A Phase 1/2 Study of Combination Olaparib and Radium-223 in Men With Metastatic Castration-Resistant Prostate Cancer With Bone Metastases (COMRADE)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 132
- 试验地点
- 38
- 主要终点
- Radiographic progression-free survival (rPFS)
研究概览
简要总结
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). PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. 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 help treat patients with castration-resistant prostate cancer.
详细描述
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) of olaparib in combination with radium Ra 223 dichloride (radium-223). (Phase I) II. Evaluate the radiographic progression-free survival (rPFS). (Phase II)
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Participants must be male aged >= 18 years of age
- •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:
- •Hypocalcemia
- •Hypophosphatemia
- •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
排除标准
- •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
研究组 & 干预措施
Phase II Arm I (radium Ra 223 dichloride, olaparib)
Patients in Phase II Arm I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Biospecimen Collection (Procedure)
Phase II Arm I (radium Ra 223 dichloride, olaparib)
Patients in Phase II Arm I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Laboratory Biomarker Analysis (Other)
Phase II Arm I (radium Ra 223 dichloride, olaparib)
Patients in Phase II Arm I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Phase II Arm I (radium Ra 223 dichloride, olaparib)
Patients in Phase II Arm I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Radium Ra 223 Dichloride (Radiation)
Phase II Arm II (radium Ra 223 dichloride)
Patients in Phase 2 Arm II 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Laboratory Biomarker Analysis (Other)
Phase II Arm I (radium Ra 223 dichloride, olaparib)
Patients in Phase II Arm I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Computed Tomography (Procedure)
Phase II Arm I (radium Ra 223 dichloride, olaparib)
Patients in Phase II Arm I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Biopsy Procedure (Procedure)
Phase II Arm II (radium Ra 223 dichloride)
Patients in Phase 2 Arm II 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Computed Tomography (Procedure)
Phase I (radium Ra 223 dichloride, olaparib)
Patients in Phase I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Biopsy Procedure (Procedure)
Phase II Arm I (radium Ra 223 dichloride, olaparib)
Patients in Phase II Arm I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Quality-of-Life Assessment (Other)
Phase II Arm II (radium Ra 223 dichloride)
Patients in Phase 2 Arm II 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Biopsy Procedure (Procedure)
Phase II Arm II (radium Ra 223 dichloride)
Patients in Phase 2 Arm II 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Biospecimen Collection (Procedure)
Phase II Arm II (radium Ra 223 dichloride)
Patients in Phase 2 Arm II 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Quality-of-Life Assessment (Other)
Phase II Arm II (radium Ra 223 dichloride)
Patients in Phase 2 Arm II 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Radium Ra 223 Dichloride (Radiation)
Phase I (radium Ra 223 dichloride, olaparib)
Patients in Phase I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Laboratory Biomarker Analysis (Other)
Phase I (radium Ra 223 dichloride, olaparib)
Patients in Phase I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Phase I (radium Ra 223 dichloride, olaparib)
Patients in Phase I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Quality-of-Life Assessment (Other)
Phase I (radium Ra 223 dichloride, olaparib)
Patients in Phase I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Radium Ra 223 Dichloride (Radiation)
Phase II Arm II (radium Ra 223 dichloride)
Patients in Phase 2 Arm II 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Phase I Radium223+Olaparib dose level 1
Dose level I: Radium223 plus olaparib 200 mg orally twice daily
干预措施: Olaparib (Drug)
Phase I Radium223+Olaparib dose level 2
Dose level II: Radium223 plus olaparib 300 mg orally twice daily
干预措施: Olaparib (Drug)
Phase II Arm I (radium Ra 223 dichloride, olaparib)
Patients in Phase II Arm I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Olaparib (Drug)
Phase I (radium Ra 223 dichloride, olaparib)
Patients in Phase I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Biospecimen Collection (Procedure)
Phase I (radium Ra 223 dichloride, olaparib)
Patients in Phase I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Computed Tomography (Procedure)
Phase I (radium Ra 223 dichloride, olaparib)
Patients in Phase I 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. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
干预措施: Olaparib (Drug)
结局指标
主要结局
Radiographic progression-free survival (rPFS)
时间窗: 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).
Maximum tolerated dose of olaparib and radium Ra 223 dichloride
时间窗: Up to 2 years
Phase I: Maximum Tolerated Dose
时间窗: 56 days
Determine the maximum tolerated dose (MTD) of olaparib in combination with radium Ra 223 dichloride (radium-223). (Phase I)
Phase II: Radiographic Progression-free Survival (rPFS)
时间窗: From randomization to date of radiographic progression or death due to any cause, whichever occurs first, or censored at the date of last disease assessment. Up to approximately 2 years
Radiographic progression is defined by Prostate Cancer Working Group 3 criteria for bone metastases and RECIST version 1.1 for non-bone metastases. Median rPFS 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). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions",
次要结局
- Radiographic progression free survival (rPFS)(Up to 2 years)
- Prostate specific antigen (PSA) response(Up to 2 years)
- Alkaline phosphatase (ALP) response(Up to 2 years)
- Tumor response(Up to 2 years)
- Prostate specific antigen (PSA) progression(From randomization to PSA progression by Prostate Cancer Working Group (PCWG) 3 criteria, assessed up to 2 years)
- ALP progression(From randomization to the date of first ALP progression, assessed up to 2 years)
- Symptomatic skeletal event (SSE)(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)
- Overall survival (OS)(From randomization to the date of death due to any cause, assessed up to 2 years)
- Incidence of adverse events(Up to 2 years)
- Phase II: rPFS in Patients Without Prior Docetaxel(Up to approximately 2 years after randomization)
- Phase II: rPFS in Patients With Prior Docetaxel(Up to approximately 2 years after randomization)
- Phase II: rPFS in Patients With ≤ 20 Bone Lesions(Up to approximately 2 years after randomization)
- Phase II: rPFS in Patients With > 20 Bone Lesions(Up to approximately 2 years after randomization)
- Phase II: Overall Survival (OS)(From randomization to the date of death due to any cause, or censored at the date of last follow-up, assessed up to 3.5 years)