Nivolumab and Bevacizumab with or without Rucaparib in Treating Patients with Relapsed Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer

Inclusion Criteria

• Participants must have histologic or cytologic confirmation of epithelial ovarian cancer, fallopian tube or peritoneal cancer; all histologies (including serous, mucinous, endometrioid, clear cell, malignant mixed mesodermal tumor [MMMTs], and mixed histologies) are eligible; all tumor grades are eligible
• Participants must have received a first-line platinum-based chemotherapy regimen
• Participants must have relapsed disease despite standard therapy
• For Cohorts 1 and 2: Participants with platinum-resistant or platinum-sensitive disease (within 12 months) are eligible; platinum-resistant disease is defined as relapse within 6 months after the last dose of platinum-based chemotherapy; platinum-sensitive disease is defined as relapse greater than 6 months after the last dose of platinum-based chemotherapy; participants with platinum-sensitive disease who have experienced relapse within 6 to 12 months after the last dose of platinum-based chemotherapy are eligible; participants with primary platinum-refractory disease (defined as progression during or relapsed within 2 months of their initial platinum-based chemotherapy) are not eligible
• For Cohort 3: Participants must have platinum-sensitive disease and have experienced relapse within 6 to 12 months (i.e., 180 to 365 days) after the last dose of platinum-based chemotherapy
• Participants must have received no more than 3 prior chemotherapy or cytotoxic regimens; there is no limit to the number of prior hormonal therapies
• Participants must have measurable disease by RECIST 1.1 criteria
• Participants who have received prior bevacizumab are eligible unless there is evidence of unacceptable toxicity due to prior bevacizumab exposure
• Participants may not have received any prior treatment with an anti-PD-1, anti PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Participants must have stopped any hormonal therapy at least 1 week prior to treatment with nivolumab and bevacizumab; participants may continue on hormone replacement therapy administered for post-menopausal symptoms
• Age >=18 years
• Estimated life expectancy of greater than 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• White blood cells (WBC) >= 2,000/uL (within 14 days prior to registration)
• Absolute neutrophil count >= 1,500/uL (within 14 days prior to registration)
• Platelets >= 100,000/mcL (within 14 days prior to registration)
• Hemoglobin >= 9.0 g/dL (within 14 days prior to registration)
• Serum creatinine less than or equal to the institutional upper limit of normal (ULN) or creatinine clearance (CrCl) >= 60 mL/min (calculated using the Cockcroft-Gault formula) for participants with serum creatinine levels above institutional ULN (within 14 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional ULN (within 14 days prior to registration)
• Total bilirubin =< 1.5 x institutional ULN (except participants with Gilbert syndrome, who can have total bilirubin =< 3.0 x institutional ULN with direct bilirubin that is within institutional ULN) (within 14 days prior to registration)
• Coagulation parameters (international normalized ratio [INR], activated partial thromboplastin time [aPTT]) =< 1.25 x institutional ULN (within 14 days prior to registration)
• Patients with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible; patients with stage IA endometrial cancer are eligible if the following conditions are met: without vascular or lymphatic invasion AND no serous, clear cell or grade 3 histology; patients with early stage I or II cancers treated with curative intent who have no evidence of recurrent cancer 3 years following diagnosis and judged by the investigator to be at low risk of recurrence are eligible
• Participants must have biopsiable disease and be willing to undergo pre-treatment biopsy, or have an archival tumor sample obtained < 20 months prior to study entry
• Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; additionally, women under the age of 62 who are not surgically sterile must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL to document postmenopausal status * Nivolumab, bevacizumab, and rucaparib may each cause fetal harm or risk to human pregnancy; for this reason, WOCBP must agree to use appropriate method(s) of contraception for 6 months after the last dose of study treatment, per Food and Drug Administration (FDA) recommendations on use of contraception following bevacizumab; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; patients receiving rucaparib should immediately discontinue rucaparib if they should become pregnant or suspect they are pregnant
• WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of study treatments
• Women must not be breastfeeding
• Ability to understand and the willingness to sign a written informed consent document
• Specific criteria for Cohorts 2 and 3: Patients must have undergone germline BRCA testing and must not have a deleterious or suspected deleterious BRCA mutation. Where tumor testing has been performed, patients with a deleterious or suspected deleterious somatic BRCA mutation are also not eligible

Exclusion Criteria

• Patients with primary platinum-refractory disease are ineligible; primary platinum-refractory disease is defined as relapse less than 2 months after initial platinum-based chemotherapy
• Patients with platinum-sensitive disease with relapse greater than 12 months after the last dose of platinum-based chemotherapy are ineligible
• Participants who have had chemotherapy or radiotherapy within 3 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier
• Participants may not be receiving any other investigational agents nor have participated in an investigational trial within the past 4 weeks
• Participants must agree not to use natural herbal products or other “folk remedies” while participating in this study
• Patients with a history of allergic reactions attributed to bevacizumab or to compounds of similar chemical or biologic composition to nivolumab or bevacizumab are excluded
• Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 6 months after treatment is complete and within 28 days prior to the first dose of nivolumab and bevacizumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
• Patients with any of the following cardiovascular diseases are excluded: * History of myocardial infarction within six months * Unstable angina * Angina pectoris that requires the use of anti-anginal medication * History of documented congestive heart failure (New York Heart Association [NYHA] classification of III or IV) or documented cardiomyopathy * Valvular disease with documented compromise in cardiac function * If cardiac function assessment is clinically indicated or performed: left ventricular ejection fraction (LVEF) less than normal per institutional guidelines, or < 55%, if threshold for normal not otherwise specified by institutional guidelines; patients with the following risk factor should have a baseline cardiac function assessment: ** Prior treatment with anthracyclines * Any prior history of hypertensive crisis or hypertensive encephalopathy * Patients may not have any evidence of pre-existing inadequately controlled hypertension (defined as a systolic blood pressure [BP] of > 140 mmHg or a diastolic BP of > 90 mmHg), and must have a normal blood pressure (=< 140/90 mmHg) taken in the clinic setting by a medical professional within 2 weeks prior to starting study * Clinically significant peripheral vascular disease * Vascular disease including aortic aneurysm or dissection * History of stroke, transient ischemic attack or subarachnoid hemorrhage * Ventricular arrhythmias except for benign premature ventricular contractions * Cardiac conduction abnormality requiring a pacemaker * Known history of QT/corrected QT interval (QTc) prolongation or torsades de pointes * QTc prolongation > 470 msec or other significant electrocardiogram (ECG) abnormality noted during screening
• Grade 2 or higher proteinuria (2+ or higher protein on urinalysis or urine protein: creatinine [UPC] ratio >= 1.0; if both tests are performed, UPC should be used to evaluate eligibility) or hematuria
• Participants may not have evidence of a bowel obstruction, abdominal fistula, or intra-abdominal abscess within 6 months of study entry; participants with current signs or symptoms suggestive of bowel obstruction including early or partial obstruction are ineligible; participants with a history of gastrointestinal perforation at any time point are ineligible
• Non-healing wound, ulcer or bone fracture
• Serious active infection requiring intravenous antibiotics and/or hospitalization at study entry
• Current dependency on IV hydration or total parenteral nutrition (TPN)
• Any patient with a history of major depressive episode, bipolar disorder, obsessive/compulsive disorder, schizophrenia, a history of suicide attempt or ideation, or homicide/homicidal ideation as judged by the investigator and/or based on recent psychiatric assessment may not participate in this study without discussion with and agreement of the study principal investigator (PI)
• Uncontrolled current illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
• Patients are excluded if they have an active, known or suspected autoimmune disease other than the following: vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
• Patients are excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration, with the exception of a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen); participants are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption)
• Patients are excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• Patients are excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Evidence of prior or current coagulopathy or bleeding diathesis
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting nivolumab and bevacizumab
• History of severe infusion reactions to monoclonal antibody therapy
• Specific criteria for Cohorts 2 and 3: Patients who have received a prior PARP inhibitor are not allowed to enroll to Cohort 2 or Cohort 3 of the trial
• Specific criteria for Cohorts 2 and 3: Patients are excluded from Cohort 2 and Cohort 3 should they have pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the investigator, interfere with absorption of rucaparib