A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF TALAZOPARIB WITH ENZALUTAMIDE IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- Pfizer
- 入组人数
- 1,054
- 试验地点
- 649
- 主要终点
- Number of Participants With All-Causality Clustered Treatment-Emergent Cytopenias by PT and Max CTCAE Grade Occuring Anytime After Dosing - Part 1
研究概览
简要总结
This study compares rPFS in men with mCRPC treated with talazoparib plus enzalutamide vs. enzalutamide after confirmation of the starting dose of talazoparib in combination with enzalutamide.
详细描述
Part 1 is an open-label, non-randomized, safety and PK run-in study designed to confirm the starting dose of talazoparib in combination with enzalutamide through assessment of target safety events and PK at select sites. Part 2 is a randomized, double-blind, placebo-controlled, multinational study comparing talazoparib plus enzalutamide vs. placebo plus enzalutamide in patients with mCRPC.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blind
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
- •Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features
- •Asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) (score on BPI-SF Question #3 must be < 4).
- •For enrollment into Part 2 only (optional in Part 1): assessment of DDR mutation status
- •Consent to a saliva sample collection for a germline comparator unless prohibited by local regulations or ethics committee decision (optional for patients in Part 1).
- •Surgically or medically castrated, with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.
- •Metastatic disease in bone documented on bone scan or in soft tissue documented on CT/MRI scan.
- •Progressive disease at study entry in the setting of medical or surgical castration as defined by 1 or more of the following 3 criteria:
- •Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA values from 3 consecutive assessments with an interval of at least 7 days between assessments..
- •Soft tissue disease progression as defined by RECIST 1.
- •Bone disease progression defined by Prostate Cancer Working Group 3 (PCWG3) with 2 or more new metastatic bone lesions on a whole body radionuclide bone scan.
- •Ongoing bisphosphonate or denosumab use prior to Day 1 (Part 1) or randomization (Part 2) is allowed but not mandatory.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤
- •Life expectancy ≥ 12 months as assessed by the investigator.
- •Able to swallow the study drug and have no known intolerance to study drugs or excipients.
- •Must agree to use a condom when having sex with a partner from the time of the first dose of study drug through 4 months after last dose of study treatment. Must also agree for female partner of childbearing potential to use an additional highly effective form of contraception from the time of the first dose of study treatment through 4 months after last dose of study treatment when having sex with a non pregnant female partner of childbearing potential.
- •Must agree not to donate sperm from the first dose of study drug to 4 months after the last dose of study drug.
- •Evidence of a personally signed and dated informed consent document (and molecular prescreening consent if appropriate) indicating that the patient [or a legally acceptable representative/legal guardian] has been informed of all pertinent aspects of the study.
- •Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
排除标准
- •Any prior systemic cancer treatment initiated in in the non metastatic CRPC and mCRPC disease state.
- •Patients whose only evidence of metastasis is adenopathy below the aortic bifurcation.
- •Prior treatment with second-generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer.
- •Prior treatment with platinum-based chemotherapy within 6 months (from the last dose) prior to Day 1 (Part 1) or randomization (Part 2), or any history of disease progression on platinum-based therapy within 6 months (from the last dose).
- •Treatment with cytotoxic chemotherapy, biologic therapy including sipuleucel T, or radionuclide therapy received in the castration-sensitive prostate cancer is NOT exclusionary if discontinued in the 28 days prior to Day 1 (Part 1) or randomization (Part 2).
- •Treatment with any investigational agent within 4 weeks before Day 1 (Part 1) or randomization (Part 2).
- •Prior treatment with opioids for pain related to either primary prostate cancer or metastasis within 28 days prior to Day 1 (Part 1) or randomization (Part 2).
- •Current use of potent P-gp inhibitors within 7 days prior to Day 1 (Part 1) or randomization (Part 2).
- •Major surgery (as defined by the investigator) within 2 weeks before Day 1 (Part 1) or randomization (Part 2), or palliative localized radiation therapy within 3 weeks before randomization (Part 2).
- •Clinically significant cardiovascular disease
- •Significant renal dysfunction as defined by any of the following laboratory abnormalities:
- •Renal: eGFR < 30 mL/min/1.73 m2 by the MDRD equation (available via www.mdrd.com).
- •Patients enrolled in Part 1 only: Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2) at screening.
- •Significant hepatic dysfunction as defined by any of the following laboratory abnormalities on screening labs:
- •Total serum bilirubin >1.5 times the upper limit of normal (ULN) (>3 × ULN for patients with documented Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation).
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times ULN (>5 × ULN if liver function abnormalities are due to hepatic metastasis).
- •Albumin <2.8 g/dL
- •Absolute neutrophil count < 1500/µL, platelets < 100,000/µL, or hemoglobin < 9 g/dL (may not have received growth factors or blood transfusions within 14 days before obtaining the hematology values at screening).
- •Known or suspected brain metastasis or active leptomeningeal disease.
- •Symptomatic or impending spinal cord compression or cauda equina syndrome.
- •Any history of myelodysplastic syndrome, acute myeloid leukemia, or prior malignancy except any of the following:
- •Carcinoma in situ or non melanoma skin cancer
- •Any prior malignancies ≥3 years before randomization with no subsequent evidence of recurrence or progression regardless of the stage.
- •Stage 0 or Stage 1 cancer <3 years before randomization that has a remote probability of recurrence or progression in the opinion of the investigator
- •Gastrointestinal disorder affecting absorption.
- •Fertile male subjects who are unwilling or unable to use highly effective methods of contraception for the duration of the study and for 4 months after the last dose of investigational product.
- •Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.
- •Other acute or chronic medical (concurrent disease, infection, or comorbidity) or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that interferes with ability to participate in the study, may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
- •History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke, significant brain trauma). Also, history of loss of consciousness or transient ischemic attack within 12 months of randomization (Part 2).
研究组 & 干预措施
Combination arm
Talazoparib plus enzalutamide
干预措施: Talazoparib with enzalutamide (Drug)
Monotherapy arm
Ezalutamide plus placebo
干预措施: Placebo with enzalutamide (Drug)
结局指标
主要结局
Number of Participants With All-Causality Clustered Treatment-Emergent Cytopenias by PT and Max CTCAE Grade Occuring Anytime After Dosing - Part 1
时间窗: Post dose on Day 1 up to 28 days after the last dose of study intervention, or before new systemic antineoplastic therapy, whichever occurred first (maximum of 235.14 weeks)
An AE was any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship. TEAEs are defined as newly occurring AEs or those worsening after first dose. As per CTCAE version 4, Grade 1=mild AE; Grade 2=moderate AE; Grade 3=severe AE; Grade 4=life-threatening or disabling AE; Grade 5=death related to an AE. MedDRA v25.0 coding dictionary applied. PTs for the cluster terms are: ANEMIA, including Anemia, Hematocrit decreased, Hemoglobin decreased, and Red blood cell count decreased; THROMBOCYTOPENIA, including, Thrombocytopenia and Platelet count decreased; NEUTROPENIA, including Febrile neutropenia, Neutropenia and Neutrophil count decreased; LEUKOPENIA, including Leukopenia, White blood cell count decreased. Events in any grade with at least 1 occurrence in participants are reported for this outcome measure. Results as of 16 Aug 2022 are reported.
Number of Participants With Treatment-Related Clustered Treatment-Emergent Cytopenias by PT and Max CTCAE Grade in >=10% of Participants Occuring Anytime After Dosing - Part 1
时间窗: Post dose on Day 1 up to 28 days after the last dose of study intervention, or before new systemic antineoplastic therapy, whichever occurred first (maximum of 235.14 weeks)
An AE was any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship. TEAEs are newly occurring AEs or those worsening after first dose. Treatment-related AE was any AE attributed to study intervention in a participant who received study intervention. As per CTCAE version 4, Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling; Grade 5=death related to an AE. MedDRA v25.0 coding dictionary applied. PTs for the cluster terms are: ANEMIA, including Anemia, Hematocrit decreased, Hemoglobin decreased, and Red blood cell count decreased; THROMBOCYTOPENIA, including, Thrombocytopenia and Platelet count decreased; NEUTROPENIA, including Febrile neutropenia, Neutropenia and Neutrophil count decreased; LEUKOPENIA, including Leukopenia, White blood cell count decreased. Events in any grade with incidence in \>=10% of participants are reported. Results as of 16 Aug 2022 are reported.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Occuring Within the First 66 Days of Dosing - Part 1
时间窗: Post dose on Day 1 up to Day 66 in Part 1
An adverse event (AE) was any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship. TEAEs are defined as newly occurring AEs or those worsening after first dose. As per Common Terminology Criteria for Adverse Events (CTCAE) version 4, Grade 1= mild AE; Grade 2= moderate AE; Grade 3= severe AE; Grade 4= life-threatening or disabling AE; Grade 5= death related to an AE. Serious TEAE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were determined according to the investigator's assessment. Results as of 16 Aug 2022 are reported.
