Gynecologic Cancers

The Fanconi Anemia BRCA Pathway as a Predictor of Benefit from Bevacizumab in a Large Phase III Clinical Trial in Ovarian Cancer

Elizabeth M Swisher, MD, Principal Investigator

Ovarian cancer is the most deadly gynecologic cancer and most women diagnosed with ovarian cancer already have disease that has spread beyond the pelvis (Stage III and IV). Aggressive surgery and combination chemotherapy has been the mainstay of therapy for ovarian cancer for many years, but even so, few women with advanced stage ovarian cancer are cured. Recently, many biologic agents have been developed which target specific cellular pathways on which cancers depend. Bevacizumab is a biologic therapy which slows the formation of new blood vessels (angiogenesis), a process on which cancers rely to grow and spread. Bevacizumab was the first FDA approved anti-angiogenesis agent and has proved to be an active and well tolerated drug to treat recurrent ovarian cancer. Given its activity against recurrent disease, the Gynecologic Oncology Group (GOG), the main clinical trials organization for ovarian cancer in the United States, initiated in 2005 a large phase III randomized clinical trial of bevacizumab added to standard chemotherapy in newly diagnosed women with stage III and IV ovarian, peritoneal or fallopian tube cancer. This clinical trial, called GOG218, was designed to test whether adding bevacizumab increased progression free survival (PFS), the length of time between starting treatment and documentation of new cancer growth. The study was not designed to test the impact of bevacizumab on how long the patients lived (overall survival). Women treated in GOG218 with an additional 48 weeks of bevacizumab after initial chemotherapy + bevacizumab had an increase in PFS by 3.8 months. While this improvement in PFS met the study goal of success, doctors and insurers have been hesitant to embrace the use of bevacizumab for newly diagnosed ovarian cancers because of increased cost and toxicity. It is likely that only some women with ovarian cancer benefit from the addition of bevacizumab. If we could identify who are the women likely to benefit, before treatment begins, we could use bevacizumab more selectively, and thereby decrease cost and toxicity. Biomarkers are tests that can predict disease, outcomes, or the benefit of specific therapies. Despite more than a decade of clinical use and much research effort, no validated biomarkers exist that predict response to anti-angiogenesis drugs. Most of the biomarker research for this drug class has focused on the angiogenesis pathway, evaluating proteins or genes that directly impact angiogenesis. In this proposal, we take a different strategy. We believe that we can predict which women with ovarian cancer will benefit from the addition of bevacizumab by evaluating a DNA repair pathway that is known to influence the response to the most effective chemotherapy class in ovarian cancer, platinum drugs. This DNA repair pathway includes the genes known to cause hereditary ovarian cancer, BRCA1, BRCA2, and other related genes. We predict that women with mutations in genes in this pathway will not receive any benefit from bevacizumab while women without mutations will have an increase in PFS when treated with extended bevacizumab. The majority of women who were treated on GOG218 donated blood samples for this type of research. For, this proposal we will use a portion of blood DNA already available from 1,270 women treated on GOG218. We will test their blood for mutations in 35 different genes using modern sequencing technologies and relate our findings to the trial outcomes. Many of these genes have not been previously evaluated for inherited mutations in women with ovarian cancer, so we may also identify new genes that cause ovarian cancer. If our proposal is successful, testing for germline mutations in this DNA repair pathway could, in the near future (within two years), direct therapeutic choices; women without mutations would get chemotherapy combined with bevacizumab, while mutation carriers would receive chemotherapy combined with a new biologic agent, the PARP inhibitors. Additionally, we may discover novel ovarian cancer susceptibility genes, which would improve our ability to detect hereditary risk before women get cancer, thereby increasing the fraction of ovarian cancers that are preventable. Furthermore, our predictor of anti-angiogenesis response would likely also be applicable to women with recurrent ovarian cancer and may also be applicable to other types of malignancy.

Funding Source: Department of Defense (DOD) Pilot Award
End Date: 8-31-15


Defining Genomic Scarring and Functional DNA Variants that Predict Response to PARP Inhibitors in a Clinical Trial for Recurrent Ovarian Cancer

Elizabeth M Swisher, MD, Co-Principal Investigator with Toshiyasu Taniguchi, MD, PHD

Ovarian carcinoma is the most deadly gynecologic cancer, causing almost 15,000 deaths annually in the U.S. Accordingly, new treatment modalities are urgently needed for both primary and recurrent disease. A major current goal in oncology is to increasingly personalize therapy by tailoring treatment choices to the specific genetic alterations in a given cancer. PARP inhibitors are relatively new therapeutic agents that demonstrate substantial promise in early phase clinical trials, particularly in hereditary ovarian carcinoma that occurs in women with inherited BRCA1 and BRCA2 mutations. PARP inhibitors are also likely to be effective in a subset of nonhereditary (sporadic) ovarian carcinomas, but which subset of cancers will respond is not certain. Because the addition of biologic therapies like PARP inhibitors to standard chemotherapy has the potential to not only improve outcomes, but also increase cost and toxicity, it is important to develop tests or biomarkers that help identify women most likely to benefit from the therapy. We propose to apply modern molecular technologies to develop a novel assay of "genomic scarring" in the cancer that may predict which patients will achieve the best response from PARP inhibitors. First, we will use existing cancers banked at our institution to develop and refine the assay of genomic scarring. Second, we will test how well this new assay works in a prospective clinical trial of the PARP inhibitor rucaparib in women with recurrent sporadic ovarian carcinoma. In another set of experiments, we will test a series of rare inherited genetic changes and determine for each one whether it led to the development of ovarian cancer and whether it may be associated with response to a PARP inhibitor. Together, these experiments are designed to lead to a clinically useful test that can identify the subset of women with ovarian carcinoma most likely to benefit from PARP inhibitor treatment. Such a predictive test will facilitate the rational and cost effective application of PARP inhibitors in the therapy of inherited and sporadic ovarian carcinomas, bringing us a step closer to personalized therapy for ovarian cancer. It is likely that biomarkers developed from this trial would also be applicable other cancer types.

Funding Source: Fred Hutchinson Cancer Research Center
End Date: 10-31-16


Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma

Elizabeth M Swisher, MD, Principal Investigator

Ovarian carcinoma is the most deadly gynecologic cancer and new treatment modalities are urgently needed for both primary and recurrent disease. PARP inhibitors are relatively new therapeutic agents which demonstrate great promise, particularly in hereditary ovarian carcinoma that occurs in women with inherited BRCA1 and BRCA2 mutations. PARP inhibitors are also likely to be effective in a subset of nonhereditary (sporadic) ovarian carcinoma, but which subset is not certain. The addition of biologic therapies like PARP inhibitors to standard chemotherapy regimens increases cost and toxicity, but has the potential to improve outcomes. The intelligent and cost-effective application of PARP inhibitors requires developing tests or biomarkers that help predict which women will benefit from the therapy. We propose to use modern sequencing and molecular technologies in existing samples at two institutions to develop a biomarker of PARP inhibitor response. We will then test the validity of this biomarker in a prospective clinical trial of the PARP inhibitor rucaparib in women with recurrent sporadic ovarian carcinoma. These experiments will lead to a clinically useful test which can predict which subset of women with both sporadic and hereditary ovarian carcinoma will benefit from PARPi treatment. Such a predictive test will facilitate the rational and cost effective application of PARPis in the therapy of ovarian carcinoma. It is likely that biomarkers developed from this trial would be applicable in hereditary as well as sporadic ovarian carcinoma and might also be applicable to other cancer types.

Funding Source: Department of Defense (DOD) Synergistic Translational Leverage Award
End Date: 9-29-16


A Phase I Study to Evaluate the Safety, Pharmacokinetics and Oral Bioavailability of Veliparib Extended-Release Formulations in Subjects with Solid Tumors

Elizabeth M Swisher, MD, Principal Investigator

1) Assess and compare the bioavailability of three test extended release (ER) formulations
of veliparib with that of the current immediate release formulation of veliparib
2) Evaluate the potential effect of food on the oral bioavailability of three test extended release
(ER) formulations of veliparib
3) Establish the Maximum Tolerated Dose (MTD) and to establish the recommended Phase 2 dose
(RPTD) and schedule for one or more of the ER formulations
4) Secondary objectives are to assess the safety and tolerability of the ER formulations

Funding Source: Abbott Laboratories
End Date: 8-6-16 


The FA-BRCA Pathway and Response to Platinum and PARP Inhibitors in Ovarian, Tubal and Peritoneal Carcinomas

Elizabeth M Swisher, MD, Principal Investigator

Ovarian carcinoma is the most deadly gynecologic cancer, causing almost 15,000 deaths annually in the U.S. Most women with ovarian cancer are treated with a combination of surgery and platinum chemotherapy. Even though the majority of women respond well to this treatment initially, eventually their cancers recur and develop resistance to platinum and other types of chemotherapy. Accordingly, new treatment modalities are urgently needed for both primary and recurrent disease. PARP inhibitors are relatively new therapeutic agents that have demonstrated substantial promise in early phase clinical trials, particularly in hereditary ovarian carcinoma that occurs in women with inherited BRCA1 and BRCA2 mutations. PARP inhibitors are also likely to be effective in a subset of nonhereditary (sporadic) ovarian carcinomas, but which subset of cancers will respond is not certain. Because the addition of biologic therapies like PARP inhibitors to standard chemotherapy has the potential to not only improve outcomes, but also increase cost and toxicity, it is important to develop tests or biomarkers that help identify women most likely to benefit from the therapy. It is also useful to predict which cancers are resistant to platinum and should be treated with other drugs. Currently, such tests or biomarkers have not been identified. We propose to apply modern sequencing and molecular technologies to existing samples at two institutions to develop a biomarker of response and resistance to DNA damaging agents. We will then test the validity of this biomarker in a mouse model of ovarian cancer. These experiments are designed to lead to a clinically useful test that can identify the subset of women with ovarian carcinoma most likely to benefit from PARP inhibitor treatment and those unlikely to respond to PARP inhibitors or to platinum chemotherapy. Such a predictive test will allow personalized treatments for women with ovarian cancer, which is likely to improve survival and quality of life. This strategy will also allow women with ovarian cancer to avoid treatments unlikely to work, thereby avoiding unnecessary cost and toxicity.

Funding Source: Ovarian Cancer Research Fund (OCRF)
End Date: 12-31-15


EP-100, a Novel LHRH Receptor-Targeted, Membrane-Disrupting Peptide, plus Paclitaxel versus Paclitaxel alone for Refractory or Recurrent Ovarian Cancer: a Phase II, Randomized, Multi-center Trial

Renata R Urban, MD, Principal Investigator

Funding Source: Esperance Pharmaceuticals
End Date: 3/31/17


GSK OMB Clinical Trial

Benjamin E Greer, MD, Principal Investigator

This is a multicenter, parallel, active comparator controlled, open-label, randomized (1:1) phase III study of single agent ofatumumab compared to single agent rituximab in subjects with rituximab-sensitive grade 1, 2, and 3A follicular lymphoma that has relapsed at least 6 months after completing their last prior treatment with single agent rituximab or a rituximab-containing regimen. Subjects must have attained a CR or PR to their last prior rituximab containing therapy lasting at least six months beyond the end of rituximab therapy. Subjects will be stratified by type of last prior rituximab therapy (monotherapy vs. combination therapy) and FLIPI-1 score (0-2 vs. 3-5). Subjects will receive four weekly doses of single agent ofatumumab (1000 mg) or single agent rituximab (375 mg/m2), followed by ofatumumab (1000 mg) or rituximab (375 mg/m2) every 2 months for four additional doses. Therefore, subjects will receive a total of eight doses of anti-CD20 antibody over 9 months. Response will be assessed after dose 4, dose 6 and dose 8, using modified 2007 Revised Response Criteria for Malignant Lymphoma. The primary endpoint is progression free survival by intent-to-treat analysis. Subjects will continue to be evaluated after completion of therapy until the end of the designated follow-up period (total study duration of 200 weeks) or until they meet the withdrawal criteria.

Funding Source: GlaxoSmithKline, Inc.
End Date: 12-31-18


Immune profiling of BRCA1 and platinum resistance in ovarian cancer

John B Liao, MD, PhD, Principal Investigator

BRCA1, in addition to its role in genetic predisposition for ovarian cancer, also has been implicated in prognosis and platinum resistance. Ovarian cancer is immunogenic. There is an increasing body of evidence showing vital interactions between chemotherapy response and the immune system. We have shown that ovarian cancer patients are capable of generating humoral and cellular immune responses specific for BRCA1. We have also shown that serum antibodies recognizing BRCA1 present prior to receiving chemotherapy are associated with primary platinum resistant disease in patients with advanced ovarian cancer.

We hypothesize that further study of BRCA1 as a tumor antigen will lead its use as both a biomarker and a target for immune therapy in the treatment of ovarian cancer. To accomplish this we propose to:

1. Immunologically dissect humoral immune recognition of BRCA1 using mutational analysis and oncogenic splice variants to isolate epitopes critical to the emergence of platinum resistance for use as biomarker.

2. Analyze BRCA1 sequence for candidate MHC class II epitopes and measure proinflammatory and immunosuppressive immune responses in ovarian cancer patients for a vaccine to prevent chemoresistance.

3. Evaluate therapeutic vaccination using selected BRCA1 peptides in mouse models for ovarian cancer to decrease platinum resistance and correlate anti-tumor effects with humoral and cellular immune responses.

Funding Source: US Department of Defense
End Date: 9-1-19


Molecular Biomarkers to Predict PARP Inhibitor Response in Ovarian Cancer

Barbara S Norquist, MD, Principal Investigator

PARP inhibitors are a promising new class of drugs for the treatment of ovarian cancer. They work by taking advantage of a cancer's inability to repair its own DNA. Ovarian cancers from women who carry mutations in the DNA repair genes BRCA1 and BRCA2 have defective DNA repair, and are uniquely susceptible to PARP inhibitors. Mutations in other genes affecting DNA repair, either those that are inherited or those that develop within cancers may also predict response to PARP inhibitors. Other measurable features within the tumor may also predict response. We seek to measure multiple biomarkers in both blood and tumors in order to predict response to PARP inhibitors. We will do this by assessing blood and tumor samples from women enrolled in a clinical trial of the PARP inhibitor rucaparib for recurrent ovarian cancer. We will use advanced genomic sequencing to test blood and tumors for mutations in a panel of 56 DNA-repair genes, along with other changes that might predict defective DNA repair. We will then look at those findings to see which features were most predictive of responding to the PARP inhibitor on the clinical trial. We hope to use these data to develop clinically useful tests to predict which women with ovarian cancer will have the best chance of responding to a PARP inhibitor, to allow the most rational and cost effective use of this promising therapy.

Funding Source: Ovarian Cancer Research Fund (OCRF)
End Date: 6-30-17