Dana Farber Webchat: The Latest in Ovarian Cancer Treatment & Research

The latest developments in ovarian cancer treatment and research are addressed in the video below via a Dana-Farber Cancer Institute webchat that was conducted on September 16, 2014.

The Susan F. Smith Center for Women’s Cancers at the Dana-Farber Cancer Institute conducted a live video webchat panel with Ursula Matulonis, M.D., medical director of the Gynecologic Oncology Program, and gynecologic oncologists Panos Konstantinopoulos, M.D., Ph.D., and Susana Campos, M.D., MPH. The live webchat was held on September 16, 2014.

The general webchat topics addressed by the Dana-Farber doctors are listed below. For your convenience, we also provided the approximate video start time associated with each discussion topic. The entire video runs 49 minutes and 20 seconds.

  • Various types/subtypes of ovarian cancer and treatment differences. [1:40 minutes]
  • CA-125 and other ovarian cancer biomarkers. [5:10 minutes]
  • Areas of ongoing ovarian cancer research. [9:28 minutes]
  • Ovarian cancer treatment alternatives to standard of care chemotherapy. [13:55 minutes]
  • PARP Inhibitors & Immunotherapy. [15:03 minutes]
  • Mechanisms to reverse platinum drug resistance. [17:15 minutes]
  • Correlation between ovarian cancer and HPV (Human papillomavirus). [19:30 minutes]
  • The use of clinical trials for the treatment of ovarian cancer. [19:43 minutes]
  • Stage 1 ovarian cancer prognosis. [21:47 minutes]
  • Gene mutations related to hereditary ovarian cancer risk. [22:55 minutes]
  • Treatment options for platinum drug refractory/resistant ovarian cancer. [25:27 minutes]
  • Treatment of BRCA gene-mutated ovarian cancer patients. [27:50 minutes]
  • Ovarian cancer prevention. [30:18 minutes]
  • Promising treatments for ovarian clear cell cancer. [31:43 minutes]
  • Proper nutrition during and after ovarian cancer treatment. [33:47 minutes]
  • Symptoms associated with an ovarian cancer recurrence. [35:06 minutes]
  • Ovarian neuroendocrine cancer. [36:16 minutes]
  • Small-cell ovarian cancer. [39:22 minutes]
  • Origin of ovarian cancer. [42:41 minutes]
  • Treatment options for isolated or limited recurrent ovarian cancer tumors/lesions. [45:26 minutes]
  • Closing: Most Exciting Ovarian Cancer Developments. [47:07 minutes]

 

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: 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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2011 SGO Annual Meeting: Ovarian Cancer Abstracts Selected For Presentation

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

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

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

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

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

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

Ovarian Cancer Symptoms

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

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

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

Ovarian Cancer Screening

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Pathology

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

Ovarian Cancer Staging

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

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

Chemotherapy

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

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

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

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

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

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

Diagnostic & Prognostic Biomarkers

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

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

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

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

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

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

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

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

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

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

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

Clinical Trial Drugs & Results

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Gynecologic Practice

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

Gynecologic Surgery

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Genetic/Molecular Profiling

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Immunotherapy

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

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

Medical Imaging

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

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

Preclinical Studies

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

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

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

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

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

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

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

Preclinical Studies – Potential Therapeutic Targets

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Palliative & Supportive Care

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

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

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

Rare Ovarian Cancers

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

Survival Data

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

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

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

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

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

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

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

Survivorship

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

Other

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

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

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

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

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

Late-Breaking Abstracts

About Society of Gynecologic Oncologists (SGO)

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

About Gynecologic Oncologists

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

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

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Exelixis Reports Promising Interim Data From Ovarian Cancer Patients Treated With XL184

Exelixis reports promising interim data from ovarian cancer patients treated with XL184, including:  a  32% confirmed response rate per RECIST in patients with platinum-resistant or platinum-sensitive disease, and a 64% overall week-12 disease control rate.

Ignace Vergote, M.D., Ph.D., Head, Department of Obstetrics & Gynecology and Gynecologic Oncology, Catholic University Hospital, Leuven, Belgium

Exelixis, Inc.  today reported interim data from the cohort of patients with advanced epithelial ovarian cancer, primary peritoneal, or fallopian tube carcinoma treated with XL184 in an ongoing phase 2 adaptive randomized discontinuation trial (RDT) [1]. Ignace Vergote, M.D., Ph.D., Head of the Department of Obstetrics and Gynecology and Gynecologic Oncology at the Catholic University Hospital Leuven, Leuven, Belgium, will present the data in the Molecular-Targeted Therapies-Clinical Trials poster session (Abstract #407) on Thursday, November 18th, at the 22nd EORTC-NCI-AACR [2] Symposium on Molecular Targets and Cancer Therapeutics, being held in Berlin, Germany.

XL184 Activity in Patients with Ovarian Cancer

XL184 is an oral, potent inhibitor of MET, VEGFR2 and RET. MET overexpression has been observed in advanced ovarian cancer, and anti-VEGF pathway agents have shown clinical benefit in ovarian cancer patients. For these reasons, co-targeting of the MET and VEGF signaling pathways using XL184 may represent a promising treatment strategy.

As of the November 1, 2010 cut-off date, a total of 51 patients were enrolled into the ovarian cancer cohort, with 31 evaluable for response, and 41 evaluable for safety. The median number of prior systemic treatments was 2. Tumor shrinkage was observed in 30 of 37 (81%) patients with measurable metastatic lesions. Of 31 patients evaluable for response per RECIST (Response Evaluation Criteria In Solid Tumors), 10 (32%) achieved a confirmed partial response (PR). Stable disease (SD) was reported in 15 patients (48%) including 3 patients who achieved unconfirmed PRs. The overall week-12 disease control rate (DCR)(complete responses + partial responses + stable disease responses = DCR) was 64%.

Upon subset analysis, 5 of 17 platinumrefractory or –resistant patients (29%) evaluable for response per RECIST achieved a confirmed PR. SD was reported in 7 patients (41%) including 2 patients with unconfirmed PRs. The week-12 DCR was 59% in platinum-resistant/refractory patients. Durable responses have been observed, including 2 patients with platinum-refractory or resistant disease who remain on study for 34+ and 36+ weeks, and 3 patients with platinum-sensitive disease on study for 24, 24+, and 28+ weeks. Some patients have experienced reductions in the ovarian cancer blood marker CA125, but in general no clear concordance between CA125 changes and tumor shrinkage has been observed.

Safety data are available for 49 patients who had at least 6 weeks of follow-up. The most common grade greater-than or equal to 3 adverse events, regardless of causality were PPE (Palmar-Plantar Erythrodysesthesia) syndrome (also referred to as “hand-foot syndrome”) (12%), diarrhea (7%), fatigue, vomiting (each 5%), nausea, rash, abdominal pain, hypertension, and hypomagnesemia (each 2%).

“The activity of XL184 in women with both platinum-sensitive and platinum-resistant/refractory disease is unique and encouraging. The response rate and overall disease control rate of this oral agent are impressive especially in the group of patients with platinum refractory/resistant ovarian cancer, and compare favorably to other targeted and systemic agents in development,” said, Dr. Vergote. “I believe these encouraging data warrant further evaluation of XL184 in ovarian cancer.”

Michael M. Morrissey, Ph.D., President & Chief Executive Officer, Exelixis, Inc.

“The high response rate in patients with ovarian cancer is reflective of the broad anti-tumor activity of XL184 observed in multiple tumor types to date,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “The data from the RDT underscore the novel and differentiated clinical activity of XL184 in diverse tumor indications with predominance of either soft tissue or bone involvement.”

To access the clinical data poster mentioned in this press release, please visit www.exelixis.com.

Broad Clinical Activity of XL184 – Randomized Discontinuation Trial

XL184 has demonstrated anti-tumor activity in 9 of 12 indications studied to date. In ongoing trials, compelling activity has been observed in medullary thyroid cancer, glioblastoma, and clear cell renal cancer. In the RDT, XL184 is being evaluated in nine different tumor types, with clear signals of activity in six: prostate, ovarian, hepatocellular, breast, non-small cell lung cancer and melanoma. The adaptive RDT design allowed for rapid simultaneous assessment of the activity of XL184 across nine different tumor indications. As of the November 1, 2010 cut-off date, a total of 397 patients have been enrolled into the nine disease-specific cohorts, with 273 evaluable for response, and 312 evaluable for safety. Of 273 patients evaluable for response per RECIST, 39 achieved a PR (either confirmed or unconfirmed) and 100 had SD at week 12. The week-12 DCR for the overall population was 49%, with the highest rates occurring in hepatocellular cancer (75%), castration-resistant prostate cancer (71%), ovarian cancer (64%), melanoma (45%), non-small cell lung cancer (42%) and breast cancer (42%). Of note, a breast cancer patient with evidence of bone metastasis on bone scan demonstrated evidence of resolution on bone scan accompanied by 29% reduction in tumor size. XL184 has been generally well tolerated with a consistent adverse event profile across the nine different RDT tumor types.

About XL184

XL184, an inhibitor of tumor growth, metastasis and angiogenesis, simultaneously targets MET and VEGFR2, key kinases involved in the development and progression of many cancers, including ovarian cancer. It has recently been shown in preclinical models that treatment with selective inhibitors of VEGF signaling can result in tumors that are more invasive and aggressive compared to control treatment. In preclinical studies, upregulation of MET has been shown to occur in concert with development of invasiveness after selective anti-VEGF therapy, and may constitute a mechanism of acquired or evasive resistance to agents that target VEGF signaling. Accordingly, treatment with XL184 in similar preclinical studies resulted in tumors that were less invasive and aggressive compared to control or selective anti-VEGF treatment. Therefore, XL184 has the potential for improving outcomes in a range of indications, including those where selective anti-VEGF therapy has shown minimal or no activity.

About Exelixis

Exelixis, Inc. is a development-stage biotechnology company dedicated to the discovery and development of novel small molecule therapeutics for the treatment of cancer. The company is leveraging its biological expertise and integrated research and development capabilities to generate a pipeline of development compounds with significant therapeutic and commercial potential for the treatment of cancer. Currently, Exelixis’ broad product pipeline includes investigational compounds in phase 3, phase 2, and phase 1 clinical development. Exelixis has established strategic corporate alliances with major pharmaceutical and biotechnology companies, including Bristol-Myers Squibb Company, sanofi-aventis, GlaxoSmithKline, Genentech (a wholly owned member of the Roche Group), Boehringer Ingelheim, and Daiichi-Sankyo. For more information, please visit the company’s web site at http://www.exelixis.com.

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1/Rosner GL, Stadler W, Ratain MJ. et. al.  Randomized discontinuation design: Application to cytostatic antineoplastic agents. J Clin Oncol 20:4478-4484, 2002.  Pursuant to this design, all patients receive the investigational drug for an initial period of time. Patients with standard radiologic tumor shrinkage within that timeframe would continue investigational therapy, while those with radiologic progression or unacceptable toxicity would discontinue therapy. All patients with radiologic stable disease after the initial therapy period are then randomized to continuing or discontinuing therapy in a double-blind placebo-controlled manner. This is an enrichment strategy in which patients with the end point of interest are preferentially enrolled in the randomized portion and in which the heterogeneity of the randomized population is decreased. These two factors result in an increased power for detecting a clinically relevant difference and decrease the number of patients exposed to placebo. Importantly, the enrichment is driven by the properties of the investigational drug as opposed to clinical prognostic factors identified in historical untreated patients or patients treated with a different class of agents. In addition, the statistical behavior of the trial is not highly dependent on investigators’ assumptions regarding the “no dose effect” (i.e., non-receipt of drug = no effect)  for time to progression or stable disease rate, and thus effectively deals with uncertainty in this variable. Finally, patients may find such a trial design more appealing, resulting in brisk accrual.

2/EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

Ovarian Cancer Drug AMG 386 Shows Promise With Move To Phase 3 Trials In Australia, Canada & Europe

A new drug (AMG 386) designed to arrest ovarian cancer cell growth by inhibiting blood vessel formation is being readied for a phase 3 trial in Australia, Canada and Europe.

AMG 386, a new drug designed to arrest ovarian cancer cell growth by inhibiting blood vessel formation, is being readied for a phase 3 trial in Australia, Canada and Europe.

The attendees at the Clinical Oncological Society of Australia Annual Scientific Meeting were told on November 10th that AMG 386 offers benefits over existing treatments, extending survival in advanced ovarian cancer patients with fewer side-effects.

AMG 386 is a first-in-class investigational “peptibody” (i.e., a combination of a peptide + an antibody) that is designed to block angiogenesis by inhibiting angiopoietin-1 and -2 (Ang1 & Ang2). Angiopoietins interact with the Tie2 receptor, which mediates vascular remodeling. Ang1 and Ang2 are thought to play opposing roles, and the maturation of blood vessels appears to be controlled by their precise balance.

Gary E. Richardson, M.D., Associate Professor of Medicine, Monash University, Victoria, Australia

Associate Professor of Medicine at Monash University, Gary Richardson, presented updated data from phase 2 clinical trials (first reported in June at the American Society of Clinical Oncology) showing that AMG 386 in combination with paclitaxel not only extends survival, but is well tolerated and reduces the risk of serious complications such as bowel perforation.

“Currently the prognosis for ovarian cancer patients is poor,” Professor Richardson said. “Over 75% of patients diagnosed with ovarian cancer present with advanced disease. Current treatments will cure only about a quarter of these patients.”

“The phase 2 trials show that AMG 386 combined with paclitaxel extends survival of heavily pre-treated patients by almost two thirds (4.6 to 7.2 months). In practical terms, this does not add significantly to survival time for terminal patients, but importantly indicates real potential as a first line treatment immediately following surgery.”

Professor Richardson said the treatment worked by inhibiting angiogenesis, the process by which new blood vessels grow from existing blood vessels. “By starving the cancer cells of blood supply, they will die in greater numbers. This form of therapy is complementary to current chemotherapy treatment as it uses a different mechanism to target the cancer.”

Professor Richardson said the phase 3 trial would commence by the end of this year and involve more than 1,000 patients in Australia, Canada and western Europe.

Bruce Mann, M.D., President, Clinical Oncological Society of Australia

Clinical Oncological Society of Australia President, Professor Bruce Mann, said clinicians had been frustrated by the lack of progress in treatment for ovarian cancer. “We don’t want to get ahead of ourselves, but novel approaches like this have the potential to make a real difference in patient survival from this devastating disease.”

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