This research study is a Phase II clinical trial. Cancers are recognized by the immune
system, and under some circumstances,the immune system may control or even eliminate tumors.
An antibody is a natural protein made by our immune system that binds other proteins and
molecules to fight infection and its ill effects.
Nivolumab is an experimental antibody drug that may make the immune response more active
against Cancer. Bevacizumab is an antibody that works by stopping the formation of blood
vessels.Rucaparib is an oral pill that can block the ways cells repair their DNA, which can
cause damage to certain cancer cells.
The FDA (the U.S. Food and Drug Administration) has not approved Nivolumab for Relapsed
Ovarian, Fallopian Tube Or Peritoneal Cancer but it has been approved for other uses.
Bevacizumab has been FDA approved when used together with chemotherapy for the treatment of
Ovarian, Fallopian Tube, Or Primary Peritoneal Cancer that has returned within 6 months of a
chemotherapy that contains a platinum drug.
Rucaparib has been FDA approved for the treatment of patients with BRCA-mutated ovarian
cancer who have been treated with 2 or more prior chemotherapies or as maintenance therapy
following for women with platinum-sensitive recurrent ovarian cancer.
The combination of Nivolumab, Bevacizumab, and Rucaparib has not been approved by the FDA in
any setting.
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, 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.
- 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.
- Participants must have received no more than 3 prior chemotherapy 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.
- ECOG performance status of 0 or 1
- Screening laboratory values must meet the following criteria and should be obtained
within 14 days prior to registration:
- WBC ≥ 2,000/µL
- Neutrophils ≥ 1,500/µL
- Platelets ≥ 100,000/mcL
- Hemoglobin > 9.0 g/dL
- Serum creatinine within the institutional ULN or creatinine clearance (CrCl) ≥ 60
mL/min (calculated using the Cockgroft-Gault formula) for participants with serum
creatinine levels above institutional ULN
- AST (SGOT) / ALT (SGPT) ≤ 3 × institutional ULN
- Total bilirubin ≤ 1.5 × institutional ULN (except participants with Gilbert
Syndrome, who can have total bilirubin ≤ 3.0 × institutional ULN with direct
bilirubin that is within institutional ULN)
- Coagulation parameters (INR, aPTT) ≤ 1.25 × institutional ULN
- 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 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 HCG) within 24 hours prior to the start of study treatments.
- Women must not be breastfeeding
- Participants are permitted to use topical, ocular, intra-articular, intranasal, and
inhalational corticosteroids (with minimal systemic absorption). Physiologic
replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day
prednisone equivalents, in the absence of active autoimmune disease. 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) is permitted.
- Ability to understand and the willingness to sign a written informed consent document.
Specific criteria for Cohort 2
-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 platinum-refractory disease are ineligible. Platinum-refractory disease
is defined as relapse less than 2 months after the last dose of 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 (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:
LVEF less than normal per institutional guidelines, or < 55%, if threshold for normal not
otherwise specified by institutional guidelines
- 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 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/QTc prolongation or torsades de pointes
- QTc prolongation > 470 msec or other significant 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 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 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 Cohort 2
- Patients who have received a prior PARP inhibitor are not allowed to enroll to Cohort
2 of the trial
- Patients are excluded from Cohort 2 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.
