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.


2008 ASCO Annual Meeting Abtracts Highlight Several Drugs That Show Promise Against Drug Resistant Ovarian Cancer

There were several drugs highlighted in clinical trial abstracts presented at the 2008 American Society of Clinical Oncology (ASCO) Annual Meeting that demonstrated varying degrees of effectiveness against drug resistant (i.e., recurrence within 6 to 12 months after completion of first line treatment) and/or drug refractory (i.e., recurrence within 6 months after completion of first line treatment) ovarian cancer. By “effectiveness,” we mean generally that the drug or drug combination produced a complete response, partial response, and/or disease stabilization (and in a few cases, a significant drop in the CA-125 tumor marker) in ovarian cancer tumors. To better understand how to intrepret a medical study abstract, click here. The 2008 ASCO Annual Meeting was held in Chicago, Illinois on May 30 – June 3, 2008.

A list of the drugs/drug combinations is provided below. Any drug covered in depth through an earlier H*O*P*E*™ weblog post is noted. We also included 2008 ASCO Annual Meeting abstracts that provide “solid tumor” clinical trial results with respect to studies that enrolled patients with ovarian cancer tumors. When evaluating the potential enrollment in a clinical trial at various treatment points, an ovarian cancer survivor should evaluate trials dedicated to ovarian cancer patients in entirety, as well as general “solid tumor” trials that allow enrollment of ovarian cancer patients. Generally, a patient should give first priority to dedicated ovarian cancer trials and use the solid tumor trials as a “backup” to the ovarian cancer trials. All questions regarding the priority assigned to, or proper sequencing of, clinical trials should be discussed in detail with your doctor(s). Treatment priority and sequencing issues arise, for example, when enrollment in one clinical trial potentially disqualifies the patient for a subsequent second clinical trial based upon the protocol (i.e., inclusion/exclusion criteria) of the second trial. This example assumes that both clinical trials are currently enrolling patients when trial enrollment is being evaluated by you and your doctor.

Abbreviation Legend:

ABSTR=2008 American Society of Clinical Oncology Annual Meeting Abtract; ASCO=American Society of Clinical Oncology; CA-125=cancer antigen 125; CEA=Carcinoembryonic Antigen (Tumor Marker); CR=Complete Response; CT=Computed Tomography

CTC=Common Toxicity Criteria; DCE-MRI=Dynamic Contrast Enhanced Magnetic Resonance Imaging; DLT=Dose Limiting Toxicity; DP=Disease Progression; EOC=Epithelial Ovarian Cancer; G=Grade of Adverse Drug Effect;

GCIG=Gynecologic Cancer Intergroup; GOGGynecologic Oncology Group; MTD=Maximum Tolerable Dose; mg/m²=milligrams per metre squared; NCI=National Cancer Institute; OR=Objective Response; OS=Overall Survival;

PET=Positron Emission Tomography Scanning; PK=Pharmacokinetics; PO=Oral Administration; PR=Partial Response; PFS=Progression Free Survival; RECIST=Response Evaluation Criteria in Solid Tumors; RR=Response Rate; SD=Stable Disease

SNS-595 (Voreloxin®):

NOV-002 & Carboplatin (Paraplatin®):

  • NOV-002 plus carboplatin in platinum-resistant ovarian cancer (2008 ASCO Abstract #5593). Patients were heavily pretreated with 11/15 patients having received 3 prior [treatment] lines. Toxicity was mild-moderate with no G4 toxicity. There was no febrile neutropenia. The most common toxicities were nausea and fatigue, as well as abdominal pain and bowel obstruction thought to be related to underlying disease. To date, there is 1 patient with PR, 7 patients with SD and 5 patients with PD, with 1 patient off-trial for patient discretion. PFS is 14 weeks. Patients tolerated this regimen extremely well, with most toxicity attributable to carboplatin alone. Conclusion: The PFS was longer than expected, with a significant proportion of these platinum resistant patients achieving clinical benefit with prolonged stable disease. [61% disease control (CR+PR+SD) rate]

Picoplatin & Pegylated Liposomal Doxorubicin (Doxil®):

  • Final results of a phase I study of picoplatin and pegylated liposomal doxorubicin [e.g. Doxil™] in advanced solid tumor malignancies (2008 ASCO Annual Mtg. Abstr. #2568 ): Picoplatin is a novel, sterically hindered platinum(II) complex designed to circumvent mechanisms of platinum resistance. Given the single agent activity seen in multiple tumor types, we conducted a phase I study of picoplatin in combination with pegylated liposomal doxorubicin (PLD) in patients with advanced solid tumors. The Phase 1 trial enrolled 16 patients with advanced solid tumors who had received up to three prior regimens for metastatic disease. Patients were administered picoplatin followed by liposomal doxorubicin on day one of a 28-day cycle. Four dose levels of picoplatin and pegylated liposomal doxorubicin were tested: 100/20, 100/30, 100/40 and 120/40 (all mg/m2). A total of 62 courses of treatment were delivered to 16 patients with a median number of four cycles per patient. A total of 12 patients were evaluable for response. One patient experienced a CR (primary peritoneal cancer) and four experienced a PR (including three of five patients with ovarian cancer). Hematologic and non-hematologic toxicity were mild. Conclusion: This study suggests that picoplatin and liposomal doxorubicin is an active combination with promising results and can be given at standard dose levels with a minimal increase in toxicity. [41% disease control (CR+PR+SD) rate among evaluable patients]

Weekly Topotecan (Hycamtin™) Monotherapy:

  • Phase II study of weekly topotecan in recurrent ovarian cancer: duration of response based on a prolonged follow-up (ASCO Annual Mtg. Abstr. #16549). Nineteen patients (median age 52 yrs, range 45-72) with EOC who progressed after 3 (11/19 patients = 57.9%), 4 (7/19 patients= 36.8%) or 5 (1/19 patients= 5.3%) previous lines of chemotherapy were treated with Topotecan at the dose of 2.0 mg/m2 via a 30-minute intravenous infusion once every week until disease progression, unacceptable toxicity or when a stability of disease was reached. Results: All patients were evaluable for toxicity and clinical response. 16/19 patients enrolled (84.2%) had stage III-IV disease. Median number of chemotherapy cycles was 7 (range 3 – 12). A total of 107 cycles were administered. Dose reduction was necessary for 13% of the cycles. Main toxicities included anemia (G1-G2=57.9%), leucopenia (G1-G2=15.8%), thrombocytopenia (G1-G2=10.5%) and asthenia (20%). No one showed a CR, while 5/19 patients experienced a PR (26.4%), 6/19 patients experienced SD (31.5%), and 8/19 patients (42.1%) experienced DP. The median PFS was 12 weeks in patients with PR; SD was maintained for a median time of 14 weeks. Conclusion: The rate of patients with ongoing stable disease (31.5%) suggests that the clinical benefit of weekly topotecan may be expected also in patients with no other viable therapeutic options. [57% disease control (CR+PR+SD) rate among evaluable patients]

Azacitidine & Carboplatin:

Combretastatin A4 Phosphate (Zybrestat™) and Bevacizumab (Avastin™):

BSI-201:

Belinostat (PXD101):

SU11248/Sunitinib (Sutent®):

AZD2281 (KU-0059436):

  • AZD2281, a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study (2008 ASCO Annual Mtg. Abstr. #5510) Thirty-two patients with BRCA-deficient ovarian cancer (i.e., patients with BRCA gene mutations) the majority of whom were platinum resistant/refractory are so far evaluable for response. All evaluable patients had either received treatment for at least 8 weeks (2 cycles) or progressed prior to completion of 2 cycles. Fourteen patients have achieved PR, 13 patients meeting GCIG- CA125 criteria and 10 patients meeting RECIST criteria. Of the responders, 1 patient has been on drug > 56 weeks whilst 7 patients have maintained responses for > 24 weeks. SD was seen in an additional 8 patients, 7 of whom continue on drug and 3 patients had SD > 16 weeks. Responses were seen at all dose levels from 100mg bd and above. Conclusion: AZD2281 is well tolerated and has demonstrated compelling activity in patients with BRCA deficient ovarian cancer. Responses were seen in all patient groups including platinum resistant disease. Updated efficacy data, together with a correlation of potential predictive factors including platinum free interval will be presented on a total planned cohort of 46 patients with BRCA-deficient ovarian cancer. A randomised study in BRCA-deficient ovarian cancer has been planned. [68% disease control (CR+PR+SD) rate among evaluable patients]

Gemcitibine (Gemzar™) & Epirubicin (Ellence™):

Belinostat/PXD101, Carboplatin (Paraplatin®) & Paclitaxel (Taxol™):

Pegylated Liposomal Doxorubicin (Doxil®) & Gemcitabine (Gemzar®):

Pemetrexed/LY231514 (Altima®):

Sorafenib (Nexavar™):

  • Phase II trial of sorafenib in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study (2008 ASCO Annual Mtg. Abstr. #5537). Sorafenib is a tyrosine kinase inhibitor targeting raf and other receptor kinases (VEGF-R, PDGF-R, Flt3, c-KIT). Sorafenib may have anti-angiogenic activity through inhibition of VEGF-R. This phase II study was conducted to assess the activity and tolerability of sorafenib in patients with recurrent EOC. Methods: This was an open label multi-institutional phase II study …. Eligible patients had persistent or recurrent EOC/PPC after 1-2 prior cytotoxic regimens, measurable or detectable (e.g. by CA125) disease, and GOG performance status < 2. Patients were required to have progressed within 12 months of completing platinum based therapy. Treatment consisted of sorafenib 400 mg orally bid until disease progression or prohibitive toxicity. Primary endpoints were PFS at 6 months and toxicity by NCI criteria. Secondary endpoints were tumor response and duration of PFS/OS. Results: 73 patients were enrolled from 10/04 to 5/07 and as of 12/2007, 68 patients are evaluable (2 ineligible and 3 too early) for toxicity. Median age was 60 (range 33-80) years and prior treatment consisted of 1 regimen in 40 patients and 2 regimens in 28 patients. Significant G3 and G4 toxicities included: rash (12 patients), metabolic (10 patients), gastrointestinal (3 patients), cardiovascular (2 patients), and pulmonary (2 patients). No treatment related deaths were recorded. Only patients with measurable disease were used to assess efficacy. Among the 59 patients with measurable disease, 12 survived PFS at least 6 months. Three patients are yet to be determined. Two patients had PR; 20 had SD; 30 had DP, and 7 could not have their tumor assessed. Conclusions: Preliminary results suggest that sorafenib is tolerated in patients with recurrent EOC with dermatologic and metabolic abnormalities being the most common toxicities. Efficacy data is expected to reach maturity and be analyzed in the spring of 2007, and comprehensive results will be presented. [42% disease control (CR+PR+SD) rate among evaluable patients]

Topotecan (Hycamtin™) & Bevacizumab (Avastin™):

  • Phase II prospective study of weekly topotecan and bevacizumab in platinum refractory ovarian cancer or peritoneal cancer (OC) (2008 ASCO Annual Mtg. Abstr. #5551). Patients (pts) with platinum refractory OC have limited treatment options. Bevacizumab, an anti-angiogenesis agent has demonstrated efficacy in recurrent ovarian cancer. Bevacizumab combined with chemotherapy in other solid tumors has improved efficacy compared with bevacizumab or chemotherapy alone. Topotecan, an active drug in recurrent OC has been used in a weekly fashion with less toxicity and more acceptability than a standard 5 day regimen. Topotecan and bevacizumab have non-overlapping toxicities. We studied the efficacy and tolerability of weekly topotecan and bevacizumab in patients with platinum refractory OC. Methods: The primary objectives of this study were to evaluate PFS, OS, OR rate and toxicity of this combination regimen. Eligible pts included those with platinum refractory OC (recurrence < 6 months of platinum therapy) who had received a maximum of 2 prior chemotherapy regimens. Results: Twenty-two pts have been enrolled to date, with 11 pts remaining on study and 18 now evaluable. Best responses for the 18 evaluable pts were: 22.2% PR (n=4), 27.8% SD (n=5), and 50% DP (n=9). Eleven pts went off study due to DP (based on CT scan RECIST criteria [n=6] or general deterioration and/or bowel obstruction [n=5]). Median duration on study for the 18 evaluable pts was 15 wks (range 5-63 weeks). Four pts have had PFS >5 months. The 18 evaluable pts received a total of 91 treatment cycles. No pt went off study due to treatment related toxicity or suffered a bowel perforation. Conclusions: Combination bevacizumab and topotecan administered in a weekly fashion demonstrate good activity in platinum refractory OC with acceptable toxicity. G3-G4 Hematologic or Hypertensive Toxicities. [50% disease control (CR+PR+SD) rate among evaluable patients]

