disappeared in the majority of patients who had bone metastases when they entered the study. The majority of these patients had castration-resistant prostate cancer (CRPC), but patients with breast cancer and melanoma also had disappearance of bone metastases. Bone metastases greatly contribute to morbidity and mortality in patients with these types of cancer, which typically spread to the bone.

Due to these results, the study has been expanded to include more CRPC patients. Similarly, the high rate of lasting responses in ovarian cancer patients led researchers to also expand the study to evaluate the drug’s effect on patients with a particularly resistant form of the disease known as platinum drug resistant/refractory ovarian cancer. [emphasis added]

This study expansion results will help determine the design of future phase III trials, which will assess whether the drug extends patients lives or has other longer-term benefits among patients with specific cancer types. At present, cabozantinib is being investigated for use as a single agent. Additional studies will evaluate the efficacy and tolerability of appropriate combinations with other agents for future indications.

For the solid tumor patients collectively, the most common grade three or above adverse events were fatigue (9 percent) and hand-foot syndrome (8 percent). Dose reductions were required in 41 percent of patients due to side effects; 12 percent were removed from the trial for adverse events.

Sources:

• ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine – Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors, and Can Shrink or Eliminate Bone Metastases , Press Release, American Society of Clinical Oncology, May 18, 2011. [Adobe Reader PDF]

• Gordon MS, Vogelzang NJ, Schoffski P, et. al. Activity of cabozantinib (XL184) in soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) with advanced solid tumors. J Clin Oncol 29: 2011 (suppl; abstr 3010)(2011 ASCO Annual Meeting).

• Buckanovich R.J., Berger R, Sella A, et. al. Activity of cabozantinib (XL184) in advanced ovarian cancer patients (pts): Results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 29: 2011 (suppl; abstr 5008)(2011 ASCO Annual Meeting).

• Hussain M, Smith MR, Sweeney C., et. al. Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial. J Clin Oncol 29: 2011 (suppl; abstr 4516)(2011 ASCO Annual Meeting).

Resources:

• Cabozantinib Helps Manage Several Advanced Cancers and Shrink Bone Metastases, http://www.Cancer.net, May 18, 2011.

Cabozantinib (XL184) Clinical Trials:

• A list of open solid tumor clinical trials involving cabozantinib (XL184).

Related Libby’s H*O*P*E*™ Postings:

• Exelixis Reports Promising Interim Data From Ovarian Cancer Patients Treated With XL184, November 18, 2010.

ASCO 2011: Maintenance Therapy With PARP Inhibitors Could Play Important Role in Treatment of Recurrent Ovarian Cancer

A randomized phase II clinical trial showed that the oral PARP inhibitor drug olaparib (AZD2281), given after chemotherapy, improved progression-free survival in women with the most common type of recurrent ovarian cancer.

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

The study results from a phase II clinical trial involving maintenance therapy with the PARP (poly (ADP-ribose) polymerase) inhibitor olaparib were highlighted today in the ASCO press briefing, as summarized below.

Randomized Study Shows that Maintenance Therapy With PARP Inhibitors Could Play Important Role in Treatment of Recurrent Ovarian Cancer

A phase II randomized trial showed that maintenance treatment with the oral PARP inhibitor drug olaparib (AZD2281) improved progression-free survival by about four months in women with the most common type of relapsed ovarian cancer. This is the first randomized trial to demonstrate a benefit for maintenance therapy for recurrent ovarian cancer, and the first randomized trial in ovarian cancer of a PARP inhibitor– a novel class of molecularly targeted drugs.

The results of this study, if confirmed in larger trials, could lead to a new treatment approach for recurrent ovarian cancer in which drugs like olaparib are given over a long period of time to prevent recurrences or prolong remissions. This somewhat novel approach, called maintenance therapy, has already proven useful in lung cancer. Standard treatment for ovarian cancer includes platinum-based chemotherapy. After this regimen, patients are observed until recurrence, and then treated with another course of chemotherapy. While some tumors respond well to chemotherapy, the regimens are too toxic for patients to take continuously, and clinical trials have not shown any benefit for extended courses of chemotherapy.

Jonathan A. Ledermann, M.D., Lead Author & Principal Investigator of PARP Maintenance Study; Professor, Medical Oncology, UCL Cancer Institute, University College London

“A well-tolerated antitumor agent that could be used for months or perhaps years as maintenance therapy after standard chemotherapy could be a big step forward and ultimately extend survival,” said lead author Jonathan A. Ledermann, M.D., principal investigator of the study and Professor of Medical Oncology at UCL Cancer Institute, University College London. “This study demonstrates proof of principle for the concept of maintenance therapy in ovarian cancer using a PARP inhibitor. Our progression-free survival difference was very impressive and better than we anticipated.”

The multicenter, international study randomized 265 women with high-grade serous ovarian cancer to either olaparib or placebo. Patients were enrolled in the trial within 8 weeks of having achieved either a complete or partial response to platinum-based treatment. PARP inhibitors have been shown to work better in patients whose tumors have responded to platinum.

In the study, the progression-free survival (PFS) – the amount of time during and after treatment in which the cancer does not return – was significantly longer in the group receiving olaparib than the placebo group, with a median of 8.4 months versus 4.8 months. At the time of data analysis, half the patients randomized to olaparib (68 patients) had not relapsed and were still receiving the drug, while only 16 percent (21 patients) remained on placebo – so overall survival data were not yet available for analysis.

Adverse events were more commonly reported in the group receiving olaparib than placebo, including nausea, fatigue, vomiting, and anemia, but the majority of these were not severe. Dose reductions to manage side effects were allowed in the study and were more prevalent in the olaparib group (23 percent) compared to the placebo group (7 percent).

Olaparib inhibits the enzyme poly (ADP-ribose) polymerase — abbreviated “PARP” — which is involved in DNA (deoxyribonucleic acid) repair. Up to half of women with high-grade serous ovarian cancer – the most common type of ovarian cancer – may have a DNA repair deficiency that makes them more susceptible to treatment with PARP inhibitors.

A number of PARP inhibitors are being studied in phase II and phase III clinical trials, as single agents and in combination with standard chemotherapies and radiation, in some types of breast and ovarian cancers believed to have DNA repair defects.

Sources:

• ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine – Randomized Study Shows that Maintenance Therapy & PARP Inhibitors Could Play Important Roles in Treatment of Relapsed Ovarian Cancer, Press Release, American Society of Clinical Oncology, May 18, 2011. [Adobe Reader PDF]

• Ledermann JA, Harter P, Gourley C, et. al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). J Clin Oncol 29: 2011 (suppl; abstr 5003)(2011 ASCO Annual Meeting).

PARP Clinical Trials:

• A list of open ovarian cancer clinical trials involving PARP inhibitors.

Resources:

• Long-Term Treatment with Olaparib May Help Treat Recurrent Ovarian Cancer, http://www.Cancer.net, May 18, 2011.

