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

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ClinicalTrials.gov Identifier: NCT03317392
Recruitment Status : Recruiting
First Posted : October 23, 2017
Last Update Posted : August 5, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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. 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.

Condition or disease Intervention/treatment Phase
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 Other: Laboratory Biomarker Analysis Drug: Olaparib Radiation: Radium Ra 223 Dichloride Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 112 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 : April 30, 2020
Estimated Study Completion Date : April 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
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 continue to receive olaparib PO BID as in Phase I.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Olaparib
Given PO
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

Radiation: Radium Ra 223 Dichloride
Given IV
Other Names:
  • Alpharadin
  • BAY 88-8223
  • BAY88-8223
  • Radium 223 Dichloride
  • RADIUM RA-223 DICHLORIDE
  • Radium-223 Dichloride
  • Xofigo

Experimental: Arm II (radium Ra 223 dichloride)
Patients receive radium Ra 223 dichloride as in Arm I.
Other: Laboratory Biomarker Analysis
Correlative studies

Radiation: Radium Ra 223 Dichloride
Given IV
Other Names:
  • Alpharadin
  • BAY 88-8223
  • BAY88-8223
  • Radium 223 Dichloride
  • RADIUM RA-223 DICHLORIDE
  • Radium-223 Dichloride
  • Xofigo




Primary Outcome Measures :
  1. Maximum tolerated dose of olaparib and radium Ra 223 dichloride [ Time Frame: Up to 2 years ]
  2. 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).


Secondary Outcome Measures :
  1. 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.

  2. Prostate specific antigen (PSA) response defined by 50% decline in PSA from baseline [ Time Frame: Up to 2 years ]
    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.

  3. Alkaline phosphatase (ALP) response defined as >= 30% reduction of the blood level, compared to the baseline value [ 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.


Other Outcome Measures:
  1. Change in levels of serum lactate dehydrogenase (LDH) [ Time Frame: 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.

  2. 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.

  3. Homologous recombination deficiency (HRD) [ 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 HRD gene mutation status.

  4. 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.

  5. 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
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

Information from the National Library of Medicine

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


Locations
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United States, California
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Site Public Contact    858-822-5354    cancercto@ucsd.edu   
Principal Investigator: Rana R. McKay         
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Site Public Contact    916-734-3089      
Principal Investigator: Mamta Parikh         
United States, Michigan
Wayne State University/Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Site Public Contact    313-576-9790    ctoadmin@karmanos.org   
Principal Investigator: Ulka N. Vaishampayan         
United States, Missouri
Siteman Cancer Center at West County Hospital Recruiting
Creve Coeur, Missouri, United States, 63141
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Hiram A. Gay         
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Hiram A. Gay         
Siteman Cancer Center-South County Recruiting
Saint Louis, Missouri, United States, 63129
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Hiram A. Gay         
Siteman Cancer Center at Saint Peters Hospital Recruiting
Saint Peters, Missouri, United States, 63376
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Hiram A. Gay         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Site Public Contact    888-275-3853      
Principal Investigator: James L. Abbruzzese         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Edmund Folefac         
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Site Public Contact    412-647-8073      
Principal Investigator: Daniel Lee         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Rana R McKay Yale University Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03317392     History of Changes
Other Study ID Numbers: NCI-2017-01920
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: August 5, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Carcinoma
Prostatic Neoplasms
Adenocarcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Olaparib
Radium Ra 223 dichloride
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents