This is a phase 1/phase 2a study of the combination of immune checkpoint inhibitor
(nivolumab) in combination with the PARP inhibitor (rucaparib) for patients with metastatic
castration resistant prostate cancer (mCRPC) and metastatic/recurrent endometrial cancer.
In the phase 1 portion, the safety of the combination dosing will be determined. If the
combination dosing is determined to be safe and feasible, the study will move onto phase 2a.
In the phase 2a portion, participants will be randomized to receive either: rucaparib alone,
nivolumab alone, or combination therapy (rucaparib and nivolumab).
- Patients must have the ability to understand and the willingness to signed a written
informed consent document.
- Patients must have histologically or cytologically confirmed CRPC or endometrial
cancer that is metastatic. Evidence of disease progression on a prior therapy is not
- Patients must have at least one lesion that is amenable to biopsy and the treating
physician must deem this safe.
- Patient must be willing to undergo two mandatory research-only biopsies.
- Prostate cancer patients:
- Patients must be surgically or medically castrated, with serum testosterone
levels ≤ 50 ng/mL Patients being treated with Gonadotropin-releasing hormone
(GnRH) agonists must have such therapy continued throughout the study.
- Patients should have received at least one androgen receptor (AR)-targeted
therapy with abiraterone acetate or enzalutamide. Multiple lines of prior
AR-targeted therapy and chemotherapy are permitted. A washout of two weeks from
prior endocrine therapy (other than GnRH agonist); four weeks washout period from
prior cytotoxic chemotherapy or other anticancer agents is required (prior to day
1 of study therapy); six weeks washout period to allow for anti-androgen
withdrawal for patients managed with antiandrogen therapy such as bicalutamide.
- Endometrial cancer patients:
- An unlimited number of prior hormonal and/or chemotherapy regimens are permitted.
A washout of two weeks from prior endocrine therapy (other than GnRH agonist) and
four weeks from prior cytotoxic chemotherapy or other anticancer agents is
required (prior to day 1 of study therapy).
- At least 5 days should have elapsed since any non-study related minor surgical
procedure and at least 21 days since any major surgical procedure prior to the first
dose of rucaparib and the first dose of nivolumab.
- Must have an ability to swallow pills or capsules. Patients should have no current
clinical evidence of bowel obstruction.
- Age must be ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status must be ≤ 1
- Patients must have normal hepatic, renal and marrow function as defined below:
- hemoglobin > 10 g/dL
- leukocytes ≥ 3,000/mcL
- absolute neutrophil count ≥ 1,500/mcL
- platelets ≥ 150,000/mcL
- total bilirubin within normal institutional limits
- alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 ×
institutional upper limit of normal
- creatinine within normal institutional limits OR creatinine clearance ≥ 60
mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
- Prior palliative radiotherapy must have been completed at least 2 weeks prior to first
dose of study drug. Subjects with symptomatic tumor lesions at baseline that may
require palliative radiotherapy within 4 weeks of first dose of study drug are
strongly encouraged to receive palliative radiotherapy prior to enrollment.
- Reproductive Status: Rucaparib caused post-implantation loss (100% early resorptions)
at all doses administered in an embryo-fetal development study. Based on its mechanism
of action, nivolumab can cause fetal harm when administered to a pregnant woman.
Pregnant women are therefore not eligible for this study.
- Women of child-bearing potential (WOCBP) must have a negative serum pregnancy
test result less than 3 days prior to administration of the first dose of
- WOCBP must not be considering getting pregnant during the study.
- WOCBP and their male partners must agree to use a highly effective, reliable form
of contraception during treatment; for 6 months following the last dose of
rucaparib; and for at least 5 months following the last dose of nivolumab.
- Men who are sexually active with WOCBP must agree to use a highly effective,
reliable form of contraception during treatment; 6 months following the last dose
of rucaparib; and for a period of 7 months after the last dose of nivolumab .
- In addition to the above methods of contraception, use of a condom by male
patients is recommended to prevent transfer of drug through semen.
- Patients with active, known, or suspected autoimmune disease. Subjects with vitiligo,
type I diabetes, mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, childhood
asthma that is not currently active, or conditions not expected to recur in the
absence of an external trigger are permitted to enroll.
- Patients with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration except for adrenal replacement steroid doses > 10 mg
daily prednisone equivalent in the absence of active autoimmune disease. Note:
Treatment with a short course of steroids (< 5 days) up to 7 days prior to initiating
study drug is permitted.
- Patients who are receiving any other investigational agents.
- Prior exposure to PD-1 or PD-L1 inhibitors, other immune checkpoint inhibitors (e.g.
anti-LAG-3, and anti-CTLA-4 antibodies), or PARP inhibitors.
- Patients with a "currently active" second invasive malignancy other than non-melanoma
skin cancers. Patients are not considered to have a "currently active" malignancy if
they have completed therapy and have been free of disease for ≥ 1 years.
- Patients with known and untreated or progressing brain metastases are excluded from
this clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events. Patients whose brain metastases have been treated with
surgery and/or radiotherapy and are without evidence of progression on scan for at
least 4 weeks, and are off steroids or antiseizure medications, will be eligible .
- Patients with symptomatic or impending spinal cord compression are not eligible unless
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab or rucaparib.
- Based on in vitro CYP interaction studies, caution should be used for concomitant
medications with a narrow therapeutic window that are substrates of CYP2C19, CYP2C9,
and/or CYP3A. Selection of an alternate concomitant medication is recommended. Caution
should also be exercised for concomitant use of certain statin drugs (e.g.
rosuvastatin and fluvastatin) due to potential increase in exposure from inhibition of
BCRP and CYP2C9. An updated list of clinically relevant P450 drug interactions (e.g:
Flockhart Table http://medicine.iupui.edu/clinpharm/ddis/main-table/) should be
reviewed while screening patients for study.
- Patients taking warfarin should have international normalized ration (INR)
monitored regularly according to standard institutional practices
- Because rucaparib is a moderate inhibitor of P-gp in vitro, caution should be
exercised for patients receiving rucaparib and requiring concomitant medication
with digoxin. Patients taking digoxin should have their digoxin levels monitored
after starting rucaparib and then regularly per standard clinical practice.
- Patients on parenteral nutrition are not eligible. Patients must not have a
pre-existing duodenal stent or any gastrointestinal disorder or defect that would, in
the opinion of the treating investigator, interfere with absorption of rucaparib.
- Uncontrolled intercurrent illness including, but not limited to, requirement for
oxygen therapy, ongoing or active infection other than minor urinary tract infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
- Known history of chronic hepatitis B or C as evidenced by:
- Positive test for hepatitis B surface antigen
- Positive test for qualitative hepatitis C viral load (by polymerase chain
- Note: Subjects with positive hepatitis C antibody and negative quantitative
hepatitis C by polymerase chain reaction (PCR) are eligible.
- Human Immunodeficiency Virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
rucaparib. In addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy.
- Prior organ allograft or allogeneic bone marrow transplantation.
- Adverse effect of prior therapy not improved to Common Terminology Criteria for
Adverse Events (CTCAE) Grade 1 or below with the exception of alopecia or lymphopenia.
Ongoing Grade 2 non-hematologic toxicity (e.g. neuropathy) related to most recent
treatment regimen may be permitted with prior advanced approval from the Lead
- Initiated denosumab or bisphosphonate therapy or adjusted denosumab or bisphosphonate
dose/regimen within 4 weeks prior to first dose of rucaparib. Patients on a stable
denosumab or bisphosphonate regimen are eligible and may continue treatment.
- Evidence or history of active or latent tuberculosis infection including purified
protein derivative (PPD) recently converted to positive.
- Use of non-oncology vaccines containing live virus for prevention of infectious
diseases within 12 weeks prior to study drug. The use of inactivated seasonal
influenza vaccines, e.g., Fluzone®, will be permitted on study without restriction.