Related WORD of HOPE™ Ovarian Cancer Podcasts:

• 10 Exciting Ovarian Cancer Research Topics from 2010 — PARP Inhibitors & BRCA Gene-Mutated Ovarian Cancer (Topic #2 of 10) [Podcast Episode #2].

Related Libby’s H*O*P*E*™ Postings:

• PARP Inhibitor MK-4827 Shows Anti-Tumor Activity in First Human Clinical Study, November 17, 2010.

• New Assay Test Predicts That 50% of Ovarian Cancers Will Respond To In Vitro PARP Inhibition, November 11, 2010.

• PARP Inhibitor Olaparib Benefits Women With Inherited Ovarian Cancer Based Upon Platinum Drug Sensitivity, April 23, 2010.

• UPCI Launches Clinical Trial for Patients with Hereditary Breast and Ovarian Cancers, May 12, 2009.

Related Libby’s H*O*P*E*™ Videos Re PARP Inhibitors

• PARP Inhibitor MK4827 Active in Ovarian Cancer, MedPage Today, 2011 Society of Gynecologic Oncologists (SGO) Annual Meeting, March 23, 2011.

• PARP Inhibitors and Ovarian Cancer, Katherine Bell-McGuinn, M.D., Ph.D., Medical Oncologist, Memorial Sloan-Kettering Cancer Center, September 22, 2010.

• The role of homologous recombination in cancer & PARP inhibitors, Prof. Thomas Helleday, Gray Institute for Radiation Oncology, 2010 European Association For Cancer Research (EACR) Annual Mtg, ecancer.tv, August 18, 2010.

• PARP Inhibitors: Professor Hilary Calvert discusses his work on PARP inhibitor, Prof. Hilary Calvert, University College London, ecancer.tv, July 20, 2010.

2011 ASCO: Screening With CA-125 & Transvaginal Ultrasound Does Not Reduce Ovarian Cancer Death Rate, Results in High Number of False Positives

Findings from a large, long-term study – the Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial – showed that using a CA-125 blood test and transvaginal ultrasound for early detection of ovarian cancer did not reduce the risk of dying from the disease, and resulted in a large number of false positives and related follow-up procedures.

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Ill. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

The study results from a large clinical trial involving ovarian cancer screening were highlighted in today’s press briefing as summarized below.

Screening with CA-125 and Transvaginal Ultrasound Does Not Reduce Ovarian Cancer Death Rate, Results in High Number of False Positives

A randomized, multicenter screening study of nearly 80,000 women in the general population showed that using a CA-125 blood test and transvaginal ultrasound for early detection of ovarian cancer did not reduce the risk of dying from the disease, and resulted in a large number of false positives and related biopsies and follow-up procedures. The results indicate that while these tests are widely and appropriately used to evaluate symptoms, and to gauge disease status and effectiveness of treatment in women already diagnosed with ovarian cancer, they are not useful in screening the general population.

Saundra S. Buys, M.D., Medical Director, Huntsman Cancer Institute’s High Risk Breast Cancer Clinic; Professor, Depart. of Internal Medicine, Univ. of Utah School of Medicine

“There hasn’t been a good method for the early detection of ovarian cancer, and our hypothesis was that CA-125 and transvaginal ultrasound, which are useful in measuring disease, would also identify ovarian cancer early, at a stage in which it is more likely to be cured,” said lead author Saundra Buys, M.D., professor of medicine at the University of Utah and Huntsman Cancer Institute in Salt Lake City. “The results were disappointing, but not necessarily surprising. The study shows that the available tests are not effective and may actually cause harm because of the high number of false positives. These results point to the continued need for more precise and effective screening tools for this disease.”

In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 78,216 women ages 55 to 74 were assigned to either annual screening (39,105 women) or usual care (39,111 women) between 1993 and 2001. Women in the screening arm were offered annual CA-125 testing for six years and transvaginal ultrasound for four, and followed for up to 13 years. Those in the usual care arm were not offered the screening tests.

The results showed no statistically significant difference in ovarian cancer cases or mortality between the two arms. Ovarian cancer was diagnosed in 212 women in the screening group arm compared to 176 in the usual care arm; 118 women in the screening arm died from ovarian cancer, while 100 died from ovarian cancer in the usual care group.

Among women in the screening arm, there were a high number of false positives – 3,285 false positives, compared to just 212 true positives. Of women who had a false positive test, 1,080 underwent surgery for biopsy – the procedure generally required to evaluate positive test results; 163 of them had serious complications.

The authors emphasized that the study results don’t apply to screening women with symptoms or abnormal findings on physical examination. [emphasis added] Physical examination based on symptoms and appropriate follow-up testing remains the best available approach for ovarian cancer detection.

[Note: This summary contains updated data and a correction from the original abstract. Correction:  Of the 3,285 women who received a false positive exam, 1,080 underwent surgery. Of those surgical patients, 163 encountered at least one serious complication.]

Sources:

• ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine – Screening with CA-125 and Transvaginal Ultrasound Does Not Reduce Ovarian Cancer Death Rate, Results in High Number of False Positives, Press Release, American Society of Clinical Oncology, May 18, 2011. [Adobe Reader PDF]

• Buys SS, Partridge E, Black A, et. al. Effect of screening on ovarian cancer mortality in the prostate, lung, colorectal and ovarian (PLCO) cancer randomized screening trial. J Clin Oncol 29: 2011 (suppl; abstr 5001)(2011 ASCO Annual Meeting).

Resources:

• Screening Does Not Reduce Deaths from Ovarian Cancer for the General Population, http://www.Cancer.net, May 18, 2011.

Phenoxodiol Used In Combination With Platinum or Taxane-Based Chemotherapy Is Active In Platinum & Taxane-Resistant Ovarian Cancer

Phase II clinical study results suggests phenoxodiol is active in platinum and taxane drug-resistant ovarian cancer patients when administered intravenously in combination with platinum or taxane-based chemotherapy

Marshall Edwards, Inc., an oncology company focused on the clinical development of novel therapeutics targeting cancer metabolism, recently announced the publication of results from a phase II clinical trial of intravenous phenoxodiol in combination with cisplatin or paclitaxel in women with platinum–refractory/resistant ovarian cancer. The publication is now available on the International Journal of Gynecological Cancer website, and the print edition will appear the May issue of the journal.

The study, conducted at Yale-New Haven Hospital, showed that the combination of intravenous phenoxodiol, a novel NADH oxidase inhibitor, with cisplatin (a platinum-based chemotherapy) or paclitaxel (a taxane-based chemotherapy), was well tolerated.

Robert D. Mass, M.D., Acting Chief Medical Officer, Marshall Edwards.

In the study, 32 patients were randomized to one of two treatment arms according to their previous treatment responses: (1) platinum refractory/resistant patients received weekly cisplatin (40 mg/m intravenous), combined with weekly phenoxodiol (3 mg/kg); and (2) taxane refractory/resistant patients received weekly paclitaxel (80 mg/m intravenous), combined with weekly phenoxodiol (3 mg/kg). The study patients continued on treatment until complete response, disease progression, unacceptable toxicity, or voluntary withdrawal.