Number of Participants With All-Causality TEAEs During the Overall Period of Part 1
时间窗: Post dose on Day 1 up to 28 days after the last dose of study intervention, or before new systemic antineoplastic therapy, whichever occurred first (maximum of 235.14 weeks)
An adverse event (AE) was any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship. TEAEs are defined as newly occurring AEs or those worsening after first dose. As per CTCAE version 4, Grade 1= mild AE; Grade 2= moderate AE; Grade 3= severe AE; Grade 4= life-threatening or disabling AE; Grade 5= death related to an AE. Serious TEAE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were determined according to the investigator's assessment. Results as of 16 Aug 2022 are reported.
Blinded Independent Central Review (BICR) Assessed Radiographic Progression-Free Survival (rPFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for All-Comers - Part 2 Cohort 1
时间窗: From the start of treatment to the time of first documented progression, or death (maximum up to 42 months)
rPFS is defined as the time from the date of randomization to first objective evidence of radiographic progression as assessed in soft tissue per RECIST 1.1, or death, whichever occurs first. Soft tissue disease status was assessed at regular intervals during the course of the study by computed tomography (CT) of chest and CT or magnetic resonance imaging (MRI) of abdomen and pelvis. Progression is defined using RECIST 1.1 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. Results as of 16 Aug 2022 are reported for this outcome measure.
BICR Assessed rPFS Per RECIST 1.1 in Patients With DDR Deficiencies - Part 2
时间窗: From the start of treatment to the time of first documented progression, or death (maximum up to 38 months)
rPFS is defined as the time from the date of randomization to first objective evidence of radiographic progression as assessed in soft tissue per RECIST 1.1, or death, whichever occurs first. Soft tissue disease status was assessed at regular intervals during the course of the study by CT of chest and CT or MRI of abdomen and pelvis. Results as of 03 Oct 2022 are reported for this outcome measure.
Number of Participants With All-Causality Clustered Treatment-Emergent Cytopenias by Preferred Term (PT) and Max CTCAE Grade Occuring Within the First 66 Days of Dosing - Part 1
时间窗: Post dose on Day 1 up to Day 66 in Part 1
An AE was any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship. TEAEs are defined as newly occurring AEs or those worsening after first dose. As per CTCAE version 4, Grade 1=mild AE; Grade 2=moderate AE; Grade 3=severe AE; Grade 4=life-threatening or disabling AE; Grade 5=death related to an AE. Medical Dictionary for Regulatory Activities (MedDRA) v25.0 coding dictionary applied. PTs for the cluster terms are: ANEMIA, including Anemia, Hematocrit decreased, Hemoglobin decreased, and Red blood cell count decreased; THROMBOCYTOPENIA, including, Thrombocytopenia and Platelet count decreased; NEUTROPENIA, including Febrile neutropenia, Neutropenia and Neutrophil count decreased; LEUKOPENIA, including Leukopenia, White blood cell count decreased. Events in any grade with at least 1 occurrence in participants are reported for this outcome measure. Results as of 16 Aug 2022 are reported.
Number of Participants With Treatment-Related TEAEs During the Overall Period of Part 1
时间窗: Post dose on Day 1 up to 28 days after the last dose of study intervention, or before new systemic antineoplastic therapy, whichever occurred first (maximum of 235.14 weeks)
An AE was any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship. TEAEs are defined as newly occurring AEs or those worsening after first dose. Treatment-related AE was any untoward medical occurrence attributed to study intervention in a participant who received study intervention. As per CTCAE version 4, Grade 1= mild AE; Grade 2= moderate AE; Grade 3= severe AE; Grade 4= life-threatening or disabling AE; Grade 5= death related to an AE. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were determined according to the investigator's assessment. Results as of 16 Aug 2022 are reported.
次要结局
未报告次要终点