Gynecologic Cancers

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 


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


Behavioral and neural response to cognitive training in gynecologic cancer survivors

Heidi J Gray, MD, Principal Investigator

Many cancer survivors experience late effects of their cancer treatment. Following treatment, patients attempt to navigate back to prior roles, including return to work. However, some patients experience late effects of their treatment on cognitive functioning which has been commonly called 'chemo brain'. The proposed project will examine whether a cognitive training intervention improves symptoms, objective performance and neural networks in cancer survivors suffering from cognitive dysfunction related to cancer treatment.

Funding Source: UW Royalty Research Fund
End Date: 8-15-16


Mechanisms of PARP Inhibitor Resistance in Ovarian Cancer

Elizabeth M Swisher, MD, Principal Investigator

Dr. Swisher will assess genomic scarring and deeply sequence for mutations in >50 DNA repair genes in all clinical samples from subjects treated on PARP inhibitors including paired blood, primary tumor and recurrent tumor from each case. All somatic mutations will be verified by Sanger sequencing. Additionally samples with known germline mutations will be evaluated for secondary somatic or reversion mutations. In these cases, primary and recurrent tumor will be carefully isolate with laser capture microdissection and sequenced for the known mutation with haplotyping of SNPs in the cancer when reversions are suspected. Dr. Swisher will coordinate her results with Dr. Kaufmann and compare to clinical outcomes including the in vivo response to the PARP inhibitor.

Funding Source: Mayo Clinic (NIH)
End Date: 1-31-16


Cancer Risks Associated with Inherited Mutations in Ovarian Cancer Susceptibility Genes Beyond BRCA1 and BRCA2

Elizabeth M Swisher, MD, Principal Investigator

Ovarian cancer is the most deadly cancer of the female reproductive tract. Women with early stage ovarian cancer have a high cure rate, but there is no good test that can detect ovarian cancer at an early, curable stage. A large fraction of ovarian cancer is hereditary, women get cancer because they have inherited an alteration or mutation in a cancer gene that they inherited from either their mother or father. Inherited mutations in two genes, BRCA1 and BRCA2, account for about 15% of all ovarian cancers. Women with BRCA1 and BRCA2 mutations have a very high lifetime risk of ovarian cancer (20-40%). For these women, the current recommendation is to undergo preventive surgery to remove the ovaries and fallopian tubes after completing childbearing. This surgery induces early menopause, but saves lives by decreasing the risk of both breast and ovarian cancer. Our group has recently discovered that inherited mutations in another dozen genes cause another 5-6% of cases. However, for these genes, the lifetime risk of ovarian cancer is less certain and the role of preventive surgery has not been established. One-third of women who get hereditary ovarian cancer have no known family history of breast or ovarian cancer, so relying on family history will not identify all women at risk. In the near future, women could get a single genetic test that would identify mutations in all ovarian cancer genes. The technology already exists to sequence many genes cheaply in a single cancer risk test, but before such a test could be broadly used to prevent ovarian cancer, we need a better understanding of risks associated with various ovarian cancer genes. Most previous studies of ovarian cancer genetics have focused only on the BRCA1 and BRCA2 genes and have studied mostly white women. Our study will correct the knowledge deficit by evaluating all known ovarian cancer genes and, for the first time, include a large number of African American women with ovarian cancer. We will also discover new ovarian cancer genes by testing all genes in families with multiple women with ovarian cancer. Our immediate goal is to refine the understanding of inherited ovarian cancer risks. The long-term goal is to use this information to devise tailored cancer prevention plans for women based on their identified risk in order to eliminate hereditary ovarian cancer. Women at high risk of ovarian cancer could be identified before they get cancer, undergo preventive surgery, and live longer cancer-free lives. For example, some women may have a very high ovarian cancer risk that justifies preventive surgery before menopause, while other women are at increased risk of ovarian cancer later in their lives and could undergo preventive surgery after menopause. The large fraction of ovarian cancer caused by inherited mutations in a variety of genes provides an important opportunity to reduce the incidence and death rate of ovarian cancer, which is a major goal of the Department of Defense’s Ovarian Cancer Research Program. Hereditary ovarian cancer disproportionately strikes younger women, leading to many years of life lost. Thus, hereditary ovarian cancer has a major impact on productivity and family life, including those of military families. This proposal will acquire important information to define the hereditary risk of ovarian cancer, which will lead to personalized prevention strategies to save lives of both white and minority women.

Funding Source: US Department of Defense
End Date: 12-31-15