In the cisplatin study arm, there were 3 partial responses, 9 patients (56%) achieved stable disease, 4 patients (25%) progressed, and the overall best response rate was 19%. In the paclitaxel study arm, there was one complete response and 2 partial responses, 8 patients (53%) achieved stable disease, 4 patients (27%) progressed, and the overall best response rate was 20%. Response rate in this study was defined as the percentage of patients whose tumor demonstrated a radiologically confirmed reduction or disappearance after treatment.

There were no treatment-related deaths in the study, and there was only one treatment-related hospitalization and two grade 4 (i.e., life-threatening or disabling) adverse events.

Based upon the foregoing results, the researchers concluded that the combination of intravenous phenoxodiol with cisplatin or paclitaxel was well tolerated.  Moreover, the researchers stated that the cisplatin-phenoxodiol combination was particularly active and warrants further study in patients with platinum-resistant ovarian cancer.

“These results suggest that the combination of intravenous phenoxodiol with cisplatin has a good safety profile and may be capable of reversing resistance to platinum-based chemotherapy,” said lead author Michael G. Kelly, M.D., a gynecologic oncologist at Tufts Medical Center and former fellow at Yale University School of Medicine.” This study provides early clinical proof-of-concept for the combination of NADH oxidase inhibitors with standard-of-care chemotherapy and lays the groundwork for the development of more potent next-generation compounds.”

To date, phenoxodiol, an investigational drug, has been introduced into more than 400 patients in multiple clinical trials via oral or intravenous routes and has been well tolerated. Marshall Edwards has identified a next-generation compound called “NV-143,” which has demonstrated significantly more activity than phenoxodiol against a broad range of tumor cell lines. In addition to being more active as a single agent, NV-143 appears to be superior in its ability to synergize with platinum-based chemotherapy in pre-clinical studies. As a result, Marshall Edwards plans to initiate a phase I clinical trial of intravenous NV-143 later this year, followed immediately thereafter by randomized phase II trials in combination with chemotherapy.

“These published results combined with data from previous studies reinforce our conclusion that intravenous administration is the optimal route of delivery for this class of drugs and give us added confidence moving forward as we develop our next-generation compound NV-143 for the clinic,” said Robert D. Mass, M.D., Acting Chief Medical Officer of Marshall Edwards.

About Marshall Edwards

Marshall Edwards, Inc. is a San Diego-based oncology company focused on the clinical development of novel anti-cancer therapeutics. The Company’s lead programs focus on two families of small molecules that result in the inhibition of tumor cell metabolism. The first and most advanced is a NADH oxidase inhibitor program that includes lead drug candidate NV-143. The second is a mitochondrial inhibitor program that includes NV-128 and its next-generation candidate NV-344. Both programs are expected to advance into the clinic in 2011. For more information, visit www.marshalledwardsinc.com.

About Novogen Limited

Novogen Limited is an Australian biotechnology company based in Sydney, Australia. Novogen has a consumer healthcare business, and conducts research and development on oncology therapeutics through its 71.3% owned subsidiary, Marshall Edwards, Inc.

Sources:

• Study Suggests Phenoxodiol Active when Administered Intravenously in Combination with Platinum-Based Chemotherapy for Ovarian Cancer, Press Release, Marshall Edwards, Inc., March 21, 2011.

• Kelly MG, Mor G, Husband A, et. al. Phase II Evaluation of Phenoxodiol in Combination With Cisplatin or Paclitaxel in Women With Platinum/Taxane-Refractory/Resistant EpithelialOvarian, Fallopian Tube, or Primary Peritoneal Cancers. Int J Gynecol Cancer. 2011 Mar 15. [Epub ahead of print] PubMed PMID: 21412168.

• Multi-Center, Phase Ib/IIa Safety and Preliminary Efficacy Study of Phenoxodiol (Intravenous Dosage Form) as a Chemo-Sensitizing Agent for Cisplatin and Paclitaxel in Epithelial Ovarian Cancer or Primary Peritoneal Cancer That is Platinum- and/or Taxane-Refractory or Resistant, Clinical Trial Summary, NCT00091377, ClinicalTrials.gov.

2011 NCCN Conference: New Treatment Options Lead to Steady Progress Against Ovarian Cancer

Recommendations stemming from recent clinical trials highlight notable updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Ovarian Cancer at the National Comprehensive Cancer Network® (NCCN®) 16th Annual Conference.

Robert J. Morgan, Jr., M.D., Professor of Medical Oncology, City of Hope Comprehensive Cancer Center; Chair, NCCN Guidelines Panel for Ovarian Cancer

Although finding effective screening tools remains a priority, new treatment options for women with ovarian cancer, such as the ones outlined in the updated NCCN Guidelines for Ovarian Cancer,[1] are vital to making steady progress against the disease according to Robert J. Morgan, Jr., M.D., of City of Hope Comprehensive Cancer Center and chair of the NCCN Guidelines Panel for Ovarian Cancer. Dr. Morgan outlined significant updates to the NCCN Guidelines during a recent presentation at the NCCN 16th Annual Conference.

The NCCN Guidelines address epithelial ovarian cancer (including borderline or low malignant potential) and less common histopathologies, including malignant germ neoplasms, carcinosarcomas, and sex cord-stromal tumors. They also discuss fallopian tube cancer and primary peritoneal cancer, which are less common neoplasms that are managed in a similar manner to epithelial ovarian cancer.

“Regardless of the type of cancer, the NCCN Guidelines for Ovarian Cancer reflect the importance of stage and grade of disease on prognosis and treatment recommendations,” said Dr. Morgan.

The NCCN Guidelines continue to recommend that women with borderline epithelial ovarian cancer of low malignant potential be primarily surgically managed. In contrast to patients with frankly invasive ovarian carcinoma, women with borderline disease tend to be younger and are often diagnosed with stage I disease.

“The benefits of postoperative chemotherapy has not been demonstrated for patients who have no microscopically demonstrable invasive implants, said Dr. Morgan. “Even patients with advanced stage disease at presentation have an excellent prognosis and chemotherapy should be avoided.”

The NCCN Guidelines recommend surgery limited to a unilateral salpingo-oophorectomy (USO) (preserving the uterus and contralateral ovary) for women who wish to maintain their fertility, and standard ovarian cancer debulking surgery is recommended for those not concerned about fertility preservation.

On the contrary, in women diagnosed with stage II, III, or IV epithelial ovarian cancer, the NCCN Guidelines recommend intraperitoneal chemotherapy for first-line therapy and have been updated to include dose-dense paclitaxel (Taxol®:, Bristol-Myers Squibb) as a possible treatment option.

Dr. Morgan noted that in a recent clinical trial, dose-dense weekly paclitaxel with carboplatin (Paraplatin®:, Bristol-Myers Squibb) showed an increase in both progression-free survival and overall survival when compared with conventional intraperitoneal chemotherapy of weekly carboplatin/paclitaxel.[2]

“However, the dose-dense regimen is more toxic, and patients discontinued dose-dense paclitaxel therapy more often than those receiving standard therapy,” stated Dr. Morgan. “As with all treatment decisions, the patient needs to weigh the potential benefits and risks and discuss them thoroughly with their physician.”

Dr. Morgan discussed two additional phase 3 trials assessing bevacizumab (Avastin®:, Genentech/Roche) combined with carboplatin/paclitaxel in the upfront setting compared to carboplatin/paclitaxel alone.[3-4] Although data regarding overall survival and quality of life have not been reported yet, the studies did indicate that the median progression-free survival increased in patients receiving bevacizumab as a first line and maintenance therapy.

“Only modest improvements in progression-free survival were observed in both of these trials. The NCCN Guidelines Panel prefers to await mature results of these trials prior to recommending the routine addition of bevacizumab to carboplatin/paclitaxel,” said Dr. Morgan.

As such, the updated NCCN Guidelines includes new language detailing the Panel’s view on bevacizumab encouraging participation in ongoing clinical trials that are further investigating the role of anti-angiogenesis agents in the treatment of ovarian cancer, both in the upfront and recurrence settings.

Biomarkers continue to emerge as an area of interest in predicting future patterns of the disease. In patients with ovarian cancer, Dr. Morgan discussed the value of monitoring CA-125 levels in regards to a recent study[5] comparing early versus delayed treatment of relapsed ovarian cancer.

“Often, levels of CA-125 have been shown to rise prior to a clinical or symptomatic relapse in women with ovarian cancer. This trial looked at whether there was a benefit of early treatment on the basis of increased CA-125 concentrations compared with delayed treatment on the basis of clinical recurrence,” said Dr. Morgan.

The study, which was published in The Lancet, found that there was no survival benefit to early institution of treatment based on increased CA-125 levels and that the quality of life was superior in patients in the late treatment arm.

“The results of the trial suggest that the utility of the routine monitoring of CA-125 levels in limited,” said Dr. Morgan. “The NCCN Guidelines Panel encourages patients and their physicians to actively discuss the pros and cons of CA-125 monitoring based upon these findings and have updated the NCCN Guidelines to include language supporting this recommendation.”

Virtually all drugs used in oncology have the potential to cause adverse drug reactions while being infused, which can be classified as either infusion or allergic reactions. Recently, hypersensitivity to platinum compounds has been recognized as a potential issue for patients being administered these compounds.

“Platinum compounds remain very important in the treatment of ovarian cancer in both the upfront and recurrence settings, so it was important to design strategies to allow for the safe desensitization of these agents in patients who develop allergies,” said Dr. Morgan.

Standard desensitization regimens include slowly increasing infusion concentrations over several hours. However, Dr. Morgan noted that these procedures must be done in a specific manner in order to be safely administered and pointed to the recommendations within the updated NCCN Guidelines discussing the management of drug reactions.

In conclusion, Dr. Morgan emphasized that although steady progress is being made in the treatment of ovarian cancer, further trials are necessary to investigate the role of targeted agents alone and in combination in newly diagnosed and recurrent ovarian cancer. In addition, enrollment of patients with ovarian cancer must be encouraged.

The NCCN Guidelines are developed and updated through an evidence-based process with explicit review of the scientific evidence integrated with expert judgment by multidisciplinary panels of expert physicians from NCCN Member Institutions. The most recent version of this and all NCCN Guidelines are available free of charge at NCCN.org. The NCCN Guidelines for Patients™: Ovarian Cancer is available at NCCN.com.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. For more information, visit NCCN.org.

The NCCN Member Institutions are:

• City of Hope Comprehensive Cancer Center
• Dana-Farber/Brigham and Women’s Cancer Center
• Massachusetts General Hospital Cancer Center
• Duke Cancer Institute
• Fox Chase Cancer Center
• Huntsman Cancer Institute at the University of Utah
• Fred Hutchinson Cancer Research Center / Seattle Cancer Care Alliance
• The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Robert H. Lurie Comprehensive Cancer Center of Northwestern University
• Memorial Sloan-Kettering Cancer Center
• H. Lee Moffitt Cancer Center & Research Institute
• The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute
• Roswell Park Cancer Institute
• Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
• St. Jude Children’s Research Hospital / University of Tennessee Cancer Institute
• Stanford Comprehensive Cancer Center
• University of Alabama at Birmingham Comprehensive Cancer Center
• UCSF Helen Diller Family Comprehensive Cancer Center
• University of Michigan Comprehensive Cancer Center
• UNMC Eppley Cancer Center at The Nebraska Medical Center
• The University of Texas MD Anderson Cancer Center
• Vanderbilt-Ingram Cancer Center

References:

1/ Ovarian Cancer Including Fallopian Tube Cancer & Primary Peritoneal Cancer, Version 2.2011, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™), National Comprehensive Cancer Network. [PDF Adobe Reader Document – requires free registration and log-in at NCCN.org]

2/ Katsumata N, Yasuda M, Takahashi F, et. al. Japanese Gynecologic Oncology Group. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009 Oct 17;374(9698):1331-8. Epub 2009 Sep 18. PubMed PMID: 19767092.

3/ Burger RA, Brady MF, Bookman MA, et. al.  Phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC):  a Gynecologic Oncology Group study.  J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1).

4/ Perren T, Swart AM, Pfisterer J, et. al. ICON7: A phase III randomized gynecologic cancer intergroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab, versus chemotherapy alone in women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC).Ann Oncol 21;viii2, 2010 (suppl 8; abstr LBA4).

5/Rustin G, van der Burg M, Griffin C, et. al. Early versus delayed treatment of relapsed ovarian cancer. Lancet. 2011 Jan 29;377(9763):380-1. PubMed PMID: 21277438.

Source:

• New Treatment Options Lead to Steady Progress Against Ovarian Cancer; Clinical Trials Remain Imperative, Press Release, National Comprehensive Cancer Network, March 14, 2011.

Additional 2011 NCCN Annual Meeting Information

• NCCN Panel Calls for Higher Standards, Better Ways of Translating Molecular Genetics into Clinical Practice, Press Release, National Comprehensive Cancer Network, March 14, 2011.

2011 SGO Annual Meeting: Ovarian Cancer Abstracts Selected For Presentation

The March 2011 supplemental issue of Gynecologic Oncology sets forth the ovarian cancer and ovarian cancer-related medical abstracts selected by the Society of Gynecologic Oncologists for presentation at its 42nd Annual Meeting on Women’s Cancer™, which is being held in Orlando, Florida from March 6-9, 2011.

The Society of Gynecologic Oncologists (SGO) is hosting its 42nd Annual Meeting on Women’s Cancer™ (March 6–9, 2011) in Orlando, Florida. The SGO Annual Meeting attracts more than 1,700 gynecologic oncologists and other health professional from around the world.

In connection with this premier gynecologic cancer event, 651 abstracts, and 27 surgical films were submitted for consideration. After careful discussion and deliberation, the SGO selected 51 abstracts for oral presentation (27 Plenary session papers, 24 Focused Plenary papers, and 42 Featured Posters, presented in a new, electronic format), along with 227 for poster presentation. Of the 27 surgical films originally submitted, five films were selected for presentation during a featured Focused Plenary session.

The ovarian cancer abstracts listed below were obtained from the March 2011 supplemental issue of Gynecologic Oncology. Each abstract bears the number that it was assigned in the Gynecologic Oncology journal table of contents.

Please note that we provide below (under the heading “Additional Information”) Adobe Reader PDF copies of the 2011 SGO Annual Meeting program summary and the medical abstract booklet (includes all gynecologic cancer topics). If you require a free copy of the Adobe Reader software, please visit http://get.adobe.com/reader/otherversions/.

For your convenience, we listed the 2011 SGO Annual Meeting ovarian cancer abstracts under the following subject matter headings:  (1) ovarian cancer symptoms, (2) ovarian cancer screening, (3) pathology, (4) ovarian cancer staging, (5) chemotherapy, (6) diagnostic and prognostic biomarkers, (7) clinical trial drugs and results, (8) hereditary breast & ovarian cancer syndrome (BRCA gene deficiencies & Lynch Syndrome), (9) gynecologic practice, (10) gynecologic surgery, (11) genetic/molecular profiling, (12) immunotherapy, (13) medical imaging, (14) preclinical studies – general, (15) preclinical studies – potential therapeutic targets, (16) palliative and supportive care, (17) rare ovarian cancers, (18) survival data, (19) survivorship, (20) other, (21) late breaking abstracts.

Ovarian Cancer Symptoms

142. Utility of symptom index in women at increased risk for ovarian cancer. (SGO Abstract #140)

184. Symptom-triggered screening for ovarian cancer: A pilot study of feasibility and acceptability. (SGO Abstract #182)

187. Women without ovarian cancer reporting disease-specific symptoms. (SGO Abstract #185)

Ovarian Cancer Screening

12. Ovarian cancer: Predictors of primary care physicians’ referral to gynecologic oncologists. (SGO Abstract #10)

84. Long-term survival of patients with epithelial ovarian cancer detected by sonographic screening. (SGO Abstract #82)

90. Significant endometrial pathology detected during a transvaginal ultrasound screening trial for ovarian cancer. (SGO Abstract #88)

109. Detection of the tissue-derived biomarker peroxiredoxin 1 in serum of patients with ovarian cancer: A biomarker feasibility study. (SGO Abstract #107)

113. Epithelial ovarian cancer tumor microenvironment is a favorable biomarker resource. (SGO Abstract #111)

127. Stop and smell the volatile organic compounds: A novel breath-based bioassay for detection of ovarian cancer. (SGO Abstract #125)

144. Incidental gynecologic FDG-PET/CT findings in women with a history of breast cancer. (SGO Abstract #142)

156. Discovery of novel monoclonal antibodies (MC1–MC6) to detect ovarian cancer in serum and differentiate it from benign tumors. (SGO Abstract #154)

158. Evaluation of the risk of ovarian malignancy algorithm (ROMA) in women with a pelvic mass presenting to general gynecologists. (SGO Abstract #156)

162. Human epididymis protein 4 increases specificity for the detection of invasive epithelial ovarian cancer in premenopausal women presenting with an adnexal mass. (SGO Abstract #160)

163. Identification of biomarkers to improve specificity in preoperative assessment of ovarian tumor for risk of cancer. (SGO Abstract #161)

171. OVA1 has high sensitivity in identifying ovarian malignancy compared with preoperative assessment and CA-125. (SGO Abstract #169)

172. OVA1 improves the sensitivity of the ACOG referral guidelines for an ovarian mass. (SGO Abstract #170)

182. Sonographic predictors of ovarian malignancy. (SGO Abstract #180)

237. Management of complex pelvic masses using the OVA1 test: A decision analysis. (SGO Abstract #235)

241. Three-dimensional power doppler angiography as a three-step technique for differential diagnosis of adnexal masses: A prospective study. (SGO Abstract #239)

Pathology

145. Accuracy of frozen-section diagnosis of ovarian borderline tumor. (SGO Abstract #143)

Ovarian Cancer Staging

31. Should stage IIIC ovarian cancer be further stratified by intraperitoneal versus retroperitoneal-only disease? A Gynecologic Oncology Group study. (SGO Abstract #29)

173. Peritoneal staging biopsies in early-stage ovarian cancer: Are they necessary? (SGO Abstract #171)

Chemotherapy

29. Treatment of chemotherapy-induced anemia in patients with ovarian cancer: Does the use of erythropoiesis-stimulating agents worsen survival? (SGO Abstract #27)

69. Intraperitoneal chemotherapy for recurrent ovarian cancer appears efficacious with high completion rates and low complications. (SGO Abstract #67)

174. Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer. (SGO Abstract #172)

177. Sequencing of therapy and outcomes associated with use of neoadjuvant chemotherapy in advanced epithelial ovarian cancer in the Medicare population. (SGO Abstract #175)

179. Should we treat patients with ovarian cancer with positive retroperitoneal lymph nodes with intraperitoneal chemotherapy? Impact of lymph node status in women undergoing intraperitoneal chemotherapy. (SGO Abstract #177)

229. Predictors and effects of reduced relative dose intensity in women receiving their primary course of chemotherapy for ovarian cancer. (SGO Abstract #227)

Diagnostic & Prognostic Biomarkers

128. Stress and the metastatic switch in epithelial ovarian carcinoma. (SGO Abstract #126)

130. The cytoskeletal gateway for tumor aggressiveness in ovarian cancer is driven by class III β-tubulin. (SGO Abstract #128)

134. True blood: Platelets as a biomarker of ovarian cancer recurrence. (SGO Abstract #132)

148. CA-125 changes can predict optimal interval cytoreduction in patients with advanced-stage epithelial ovarian cancer treated with neoadjuvant chemotherapy. (SGO Abstract #146)

149. CA-125 surveillance for women with ovarian, fallopian tube or primary peritoneal cancers: What do survivors think? (SGO Abstract #147)

150. Calretinin as a prognostic indicator in granulosa cell tumor. (SGO Abstract #148)

135. Tumor expression of the type I insulin-like growth factor receptor is an independent prognostic factor in epithelial ovarian cancer. (SGO Abstract #133)

147. C-terminal binding protein 2: A potential marker for response to histone deacetylase inhibitors in epithelial ovarian cancer. (SGO Abstract #145)

157. Elevated serum adiponectin levels correlate with survival in epithelial ovarian cancers. (SGO Abstract #155)

175. Prognostic impact of prechemotherapy HE4 and CA-125 levels in patients with ovarian cancer. (SGO Abstract #175)

178. Serum HE4 level is an independent risk factor of surgical outcome and prognosis of epithelial ovarian cancer. (SGO Abstract #176)

Clinical Trial Drugs & Results

8. MicroRNA as a novel predictor of response to bevacizumab in recurrent serous ovarian cancer: An analysis of The Cancer Genome Atlas. (SGO Abstract #6)

9. Prospective investigation of risk factors for gastrointestinal adverse events in a phase III randomized trial of bevacizumab in first-line therapy of advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer: A Gynecologic Oncology Group study. (SGO Abstract #7)

10. First in human trial of the poly(ADP)-ribose polymerase inhibitor MK-4827 in patients with advanced cancer with antitumor activity in BRCA-deficient and sporadic ovarian cancers.  (SGO Abstract #8)

30. An economic analysis of intravenous carboplatin plus dose-dense weekly paclitaxel versus intravenous carboplatin plus every three-weeks paclitaxel in the upfront treatment of ovarian cancer. (SGO Abstract #28)

51. BRCA1-deficient tumors demonstrate enhanced cytotoxicity and T-cell recruitment following doxil treatment. (SGO Abstract #49)

54. A novel combination of a MEK inhibitor and fulvestrant shows synergistic antitumor activity in estrogen receptor-positive ovarian carcinoma. (SGO Abstract #52)

68. An economic analysis of bevacizumab in recurrent treatment of ovarian cancer. (SGO Abstract #66)

71. A phase II study of gemcitabine, carboplatin and bevacizumab for the treatment of platinum-sensitive recurrent ovarian cancer. (SGO Abstract #69)

72. A phase I clinical trial of a novel infectivity-enhanced suicide gene adenovirus with gene transfer imaging capacity in patients with recurrent gynecologic cancer. (SGO Abstract #70)

73. A phase I study of a novel lipopolymer-based interleukin-12 gene therapeutic in combination with chemotherapy for the treatment of platinum-sensitive recurrent ovarian cancer. (SGO Abstract #71)

74. AMG 386 combined with either pegylated liposomal doxorubicin or topotecan in patients with advanced ovarian cancer: Results from a phase Ib study. (SGO Abstract #72)

86. Pressure to respond: Hypertension predicts clinical benefit from bevacizumab in recurrent ovarian cancer. (SGO Abstract #84)

152. Changes in tumor blood flow as estimated by dynamic-contrast MRI may predict activity of single-agent bevacizumab in recurrent epithelial ovarian cancer and primary peritoneal cancer: An exploratory analysis of a Gynecologic Oncology Group phase II trial. (SGO Abstract #150)

153. Comparing overall survival in patients with epithelial ovarian, primary peritoneal or fallopian tube cancer who received chemotherapy alone versus neoadjuvant chemotherapy followed by delayed primary debulking. (SGO Abstract #151)

154. Consolidation paclitaxel is more cost-effective than bevacizumab following upfront treatment of advanced ovarian cancer. (SGO Abstract #152)

193. Pegylated liposomal doxorubicin with bevacizumab in the treatment of platinum-resistant ovarian cancer: Toxicity profile results. (SGO Abstract #191)

194. Phase II Trial of docetaxel and bevacizumab in recurrent ovarian cancer within 12 months of prior platinum-based chemotherapy. (SGO Abstract #192)

195. A phase I/II trial of IDD-6, an autologous dendritic cell vaccine for women with advanced ovarian cancer in remission. (SGO Abstract #193)

183. STAC: A phase II study of carboplatin/paclitaxel/bevacizumab followed by randomization to either bevacizumab alone or erlotinib and bevacizumab in the upfront management of patients with ovarian, fallopian tube or peritoneal cancer. (SGO Abstract #181)

228. Is it more cost-effective to use bevacizumab in the primary treatment setting or at recurrence? An economic analysis. (SGO Abstract #226)

240. The use of bevacizumab and cytotoxic and consolidation chemotherapy for the upfront treatment of advanced ovarian cancer: Practice patterns among medical and gynecologic oncology SGO members. (SGO Abstract #238)

Hereditary Breast & Ovarian Cancer Syndrome (BRCA gene deficiencies & Lynch Syndrome)

39. BRCAness profile of ovarian cancer predicts disease recurrence. (SGO Abstract #37)

52. A history of breast carcinoma predicts worse survival in BRCA1 and BRCA2 mutation carriers with ovarian carcinoma. (SGO Abstract #52)

137. Does genetic counseling for women at high risk of harboring a deleterious BRCA mutation alter risk-reduction strategies and cancer surveillance behaviors? (SGO Abstract #135)

138. Hereditary breast and ovarian cancer syndrome based on family history alone and implications for patients with serous carcinoma. (SGO Abstract #138)

139. Management and clinical outcomes of women with BRCA1/2 mutations found to have occult cancers at the time of risk-reducing salpingo-oophorectomy. (SGO Abstract #137)

141. The impact of BRCA testing on surgical treatment decisions for patients with breast cancer. (SGO Abstract #139)

136. Compliance with recommended genetic counseling for Lynch syndrome: Room for improvement. (SGO Abstract #134)

Gynecologic Practice

81. Availability of gynecologic oncologists for ovarian cancer care. (SGO Abstract #79)

Gynecologic Surgery

19. Single-port paraaortic lymph node dissection. (SGO Abstract #17)

20. Robotic nerve-sparing radical hysterectomy type C1. (SGO Abstract #18)

21. Urinary reconstruction after pelvic exenteration: Modified Indiana pouch. (SGO Abstract #19)

22. Intrathoracic cytoreductive surgery by video-assisted thoracic surgery in advanced ovarian carcinoma. (SGO Abstract #20)

26. Cost comparison of strategies for the management of venous thromboembolic event risk following laparotomy for ovarian cancer. (SGO Abstract #24)

28. Primary debulking surgery versus neoadjuvant chemotherapy in stage IV ovarian cancer. (SGO Abstract #26)

33. Does the bedside assistant matter in robotic surgery: An analysis of patient outcomes in gynecologic oncology. (SGO Abstract #31)

48. Defining the limits of radical cytoreductive surgery for ovarian cancer. (SGO Abstract #46)

87. Prognostic impact of lymphadenectomy in clinically early-stage ovarian malignant germ cell tumor. (SGO Abstract #85)

93. Secondary cytoreductive surgery: A key tool in the management of recurrent ovarian sex cord–stromal tumors. (SGO Abstract #91)

146. Advanced-stage ovarian cancer metastases to sigmoid colon mesenteric lymph nodes: Clinical consideration of tumor spread and biologic behavior. (SGO Abstract #144)

155. Cytoreductive surgery for serous ovarian cancer in patients 75 years and older. (SGO Abstract #153)

168. Intraperitoneal catheters placed at the time of bowel surgery: A review of complications. (SGO Abstract #166)

169. Laparoscopic versus laparotomic surgical staging for early-stage epithelial ovarian cancer. (SGO Abstract #167)

170. Oncologic and reproductive outcomes of cystectomy compared with oophorectomy as treatment for borderline ovarian tumor. (SGO Abstract #168)

180. Significance of perioperative infectious disease in patients with ovarian cancer. (SGO Abstract #178)

185. The feasibility of mediastinal lymphadenectomy in the management of advanced and recurrent ovarian carcinoma. (SGO Abstract #183)

235. Incidence of venous thromboembolism after robotic surgery for gynecologic malignancy: Is dual prophylaxis necessary? (SGO Abstract #233)

286. Charlson’s index: A validation study to predict surgical adverse events in gynecologic oncology. (SGO Abstract #284)

288. Cost-effectiveness of extended postoperative venous thromboembolism prophylaxis in gynecologic pncology patients. (SGO Abstract #286)

302. Integration of and training for robot-assisted surgery in a gynecologic oncology fellowship program. (SGO Abstract #300)

303. Outcomes of patients with gynecologic malignancies undergoing video-assisted thorascopic surgery and pleurodesis for malignant pleural effusion. (SGO Abstract #301)

304. Perioperative and pathologic outcomes following robot-assisted laparoscopic versus abdominal management of ovarian cancer. (SGO Abstract #302)

307. Predictive risk factors for prolonged hospitalizations after gynecologic laparoscopic surgery. (SGO Abstract #305)

309. Robot-assisted surgery for gynecologic cancer: A systematic review. (SGO Abstract #307)

310. Robotic radical hysterectomy: Extent of tumor resection and operative outcomes compared with laparoscopy and exploratory laparotomy. (SGO Abstract #308)

315. Utilization of specialized postoperative services in a comprehensive surgical cytoreduction program. (SGO Abstract #313)

Genetic/Molecular Profiling

5. A 3’ UTR KRAS variant as a biomarker of poor outcome and chemotherapy resistance in ovarian cancer. (SGO Abstract #3)

15. XPC single-nucleotide polymorphisms correlate with prolonged progression-free survival in advanced ovarian cancer. (SGO Abstract #13)

16. Genomewide methylation analyses reveal a prominent role of HINF1 network genes, via hypomethylation, in ovarian clear cell carcinoma. (SGO Abstract #14)

49. Loss of ARID1A is a frequent event in clear cell and endometrioid ovarian cancers. (SGO Abstract #47)

53. Genetic variants in the mammalian target of rapamycin (mTOR) signaling pathway as predictors of clinical response and survival in women with ovarian cancer. (SGO Abstract #51)

55. BAD apoptosis pathway expression and survival from cancer. (SGO Abstract #53)

59. Molecular profiling of advanced pelvic serous carcinoma associated with serous tubal intraepithelial carcinoma. (SGO Abstract #57)

82. Biologic roles of tumor and endothelial delta-like ligand 4 in ovarian cancer. (SGO Abstract #80)

85. MicroRNA 101 inhibits ovarian cancer xenografts by relieving the chromatin-mediated transcriptional repression of p21waf1/cip1. (SGO Abstract #83)

102. Association between global DNA hypomethylation in leukocytes and risk of ovarian cancer. (SGO Abstract #100)

103. Cisplatin, carboplatin, and paclitaxel: Unique and common pathways that underlie ovarian cancer response. (SGO Abstract #101)

106. Comparison of mTOR and HIF pathway alterations in the clear cell carcinoma variant of kidney, ovary and endometrium. (SGO Abstract #104)

107. Concordant gene expression profiles in matched primary and recurrent serous ovarian cancers predict platinum response. (SGO Abstract #105)

111. Differential microRNA expression in cis-platinum-resistant versus -sensitive ovarian cancer cell lines. (SGO Abstract #109)

112. DNA methylation markers associated with serous ovarian cancer subtypes. (SGO Abstract #110)

118. MicroRNA and messenger RNA pathways associated with ovarian cancer cell sensitivity to topotecan, gemcitabine and doxorubicin. (SGO Abstract #116)

119. Molecular profiling of patients with curatively treated advanced serous ovarian carcinoma from The Cancer Genome Atlas. (SGO Abstract #117)

125. Proteomic analysis demonstrates that BRCA1-deficient epithelial ovarian cancer cell lines activate alternative pathways following exposure to cisplatin. (SGO Abstract #123)

132. The tumor suppressor KLF6, lost in a majority of ovarian cancer cases, represses VEGF expression levels. (SGO Abstract #130)

126. Quantitative PCR array identification of microRNA clusters associated with epithelial ovarian cancer chemoresistance. (SGO Abstract #124)

160. Genes functionally regulated by methylation in ovarian cancer are involved in cell proliferation, development and morphogenesis. (SGO Abstract #158)

181. Single-nucleotide polymorphism in DNA repair and drug resistance genes alone or in combination in epithelail ovarian cancer. (SGO Abstract #179)

278. Expression patterns of p53 and p21 cell cycle regulators and clinical outcome in women with pure gynecologic sarcomas. (SGO Abstract #276)

Immunotherapy

98. Ab-IL2 fusion proteins mediate NK cell immune synapse formation in epithelial ovarian cancer by polarizing CD25 to the target cell–effector cell interface. (SGO Abstract #96)

124. Proteasome inhibition increases death receptors and decreases major histocompatibility complex I expression: Pathways to exploit in natural killer cell immunotherapy. (SGO Abstract #122)

Medical Imaging

164. Impact of FDG-PET in suspected recurrent ovarian cancer and optimization of patient selection for cytoreductive surgery. (SGO Abstract #162)

294. The clinical and financial implications of MRI of pelvic masses. (SGO Abstract #292)

Preclinical Studies

11. A unique microRNA locus at 19q13.41 sensitizes epithelial ovarian cancers to chemotherapy. (SGO Abstract #9)

14. Common single-nucleotide polymorphisms in the BNC2, HOXD1 and MERIT40 regions contribute significantly to racial differences in ovarian cancer incidence. (SGO Abstract #12)

46. Development of a preclinical serous ovarian cancer mouse model. (SGO Abstract #44)

56. Examination of matched primary and recurrent ovarian cancer specimens supports the cancer stem cell hypothesis. (SGO Abstract #54)

58. Modeling of early events in serous carcinogenesis: Molecular prerequisites for transformation of fallopian tube epithelial cells. (SGO Abstract #56)

101. Antiproliferative activity of a phenolic extract from a native Chilean Amaranthaceae plant in drug-resistant ovarian cancer cell lines. (SGO Abstract #99)

115. Identification and characterization of CD44+/CD24–ovarian cancer stem cell properties and their correlation with survival. (SGO Abstract #113)

Preclinical Studies – Potential Therapeutic Targets

57. Hypoxia-mediated activation of signal transducer and activator of transcription 3 (STAT3) in ovarian cancer: A novel therapeutic strategy using HO-3867, a STAT3 inhibitor (and novel curcumin analog). (SGO Abstract #55)

61. The ubiquitin ligase EDD mediates platinum resistance and is a target for therapy in epithelial ovarian cancer. (SGO Abstract #59)

97. A novel hedgehog pathway smoothened inhibitor (BMS-833923) demonstrates in vitro synergy with carboplatin in ovarian cancer cells. (SGO Abstract #95)

100. AMPK activation mimics glucose deprivation and induces cytotoxicity in ovarian cancer cells. (SGO Abstract #98)

104. Clinical significance of vascular cell adhesion molecule 1 (VCAM-1) in the ovarian cancer microenvironment. (SGO Abstract #102)

105. Combined erbB/VEGFR blockade has improved anticancer activity over single-pathway inhibition in ovarian cancer in vivo. (SGO Abstract #103)

114. EZH2 expression correlates with increased angiogenesis in ovarian carcinoma. (SGO Abstract #112)

116. Induction of apoptosis in cisplatin-resistant ovarian cancer cells by G-1, a specific agonist of the G-protein-coupled estrogen receptor GPR30. (SGO Abstract #114)

120. Neuropilin-1 blockade in the tumor microenvironment reduces tumor growth. (SGO Abstract #118)

129. Targeting the hedgehog pathway reverses taxane resistance in ovarian cancer. (SGO Abstract #127)

121. Ovarian cancer lymph node metastases express unique cellular structure and adhesion genes. (SGO Abstract #119)

122. Overexpression of fibroblast growth factor 1 and fibroblast growth factor receptor 4 in high-grade serous ovarian carcinoma: Correlation with survival and implications for therapeutic targeting. (SGO Abstract #120)

131. The pattern of H3K56 acetylation expression in ovarian cancer. (SGO Abstract #129)

133. Thinking outside of the tumor: Targeting the ovarian cancer microenvironment. (SGO Abstract #131)

161. Horm-A domain-containing protein 1 (HORMAD1) and outcomes in patients with ovarian cancer. (SGO Abstract #159)

165. Influence of the novel histone deacetylase inhibitor panobinostat (LBH589) on the growth of ovarian cancer. (SGO Abstract #163)

166. Inhibition of stress-induced phosphoprotein 1 decreases proliferation of ovarian cancer cell lines. (SGO Abstract #164)

167. Insulin-like growth factor receptor 1 pathway signature correlates with adverse clinical outcome in ovarian cancer. (SGO Abstract #165)

230. Therapeutic synergy and resensitization of drug-resistant ovarian carcinoma to cisplatin by HO-3867. (SGO Abstract #228)

Palliative & Supportive Care

159. Factors associated with hospice use in ovarian cancer. (SGO Abstract #226)

190. Age-related preferences regarding end-of-life care discussions among gynecologic oncology patients. (SGO Abstract #188)

192. Palliative care education in gynecologic oncology: A survey of the fellows. (SGO Abstract #190)

Rare Ovarian Cancers

151. Carcinosarcoma of the ovary: A case–control study. (SGO Abstract #149)

Survival Data

80. Ten-year relative survival for epithelial ovarian cancer. (SGO Abstract #78)

83. Impact of beta blockers on epithelial ovarian cancer survival. (SGO Abstract #81)

176. Revisiting the issue of race-related outcomes in patients with stage IIIC papillary serous ovarian cancer who receive similar treatment. (SGO Abstract #174)

186. The impact of diabetes on survival in women with ovarian cancer. (SGO Abstract #184)

284. Survival following ovarian versus uterine carcinosarcoma. (SGO Abstract #282)

285. The unique natural history of mucinous tumors of the ovary. (SGO Abstract #283)

292. Stage IC ovarian cancer: Tumor rupture versus ovarian surface involvement. (SGO Abstract #290)

Survivorship

191. Menopausal symptoms and use of hormone replacement therapy: The gynecologic cancer survivors’ perspective. (SGO Abstract #189)

Other

4. From guidelines to the front line: Only a minority of the Medicare population with advanced epithelial ovarian cancer receive optimal therapy. (SGO Abstract #2)

32. Efficacy of influenza vaccination in women with ovarian cancer. (SGO Abstract #30)

91. Women with invasive gynecologic malignancies are more than 12 times as likely to commit suicide as are women in the general population. (SGO Abstract #89)

231. Attrition of first-time faculty in gynecologic oncology: Is there a difference between men and women? (SGO Abstract #229)

238. Relative impact of cost drivers on the increasing expense of inpatient gynecologic oncology care. (SGO Abstract #236)

Late-Breaking Abstracts

• Adherence with National Comprehensive Cancer Network (NCCN) Guidelines Associated with Improved Survival in Ovarian Cancer Patients, A Study of 144,449 Patients From the National Cancer Data Base: A Project from The Society of Gynecologic Oncologists (SGO) Quality and Outcomes Committee.

About Society of Gynecologic Oncologists (SGO)

The SGO is a national medical specialty organization of physicians and allied healthcare professionals who are trained in the comprehensive management of women with malignancies of the reproductive tract. Its purpose is to improve the care of women with gynecologic cancer by encouraging research, disseminating knowledge which will raise the standards of practice in the prevention and treatment of gynecologic malignancies, and cooperating with other organizations interested in women’s health care, oncology and related fields. The Society’s membership, totaling more than 1,400, is primarily comprised of gynecologic oncologists, as well as other related medical specialists including medical oncologists, radiation oncologists, nurses, social workers and pathologists. SGO members provide multidisciplinary cancer treatment including chemotherapy, radiation therapy, surgery and supportive care. More information on the SGO can be found at www.sgo.org.

About Gynecologic Oncologists

Gynecologic oncologists are physicians committed to the comprehensive treatment of women with cancer. After completing four years of medical school and four years of residency in obstetrics and gynecology, these physicians pursue an additional three to four years of training in gynecologic oncology through a rigorous fellowship program overseen by the American Board of Obstetrics and Gynecology. Gynecologic oncologists are not only trained to be skilled surgeons capable of performing wide-ranging cancer operations, but they are also trained in prescribing the appropriate chemotherapy for those conditions and/or radiation therapy when indicated. Frequently, gynecologic oncologists are involved in research studies and clinical trials that are aimed at finding more effective and less toxic treatments to further advance the field and improve cure rates.

Studies on outcomes from gynecologic cancers demonstrate that women treated by a gynecologic oncologist have a better likelihood of prolonged survival compared to care rendered by non-specialists. Due to their extensive training and expertise, gynecologic oncologists often serve as the “team captain” who coordinates all aspects of a woman’s cancer care and recovery. Gynecologic oncologists understand the impact of cancer and its treatments on all aspects of women’s lives including future childbearing, sexuality, physical and emotional well-being—and the impact cancer can have on the patient’s whole family.

Sources:

• Abstracts Presented For The 42nd Annual Meeting of the Society of Gynecologic Oncologists. Gyn Oncol 2011: Vol 120; Supplement 1; S1-S150.

• The Role of Gynecologic Oncologists, Women’s Cancer Network™.

Additional Information:

• 2011 Society of Gynecologic Oncologists Annual Meeting Program Summary. [Adobe Reader PDF document]

• 2011 Society of Gynecologic Oncologists Annual Meeting Abstract Booklet (includes all gynecologic cancer topics). [Adobe Reader PDF document]