Testing the Safety of Different Doses of Olaparib Given Radium-223 for Men With Advanced Prostate Cancer With Bone Metastasis
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|ClinicalTrials.gov Identifier: NCT03317392|
Recruitment Status : Recruiting
First Posted : October 23, 2017
Last Update Posted : December 5, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Castration-Resistant Prostate Carcinoma Metastatic Prostate Adenocarcinoma Stage IVB Prostate Cancer AJCC v8||Other: Laboratory Biomarker Analysis Drug: Olaparib Other: Quality-of-Life Assessment Radiation: Radium Ra 223 Dichloride||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||133 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1/2 Study of Combination Olaparib and Radium-223 in Men With Metastatic Castration-Resistant Prostate Cancer With Bone Metastases (COMRADE)|
|Actual Study Start Date :||October 12, 2018|
|Estimated Primary Completion Date :||November 30, 2023|
|Estimated Study Completion Date :||November 30, 2023|
Experimental: 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.
Other: Laboratory Biomarker Analysis
Other: Quality-of-Life Assessment
Other Name: Quality of Life Assessment
Radiation: Radium Ra 223 Dichloride
Experimental: 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.
Other: Laboratory Biomarker Analysis
Other: Quality-of-Life Assessment
Other Name: Quality of Life Assessment
Radiation: Radium Ra 223 Dichloride
- Maximum tolerated dose of olaparib and radium Ra 223 dichloride [ Time Frame: Up to 2 years ]
- 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).
- Radiographic progression free survival (rPFS) [ Time Frame: Up to 2 years ]Treatment comparison in rPFS will be conducted in pre-defined subgroups, including homologous recombination deficiency status (yes/no), disease extent (=< 20 or > 20 bone lesions) and prior docetaxel (yes or no). Cox regression hazard ratios (for treatment comparison) along two-sided 80% CI will be provided for each subgroup.
- Prostate specific antigen (PSA) response [ Time Frame: Up to 2 years ]Will be defined by 50% decline in PSA from baseline. Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Response rate by different criteria will be summarized as number and percentage of participants by treatment arm with two-sided 80% CI and compared between groups using Fisher's exact tests.
- Alkaline phosphatase (ALP) response [ Time Frame: Up to 2 years ]Will be defined as >= 30% reduction of the blood level, compared to the baseline value. Will be assessed by RECIST 1.1. Response rate by different criteria will be summarized as number and percentage of participants by treatment arm with two-sided 80% CI and compared between groups using Fisher's exact tests.
- Tumor response [ Time Frame: Up to 2 years ]Will be assessed by RECIST 1.1. Response rate by different criteria will be summarized as number and percentage of participants by treatment arm with two-sided 80% CI and compared between groups using Fisher's exact tests.
- 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 ]Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
- ALP progression [ Time Frame: From randomization to the date of first ALP progression, assessed up to 2 years ]Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
- 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 ]Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
- Overall survival (OS) [ Time Frame: From randomization to the date of death due to any cause, assessed up to 2 years ]Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
- Incidence of adverse events [ Time Frame: Up to 2 years ]Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5. Adverse events will be summarized according to grade, overall and by treatment arm, as number and percentage of participants. All adverse events resulting in discontinuation, dose modification, and/or dosing interruption, and/or treatment delay of drug will also be summarized by treatment arm.
- Change in levels of serum lactate dehydrogenase (LDH) [ Time Frame: Baseline up to 2 years ]Will be summarized at baseline and each cycle with descriptive statistics. Percent change from baseline or status change (e.g. from normal to abnormal defined by institution upper limit level) will be reported and compared between treatment arms at selected timepoints using Wilcoxon rank sum test or Fisher's exact test as appropriate.
- Frequency of mutations in the deoxyribonucleic acid (DNA) repair pathway [ Time Frame: Up to 2 years ]Will be determined by Oncopanel testing. Gene mutation frequencies and mean +/- standard deviation of quantitative biomarkers will be summarized by arm and in overall population at baseline and/or at time of progression.
- Homologous recombination deficiency [ Time Frame: Up to 2 years ]Cox regression or logistic regression will be conducted to explore the association of rPFS or treatment response (PSA or tumor response) with homologous recombination gene mutation status.
- Prevalence of germline mutations in homologous recombination genes [ Time Frame: Up to 2 years ]Their correlation with family history of cancers as determined by the Family History Questionnaire and PSA response will be evaluated using Fisher's exact test or logistic regression as appropriate in all patients and/or by treatment arm as exploratory analyses.
- Quality of life (QOL) [ Time Frame: Baseline up to 2 years ]Will be measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and Brief Pain Inventory (BPI). For each treatment group, calculated QOL scores will be summarized at baseline and each time point. Changes from baseline will be graphically presented. The effect of treatment will be evaluated using a repeated measures model to incorporate assessments across time into a single analysis, using model contrasts to compare treatment groups at selected time points.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||Male|
|Accepts Healthy Volunteers:||No|
- 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
- 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 days prior to administration of study treatment)
- Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days prior to administration of study treatment)
- Platelets >= 100,000/mcL (within 28 days prior to administration of study treatment)
- Hemoglobin >= 10 g/dL (transfusions permitted) (within 28 days prior to administration of study treatment)
- Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN) (within 28 days prior to administration of study treatment); for subjects with Gilbert's disease =< 3.0 mg/dL
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutional ULN (within 28 days prior to administration of study treatment)
- Creatinine clearance >= 51 ml/min as defined by Cockcroft-Gault equation (within 28 days prior to administration of study treatment)
Participants should be receiving an osteoclast targeting agent including either bisphosphonates or denosumab except in patients with contraindications as determined by the treating investigator including:
- Renal impairment including those with a glomerular filtration rate < 35 mL/min using the Cockcroft-Gault equation
- Hypersensitivity to drug formulation
- Dental condition or need for dental intervention that per the investigator would increase the risk of osteonecrosis of the jaw
- 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
- 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
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 (as determined on 2 or more time points within a 24 hour period if the first ECG demonstrates a prolonged corrected QT interval) or family history of long QT syndrome
- 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 4 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03317392
|Principal Investigator:||Rana R McKay||Yale University Cancer Center LAO|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2017-01920 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10096 ( Other Identifier: Yale University Cancer Center LAO )
10096 ( Other Identifier: CTEP )
UM1CA186689 ( U.S. NIH Grant/Contract )
UM1CA186709 ( U.S. NIH Grant/Contract )
|First Posted:||October 23, 2017 Key Record Dates|
|Last Update Posted:||December 5, 2022|
|Last Verified:||December 2022|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Genital Neoplasms, Male
Neoplasms by Site
Poly(ADP-ribose) Polymerase Inhibitors
Radium Ra 223 dichloride
Molecular Mechanisms of Pharmacological Action