Clinical Trials /

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

NCT03317392

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 (metastatic). 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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01920
  • SECONDARY ID: NCI-2017-01920
  • SECONDARY ID: 10096
  • SECONDARY ID: 10096
  • SECONDARY ID: UM1CA186689
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT03317392

Conditions

  • Castration-Resistant Prostate Carcinoma
  • Prostate Adenocarcinoma
  • Prostate Carcinoma Metastatic in the Bone
  • Testosterone Less Than 50 ng/dL

Interventions

DrugSynonymsArms
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Arm I (radium Ra 223 dichloride, olaparib)

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (radium Ra 223 dichloride, olaparib)ExperimentalPatients 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.
  • Olaparib
Arm II (radium Ra 223 dichloride)ExperimentalPatients receive radium Ra 223 dichloride as in Arm I.

    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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Male
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Maximum tolerated dose of olaparib and radium Ra 223 dichloride
    Time Frame:Up to 2 years
    Safety Issue:
    Description: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

    Measure:Radiographic progression free survival (rPFS)
    Time Frame:Up to 2 years
    Safety Issue:
    Description: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.
    Measure:Prostate specific antigen (PSA) response defined by 50% decline in PSA from baseline
    Time Frame:Up to 2 years
    Safety Issue:
    Description: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.
    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:
    Description: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.
    Measure:Tumor response
    Time Frame:Up to 2 years
    Safety Issue:
    Description: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.
    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:
    Description:Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
    Measure:ALP progression
    Time Frame:From randomization to the date of first ALP progression, assessed up to 2 years
    Safety Issue:
    Description:Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
    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:
    Description:Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
    Measure:Overall survival (OS)
    Time Frame:From randomization to the date of death due to any cause, assessed up to 2 years
    Safety Issue:
    Description:Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
    Measure:Incidence of adverse events
    Time Frame:Up to 2 years
    Safety Issue:
    Description: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.

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated