Tag Archives: Clinical Trial Results

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

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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:
Related Libby’s H*O*P*E* Video:
Related Libby’s H*O*P*E*™ Postings:

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

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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:

High-Dose Stereotactic Body Radiation Therapy Effective Treatment For Patients With Low Volume Lung or Liver Metastases

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Libby’s H*O*P*E*™ previously reported on potential treatments for “oligometastasis,” which is defined as cancer that spreads to a few distant body sites, on June 23, 2008 and August 17, 2008.  Two related U.S. multi-institutional, phase I/II clinical studies and one Canadian Phase I clinical study reported recently results from an evaluation of the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with liver or lung metastases.  A description of each study and its findings is provided below.  In addition, we have provided an excerpt from an editorial published in the Journal of Clinical Oncologythat comments upon the lessons learned from the three SBRT clinical studies described below, as well as other related studies.

Libby’s H*O*P*E*™ previously reported on potential treatments for “oligometastasis,” which is defined as cancer that spreads to a few distant body sites, on June 23, 2008 and August 17, 2008.  Two related U.S. multi-institutional, phase I/II clinical studies and one Canadian Phase I clinical study reported recently results from an evaluation of the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with liver or lung metastases.  A description of each study and its findings are provided below.  In addition, we have provided an excerpt from an editorial published in the Journal of Clinical Oncology that comments upon the lessons learned from the three SBRT clinical studies described below, as well as other related studies.

sbrtU.S. SBRT Liver Metastases Study

In the first U.S. clinical study, patients with one to three hepatic lesions (with maximum individual tumor diameters less than 6 cm) were enrolled and treated on a multi-institutional, phase I/II clinical trial in which they received SBRT delivered in three fractions. During the phase I clinical study, the total radiation dose was safely escalated from 36 Gy to 60 Gy. During the phase II portion of the clinical study, the dose was 60 Gy. The study primary end point was local control of the hepatic metastases. Hepatic metastatic lesions with at least 6 months of radiographic follow-up were considered assessable for local control. The study secondary end points were toxicity and survival.

As part of this clinical study, 47 patients with 63 lesions were treated with SBRT. Among those patients, 69% had received at least one prior systemic therapy regimen for metastatic disease (range, 0 to 5 regimens), and 45% had extra-hepatic disease at study entry. Forty-nine discrete lesions were assessable for local control. Median follow-up for assessable lesions was 16 months (range, 6 to 54 months). The median maximal tumor diameter was 2.7 cm (range, 0.4 to 5.8 cm). Based upon this criteria, the researchers reported the following findings:

  • Only one patient experienced grade 3 or higher toxicity (2%);
  • Local progression occurred in only three lesions at a median of 7.5 months (range, 7 to 13 months) after SBRT;
  • Actuarial in-field local control rates at one and two years after SBRT were 95% and 92%, respectively;
  • Among lesions with maximal diameter of 3 cm or less, 2-year local control was 100%; and
  • Median survival was 20.5 months.

Based upon the foregoing, the U.S. researchers concluded that the multi-institutional, phase I/II clinical study demonstrates that high-dose liver SBRT is safe and effective for the treatment of patients with one to three liver metastases.

Canadian SBRT Liver Metastases Study

In the phase I Canadian clinical study, patients with liver metastases who were inoperable or medically unsuitable for resection, and were not candidates for standard therapies, were eligible for this individualized SBRT study. Individualized radiation doses were chosen to maintain the same nominal risk of radiation-induced liver disease (RILD) for three estimated risk levels (5%, 10%, and 20%).  Additional patients were treated at the maximal study dose (MSD) in an expanded cohort.  Median SBRT dose was 41.8 Gy (range, 27.7 to 60 Gy) in six fractions over 2 weeks.  Based upon this criteria, the Canadian researchers reported the following findings:

  • Sixty-eight patients with inoperable colorectal (n = 40), breast (n = 12), or other (n = 16) liver metastases were treated;
  • Median tumor volume was 75.2 mL (range, 1.19 to 3,090 mL);
  • The highest RILD risk level investigated was safe, with no dose-limiting toxicity;
  • Two patients experienced grade 3 liver enzyme changes, but no RILD or other grade 3 to 5 liver toxicity was seen, resulting in a low estimated risk of serious liver toxicity;
  • Six patients (9%) experienced acute grade 3 toxicities (two gastritis, two nausea, lethargy, and thrombocytopenia) and one (1%) patient experienced grade 4 toxicity (thrombocytopenia);
  • The 1-year local control rate was 71%; and
  • The median overall survival was 17.6 months.

Based upon the foregoing, the Canadian researchers concluded that individualized six-fraction liver metastases SBRT is safe, with sustained local control observed in the majority of patients.

U.S. SBRT Lung Metastases Study

In the third study, patients with one to three lung metastases (with cumulative maximum tumor diameter smaller than 7 cm) were enrolled and treated as part of a U.S. multi-institutional phase I/II clinical study in which they received SBRT delivered in 3 fractions.  During the phase I clinical study, the total dose was safely escalated from 48 to 60 Gy. During the phase II portion of the clinical study, the phase II dose was 60 Gy.  The study primary end point was local control.  Metastatic lung lesions with at least 6 months of radiographic follow-up were considered assessable for local control.  The study secondary end points included toxicity and survival.

As part of this study, 38 patients with 63 lesions were enrolled and treated at three U.S. participating institutions. Among those patients, 71% received at least one prior systemic regimen for metastatic disease and 34% had received at least two prior regimens (range, 0 to 5 regimens). Two patients had local recurrence after prior surgical resection. Fifty lesions were assessable for local control.  Median follow-up for assessable lesions was 15.4 months (range, 6 to 48 months). The median gross tumor volume was 4.2 mL (range, 0.2 to 52.3 mL). Based upon this criteria, the researchers reported the following findings:

  • There was no grade 4 toxicity;
  • The incidence of any grade 3 toxicity was 8% (3 of 38 patients);
  • Symptomatic pneumonitis occurred in one patient (2.6%);
  • Actuarial local control at one and two years after SBRT was 100% and 96%, respectively;
  • Local progression occurred in one patient, 13 months after SBRT; and
  • Median survival was 19 months.

Based upon the foregoing, the U.S. researchers concluded that the multi-institutional phase I/II clinical study demonstrates that high-dose SBRT is safe and effective for the treatment of patients with one to three lung metastases.

Using a Bigger Hammer: The Role of Stereotactic Body Radiotherapy in the Management of Oligometastases – Journal of Clinical Oncology Editorial

“… What can we learn from these three trials [described above]?

First, we have learned once again that it is possible to conduct prospective trials of new technological approaches. This is an important lesson. This is how future technologies, such as proton therapy, should be tested.

Second, although the poor overall survival of patients in these trials competes with the risk of local relapse, possibly leading to overestimation of the probability of local control at 2 years, it seems likely that SBRT is a good treatment for such patients. It would seem that a standardized dose/fractionation scheme, such as 60Gyin three fractions, works well for tumors smaller than 3 cm; larger ones may benefit from an individualized approach, such as described by Lee et al. [Canadian study decribed above, ftnote omitted]. However, we must continue to remember past experiences with hypofractionation of large volumes, which can produce severe late normal-tissue effects, especially fibrosis. Even if small volumes are irradiated, catastrophic complications can occur.  In the case of lung cancer, severe unacceptable complications (bronchial fibrosis or hemorrhage) have been associated with treatment of lesions within 2 cm of major airways.  A more protracted (five-fraction) regimen is about to be tested in a Radiation Therapy Oncology Group (RTOG) trial that will open in the coming months that will determine if these toxicities can be avoided.  Lesions close to the chest wall may also benefit from a more protracted fractionation to avoid rib fractures.  In the case of medial or central liver lesions, hypofractionation can cause intestinal obstruction or biliary fibrosis.

