Rucaparib and Nivolumab in Patients With Prostate or Endometrial Cancer

• Sponsor: University of Chicago (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03572478
• Collaborator: Bristol-Myers Squibb (Industry), Clovis Oncology, Inc. (Industry)
• Enrollment: 12
• Location: 1
• Arms: 4
• Actual Duration (Months): 25.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer; Endometrial Cancer	Drug: Rucaparib; Drug: Nivolumab	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib/IIa Study of Rucaparib (PARP Inhibitor) Combined With Nivolumab in Metastatic Castrate - Resistant Prostate Cancer and Advanced/Recurrent Endometrial Cancer
• Actual Study Start Date: Aug 14, 2018
• Actual Primary Completion Date: Feb 29, 2020
• Actual Study Completion Date: Oct 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combination Therapy (Phase 1b Cohort) Participants will receive rucaparib plus nivolumab in 4 week cycles.	Drug: Rucaparib; 600 mg taken by mouth twice daily.; Other Names: Rubraca(R) ; Drug: Nivolumab; 480 mg given by intravenous (IV) infusion every 4 weeks.; Other Names: Opdivo(R)
Experimental: Rucaparib (Phase 2b Randomized Cohort) Participants randomized to receive rucaparib alone in 4 week cycles.	Drug: Rucaparib; 600 mg taken by mouth twice daily.; Other Names: Rubraca(R)
Experimental: Nivolumab (Phase 2b Randomized Cohort) Participants randomized to receive nivolumab alone in 4 week cycles.	Drug: Nivolumab; 480 mg given by intravenous (IV) infusion every 4 weeks.; Other Names: Opdivo(R)
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; 600 mg taken by mouth twice daily.; Other Names: Rubraca(R) ; Drug: Nivolumab; 480 mg given by intravenous (IV) infusion every 4 weeks.; Other Names: Opdivo(R)

Outcome Measures

Primary Outcome Measures

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

2. Frequency of Patients With T Cell Inflammation in the Tumor Compared Between Treatment Arms (Phase 2) [4 weeks]

Secondary Outcome Measures

1. Time to Disease Progression in Prostate Cancer Patients (Phase 2) [24 months]

2. Time to Disease Progression in Endometrial Cancer Patients (Phase 2) [24 months]

3. Response Rate in Prostate Cancer Patients (Phase 2) [24 months]

4. Response Rate in Endometrial Cancer Patients (Phase 2) [24 months]

5. Changes in Number of T Cells in Tumor Samples Compared Between Treatment Arms (Phase 2) [4 weeks]

6. Correlation of Change in T Cells in Tumor Samples and PTEN Mutation Status (Phase 2) [4 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Medical Center	Chicago	Illinois	United States	60637

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Walter Stadler, MD, University of Chicago

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 1, 2019

More Information

Publications

None provided.

• Responsible Party: University of Chicago
• ClinicalTrials.gov Identifier: NCT03572478
• Other Study ID Numbers: IRB18-0154
• First Posted: Jun 28, 2018
• Last Update Posted: Mar 9, 2021
• Last Verified: Feb 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Prostatic Neoplasms; Endometrial Neoplasms; Nivolumab; Rucaparib

Study Results

Participant Flow

Pre-assignment Detail	The study was terminated due to lack of efficacy such that participants were enrolled only in phase 1 cohort (single arm).

Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
Overall Participants	12
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	72
Sex: Female, Male (Count of Participants)
Female	1 8.3%
Male	11 91.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 25%
White	9 75%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Dose Limiting Toxicities (DLT) (Phase 1)
Description	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
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Two patients were not evaluable for DLT due to rapidly progressive disease.

Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
Measure Participants	10
Number [percentage of participants]	50 416.7%

2. Primary Outcome

Title	Frequency of Patients With T Cell Inflammation in the Tumor Compared Between Treatment Arms (Phase 2)
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Phase 2 cohort.

Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
Measure Participants	0

3. Secondary Outcome

Title	Time to Disease Progression in Prostate Cancer Patients (Phase 2)
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Phase 2 cohort.

Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
Measure Participants	0

4. Secondary Outcome

Title	Time to Disease Progression in Endometrial Cancer Patients (Phase 2)
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Phase 2 cohort.

Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
Measure Participants	0

5. Secondary Outcome

Title	Response Rate in Prostate Cancer Patients (Phase 2)
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Phase 2 cohort.

Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
Measure Participants	0

6. Secondary Outcome

Title	Response Rate in Endometrial Cancer Patients (Phase 2)
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Phase 2 cohort.

Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
Measure Participants	0

7. Secondary Outcome

Title	Changes in Number of T Cells in Tumor Samples Compared Between Treatment Arms (Phase 2)
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Phase 2 cohort.

Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
Measure Participants	0

8. Secondary Outcome

Title	Correlation of Change in T Cells in Tumor Samples and PTEN Mutation Status (Phase 2)
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Phase 2 cohort.

Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
Measure Participants	0

Adverse Events

Time Frame	Adverse event data were collected up to 28 days after the end of treatment
Arm/Group Title	Combination Therapy (Phase 1 Cohort)
Arm/Group Description	Although we initially planned to conduct phase 1/2a study in the protocol, participants were enrolled only in phase 1 cohort. Participants will receive rucaparib plus nivolumab in 4 week cycles. Rucaparib: 600 mg taken by mouth twice daily. Nivolumab: 480 mg given by intravenous (IV) infusion every 4 weeks.
All Cause Mortality
	Combination Therapy (Phase 1 Cohort)
	Affected / at Risk (%)	# Events
Total	7/12 (58.3%)
Serious Adverse Events
	Combination Therapy (Phase 1 Cohort)
	Affected / at Risk (%)	# Events
Total	4/12 (33.3%)
Blood and lymphatic system disorders
anemia	1/12 (8.3%)
Gastrointestinal disorders
Abdominal pain	1/12 (8.3%)
nausea	1/12 (8.3%)
vomiting	1/12 (8.3%)
diarrhea	1/12 (8.3%)
General disorders
death	1/12 (8.3%)
Metabolism and nutrition disorders
anorexia	1/12 (8.3%)
Nervous system disorders
neoplasms benign, malignant and unspecified	1/12 (8.3%)
Renal and urinary disorders
acute kidney injury	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/12 (8.3%)
Other (Not Including Serious) Adverse Events
	Combination Therapy (Phase 1 Cohort)
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Anemia	8/12 (66.7%)
Gastrointestinal disorders
Abdominal pain	1/12 (8.3%)
Constipation	1/12 (8.3%)
Diarrhea	1/12 (8.3%)
Dyspepsia	1/12 (8.3%)
Esophageal obstruction	1/12 (8.3%)
Nausea	7/12 (58.3%)
Vomiting	2/12 (16.7%)
General disorders
Edema limbs	2/12 (16.7%)
Fatigue	7/12 (58.3%)
Pain	2/12 (16.7%)
Investigations
Alanine aminotransferase increased	8/12 (66.7%)
Alkaline phosphatase increased	5/12 (41.7%)
Aspartate aminotransferase increased	8/12 (66.7%)
Creatinine increased	2/12 (16.7%)
Lymphocyte count decreased	4/12 (33.3%)
Lymphocyte count increased	1/12 (8.3%)
Neutrophil count decreased	2/12 (16.7%)
Platelet count decreased	5/12 (41.7%)
Weight loss	4/12 (33.3%)
White blood cell decreased	1/12 (8.3%)
Metabolism and nutrition disorders
Anorexia	9/12 (75%)
Hyperglycemia	1/12 (8.3%)
Hyperkalemia	1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/12 (16.7%)
Generalized muscle weakness	2/12 (16.7%)
Pain in extremity	1/12 (8.3%)
Nervous system disorders
Dizziness	1/12 (8.3%)
Dysgeusia	2/12 (16.7%)
Peripheral sensory neuropathy	1/12 (8.3%)
Renal and urinary disorders
Acute kidney injury	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/12 (8.3%)
Dyspnea	1/12 (8.3%)
Hypoxia	1/12 (8.3%)
Skin and subcutaneous tissue disorders
Pruritus	1/12 (8.3%)
Rash maculo-papular	1/12 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.