Lapatinib (Tykerb™), Carboplatin (Paraplatin®) & Paclitaxel (Taxol™):

  • Phase I/II lapatinib plus carboplatin and paclitaxel in stage III or IV relapsed ovarian cancer patients (2008 ASCO Annual Mtg. Abstr. #5556). The purpose of this study was to establish the MTD and evaluate DLTs and response to therapy of combination therapy with carboplatin/paclitaxel and lapatinib, an oral dual tyrosine kinase inhibitor of both ErbB1 and ErbB2, in Stage III /IV relapsed ovarian cancer. Methods: This was an open-label, multicenter, phase I/II study of carboplatin/paclitaxel in combination with single agent lapatinib in Stage III/IV relapsed ovarian cancer patients. Measurable disease, adequate organ function and ECOG performance status of 0-2 were required. Results: 25 ovarian cancer patients are enrolled and four are too early to be evaluable. The median age is 57 (range 39-81). The median number of prior therapeutic regimens is 4 (range 1-10). GI toxicities were primarily < grade 2 and were successfully treated with aggressive bowel management. 10 patients (pts) experienced G3 toxicities. 4 pts- leukopenia, 2 pts-neutropenia, 2 pts-hyperglycemia, 2 pts-allergic reactions to carboplatin, 1 pt-thrombocytopenia, 1 pt-lymphopenia, 1 pt-hypokalemia, 1 pt-nausea, 1 pt-diarrhea, 1 pt-bowel obstruction. Response to therapy to date is: CR=21%, PR=29%, SD=29%, PD=21%. Two patients who were in complete remission both stopped IV chemotherapy and were maintained only with lapatinib. One is still in remission after six months and one relapsed. Conclusions: Lapatinib, an oral targeted molecular therapy which inhibits both EGFR 1 and 2 tyrosine kinase activity, can be safely administered with a weekly regimen of carboplatin and paclitaxel in heavily pretreated, ovarian cancer patients. The high response rates seen warrant further investigation. [79% disease control (CR+PR+SD) rate among evaluable patients]

Ifomide, Epirubicin, & Cisplatin:

NKTR-102 (Pegylated irinotecan):

  • Phase I dose finding and pharmacokinetic study of NKTR-102 (PEGylated irinotecan): Early evidence of anti-tumor activity (2008 ASCO Annual Mtg. Abstr. #13518 ). NKTR-102 is a novel pegylated form of irinotecan with superior efficacy against a range of xenografts compared with irinotecan. Sustained tumor inhibition is associated with increased SN38 exposure. A phase I trial of NKTR-102 was conducted to establish the MTD and to characterize safety and PK in patients (pts) with refractory solid tumors. No CTC Grade 4 toxicity was observed. G3 diarrhea was dose limiting. Other toxicities included transient uncomplicated G3 neutropenia and transient infusion related visual disturbance. PK data are available for 12 pts. Two partial responses were observed in pts with advanced cervical cancer and small cell lung cancer. Anti-tumor activity was seen in 4 other pts; ovarian: CA-125 decreased from 2557 to 518, Hodgkin’s disease: 28% radiologic improvement with symptomatic benefit, adrenocortical: cortisol levels normalized, metabolic response by PET, esophageal: CEA decreased from 35.5 to 13.6, metabolic response by PET. Conclusions: NKTR-102 shows early evidence of activity in a wide spectrum of tumors. Cumulative SN38 exposure is 1.2 to 6.5 fold higher than that predicted for irinotecan. Toxicity is manageable; diarrhea (not neutropenia) is dose limiting.

ON 01910.Na:

  • Phase I study of ON 01910.Na, a novel polo-like kinase 1 pathway modulator, administered as a weekly 24-hour continuous infusion in patients with advanced cancer (2008 ASCO Annual Mtg. Abstr. #2515). ON 01910.Na induces G2/M cell cycle arrest, apoptosis, and cell death in a broad spectrum of cancer cells, but not in non-neoplastic cells. In vitro, cell killing is dependent on drug exposure time. Based on these preclinical findings, a weekly 24hr continuous infusion (CI) study to determine safety and MTD of ON 01910.Na was initiated. Methods: Patients with advanced cancers received ON 01910.Na as a weekly 24hr CI. Twenty-three pts (7:16 M:F, 45-80 yrs) have received ON 01910.Na. G2 toxicities (2-grade increase over baseline) included fatigue (3 pts) and anorexia (1 pt). Fatigue (11/23 pts) was the most common side effect, with no G3 or greater fatigue observed. Overall, three G3 events occurred, none of which were drug-related. The best response was a pt with advanced ovarian cancer who maintained stable disease for 36 wks of treatment. Conclusions: ON 01910.Na is well tolerated as a weekly 24h continuous infusion. In the dose range studied, the drug exhibited non-linear kinetics with rapid attainment of plasma concentrations that are cytotoxic to cancer cells in vitro, but have limited end-organ toxicity in vivo. Study data continues to accrue, and we expect to recommend a phase II dose shortly. Further analysis and combination phase I studies are planned.

BAY 73-4506:

  • Phase I study of BAY 73-4506, an inhibitor of oncogenic and angiogenic kinases, in patients with advanced solid tumors: Final results of a dose-escalation study (2008 ASCO Annual Mtg. Abstr. #2558 ). BAY 73-4506 is a potent tyrosine kinase inhibitor of receptor tyrosine kinases (VEGFR, PDGF, RET, KIT, FGFR) and serine/threonine kinases (raf and p38MAPK). In tumor xenograft models, BAY 73-4506 demonstrated a broad spectrum antitumor activity. Methods: This phase I study was a dose-escalation trial investigating the safety, PK, and pharmacodynamic (PD) profile of BAY 73-4506, given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers including DCE-MRI, soluble VEGFR-2 (sVEGFR-2) and VEGF plasma levels were assessed at each cycle. Tumor response was evaluated as per RECIST. Results: 52 patients (pts) with solid tumors and progressive disease were enrolled and treated with doses of 10 to 220 mg once daily. Frequent tumor types included colorectal cancer (CRC) (31%), malignant melanoma (10%), and ovarian cancer (10%). The median treatment duration was 49.5 days (min. 3, max. 609). Drug-related adverse events (AEs) of all grades reported in >20% of pts were hoarseness (54%), dermatological toxicities (50%; CTC G3-G4: 13%), mucositis (35%), diarrhea (25%; CTC 3: 2%), fatigue (23%; CTC 3: 2%), and hypertension (23%; CTC 3: 6%). Treatment-related AEs leading to dose reduction, interruption or discontinuation were hand foot skin reaction (15%), diarrhea (8%), and thrombopenia (6%). Of the 33 evaluable pts, 9% achieved a partial response (PR), 64% had stable disease (SD), at least 7 weeks after start of treatment, and 48% had SD or PR for more than 11 weeks. Conclusions: The recommended phase II dose for BAY 73-4506 is 160 mg daily, using the 21 days on/7 days off treatment schedule. Clinical activity (PR+SD) has been demonstrated in 73% of the evaluable pts. An extension cohort (dose level 160 mg) has been started.