Finally, we should recognize that the methodology used in these trials applies to patients with relatively normal liver and lung functions.  At this time, it is not clear how to account for organ dysfunction in patients with lung cancer or primary liver tumors.  Certainly, differences in tolerance to radiation between patients with liver metastases and those with primary liver tumors have been observed before [ftnote omitted].  Therefore, although SBRT seems to have given us a bigger hammer, we still have much to learn about how and when to strike the nails.”

Primary Sources:

2009 Society of Gynecologic Oncologists Annual Meeting Ovarian Cancer Highlights

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From February 5th through 8th, 2009, the Society of Gynecologic Oncologists’ (SGO) held its 40th Annual Meeting on Women’s Cancer in San Antonio, Texas. The meeting, viewed as the preeminent scientific and educational conference for women’s cancer care specialists, featured more than 350 scientific oral and poster presentations as well as educational sessions dealing with advances in the care and treatment of women’s cancers.

40thsgobanner2

From February 5th through 8th, 2009, the Society of Gynecologic Oncologists‘ (SGO)  held its 40th Annual Meeting on Women’s Cancer in San Antonio, Texas.  The meeting, viewed as the preeminent scientific and educational conference for women’s cancer care specialists, featured more than 350 scientific oral and poster presentations as well as educational sessions dealing with advances in the care and treatment of women’s cancers.  Several important presentations relating to ovarian cancer were made during the meeting and are highlighted below:

  • SGO: IVF Confers Slight Long-Term Risk of Ovarian Cancer, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 6, 2009 [Presentation Source:  Burger C, et al; The risk of borderline and invasive ovarian tumors after ovarian stimulation for in vitro fertilization in a large Dutch cohort after 15 years of follow-up, SGO 2009; 112(Suppl 1): Abstract 6].
  • SGO: Optimal Surgery Holds Benefits in Ovarian Cancer with Upper Abdominal Disease, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 6, 2009 [Presentation Source:  Zivanovic O, et al; Upper abdominal disease cephalad to the greater omentum and the impact on progression-free survival in patients with stage IIIC ovarian cancer;  SGO 2009; 112(Suppl 1): Abstract 1].
  • SGO: Rectovaginal Nodules Predict Bowel Perforation Risk with Bevacizumab, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 9, 2009 [Presentation Source:  Richardson DL, et al; Which factors predict bowel complications in patients with recurrent epithelial ovarian cancer being treated with bevacizumab? SGO 2009; 112(Suppl 1): Abstract 41].
  • Low Completion Rates for GOG 172 Intraperitoneal Chemotherapy Regimen: See Aletti G, et al Intraperitoneal chemotherapy for ovarian cancer: Exploring the “dark side” of the moon” SGO 2009; 112(Suppl 1): Abstract 40 (Source:  SGO: Few Ovarian Cancer Patients Tolerate Intraperitoneal Regimen, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 11, 2009).
  • Vermillion Presents Critical Data From Its OVA1 Clinical Trial, Vermillion Inc. News Release, February 10, 2009 [Presentation based upon a study entitled, A biomarker panel for distinguishing between malignant and benign ovarian tumors, which was co-authored by Fred Ueland, MD, Associate Professor of Gynecologic Oncology at the University of Kentucky and Principal Investigator of the OVA1 clinical trial, and Zhen Zhang, PhD, Associate Professor of Pathology at the Johns Hopkins University School of Medicine as well as Vermillion scientists].

About the Society of Gynecologic Oncologists

The SGO is a national medical specialty organization of physicians 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 1280, is primarily comprised of gynecologic oncologists, as well as other related medical specialists including medical oncologists, radiation oncologists 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 http://www.sgo.org.

Imatinib & Docetaxel Produce Modest Response Against Recurrent Platinum Resistant/Refractory Ovarian Cancer

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A combination of imatinib mesylate (Gleevec®) and docetaxel (Taxotere®) produced only a modest response in patients with recurrent, platinum-resistant or refractory ovarian cancer, according to the results of a Phase II clinical trial conducted by the Hoosier Oncology Group at Indiana University Cancer Center.

Background

A combination of imatinib mesylate (Gleevec®) and docetaxel (Taxotere®) produced only a modest response in patients with recurrent, platinum–resistant or refractory ovarian cancer, according to the results of a Phase II clinical trial conducted by the Hoosier Oncology Group at Indiana University Cancer Center.

Imatinib mesylate (Imatinib) is an inhibitor of the (i) receptor tyrosine kinases (RTKs) for platelet-derived growth factor (PDGF) and stem cell factor (SCF), and (ii) c-Kit. RTKs are key regulators of normal cellular processes, and may play a critical role in the development and progression of many types of cancer. PDGF is one of the numerous growth factors, or proteins, that regulate cell growth and division. In particular, it plays a significant role in new blood vessel formation (angiogenesis) from existing blood vessels. SCF is a growth factor, or protein, important for the survival, proliferation, and differentiation of hematopoietic stem cells that give rise to all types of blood cells. C-kit is a protein that is expressed on the surface of hematopoietic stem cells as well as other cell types, and binds to stem cell factor (a substance that causes certain types of cells to grow). Docetaxel, a chemotherapy drug, promotes cell growth arrest.

Based upon the foregoing, the trial investigators hypothesized that use of imatinib (in tandem with docetaxel) would inhibit or block the RTKs for PDGF & SCF and the c-kit receptor, and cause tumor disruption by enhancing the effect of chemotherapy while controlling tumor angiogenesis. Also, the combination of imatinib and docetaxel previously produced synergistic effects in-vitro (in the laboratory) and in-vivo (in mice). As a monotherapy, and prior to this trial, docetaxel produced single agent activity in ovarian cancer with response rates of 30% to 40% in the platinum refractory setting.

The Imatinib/Docetaxel Phase II Clinical Trial

Pursuant to trial eligibility criteria, all patients had recurrent, platinum-resistant, or refractory epithelial ovarian cancer that expressed PDGFR or c-kit, as determined by immunohistochemistry. This screening resulted in the enrollment of 23 patients with the following tumor characteristics: 4 patients had c-kit-positive/PDGFR-negative tumors, 11 patients had PDGFR-positive/c-kit-negative tumors, and 8 patients had c-kit-positive/PDGFR-positive tumors. The median patient age was 56 years (ranging from 33 to 76 years). Enrolled patients had received a median of 3 prior lines of treatment.

The overall response rate was 21.7%, which included 1 complete response (CR) and 4 partial responses (PR). An additional 3 patients had stable disease for more than 4 months. The trial investigators determined that the expression of PDGFR and/or c-kit, did not predict response to this combination therapy. The most common adverse events encountered were fatigue (83%), nausea (74%), diarrhea (61%), anorexia (52%), and edema (65%), and the majority of those events were grade 1 or 2 events.

