A Phase 1/2 Study of Combination Olaparib and Radium-223 in Men With Metastatic Castration-Resistant Prostate Cancer With Bone Metastases (COMRADE)

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A Phase 1/2 Study of Combination Olaparib and Radium-223 in Men With Metastatic Castration-Resistant Prostate Cancer With Bone Metastases (COMRADE)

Condition: Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Prostate Adenocarcinoma, Prostate Carcinoma Metastatic in the Bone, PSA Level Greater Than or Equal to Two, PSA Progression

Intervention:

  • Other: Laboratory Biomarker Analysis
  • Drug: Olaparib
  • Radiation: Radium Ra 223 Dichloride

Purpose: 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.

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03317392

Sponsor: National Cancer Institute (NCI)

Primary Outcome Measures:

  • Measure: Maximum tolerated dose of olaparib and radium Ra 223 dichloride
  • Time Frame: Up to 2 years
  • Safety Issue:
  • Measure: Radiographic progression-free survival (rPFS)
  • Time Frame: Up to 2 years
  • Safety Issue:

Secondary Outcome Measures:

  • Measure: Radiographic progression free survival (rPFS)
  • Time Frame: Up to 2 years
  • Safety Issue:
  • Measure: Prostate specific antigen (PSA) response defined by 50% decline in PSA from baseline
  • Time Frame: Up to 2 years
  • Safety Issue:
  • Measure: Alkaline phosphatase (ALP) response defined as >= 30% reduction of the blood level, compared to the baseline value
  • Time Frame: Up to 2 years
  • Safety Issue:
  • Measure: Tumor response
  • Time Frame: Up to 2 years
  • Safety Issue:
  • Measure: Prostate specific antigen (PSA) progression
  • Time Frame: From randomization to PSA progression by Prostate Cancer Working Group (PCWG) 3 criteria, assessed up to 2 years
  • Safety Issue:
  • Measure: ALP progression
  • Time Frame: From randomization to the date of first ALP progression, assessed up to 2 years
  • Safety Issue:
  • Measure: Symptomatic skeletal event (SSE)
  • Time Frame: 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
  • Safety Issue:
  • Measure: Overall survival (OS)
  • Time Frame: From randomization to the date of death due to any cause, assessed up to 2 years
  • Safety Issue:
  • Measure: Incidence of adverse events
  • Time Frame: Up to 2 years
  • Safety Issue:

Estimated Enrollment: 112

Study Start Date: October 12, 2018

Phase: Phase 1/Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

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:

  • UC San Diego Moores Cancer Center
  • La Jolla California 92093 United States
  • University of California Davis Comprehensive Cancer Center
  • Sacramento California 95817 United States
  • Wayne State University/Karmanos Cancer Institute
  • Detroit Michigan 48201 United States
  • Siteman Cancer Center at West County Hospital
  • Creve Coeur Missouri 63141 United States
  • Washington University School of Medicine
  • Saint Louis Missouri 63110 United States
  • Siteman Cancer Center-South County
  • Saint Louis Missouri 63129 United States
  • Siteman Cancer Center at Saint Peters Hospital
  • Saint Peters Missouri 63376 United States
  • Duke University Medical Center
  • Durham North Carolina 27710 United States
  • Ohio State University Comprehensive Cancer Center
  • Columbus Ohio 43210 United States
  • University of Pittsburgh Cancer Institute (UPCI)
  • Pittsburgh Pennsylvania 15232 United States

View trial on ClinicalTrials.gov

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