“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

DendriticCellVaccine

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.

AdoptiveTcells

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. 

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

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 responsepartial 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 Clinical Trial Information

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 Eventsgrade 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: 

Cabozantinib (XL184) Clinical Trial Information
Related Libby’s H*O*P*E*™ Postings
Related Libby’s H*O*P*E*™ Videos

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. alOCEANS: 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. alPhase 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. alResult of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancerJ Clin Oncol 29: 2011 (suppl; abstr LBA5006) [2011 American Society of Clinical Oncology Annual Meeting].

Additional Sources & Helpful Information:

Bevacizumab (Avastin®) Clinical Trial Information

Related WORD of HOPE Ovarian Cancer Podcast™

Related Libby’s H*O*P*E*™ Postings

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:

  • EC145 PRECEDENT Trial Results — 2011 American Society of Clinical Oncology Annual Meeting Poster Presentation, June 5, 2011. [Adobe Reader PDF document]
EC145 PROCEED Clinical Trial Information:
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Related Libby’s H*O*P*E*™ Postings:

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.

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