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

Status: Active

Description

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.

Eligibility Criteria

Inclusion Criteria

  • 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 agonist/antagonist; participants receiving prior docetaxel or abiraterone for hormone sensitive disease are permitted
  • Participants must have progressive disease as defined by 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
  • Availability at the study site of formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens, when available
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%)
  • White blood cell count (WBC) >= 3,000/mcL (within 28 prior to administration of study treatment)
  • Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 prior to administration of study treatment)
  • Platelets >= 100,000/mcL (within 28 prior to administration of study treatment)
  • Hemoglobin >= 10 g/dL (transfusions permitted) (within 28 prior to administration of study treatment)
  • Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN) (within 28 prior to administration of study treatment)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutional ULN (within 28 prior to administration of study treatment)
  • Creatinine clearance >= 51 ml/min as defined by Cockcroft-Gault equation (within 28 prior to administration of study treatment)
  • The effects of olaparib and radium-223 on the developing human fetus are unknown; for this reason, men treated or enrolled on this protocol must agree to use adequate contraception and avoid sperm donation prior to the study, for the duration of study participation, and three months after discontinuation of olaparib and radium-223 administration
  • Human immunodeficiency virus (HIV)-positive with negative viral loads on stable antiretroviral regimen and CD4 count > 250 are eligible
  • Ability to understand and the willingness to sign a written informed consent document; patients with impaired decision-making who have a legal guardian (e.g., spouse) able to make informed decisions on behalf of the patient are eligible
  • Patients must be able to tolerate oral medications by mouth and not have a gastrointestinal illness that would preclude absorption of olaparib

Exclusion Criteria

  • Pathology consistent with small cell carcinoma of the prostate
  • Persistent grade > 1 CTCAE version 5.0 adverse events (except alopecia)
  • 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 cytotoxic chemotherapy, hormonal therapies (including but not limited to abiraterone, enzalutamide), investigational prostate cancer directed therapy 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
  • Clinically significant medical condition defined as: * Cerebral infarction within 6 months of study treatment * Transient ischemic attack within 3 months of study treatment * Myocardial infarction within 6 months of study treatment * Uncontrolled angina within 3 months of study treatment * Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi‐gated acquisition scan performed within 3 months of the screening visit results in a left ventricular ejection fraction that is >= 45% * History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes) * Prolonged corrected QT interval by the Fridericia correction formula on the screening electrocardiogram (ECG) > 470 msec * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place * Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at the screening visit * History of hypertensive emergency or encephalopathy within 6 months of study treatment * Deep venous thrombosis or pulmonary embolism within 3 months of study treatment
  • Major surgery within 4 weeks of study treatment; subjects with clinically relevant ongoing complications from prior surgery are not eligible
  • History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug
  • Patient unable to swallow orally administered medication
  • History of bowel obstruction within 1 month of study treatment
  • History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation within the 3 months of study treatment
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or radium-223
  • Participants receiving strong CYP3A4/5 inducers or inhibitors are ineligible; dihydropyridine calcium-channel blockers are permitted for management of hypertension; the required washout period prior to starting olaparib is 2 weeks for CYP3A inhibitors; the required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other CYP3A inducers
  • Patients with known active hepatitis (i.e. hepatitis B or C) infection
  • Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML
  • Patient having received prior allogenic bone marrow transplant or double umbilical cord blood transplantation
  • Individuals with a history of a different malignancy are ineligible except for the following circumstances: * Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or * Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: superficial bladder cancer, basal cell or squamous cell carcinoma of the skin

Locations & Contacts

California

La Jolla
UC San Diego Moores Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 858-822-5354
Email: cancercto@ucsd.edu
Sacramento
University of California Davis Comprehensive Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 916-734-3089

Michigan

Detroit
Wayne State University / Karmanos Cancer Institute
Status: Active
Contact: Site Public Contact
Phone: 313-576-9790
Email: ctoadmin@karmanos.org

Missouri

Creve Coeur
Siteman Cancer Center at West County Hospital
Status: Active
Contact: Site Public Contact
Phone: 800-600-3606
Email: info@siteman.wustl.edu
Saint Louis
Siteman Cancer Center-South County
Status: Active
Contact: Site Public Contact
Phone: 800-600-3606
Email: info@siteman.wustl.edu
Washington University School of Medicine
Status: Active
Contact: Site Public Contact
Phone: 800-600-3606
Email: info@siteman.wustl.edu
Saint Peters
Siteman Cancer Center at Saint Peters Hospital
Status: Active
Contact: Site Public Contact
Phone: 800-600-3606
Email: info@siteman.wustl.edu

New Jersey

New Brunswick
Rutgers Cancer Institute of New Jersey
Status: Active
Contact: Site Public Contact
Phone: 732-235-8675

North Carolina

Durham
Duke University Medical Center
Status: Active
Contact: Site Public Contact
Phone: 888-275-3853

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 800-293-5066
Email: Jamesline@osumc.edu

Pennsylvania

Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: Active
Contact: Site Public Contact
Phone: 412-647-8073

Trial Objectives and Outline

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.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Yale University Cancer Center LAO

Principal Investigator
Rana Ramzi McKay

Trial IDs

Primary ID 10096
Secondary IDs NCI-2017-01920
Clinicaltrials.gov ID NCT03317392