A PHASE 1 STUDY OF THE SAFETY, PHARMACOKINETICS AND ANTI-TUMOR ACTIVITY OF TALAZOPARIB, POLY (ADP-RIBOSE) POLYMERASE (PARP) INHIBITOR, IN JAPANESE PATIENTS WITH ADVANCED SOLID TUMORS
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 28
- 试验地点
- 8
- 主要终点
- Dose Escalation: Number of Participants With Dose-Limiting Toxicities (DLT)
研究概览
简要总结
This is a Phase 1 study which consists of 2 parts; Dose Escalation part and Expansion part.
The dose escalation part is open-label, and evaluates safety, preliminary efficacy and PK of single-agent talazoparib in sequential cohorts of adult patients with advanced solid tumors who are resistant to standard therapy or for whom no standard therapy is available.
In the dose escalation part, up to 18 (minimum 3) patients are expected to be enrolled depending on the observed DLTs.
The expansion part is designed to assess the efficacy, safety and PK of single-agent talazoparib at RP2D determined in the dose escalation part in adult patients with locally advanced or metastatic breast cancer who have deleterious or suspected deleterious germline BRCA1 or BRCA2 mutations.
In the expansion part, a minimum of 17 patients will be enrolled evaluable for the primary endpoint.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histological or cytological diagnosis of locally advanced or metastatic solid tumor that is resistant to standard therapy or for which no standard therapy is available.
- •ECOG Performance Status 0 or
- •Adequate Bone Marrow, Renal and Liver Function.
排除标准
- •Patients with known symptomatic brain metastases requiring steroids.
- •Current use of a strong P-gp inhibitor, strong P-gp inducer, or strong inhibitor of BCRP within 1 week or 5 half lives which ever is longer prior to the first dose of study treatment.
- •Fertile male patients and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception.
- •[Dose Expansion Part]
- •Inclusion Criteria:
- •Histologically or cytologically confirmed carcinoma of the breast.
- •Locally advanced breast cancer that is not amenable to curative radiation or surgery and/or metastatic disease.
- •Documentation of a deleterious, suspected deleterious, or pathogenic germline BRCA1 or BRCA2 mutation by Myriad Genetics' BRACAnalysis CDx test.
- •No more than 3 prior chemotherapy-inclusive regimens for locally advanced or metastatic disease.
- •Have measurable lesion by the RECIST v.1.
- •ECOG Performance Status 0-
- •Adequate Bone Marrow, Renal and Liver Function.
- •Exclusion Criteria:
- •First-line locally advanced or metastatic breast cancer with no prior neoadjuvant and adjuvant chemotherapy.
- •Prior treatment with a PARP inhibitor.
- •Objective disease progression while receiving platinum chemotherapy administered for locally advanced or metastatic disease.
- •HER2 positive breast cancer.
- •Active inflammatory breast cancer.
- •Central nervous system (CNS) metastases.
- •Current or anticipated use within 7 days prior to the first dose of study treatment, or anticipated use during the study of strong P-gp inhibitors.
- •Fertile male patients and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception.
研究组 & 干预措施
talazoparib
0.75 mg/day or 1.0 mg/day
干预措施: talazoparib (Drug)
结局指标
主要结局
Dose Escalation: Number of Participants With Dose-Limiting Toxicities (DLT)
时间窗: Cycle 1 (28 days)
DLT was defined as any of the following adverse events occurred in 1st treatment cycle and attributable to talazoparib: hematologic- grade(G) 4 neutropenia greater than (\>)7days; Febrile neutropenia \>1 hour; G greater than or equal to (\>=)3 neutropenic infection, thrombocytopenia associated with G2 hemorrhage; G4 thrombocytopenia, anemia; G3 anemia required transfusion; daily dosing interrupted for \>=7 total days in first cycle for G3 neutropenia/thrombocytopenia. Non-hematologic: any G\>=3AE except non-clinically significant laboratory abnormalities, Non-hematologic AE deemed not clinically significant, nausea, vomiting, diarrhea responded to medical intervention within 72 hours, fatigue improved to G\>=2 within 7 days. Alanine/aspartate aminotransferase (ALT/AST)\>5\*upper limit of normal(ULN) and 2\*increases above baseline values; ALT/AST\>=3\*ULN concurrent with total bilirubin (TB)\>2\*ULN; TB\>5\*ULN; failure to deliver 75percent(%) of doses due to toxicities attributable to talazoparib.
Dose Expansion: Percentage of Participants With Confirmed Objective Response (OR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment
时间窗: From start of the treatment until disease progression or death (due to any cause) whichever occurred first (maximum duration: up to 502 days)
Confirmed OR in participants was defined as the percentage of participants with complete response (CR) or partial response (PR) as best response determined by investigator as per RECIST v 1.1 and confirmed by a second image at least 4 weeks from the initial imaging showing response. As per RECIST v 1.1, CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
次要结局
- Number of Participants With Treatment Emergent Adverse Events (TEAE) Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03(From start of the treatment up to 30 days after last dose or start of new anticancer therapy, whichever occurred first (Dose escalation: maximum duration- up to 286 days; Dose expansion: maximum duration- up to 502 days))
- Dose Escalation- Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1)
- Dose Escalation- Single Dose: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1)
- Dose Expansion: Duration of Response (DOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment(From date of first documented response to date of first documented PD or death (due to any cause) whichever occurred first (maximum duration: up to 502 days))
- Number of Participants With Grade 3 or Higher Treatment-Emergent Adverse Events (AEs) Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03(From start of the treatment up to 30 days after last dose or start of new anticancer therapy, whichever occurred first (Dose escalation: maximum duration- up to 286 days; Dose expansion: maximum duration- up to 502 days))
- Number of Participants With Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Hematology(Dose escalation: Baseline up to 286 days; Dose expansion: Baseline up to 502 days)
- Dose Escalation- Single Dose: Area Under the Curve From Time Zero to Time Tau (AUCtau) for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day -7 of Cycle 1)
- Dose Escalation- Single Dose: Terminal Half-Life (t1/2) for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1)
- Dose Escalation- Multiple Dose: Maximum Observed Plasma Concentration at Steady State (Css,Max) for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1)
- Dose Escalation- Multiple Dose: Predose Concentration (Cmin) for Talazoparib(Pre dose on Day 22 of Cycle 1)
- Dose Escalation- Multiple Dose: Area Under the Curve From Time Zero to Time Tau at Steady State (AUCss,Tau) for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1)
- Dose Expansion: Time-to-Tumor Response (TTR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment(From first dose of study drug until first documentation of CR or PR (maximum duration: up to 502 days))
- Dose Expansion: Duration of Response (DOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)(From date of first documented response to date of first documented PD or death (due to any cause) whichever occurred first (maximum duration: up to 502 days))
- Number of Participants With Treatment Related Adverse Events Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03(From start of the treatment up to 30 days after last dose or start of new anticancer therapy, whichever occurred first (Dose escalation: maximum duration- up to 286 days; Dose expansion: maximum duration- up to 502 days))
- Number of Participants With Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Chemistry(Dose escalation: Baseline up to 286 days; Dose expansion: Baseline up to 502 days)
- Dose Escalation- Single Dose: Maximum Observed Plasma Concentration (Cmax) for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1)
- Dose Escalation- Multiple Dose: Apparent Oral Clearance of Talazoparib at Steady State (CL/Fss)(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1)
- Dose Escalation- Multiple Dose: Linearity Ratio (Rss) of AUC for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1; Pre dose, 0.5, 0.75, 1, 2, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1)
- Dose Escalation: Number of Participants With Abnormalities in Vital Signs(Baseline up to 286 days)
- Dose Escalation- Single Dose: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1)
- Dose Escalation- Multiple Dose: Time for Maximum Observed Plasma Concentration at Steady State (Tss,Max) for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose on Day 22 of Cycle 1)
- Dose Escalation- Multiple Dose: Accumulation Ratio (Rac) of AUCtau for Talazoparib(Pre dose, 0.5, 0.75, 1, 2, 4, 6, 8, 10 and 24 hours post dose on Day -7 and Day 22 of Cycle 1)
- Dose Escalation: Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(From start of the treatment until disease progression or death (due to any cause) whichever occurred first (maximum duration: up to 286 days))
- Dose Escalation: Duration of Response (DOR)(From date of first documented response to date of first documented PD or death (due to any cause) whichever occurred first (maximum duration: up to 286 days))
- Dose Expansion: Percentage of Participants With Confirmed Disease Control as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment(Baseline up to Week 16, Baseline up to Week 24)
- Dose Escalation- Single Dose: Apparent Oral Clearance of Talazoparib (CL/F)(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1)
- Dose Escalation- Single Dose: Apparent Volume of Distribution (Vz/F) for Talazoparib(Pre dose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post dose on Day -7 of Cycle 1)
- Dose Escalation: Progression Free Survival (PFS)(From day of first dose until disease progression or death (due to any cause) whichever occur first (maximum duration: up to 286 days))
- Dose Expansion: Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)(From start of the treatment until disease progression or death (due to any cause) whichever occurred first (maximum duration: up to 502 days))
- Dose Expansion: Percentage of Participants With Confirmed Disease Control as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)(Baseline up to Week 16, Baseline up to Week 24)
- Dose Expansion: Time-to-Tumor Response (TTR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)(From first dose of study drug until first documentation of CR or PR (maximum duration: up to 502 days))
- Dose Expansion: Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment(From day of first dose until disease progression or death (due to any cause) whichever occur first (maximum duration: up to 502 days))
- Dose Expansion: Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Blinded Independent Central Review (BICR)(From day of first dose until disease progression or death (due to any cause) whichever occur first (maximum duration: up to 502 days))
- Dose Expansion: Overall Survival (OS): Probability of Participants Who Were Event-Free at Month 12(At Month 12)
- Dose Expansion: Trough Concentrations (Ctrough) of Talazoparib(Pre dose at 0 hour on Day 1 of Cycle 2, 3, 4 and unplanned (any time during dose expansion period up to 502 days))