Last updated on August 2019

Olaparib and Radium Ra 223 Dichloride in Treating Men With Metastatic Castration-Resistant Prostate Cancer That Has Spread to the Bone


Brief description of study

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. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 work better at treating castration-resistant prostate cancer.

Detailed Study 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 enzalutamide use (yes versus no).

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 initiation of next active anti-cancer therapy (including androgen receptor[AR] signaling agents, cytotoxic chemotherapy, immunotherapy, or investigational agents).

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. 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.

X. 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.

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 continue to receive olaparib as in Phase I.

ARM II: Patients receive radium Ra 223 dichloride as in Arm I.

After completion of study treatment, patients are followed up every 6 months for 2 years.

Clinical Study Identifier: NCT03317392

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