Based upon the foregoing, the trial investigators concluded that the combination treatment of imatinib and docetaxel was tolerated in patients with heavily pretreated epithelial ovarian cancer that expressed c-kit or PDGF, but found that few patients had sustained responses or stable disease, when compared with the 30% to 40% response rate of docetaxel used as a monotherapy in a platinum refractory setting.

Sources:

Working Smarter, Not Harder: Use of Anti-Estrogen Therapy to Battle Recurrent Ovarian Cancer

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The Gynecologic Oncology department of the University of Texas, M.D. Anderson Cancer Center took a page out of the breast cancer treatment “playbook,” and conducted a single institution Phase II clinical trial using letrozole (Femara®) to treat recurrent, platinum and taxane resistant, high-grade cancer of the ovary and peritoneum. …The trial investigators concluded that 26% (8/31 pts.) of patients with ER+ … ovarian and primary peritoneal cancer derived a clinical benefit (stable disease (SD) + partial response (PR)) after treatment with letrozole (Femara®).

Pursuant to the breast cancer standard of care, breast tissue tumor is routinely analyzed to determine if it is “estrogen receptor positive” (ER positive or ER+), meaning that tumor growth is fueled by the hormone estrogen. It is well-known in the breast cancer area that hormonal therapy is a very effective treatment against breast cancer that is ER+. Sometimes referred to as “anti-estrogen therapy,” hormonal therapy blocks the ability of the hormone estrogen to turn on and stimulate the growth of breast cancer cells.

For decades, the anti-estrogen therapy of choice for treatment of ER+ breast cancer was tamoxifen. In 2005, several world-wide clinical trials reported that aromatase inhibitors (specifically, anastrozole (Arimidex®), exemestane (Aromasin®), and letrozole (Femara®) were more effective than tamoxifen in post-menopausal women with ER+ breast cancer. Aromatase inhibitor drug use is currently the standard of care for treatment of post-menopausal women with ER+ breast cancer, while tamoxifen remains the hormonal treatment of choice for pre-menopausal women.

The Gynecologic Oncology department of the University of Texas, M.D. Anderson Cancer Center took a page out of the breast cancer treatment “playbook,” and conducted a single institution Phase II clinical trial using letrozole (Femara®) to treat recurrent, platinum and taxane resistant, high-grade cancer of the ovary and peritoneum.

Thirty-three patients enrolled in the Phase II clinical trial, and each had measurable disease that tested ER+ pursuant to trial eligibility criteria. Twenty-three patients (74%) had received three or more prior chemotherapy regimens. Letrozole (Femara®) was administered at a dose of 2.5 mg orally once daily until disease progression or toxicity occurred. The median patient age was 63 years (ranging from 38 to 83 years).

The 31 patients evaluable for response received a total of 81 cycles (4 weeks per cycle) of therapy (ranging from 1 to 14 cycles per patient). The median treatment duration was 8 weeks (ranging from 4 to 52 weeks). The trial investigators reported that (i) none of the patients had a complete response (CR), (ii) 1 (3%) had a partial response (PR), and (iii) 7 (23%) had stable disease (SD). The median duration of clinical benefit (SD and PR) was 9 weeks (ranging from 7 to 46 weeks). The median follow-up for all patients was 25 weeks. All evaluable patients were monitored for toxicity. The most common adverse effects were fatigue (36%) and diaphoresis (21%). No grade 3 or 4 toxicities were reported, and no patients discontinued treatment owing to adverse effects. Eighteen patients (58%) went on to receive additional therapy with other agents.

Based upon the results above, the trial investigators concluded that 26% (8/31 pts.) of patients with ER+, platinum- and taxane-resistant, high-grade ovarian and primary peritoneal cancer derived a clinical benefit (stable disease (SD) + partial response (PR)) after treatment with letrozole (Femara®).

Sources:

Comment: Based upon the references listed above and below, it appears that the opening of clinical trials that utilize anti-estrogen therapy to treat ER+ ovarian cancer is long overdue. The “take away” from the M.D. Anderson clinical trial study results is that an ovarian cancer survivor should request her doctor to test the ovarian cancer tumor tissue obtained from surgery or biopsy for estrogen receptor positivity, so as to determine if she is eligible to use anti-estrogen therapy (within the context of a clinical trial) as part of an overall cancer treatment plan.

It is important to note that letrozole is a low side effect, oral drug. Moreover, M.D. Anderson’s letrozole monotherapy produced a 26% clinical benefit rate among ER+, platinum- and taxane-resistant, ovarian and peritoneal cancer patients, despite the fact that approximately three-quarters of the clinical trial patients were heavily pretreated with multiple lines of chemotherapy prior to their trial enrollment. It is promising to consider the potential clinical benefit that could be generated by anti-estrogen therapy in a neoadjuvant or adjuvant ovarian cancer treatment setting.

Additional Anti-Estrogen Therapy/Ovarian Cancer References:

  • Estrogen-regulated gene expression predicts response to endocrine therapy in patients with ovarian cancer, Walker G et. al.; Gynecol Oncol. 2007 Sep;106(3):461-8. Epub 2007 Jul 10. (“OBJECTIVE: To explore the predictive value of estrogen-regulated gene changes as indicators of sensitivity in ovarian cancer patients treated with the aromatase inhibitor Letrozole. … CONCLUSION: These results suggest that expression levels of certain proteins in ovarian cancers are estrogen-regulated and could help identify patients who would benefit from endocrine therapy.” [i.e., anti-estrogen therapy])
  • Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients, Smyth JF et. al.; Clin Cancer Res. 2007 Jun 15;13(12):3617-22 (“PURPOSE: To evaluate the efficacy of the aromatase inhibitor letrozole in preselected estrogen receptor (ER)-positive relapsed epithelial ovarian cancer patients and to identify markers that predict endocrine-sensitive disease. EXPERIMENTAL DESIGN: This was a phase II study of letrozole 2.5 mg daily until clinical or marker evidence of disease progression in previously treated ER-positive ovarian cancer patients with a rising CA125 that had progressed according to Rustin’s criteria. The primary end point was response according to CA125 and response evaluation criteria in solid tumors (RECIST) criteria. Marker expression was measured by semiquantitative immunohistochemistry in sections from the primary tumor. RESULTS: Of 42 patients evaluable for CA125 response, 7 (17%) had a response (decrease of >50%), and 11 (26%) patients had not progressed (doubling of CA125) following 6 months on treatment. The median time taken to achieve the CA125 nadir was 13 weeks (range 10-36). Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of >6 months. Subgroup analysis according to ER revealed CA125 response rates of 0% (immunoscore, 150-199), 12% (200-249), and 33% (250-300); P = 0.028, chi(2) for trend. Expression levels of HER2, insulin-like growth factor binding protein 5, trefoil factor 1, and vimentin were associated with CA125 changes on treatment. CONCLUSIONS: This is the first study of a hormonal agent in a preselected group of ER-positive ovarian cancer patients. A signature of predictive markers, including low HER2 expression, predicts response.)
  • The efficacy of tamoxifen in patients with advanced epithelial ovarian cancer, Karagol H et. al.; Med Oncol. 2007;24(1):39-43 (“BACKGROUND: Activity of tamoxifen as a salvage therapy in patients with advanced epithelial ovarian cancer was evaluated by a number of studies. In this study, we evaluated efficacy of tamoxifen in our patients with platinum-resistant epithelial ovarian carcinoma. … RESULTS: Twenty-nine eligible patients were included to the study. There were 1 (3%) complete response, 2 (7%) partial response, 6 (21%) stable disease, and 20 (69%) progressive disease. All patients were progressed after initiation of tamoxifen. Median progression-free survival was 4 mo (95% CI: 2.98-5.02). Disease progression of 19 (65%) patients were shown within the first 6 mo after initiation of tamoxifen. Progression-free survival was between 6 and 12 mo for 7 (24%) patients and > or =12 mo for 3 (10%) patients. The median survival after initiation of tamoxifen was 15 mo (95% CI: 7.2-22.8). No toxicity attributable to tamoxifen was seen in any of the patients. The only independent prognostic factor that had a significant predictive value for progression- free survival was the response to tamoxifen treatment (p = 0.043, hazard ratio: 0.12, 95% CI: 0.01-0.94). CONCLUSION: Considering minimal side effects and ability to cause objective responses, there is a place for tamoxifen in treatment of patients with platinum-resistant ovarian cancer. A phase III trial is required to confirm the value of the drug in patients presenting these clinical settings.”)
  • Anastrozole therapy in recurrent ovarian adult granulosa cell tumors: a report of 2 cases, Freeman SA, Modesitt SC; Gynecol Oncol. 2006 Nov;103(2):755-8. Epub 2006 Jul 25 (“BACKGROUND: Ovarian sex cord stromal tumors are frequently hormonally active, and adult granulosa cell tumors often demonstrate estrogen receptor positivity. Thus, hormonal agents have been evaluated as potential treatments for advanced stage or recurrent adult granulosa cell tumors. CASE: Two cases of patients with recurrent adult granulosa cell tumors are presented. Each patient received multiple treatment modalities including chemotherapy and had previously progressed on leuprolide. Both patients were started on anastrozole with subsequent normalization of inhibin B levels and clinical exams. They have been maintained on treatment for 14 and 18 months, respectively, and have tolerated the drug without difficulty. CONCLUSION: Aromatase inhibitors may be a viable treatment option for women with advanced stage or recurrent ovarian adult granulosa cell tumors.”)
  • Hormonal therapy in epithelial ovarian cancer, Rao GG, Miller DS; Expert Rev Anticancer Ther. 2006 Jan;6(1):43-7. (“The ovary is an endocrine and end organ. Hormones and their receptors have been associated with ovarian cancer and may be related to its causation. Some data suggest that hormonal therapies may have an effect on ovarian cancer in palliative settings. The most well studied anticancer drugs are tamoxifen, megestrol acetate, medroxyprogesterone acetate, leuprolide acetate, anastrozole and letrozole. Presently, no hormonal therapy is approved by the US FDA for the treatment of any type of ovarian malignancy or is listed as an active agent by any of the authoritative compendia. Owing to the endocrine associations with ovarian cancer, the minimal side effects of hormonal therapy and the demonstrated activity of hormonal therapies in other endocrine organ-associated malignancies, further study of hormonal therapies for ovarian cancer is warranted.”)
  • Aromatase expression in ovarian epithelial cancers, Cunat S et. al.; J Steroid Biochem Mol Biol. 2005 Jan;93(1):15-24 (” … Aromatase activity was evaluated in ovarian epithelial cancer (OEC) cell lines by the tritiated water assay and the effects of third-generation aromatase inhibitors (AIs) on aromatase activity and growth were studied. Letrozole and exemestane were able to completely inhibit aromatase activity in BG1 and PEO14 cell lines. Interestingly, both AI showed an antiproliferative effect on the estrogen responsive BG1 cell line co-expressing aromatase and ERalpha. Aromatase expression was found in ovarian epithelial normal tissues and in some ovarian epithelial cancer cells and tissues. This finding raises the possibility that some tumors may respond to estrogen and provides a basis for ascertaining an antimitogenic effect of AI in a subgroup of ovarian epithelial cancers.”)
  • Hormone therapy in epithelial ovarian cancer, Makar AP; Endocr Relat Cancer. 2000 Jun;7(2):85-93 (“Although epidemiologic studies, animal experiments and receptor studies have shown that not only normal ovaries but also many malignant ovarian tumors can be considered as endocrine related and hormone dependent, the place of hormonal therapy in the management of patients with ovarian cancer remains unsettled. Most trials of hormonal treatment in ovarian cancer have been retrospective, involved only limited numbers of patients, and lacked important patient-related data and information pertaining to tumor characteristics. In addition, a variety of hormonal preparations with different degrees of potency and in different dosages were included in these studies. A literature review shows that response to hormonal therapy even in a preterminal setting, is modest, with about 8% objective response but almost no side effects. In a similar patient setting, more toxic therapeutic agents do not yield a better response. The place of hormonal therapy in the management of patients with epithelial ovarian cancer needs more thorough evaluation in well-designed randomized trials.”)

Combination Targeted Therapy With Sorafenib & Bevacizumab Shows Antitumor Activity

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The results from a recent Phase I solid tumor clinical trial indicate that combination targeted therapy with sorafenib and bevacizumab produces anti-tumor activity (and enhanced toxicity) with respect to 43% of the ovarian cancer patients enrolled in that trial. Sorafenib (Nexavar®) inhibits the Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab (Avastin®) is a monoclonal antibody targeted against VEGF.

Dr. Elise Kohn, Principal Trial Investigator, NCI Center for Cancer Research

Dr. Elise Kohn, Principal Trial Investigator, NCI Center for Cancer Research

The results from a recent Phase I solid tumor clinical trial indicate that combination targeted therapy with sorafenib and bevacizumab produces antitumor activity (and enhanced toxicity) with respect to 43% of the ovarian cancer patients enrolled in that trial. Sorafenib (Nexavar®) inhibits the Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab (Avastin®) is a monoclonal antibody targeted against VEGF. The trial is sponsored by the National Cancer Institute (NCI) and Elise Kohn is the principal trial investigator.

The patients enrolled in the trial had advanced solid tumors, with Eastern Cooperative Oncology Group performance status of 0 to 1. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level (DL1)) or 10 mg/kg (dose level (DL2)) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD).

Thirty-nine patients were treated under the trial protocol. DL1 was the MTD and was administered to 27 patients. Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22+ months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization ≥ 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/orally at a median of four cycles (range, one to 12 cycles).

The trial investigators concluded that combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The trial investigators also noted that the rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.

Source: Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity; Azad NS et. al., J Clin Oncol. 2008 Aug 1;26(22):3709-14.

Additional Information:

IL-7 Boosts Immune Response in Cancer Patients

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” … [Recombinant human interleukin-7] rhIL-7 appears to be an effective T cell growth factor with “immune rejuvenating” properties, suggesting that it is effective in augmenting immune reactivity in hosts with impaired immunity due to any number of factors, including age, chemotherapy, and infectious disease, the authors note. In patients with both intact and deficient immune systems, the capacity of rhIL-7 to augment responses to weak antigens and to increase T cell cycling without expanding T regulatory cells might be clinically exploitable in the context of immunotherapy regimens for cancer and/or chronic infection, they write.”

“Data from a preliminary study suggest that recombinant human interleukin (r-hIL)-7 can enhance and broaden immune responses in patients with impaired immunity due to lymphocyte depletion.

The results of the phase 1 trial, published online June 23 in The Journal of Experimental Medicine, showed that when given to cancer patients, rhIL-7 induced a dramatic polyclonal prolonged expansion of CD4+ and CD8+ T cells, which in turn caused a significant broadening of circulating T cell receptor repertoire diversity. These effects were mediated primarily through an increase in peripheral T cell cycling and augmented cell survival.

Lymphopenia induced by cytotoxic chemotherapy, or pathologies such as HIV infection, can significantly weaken immune function; as a physiologic immuno-enhancer, IL-7 can enhance the restoration of T cells. CD4+ T cell recovery in adults who have experienced severe depletion requires the reemergence of a pool of naive T cells, which generally takes 18 to 24 months and might only occur in people younger than 40 to 45 years. Thus, the authors note, a strategy that can accelerate or promote the recovery of a widely diverse T cell repertoire in older people might be useful for a large number of clinical applications.

‘We know that IL-7 can enhance tumor vaccines in animals, so that would be a clear avenue of research,’ said lead author Claude Sportès, MD, senior staff clinician at the National Cancer Institute‘s Center for Cancer Research, Experimental Transplantation and Immunology Branch, in Bethesda, Maryland. ‘But it wouldn’t only have to be tumor vaccines. Hopefully we will have a trial underway in the not-too-distant future looking at how it can enhance anti-viral and other immunizations, particularly in the elderly.’

Treatment with IL-7 therapy exerted a marked effect on T cell immune reconstitution during preliminary trials with animal models. It also appeared to augment effector and memory responses to vaccination in mice; in preclinical models, IL-7 therapy was able to augment anti-tumor responses that might improve survival when combined with anti-tumor vaccines.

‘In older individuals, therapy with IL-7 could lead to a rejuvenation of the phenotype,’ explained Dr. Sportès in an interview. ‘This in turn can lead to better vaccine responses in general and, in oncology, better tumor vaccine responses.’

The implications for rhIL-7 are potentially vast, and there are many promising therapeutic avenues. ‘But as often happens in medicine,’ he cautioned, ‘things can be very promising at this stage and then fizzle out.’

First Human Trial

In this phase 1 dose-escalation study, the first initiated in a human population, Dr. Sportès and colleagues evaluated the effects of IL-7 therapy on human lymphocytes in 16 patients, between the ages of 20 to 71 years, with nonhematologic, nonlymphoid refractory cancer. The doses, extrapolated from previous mouse and primate studies, were 3, 10, 30, and 60 μg/kg, and were administered by subcutaneous injection every other day for 14 days, for a total of 8 doses.

They found that after a very transient decrease, the numbers of circulating lymphocytes and CD4+ and CD8+ T cells increased in a dose-dependent manner. At the highest dose levels, increases approached 300% for CD4+ and exceeded 400% for CD8+ T cells. Overall, the treatment induced widespread T cell cycling and was able to expand the T cell pool in human patients while preserving T cell function.

Treatment with rhIL-7 also seems to have advantages over rhIL-2, explained Dr. Sportès. The expanded T cells retained significant functional capacity, and the CD4+ T cell expansion was not accompanied by a disproportionate increase in T regulatory cells, a phenomenon that has been observed after rhIL-2 therapy. Previous data have shown that in vivo IL-2 administration in humans has minimal effects on CD8+ T cell numbers, whereas rhIL-7 effects on CD8+ T cell expansion are at least comparable to the effects on CD4+ T cells.

The researchers noted that rhIL-7 increases T cell receptor repertoire diversity, and that although it appears to selectively expand CD4+ recent thymic emigrants, naive cells, and central-memory populations, it did not have the same effect on effector T cells.

The details of the clinical trial will be the focus of a separate paper, said Dr. Sportès. ‘But it was well tolerated and we went to full-dose escalation.’

“Immune Rejuvenating” Properties

rhIL-7 appears to be an effective T cell growth factor with “immune rejuvenating” properties, suggesting that it is effective in augmenting immune reactivity in hosts with impaired immunity due to any number of factors, including age, chemotherapy, and infectious disease, the authors note.

In patients with both intact and deficient immune systems, the capacity of rhIL-7 to augment responses to weak antigens and to increase T cell cycling without expanding T regulatory cells might be clinically exploitable in the context of immunotherapy regimens for cancer and/or chronic infection, they write.”

[Quoted Source: IL-7 Therapy Boosts Immune Response in Cancer Patients, by Roxanne Nelson, Medscape Medical News, Medscape Today, July 4, 2008 (summarizing the findings of Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets; Sportes, C. et. al., J Exp Med. 2008 Jun 23. Epub ahead of print]

Encouraging Survival Data Associated With Maximal Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Using Pegylated Liposomal Doxorubicin

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A recent Phase I clinical trial reported encouraging survival data with respect to the use of maximal cytoreduction combined with hyperthermic intraperitoneal chemotherapy (HIPEC) using pegylated liposomal doxorubicin (PLD)(e.g., Doxil™) to treat patients with advanced intra-abdominal, gastrointestinal and gynecological malignancies.

HIPEC is used in conjunction with surgery and chemotherapy to treat patients with gastrointestinal tract and gynecological cancers and sarcomas that have spread to the lining of the abdomen. Even after surgical removal, cancer often recurs in the abdomen. So when the tumor spreads, it is difficult for doctors to treat with standard chemotherapy.

HIPEC involves using a using a heated sterile solution that is circulated throughout the abdominal cavity. With HIPEC treatment, patients are connected to a series of tubes and a pumping device that bathes the abdominal cavity for two hours with a heated sterile solution containing anticancer (chemotherapeutic) drugs. The high temperature of the chemotherapy increases the effect of the drug. The fluid goes through the abdomen to treat tumor cells that may remain after surgery. Both heat and direct contact with chemotherapy drugs kills the cancer cells.

Twenty-one patients were enrolled in this Phase I clinical trial. The maximum PLD dose evaluated in this trial was 100 mg/m² and was well tolerated. The most common grade 3/4 complications were superficial wound infection and prolonged ileus. One patient developed an anastomotic leak in the postoperative period, requiring re-exploration. The length of the median postoperative hospital stay was 7 days (range, 4-29 days), three patients required readmissions within 30 days, and there were no operative deaths.

The median follow-up time for was 13.7 months (range, 3-38 months). The median overall survival was 30.6 months with a median progression free survival (PFS) of 25 months. Based on these findings, the trial investigators concluded that HIPEC with PLD following maximal cytoreduction in patients with advanced abdominal-only, gastrointestinal or gynecologic malignancies is well tolerated. Moreover, the investigators stated that the encouraging survival period after cytoreduction and HIPEC with PLD suggests that a verification Phase II clinical trial is warranted.

For more information regarding the HIPEC procedure, go to HIPECTREATMENT.org. For a list of open clinical trials testing the HIPEC procedure using various chemotherapeutic agents, click here.

Sources:

New Vascular Disrupting Agent In Combination With Avastin Produces a 64% Disease Stabilization Rate in a Small Phase I Solid Tumor Clinical Trial

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In solid tumors, [vascular disrupting agents] VDA’s, such as ZYBRESTAT™, rapidly disrupt the vasculature within the tumor, reduce blood-flow, and deprive the tumor of oxygen and nutrients, resulting in tumor cell death. This disruption of the newly formed blood vessels contrasts with the action of anti-angiogenic therapies (e.g., bevacizumab/Avastin™), which are designed to prevent new blood vessel formation. … Specifically, Zybrestat™ was tested on advanced solid malignancies in Phase I clinical trial involving 14 patients. … Nine of fourteen patients experienced disease stabilization for greater than 12 weeks. Three patients experienced disease stabilization for greater than 24 weeks, with two of these patients continuing with stable disease at 47 and 29 weeks, respectively.

Based upon an abstract presentation made at the 2008 American Society of Clinical Oncology (ASCO) Annual Meeting recently held in Chicago on May 30th through June 3rd, the new vascular disrupting agent (VDA) Zybrestat™ (fosbretabulin) produced an advanced solid tumor disease stabilization rate of 64 percent.

Vascular disruption represents a new approach to a validated therapeutic strategy: depriving tumors of blood supply. In solid tumors, VDA’s, such as ZYBRESTAT™, rapidly disrupt the vasculature within the tumor, reduce blood-flow, and deprive the tumor of oxygen and nutrients, resulting in tumor cell death. This disruption of the newly formed blood vessels contrasts with the action of anti-angiogenic therapies (e.g., bevacizumab/Avastin™), which are designed to prevent new blood vessel formation. OXiGENE Inc. (OXiGENE) believes its VDA product candidates may offer advantages over current anti-angiogenic drugs, including superior efficacy and reduced side-effects.

In addition, there is a strong scientific rationale for combining VDA and anti-angiogenesis therapies. OXiGENE and its scientific collaborators have published preclinical research results showing that the combination of OXiGENE VDAs and certain anti-angiogenic drugs (i.e., monoclonal antibodies targeting vascular endothelial growth factor, or VEGF) have synergistic anti-tumor effects. Building upon these results, OXiGENE has undertaken the first-ever human clinical trial of a VDA (ZYBRESTAT) in combination with an anti-angiogenic agent (bevacizumab / AVASTIN.) The additional benefits of vascular disrupting agents include:

  • This method of treatment is designed to target newly formed abnormal blood vessels, rather than the established blood vessels found in healthy tissue, resulting in fewer side effects in the oncology setting than conventional disease treatments such as radiation and chemotherapy. VDAs are designed to address the complete spectrum of solid tumors, whereas other approaches, which directly target tumor cells, require the development of different drugs for different types of solid tumors.
  • VDAs are designed to target endothelial cells associated with new blood vessel formation, so drug resistant mutations are unlikely to occur.
  • Damaging one or two blood vessels can cause thousands of tumor cells to die.
  • The ability of VDAs to selectively target newly formed or abnormal blood vessels makes them well-suited for certain ocular diseases, such as age-related macular degeneration, in which the formation of new, abnormal blood vessels in the eye plays a key role in disease.

Specifically, Zybrestat™ was tested on advanced solid malignancies in Phase I clinical trial involving 14 patients. The patients were divided into three separate dosage cohorts, representing 45mg/m2 (cohort 1), 54mg/m2 (cohort 2) or 63mg/m2 (cohort 3) of Zybrestat™ every 14 days followed by bevacizumab (Avastin™) at a dosage of 10mg/kg four hours later. The study results indicated two grade 3/4 drug dosage limiting toxicities. Nine of fourteen patients experienced disease stabilization for greater than 12 weeks. Three patients experienced disease stabilization for greater than 24 weeks, with two of these patients continuing with stable disease at 47 and 29 weeks, respectively. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) showed statistically significant reductions in tumor perfusion/vascular permeability which reversed when Zybrestat™ was used as a monotherapy, but were sustained following the use of bevacizumab (Avastin™). The clinical trial investigators concluded that Zybrestat™ was safe and tolerable at the three dosage levels used, and noted that Zybrestat™ induced profound vascular changes in the solid tumor which were maintained by the presence of bevacizumab (Avastin™).

Sources:

Comment: ZYBRESTAT™ has broad potential therapeutic utility across a wide range of different solid tumor types, and can potentially be combined with mainstay oncology treatment modalities: chemotherapy, radiation therapy and newer, “molecularly-targeted therapies,” such as tumor angiogenesis inhibitors. Preclinical studies have demonstrated that ZYBRESTAT™ has synergistic or additive effects when incorporated in various combination regimens with all of these treatment modalities. There is a strong scientific rationale for combining ZYBRESTAT™ and tumor angiogenesis inhibiting drugs, and ZYBRESTAT™ is the first VDA to be tested in humans in combination with a tumor-angiogenesis-inhibiting drug (bevacizumab / AVASTIN®).

Voreloxin (SNS-595) Produces 48% Disease Stabilization in Treatment Resistant Ovarian Cancer Patients

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Voreloxin (at a 48 mg/m² dosage) demonstrates single agent activity in advanced platinum-resistant ovarian cancer patients (24 patients with stable disease (SD) ≥90 days, 1 patent with complete response (CR), 5 patients with partial response (PR)) as evidenced by a 48% overall disease control rate (i.e., SD + PR + CR). The results are impressive because the disease control response population includes patients with primary and secondary platinum drug resistance who have failed prior treatment with pegylated liposomal doxorubicin (Doxil®, Caelyx®, Myocet®), gemcitabine (Gemzar®), topotecan (Hycamtin®), etoposide (Eposin®, Etopophos®, Vepesid®), bevacizumab (Avastin®), and/or other various experimental agents.

The H*O*P*E*™ weblog reported the early interim success of Voreloxin (formerly known as SNS-595) in Phase II clinical trial testing on March 15, 2008. Based upon an abstract presentation that will be made by Sunesis Pharmaceuticals today at the 2008 American Society of Clinical Oncology (ASCO) Annual Meeting, the success of Voreloxin continues, despite the fact that many of the ovarian cancer patients participating in the trial experienced significant drug/treatment resistance prior to enrollment.

Specifically, Voreloxin (at a 48 mg/m² dosage) demonstrates single agent activity in advanced platinum-resistant ovarian cancer patients (24 patients with stable disease (SD) ≥90 days, 1 patent with complete response (CR), 5 patients with partial response (PR)) as evidenced by a 48% overall disease control rate (i.e., SD + PR + CR). The results are impressive because the disease control response population includes patients with primary and secondary platinum drug resistance who have failed prior treatment with pegylated liposomal doxorubicin (Doxil®, Caelyx®, Myocet®), gemcitabine (Gemzar®), topotecan (Hycamtin®), etoposide (Eposin®, Etopophos®, Vepesid®), bevacizumab (Avastin®), and/or other various experimental agents. Approximately 79% of the patient population that experienced disease control with Voreloxin at a 48mg/m² dosage received between two to four prior lines of treatment. In addition, one patient who experienced a partial response to Voreloxin at the 48 mg/m² dosage had a tumor histology identified as clear cell ovarian cancer — an aggressive form of ovarian cancer that is generally resistant to traditional therapies. It appears that there are 11 clear cell ovarian cancer patients participating in the Voreloxin Phase II trial (i.e., 7 patients in the 48 mg/m² dosage arm, and 4 patients in the 60 mg/m² dosage arm); however, there are no specific results reported for these patients (other than the one partial responder) in the 2008 ASCO Annual Meeting abstract presentation data.

Due to the earlier success of Voreloxin prior to March 15th, the trial investigators enrolled 21 new patients into the Phase II trial for purposes of testing Voreloxin at a 60 mg/m² dosage. Because these newer patients only received two cycles of Voreloxin at the higher dosage to date, they were not evaluated officially for purposes of the 2008 ASCO Annual Meeting abstract presentation data. The grade 3/4 adverse effects of Voreloxin at both dosages are reported as relatively low, therefore, trial investigators incorporated a 75 mg/m² dosage escalation into the current Phase II trial. The investigators do not indicate how many patients (currently enrolled or newly recruited) will participate in the 75 mg/m² dosage arm. Currently, a total of 86 ovarian cancer patients are enrolled in the Voreloxin Phase II trial (65 patients in the 48 mg/m² dosage arm; 21 patients in the 60 mg/m² dosage arm).

[Sources: “A Phase 2 Trial of Voreloxin (Formerly SNS-595) in Women with Platinum-Resistant Epithelial Ovarian Cancer,” 2008 American Society of Clinical Oncology Annual Meeting Presentation, May 31, 2008 (Adobe Reader PDF Document). See also, “A phase II trial of SNS-595 in women with platinum resistant epithelial ovarian cancer,” W. P. McGuire et. al., J Clin Oncol 26: 2008 (May 20 suppl; abstr 5582) (2008 ASCO Annual Mtg. Abstract); “A Phase 2 Open-Label, Multicenter Study of SNS-595 Injection in Patients With Platinum-Resistant Ovarian Cancer, National Cancer Institute ID# NCT00408603 (sets forth original Voreloxin (SNS-595) Phase II clinical trial protocol).

Updates:

Thalidomide Provides Hope to Women Diagnosed with Ovarian Cancer When Combined with Topotecan

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“We found that patients who received topotecan plus thalidomide showed an overall response rate of 47 percent compared to 21 percent response in patients who received only topotecan”‘ [Levi]Downs[Jr., M.D.] said. “In patients receiving topotecan plus thalidomide, 30 percent achieved a complete response, meaning the cancer went away, compared to 18 percent for patients only getting topotecan.” “Furthermore, patients getting topotecan plus thalidomide had a longer cancer-free period after treatment than those receiving topotecan alone,” he said.

“Thalidomide, a drug blamed in the 1950s for causing birth defects, is now showing promise as a safe and effective treatment for women with recurrent ovarian cancer, according to a study led by a University of Minnesota Cancer Center researcher.

Levi Downs, Jr., M.D., principal investigator for the multicenter, randomized Phase II clinical trial, has published the findings of this research study in the current issue of the journal Cancer. Downs is an assistant professor and a researcher of gynecologic oncology at the University of Minnesota Medical School and Cancer Center.

‘For some women, ovarian cancer has become a chronic disease,’ Downs said. ‘The standard chemotherapy regimens can put recurrent cancer in remission, often more than once. However, when the cancer resists the standard treatments, we need new options for treatment.’

The study compared the effectiveness and safety of the combination of thalidomide and topotecan, a chemotherapy often used for ovarian cancer, versus topotecan alone for treatment of recurrent epithelial ovarian cancer in patients who had received prior treatment. Epithelial ovarian cancer is a disease in which cancer cells form in the tissue that covers the ovary.

The study evaluated 75 women who were randomly assigned to receive either the combination of thalidomide and topotecan or only topotecan. This is the first randomized clinical trial to test thalidomide for recurrent ovarian cancer. Other clinical trials have shown thalidomide to be effective for treatment of multiple myeloma, a cancer of the bone marrow.

‘We found that patients who received topotecan plus thalidomide showed an overall response rate of 47 percent compared to 21 percent response in patients who received only topotecan,’ Downs said. ‘In patients receiving topotecan plus thalidomide, 30 percent achieved a complete response, meaning the cancer went away, compared to 18 percent for patients only getting topotecan.’

‘Furthermore, patients getting topotecan plus thalidomide had a longer cancer-free period after treatment than those receiving topotecan alone,’ he said. ‘What all of this means is that while thalidomide may not cure ovarian cancer, it may broaden the treatment options available to physicians and provide more hope to women diagnosed with the cancer.’

Ovarian cancer is the fifth most common cancer among women. This year in the United States, more than 25,000 women will be diagnosed with ovarian cancer, and about 16,000 will die from it. About 78 percent of women diagnosed with the cancer survive one year after diagnosis, and more than 50 percent survive five years after diagnosis.

The results of this study have led to the development of a new clinical trial at the University of Minnesota that will test the safety and effectiveness of a newer member of the class of drugs containing thalidomide properties for treatment of recurrent ovarian cancer.

This study was sponsored by Celgene Corporation, biopharmaceutical company and manufacturer of thalidomide. Cancer centers in Minnesota, Ohio, South Dakota, and California participated in this study.

[Quoted Source: Thalidomide provide more hope to women diagnosed with Ovarian Cancer, by Jennifer Davis, TopCancerNews.com, April 12, 2008.]

Selenium Added to Carboplatin & Paclitaxel Generates Significant Synergy in 40% of Ovarian Cancer Patients Tested

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According to lead author Lorna Rodriguez, M.D., PhD [appearing in the right side photo], chief of gynecologic oncology at [The Cancer Institute of New Jersey] CINJ and associate professor of obstetrics, gynecology and reproductive sciences at UMDNJ-Robert Wood Johnson Medical School, the study of 30 patients so far shows that selenium can be safely given in combination with carboplatin and paclitaxel. Furthermore, she notes, selenium may help treatment efficacy as indicated by four patients having complete disappearance of disease, and eight patients having their tumors decrease in size by more than 30 percent.

“New research findings from a top clinical investigator at The Cancer Institute of New Jersey (CINJ) indicate the potential for more targeted treatment of ovarian cancer, which is expected to claim more than 15,000 lives nationwide this year, with 480 in New Jersey. The study, to be presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago later this month, looks at the effects of a mineral called selenium in combination with the standard treatment for the disease. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.Lorna Rodriguez, M.D., Ph.D.

Currently, the standard of care involves the drugs carboplatin and paclitaxel, which have shown the ability to shrink ovarian cancer tumors; however, that shrinkage may not last for a long period due to the development of drug resistance. Previous data shows that selenium inhibits the development of a tumor’s resistance to carboplatin. The current study couples selenium with the two drugs with the goal of preventing or slowing drug resistance.

According to lead author Lorna Rodriguez, M.D., PhD [appearing in the right side photo], chief of gynecologic oncology at CINJ and associate professor of obstetrics, gynecology and reproductive sciences at UMDNJ-Robert Wood Johnson Medical School, the study of 30 patients so far shows that selenium can be safely given in combination with carboplatin and paclitaxel. Furthermore, she notes, selenium may help treatment efficacy as indicated by four patients having complete disappearance of disease, and eight patients having their tumors decrease in size by more than 30 percent. The results show that a serum marker [i.e., CD44] may predict which women will benefit from selenium therapy.

Dr. Rodriguez notes the findings could finally lead to more tailored treatment, ‘Because symptoms of ovarian cancer are often silent, many patients who are diagnosed with the disease are usually in an advanced stage. Having such a targeted treatment available to these patients could very well mean a longer survival outcome and increased quality of life.’

The CINJ team – which includes gynecologic oncologists Darlene Gibbon, M.D.; Mira Hellmann, M.D.; Wilberto Nieves-Neira, M.D.; and Ami Vaidya, M.D.; Director of Pharmacy, Susan Goodin, PharmD, FCCP, BCOP; pharmacologist Murugesan Gounder, Ph.D.; and research teaching specialist Neelakandan Muthukumaran – is planning Phase II studies for patients with ovarian and endometrial cancers in the future.

Rodriguez will be among the more than 30,000 cancer specialists from around the globe, who will showcase advances in clinical research at the annual ASCO meeting.

About The Cancer Institute of New Jersey
The Cancer Institute of New Jersey is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center, and is dedicated to improving the prevention, detection, treatment and care of patients with cancer. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice quite literally bringing research to life. The Cancer Institute of New Jersey is a center of excellence of UMDNJ-Robert Wood Johnson Medical School. To support CINJ, please call the Cancer Institute of New Jersey Foundation at 1-888-333-CINJ.”

[Quoted Source: New Treatment Implications for Ovarian Cancer Unveiled, NewsWire Medical News Release dated May 16, 2008].

Comment: This study shows promise for the use of selenium, carboplatin (Paraplatin®) and paclitaxel (Taxol®) as a potential “revised” standard of care, albeit only a small study. If the serum marker CD44 can ultimately identify those patients that will respond to this combination at the earliest point in treatment, this triple agent combination can be used as a “targeted” or “personalized” therapy. It is important to note that the selenium used in this study was administered intravenously at various dosages and was not administered as an oral vitamin supplement.

Additional Information:

2008 American Society of Clinical Oncology (ASCO) Annual Meeting Abstracts Available On-Line

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The 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) will be held on May 30th through June 3rd, 2008 in Chicago, Illinois. Under a new policy, ASCO publicly released clinical trial brief abstracts two weeks before the start of its 2008 Annual Meeting on May 30th, where full results will be presented before thousands of cancer doctors. The new ASCO policy was intended to avoid stock trading on non-public information that was believed to have occurred under a prior policy in which ASCO mailed out abstracts under embargo weeks before its annual meeting.

I have provided hyperlinks below to a variety of cancer topics that may be of interest to ovarian cancer survivors. Please note that with the exception of the first “ovarian cancer” category listed below, the remaining categories will contain abstracts that address various types of cancer. H*O*P*E*™ will provide one or more posts that address ovarian cancer abstract highlights after the completion of the 2008 ASCO Annual Meeting on June 3rd.

Gynecologic Cancer:

Ovarian Cancer

Developmental Therapeutics: Cytotoxic Chemotherapy:

Cytotoxic Chemotherapy
Drug Resistance
Pharmacology / Pharmacokinetics
Phase I Studies

Developmental Therapeutics: Immunotherapy:

Antibodies
Cell-Based Therapy
Cytokines
Other: developmental therapeutics: immunotherapy
Vaccines

Developmental Therapeutics: Molecular Therapeutics:

Antiangiogenic or Antimetastatic Agents
Cell Cycle Inhibitors
Chemoprevention
Epigenetic Strategies
Functional Imaging
Gene Therapy/Antisense Strategies
Other Novel Agents
Pharmacodynamics
Pharmacogenomics
Pro-Apoptotic Agents
Receptor-Targeted Antibodies/Ligands
Tyrosine Kinase Inhibitors
Vascular Targeting

Tumor Biology and Human Genetics:

Cancer Genetics
Epidemiology / Molecular Epidemiology
Immunobiology
Molecular Diagnostics and Staging
Molecular Targets
Other: Tumor Biology and Human Genetics
Prognostic Factors
Radiation Biology
Tumor and Cell Biology

Cancer Prevention:

Cancer Prevention

Patient Care:

Cancer in Older Patients
Cancer-Related Complications
End-of-Life Care
Other: patient care
Palliative Care
Quality-of-Life Management
Supportive Care

Health Services Research:

Health Services Research
Outcomes Research
Practice Management/Professional Issues

Small Phase I Study Reports 2 to 4 Year Ovarian Cancer Remission in 30% of Women Who Received a NY-ESO-1 Vaccine

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Three of nine patients (33%) remain in complete clinical remission at 25, 38, and 52 months, respectively.

The cancer-testis antigen NY-ESO-1 is expressed in greater than 40% of advanced epithelial ovarian cancers and represents a promising immunotherapeutic target. In a small Phase I (safety and immunogenicity) clinical trial conducted by Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, nine “high-risk” epithelial ovarian cancer patients, who were in first clinical remission after primary surgery and chemotherapy, received NY-ESO-1b peptide and Montanide ISA-51 every 3 weeks in the form of five vaccinations. The “high risk” ovarian cancer patient criterion was defined as a patient who (i) received suboptimal primary debulking (remaining tumor masses with diameter of 1.0 cm or greater), or (ii) experienced a failure to normalize the CA 125 blood tumor marker by the end of the third cycle of first-line chemotherapy. In addition, each patient enrolled in the trial was required to test positive for (i) human leukocyte antigen 2A (HLA-2A) in the blood, and (ii) NY-ESO-1 or LAGE-1 tumor expression. NY-ESO-1 tumor expression was evaluated for each patient by immunohistochemistry (IHC). LAGE-1 tumor expression was evaluated for each patient by reverse transcriptase and polymerase chain reaction (RT-PCR) analysis. For each patient, NY-ESO-1 specific humoral immunity (ELISA), T-cell immunity (tetramer and ELISPOT), and delayed-type hypersensitivity were assessed pre-vaccination and at week #1, week #4, week #7, week #10, week #13, and week #16 of the vaccination period.

The nine patients experienced treatment-related adverse events including: grade 1 fatigue, anemia, pruritus, myalgias, and hyperthyroidism; and grade 2 hypothyroidism. There were no grade 3/grade 4 adverse events. The results of the Phase I trial are set forth below.

  • Three of four patients (75%) with NY-ESO-1-positive tumor showed T-cell immunity.
  • Four of five patients (80%) with NY-ESO-1-negative tumor showed T-cell immunity.
  • At median follow-up of 11.3 months, six of nine patients (67%) have recurred, with a median progression-free survival (PFS) of 13 months.
  • Three of nine patients (33%) remain in complete clinical remission at 25, 38, and 52 months, respectively.

At the end of the Phase I trial, the trial investigators concluded that vaccination of high-risk, HLA-A2-positive epithelial ovarian cancer patients with NY-ESO-1b and Montanide has minimal toxicity and induces specific T-cell immunity in patients with both NY-ESO-1-positive and NY-ESO-1-negative tumors. Also, the trial investigators noted that additional study is necessary. For a copy of the clinical trial protocol associated with this trial, click here.

[Source: “Safety and Immunogenicity Study of NY-ESO-1b Peptide and Montanide ISA-51 Vaccination of Patients with Epithelial Ovarian Cancer in High-Risk First Remission;” Diefenbach, C.S. et. al.; Clin Cancer Res. 2008 May 1;14(9):2740-2748.]

Comment: Prior cancer vaccines targeting NY-ESO-1 overexpression in ovarian cancer tumors produced moderate success in terms of an increase in PFS. This study is particularly provocative because patients who tested positive and negative for NY-ESO-1 tumor expression experienced T-cell immunity, and “high risk” patients (including suboptimally debulked patients) experienced PFS benefit.

Related Information: