A Phase 1/2 Study of Combination Olaparib and Radium-223 in Men With Metastatic Castration-Resistant Prostate Cancer With Bone Metastases (COMRADE)
Overview
- Phase
- Phase 1
- Intervention
- Biopsy Procedure
- Conditions
- Castration-Resistant Prostate Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 145
- Locations
- 41
- Primary Endpoint
- Radiographic progression-free survival (rPFS)
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
This phase I/II trial studies the best dose and side effects of olaparib and how well it works with radium Ra 223 dichloride in treating patients with castration-resistant prostate cancer that has spread to the bone and other places in the body (metastatic). PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Radioactive drugs, such as radium Ra 223 dichloride, may carry radiation directly to tumor cells and not harm normal cells. Giving olaparib and radium Ra 223 dichloride may help treat patients with castration-resistant prostate cancer.
Detailed Description
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of olaparib in combination with radium Ra 223 dichloride (radium-223). (Phase 1) II. Evaluate the radiographic progression-free survival (rPFS). (Phase 2) SECONDARY OBJECTIVES: I. Evaluate safety and tolerability as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. II. To evaluate rPFS as stratified by disease extent (=\< 20 or \> 20 bone lesions) and prior docetaxel use (yes or no). III. Evaluate rPFS in patients harboring or lacking evidence of homologous recombination deficiency (HRD). IV. Evaluate rPFS in patients based on prior abiraterone and/or next generation androgen receptor (AR) antagonist (enzalutamide, apalutamide, darolutamide or other agent) use (yes versus no) for either hormone sensitive or castration resistant prostate cancer (CRPC). V. Evaluate prostate specific antigen (PSA) response rate as defined by \>= 50% decline in PSA from baseline. VI. Evaluate total alkaline phosphatase response defined as a reduction of \>= 30% from the baseline value, confirmed \>= 4 weeks later. VII. Evaluate time to PSA progression as defined by Prostate Cancer Clinical Trials Working Group (PCTWG) 3 criteria. VIII. Evaluate radiographic objective response rate as defined by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. IX. Evaluate time to increase in the total alkaline phosphatase (ALP) level defined as an increase of \>= 25% from baseline at \>= 12 weeks, in patients with no decrease from baseline, or as an increase of \>= 25% above the nadir, confirmed \>= 3 weeks later, in patients with an initial decrease from baseline. X. Evaluate time to first subsequent anti-cancer therapy (including AR signaling agents, cytotoxic chemotherapy, immunotherapy, or investigational agents) or death. XI. Evaluate time to first symptomatic skeletal event (SSE). XII. Evaluate overall survival (OS). EXPLORATORY OBJECTIVES: I. Evaluate impact on quality of life (QOL) as determined by Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and Brief Pain Inventory (BPI). II. Estimate the frequency of mutations in the deoxyribonucleic acid (DNA) repair pathway in patients with metastatic castration-resistant prostate cancer (CRPC) as determine by Oncopanel testing and by whole exome sequencing (WES). III. Characterize changes in ribonucleic acid (RNA) expression of DNA repair genes and immune markers by whole transcriptome sequencing (WTS) in each arm. IV. Characterize changes in immune cell, T-cell receptor (TCR), and B-cell (BCR) receptor repertoire at baseline, during treatment, and at progression in each arm. V. Evaluate changes in lactate dehydrogenase (LDH) in patients each treatment arm. VI. Assess the prevalence of germline mutations in homologous recombination genes in all enrolled patients. VII. Correlate homologous recombination gene germline mutation status with PSA response by treatment arm. VIII. Evaluate family history of cancers in the study population and correlate family cancer history with germline mutation status. IX. Correlate presence or absence of RAD51 with somatic and germline homologous recombination gene mutation status, PSA response, and PFS between treatment arms. X. Evaluate the changes in whole genome sequencing (WGS) of plasma cell-free circulating DNA (cfDNA) based patient-tumor specific signature at baseline, on treatment, and at progression. XI. Evaluate tumor mutation burden (TMB) and tumor mutational signature in plasma cfDNA at baseline and correlate to tumor tissue TMB and mutational signature. OUTLINE: This is a phase I, dose-escalation study of olaparib followed by a phase II study. PHASE I: Patients receive radium Ra 223 dichloride intravenously (IV) over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) as well as blood sample collection and a tissue biopsy during screening and on study. PHASE II: Patients are randomized to 1 of 2 arms. ARM I: Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study. ARM II: Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study. After completion of study treatment, patients are followed up every 6 months for 2 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants must be male aged \>= 18 years of age
- •Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate
- •Participants must have castrate levels of serum testosterone \< 50 ng/dL
- •Participants without orchiectomy must be maintained on luteinizing hormone releasing hormone (LHRH) agonist/antagonist; participants receiving prior docetaxel abiraterone, or next generation AR antagonist (enzalutamide, apalutamide, or darolutamide) for hormone sensitive disease are permitted
- •Participants must have progressive disease as defined by any of the following:
- •Castrate resistant disease as defined by PCWG-3 criteria; participants must have a rise in PSA on two successive determination at least one week apart and PSA levels \>= 2 ng/mL (only the screening PS needs to be \>= 2 ng/mL) and serum testosterone \< 50 ng/dL
- •Soft tissue progression as defined by RECIST version 1.1
- •Bone disease progression as defined by PCWG-3 criteria including the development of two or more new lesions on bone scan
- •Participants must have \>= 2 bone metastases by radiographic imaging and at least 1 lesion which has not been treated with prior radiation therapy
- •Participants must have tumor accessible for biopsy and be agreeable to baseline tumor biopsy; a metastatic focus is preferred but if not available and prostate is still intact prostate biopsy can be performed
Exclusion Criteria
- •Pathology consistent with small cell carcinoma of the prostate
- •Presence of visceral metastases (liver, lung, brain, etc.) or malignant lymphadenopathy exceeding 4 centimeters (cm) in short diameter
- •Prior treatment with radium-223
- •Prior treatment with olaparib or other PARPi
- •Treatment with abiraterone, apalutamide, or darolutamide within 2 weeks of treatment initiation; treatment with cytotoxic chemotherapy within 3 weeks of treatment initiation; treatment with investigational prostate cancer directed therapy within 4 weeks of treatment initiation; treatment with enzalutamide within 4 weeks of treatment initiation
- •Prior hemibody external radiotherapy
- •Palliative radiation therapy to the bone or other sites within 2 weeks of treatment initiation
- •Participants who are receiving any other investigational agents
- •Imminent or established spinal cord compression based on clinical and/or imaging findings
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring need for intravenous anti-microbials, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Arms & Interventions
Arm I (radium Ra 223 dichloride, olaparib)
Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Biopsy Procedure
Arm I (radium Ra 223 dichloride, olaparib)
Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Biospecimen Collection
Arm I (radium Ra 223 dichloride, olaparib)
Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Computed Tomography
Arm I (radium Ra 223 dichloride, olaparib)
Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Laboratory Biomarker Analysis
Arm I (radium Ra 223 dichloride, olaparib)
Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Magnetic Resonance Imaging
Arm I (radium Ra 223 dichloride, olaparib)
Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Olaparib
Arm I (radium Ra 223 dichloride, olaparib)
Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Quality-of-Life Assessment
Arm I (radium Ra 223 dichloride, olaparib)
Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Radium Ra 223 Dichloride
Arm II (radium Ra 223 dichloride)
Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Biopsy Procedure
Arm II (radium Ra 223 dichloride)
Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Biospecimen Collection
Arm II (radium Ra 223 dichloride)
Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Computed Tomography
Arm II (radium Ra 223 dichloride)
Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Laboratory Biomarker Analysis
Arm II (radium Ra 223 dichloride)
Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Magnetic Resonance Imaging
Arm II (radium Ra 223 dichloride)
Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Quality-of-Life Assessment
Arm II (radium Ra 223 dichloride)
Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention: Radium Ra 223 Dichloride
Outcomes
Primary Outcomes
Radiographic progression-free survival (rPFS)
Time Frame: Up to 2 years
Will be estimated using the Kaplan-Meier method by treatment arm. A stratified Cox proportional hazards regression model will estimate the rPFS treatment hazard ratio with 80% 2-sided confidence intervals (CIs).
Maximum tolerated dose of olaparib and radium Ra 223 dichloride
Time Frame: Up to 2 years
Secondary Outcomes
- Radiographic progression free survival (rPFS)(Up to 2 years)
- Prostate specific antigen (PSA) response(Up to 2 years)
- Alkaline phosphatase (ALP) response(Up to 2 years)
- Tumor response(Up to 2 years)
- Prostate specific antigen (PSA) progression(From randomization to PSA progression by Prostate Cancer Working Group (PCWG) 3 criteria, assessed up to 2 years)
- ALP progression(From randomization to the date of first ALP progression, assessed up to 2 years)
- Symptomatic skeletal event (SSE)(From randomization to occurrence of the first SSE, such as pathologic bone fracture, spinal cord compression, hypercalcemia of malignancy or radiation therapy or surgery to bone, described by the US Food and Drug Administration, assessed up to 2 years)
- Overall survival (OS)(From randomization to the date of death due to any cause, assessed up to 2 years)
- Incidence of adverse events(Up to 2 years)