Rucaparib and Nivolumab in Patients With Prostate or Endometrial Cancer

NCT03572478 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: IRB18-0154
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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).

Conditions

Prostate Cancer; Endometrial Cancer

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Dose Limiting Toxicities (DLT) (Phase 1)

  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

  8 weeks

• Frequency of Patients With T Cell Inflammation in the Tumor Compared Between Treatment Arms (Phase 2)

  4 weeks

Secondary Outcomes (6)

• Time to Disease Progression in Prostate Cancer Patients (Phase 2)

  24 months

• Time to Disease Progression in Endometrial Cancer Patients (Phase 2)

  24 months

• Response Rate in Prostate Cancer Patients (Phase 2)

  24 months

• Response Rate in Endometrial Cancer Patients (Phase 2)

  24 months

• Changes in Number of T Cells in Tumor Samples Compared Between Treatment Arms (Phase 2)

  4 weeks

Study Arms (4)

Combination Therapy (Phase 1b Cohort)

EXPERIMENTAL

Participants will receive rucaparib plus nivolumab in 4 week cycles.

Drug: Rucaparib; Drug: Nivolumab

Rucaparib (Phase 2b Randomized Cohort)

EXPERIMENTAL

Participants randomized to receive rucaparib alone in 4 week cycles.

Drug: Rucaparib

Nivolumab (Phase 2b Randomized Cohort)

EXPERIMENTAL

Participants randomized to receive nivolumab alone in 4 week cycles.

Drug: Nivolumab

Combination Therapy (Phase 2b Randomized Cohort)

EXPERIMENTAL

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

Interventions

Rucaparib DRUG

600 mg taken by mouth twice daily.

Also known as: Rubraca(R)

Combination Therapy (Phase 1b Cohort); Combination Therapy (Phase 2b Randomized Cohort); Rucaparib (Phase 2b Randomized Cohort)

Nivolumab DRUG

480 mg given by intravenous (IV) infusion every 4 weeks.

Also known as: Opdivo(R)

Combination Therapy (Phase 1b Cohort); Combination Therapy (Phase 2b Randomized Cohort); Nivolumab (Phase 2b Randomized Cohort)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 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 requirements.
• Known history of chronic hepatitis B or C as evidenced by:
• Positive test for hepatitis B surface antigen

Sponsors & Collaborators

• University of Chicago: lead
• Bristol-Myers Squibb: collaborator
• Clovis Oncology, Inc.: collaborator

Study Sites (1)

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms; Endometrial Neoplasms

Interventions

rucaparib; Nivolumab

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Walter STadler
• Organization: University of Chicago

wstadler@medicine.bsd.uchicago.edu

773-702-4150

Study Officials

• Walter Stadler, MD

  University of Chicago

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 19, 2018
• First Posted: June 28, 2018
• Study Start: August 14, 2018
• Primary Completion: February 29, 2020
• Study Completion: October 1, 2020
• Last Updated: March 9, 2021
• Results First Posted: February 12, 2021

Record last verified: 2021-02

Locations

US (1)