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Rucaparib and Nivolumab in Patients With Prostate or Endometrial Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03572478
Recruitment Status : Terminated (The study was terminated due to lack of efficacy.)
First Posted : June 28, 2018
Results First Posted : February 12, 2021
Last Update Posted : March 9, 2021
Bristol-Myers Squibb
Clovis Oncology, Inc.
Information provided by (Responsible Party):
University of Chicago

Tracking Information
First Submitted Date  ICMJE June 19, 2018
First Posted Date  ICMJE June 28, 2018
Results First Submitted Date  ICMJE January 26, 2021
Results First Posted Date  ICMJE February 12, 2021
Last Update Posted Date March 9, 2021
Actual Study Start Date  ICMJE August 14, 2018
Actual Primary Completion Date February 29, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 15, 2021)
  • Percentage of Participants With Dose Limiting Toxicities (DLT) (Phase 1) [ Time Frame: 8 weeks ]
    Dose limiting toxicities (DLT) is measured by patients with grade 3 or 4 toxicity within 4 weeks of starting leading to discontinuation of rucaparib for at least 1 week
  • Frequency of Patients With T Cell Inflammation in the Tumor Compared Between Treatment Arms (Phase 2) [ Time Frame: 4 weeks ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 19, 2018)
Dose limiting toxicities (DLT) rate of the combination of rucaparib and nivolumab [ Time Frame: 8 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2021)
  • Time to Disease Progression in Prostate Cancer Patients (Phase 2) [ Time Frame: 24 months ]
  • Time to Disease Progression in Endometrial Cancer Patients (Phase 2) [ Time Frame: 24 months ]
  • Response Rate in Prostate Cancer Patients (Phase 2) [ Time Frame: 24 months ]
  • Response Rate in Endometrial Cancer Patients (Phase 2) [ Time Frame: 24 months ]
  • Changes in Number of T Cells in Tumor Samples Compared Between Treatment Arms (Phase 2) [ Time Frame: 4 weeks ]
  • Correlation of Change in T Cells in Tumor Samples and PTEN Mutation Status (Phase 2) [ Time Frame: 4 weeks ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Rucaparib and Nivolumab in Patients With Prostate or Endometrial Cancer
Official Title  ICMJE A Phase Ib/IIa Study of Rucaparib (PARP Inhibitor) Combined With Nivolumab in Metastatic Castrate - Resistant Prostate Cancer and Advanced/Recurrent Endometrial Cancer
Brief Summary

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).

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Prostate Cancer
  • Endometrial Cancer
Intervention  ICMJE
  • Drug: Rucaparib
    600 mg taken by mouth twice daily.
    Other Name: Rubraca(R)
  • Drug: Nivolumab
    480 mg given by intravenous (IV) infusion every 4 weeks.
    Other Name: Opdivo(R)
Study Arms  ICMJE
  • Experimental: Combination Therapy (Phase 1b Cohort)
    Participants will receive rucaparib plus nivolumab in 4 week cycles.
    • Drug: Rucaparib
    • Drug: Nivolumab
  • Experimental: Rucaparib (Phase 2b Randomized Cohort)
    Participants randomized to receive rucaparib alone in 4 week cycles.
    Intervention: Drug: Rucaparib
  • Experimental: Nivolumab (Phase 2b Randomized Cohort)
    Participants randomized to receive nivolumab alone in 4 week cycles.
    Intervention: Drug: Nivolumab
  • Experimental: Combination Therapy (Phase 2b Randomized Cohort)
    Participants randomized to receive rucaparib plus nivolumab in 4 week cycles. Participants will receive rucaparib alone in cycle 1 and begin nivolumab on day 1 of Cycle 2.
    • Drug: Rucaparib
    • Drug: Nivolumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 20, 2020)
Original Estimated Enrollment  ICMJE
 (submitted: June 19, 2018)
Actual Study Completion Date  ICMJE October 1, 2020
Actual Primary Completion Date February 29, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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 required.
  • 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 rucaparib.
    • 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.

Exclusion Criteria:

  • 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 appropriately treated.
  • 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 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 requirements.
  • 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 reaction [PCR])
    • 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 Principal Investigator.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03572478
Other Study ID Numbers  ICMJE IRB18-0154
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Chicago
Study Sponsor  ICMJE University of Chicago
Collaborators  ICMJE
  • Bristol-Myers Squibb
  • Clovis Oncology, Inc.
Investigators  ICMJE
Principal Investigator: Walter Stadler, MD University of Chicago
PRS Account University of Chicago
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP