A Phase 1b/2 Study of ARRY-382 in Combination With Pembrolizumab, a Programmed Cell Death Receptor 1 (PD-1) Antibody, for the Treatment of Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 82
- 试验地点
- 30
- 主要终点
- Phase 1b, Part A: Number of Participants With Dose-Limiting Toxicities (DLT)
研究概览
简要总结
This is an open-label, multicenter Phase 1b/2 study to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of ARRY-382 in combination with pembrolizumab in adult patients with selected advanced solid tumors (Part A/Phase 1b); and to estimate the efficacy of the combination in three separate cohorts: 1) patients with advanced solid tumors that have progressed on prior PD-1/PD-L1inhibitors, 2) patients with platinum-resistant ovarian cancer and 3) patients with pancreatic ductal adenocarcinoma (Phase 2).
详细描述
ARRY-382 is an inhibitor of CSF1R (colony-stimulating factor-1 receptor).
Each phase of the study consists of a 28-day screening period; 21-day treatment cycles with the combination of ARRY-382 and pembrolizumab until disease progression as determined by the Investigator, unacceptable toxicity, withdrawal of consent, or death (or other discontinuation criteria are met), and a 30-day safety follow-up period. Patients in all cohorts/phases will be monitored for overall survival (OS) until 1 year after the date of the last patient's first visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase 1b/Part A
Patients in Part A will receive escalating doses of single-agent ARRY-382 in combination with 2 mg/kg pembrolizumab.
干预措施: ARRY-382 (Drug)
Phase 1b/Part A
Patients in Part A will receive escalating doses of single-agent ARRY-382 in combination with 2 mg/kg pembrolizumab.
干预措施: Pembrolizumab (Drug)
Phase 2
Patients in Phase 2 will receive the MTD/RP2D dose of ARRY-382 determined during Part A in combination with 200mg pembrolizumab.
干预措施: ARRY-382 (Drug)
Phase 2
Patients in Phase 2 will receive the MTD/RP2D dose of ARRY-382 determined during Part A in combination with 200mg pembrolizumab.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Phase 1b, Part A: Number of Participants With Dose-Limiting Toxicities (DLT)
时间窗: Cycle 1 (up to 21 days)
DLT: adverse event (AE) or abnormal laboratory value not clearly attributable to an extraneous cause, such as disease progression, intercurrent illness, or concomitant medications occurring during 21 days of Cycle 1, met 1 of the criteria A) nonhematologic AEs: recurring grade 2 pneumonitis, grade 3 events (irAE, QTcF prolongation, rash; other grade 3/4 except alopecia, nausea, diarrhea, vomiting, tumor flare, pseudoprogression, endocrinopathy); B) hematology AEs/laboratory abnormalities: grade 4 events except lymphopenia, neutropenia, electrolyte imbalances or abnormalities, grade 3 thrombocytopenia, febrile neutropenia, grade 4 AST/ALT elevation, grade 3 AST/ALT elevation lasting \>7 days, associated with bilirubin levels\>=2\*ULN or international normalized ratio \>1.5, grade 3 bilirubin elevation \>=3, CK elevation \>=grade 3 lasting, increase in creatinine \>=1.5\*baseline value, dose delay (dose interruption for \>14 days) or other (inability to receive at least 67% of ARRY-382 doses).
Phase 2 Cohorts: Objective Response Rate (ORR)
时间窗: From day of first dose to 30 days after last dose (maximum up to 13.5 months)
ORR was defined as the percentage of participants who achieved a best overall response (BOR) of complete response (CR) or partial response (PR) as determined by investigator review of radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. As per RECIST v1.1: CR = disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures less than (\<) 10 millimeter (mm). PR = at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non-target lesions must be non-progressive disease (PD). The analysis was based on confirmed responses for which CR or PR must be confirmed by repeat disease assessment studies performed no less than 4 weeks after the criteria for response were first met to qualify as CR or PR, respectively.
次要结局
- Phase 1b, Part A and Phase 2 Cohorts: Overall Survival (OS)(From day of first dose till death due to any cause or date of last contact (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Newly Occurring or Worsening Serum Chemistry Laboratory Abnormalities Graded by Common Terminology Criteria for Adverse Events (CTCAE) Grade 4.03(First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 1b, Part A: Objective Response Rate (ORR)(From day of first dose to 30 days after last dose (maximum up to 34.7 months))
- Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Newly Occurring Abnormal Liver Function Tests(First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Newly Occurring Clinically Notable Vital Sign Abnormalities(First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Plasma Concentration Versus Time Profile of Metabolite AR00470870(Pre dose of ARRY-382 (120 minutes prior to administration): on Day 15 of Cycle 1, on Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9 , 10; 1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) post dose of ARRY-382 on Day 1 of Cycle 1, 2)
- Phase 1b, Part A and Phase 2 Cohorts: Duration of Response (DOR)(From date of first documented CR or PR up to disease progression or death (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Progression-Free Survival (PFS)(From day of first dose until disease progression or death due to any cause or till last tumor assessment date (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Plasma Concentration Versus Time Profile of Metabolite AR00469099(Pre dose of ARRY-382 (120 minutes prior to administration): on Day 15 of Cycle 1, on Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9 , 10; 1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) post dose of ARRY-382 on Day 1 of Cycle 1, 2)
- Phase 1b, Part A and Phase 2 Cohorts: Area Under the Plasma Concentration-Time Curve Over a Dosing Interval at Steady-State (AUCtau, ss) for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870)(0 to 24 hrs after administration of ARRY-382 on Day 1 of Cycle 2)
- Phase 1b, Part A and Phase 2 Cohorts: Percentage of Participants With Immune-Related Response Rate (irRR)(From day of first dose till up to end of study treatment (for Phase 1b: maximum up to 33.7 months, for Phase 2: maximum up to 12.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)(First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Newly Occurring or Worsening Hematology and Coagulation Laboratory Abnormalities Graded by CTCAE Grade 4.03(First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Ctrough at Steady State for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870)(Pre dose of ARRY-382 (120 minutes prior to administration) on Day 1 of Cycle 2)
- Phase 1b, Part A and Phase 2 Cohorts: Time to Reach Maximum Observed Plasma Concentration (Tmax) for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870)(Pre dose of ARRY-382 (120 minutes prior to administration), 1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) after administration of ARRY-382 on Day 1 of Cycle 1 and 2)
- Phase 1b, Part A and Phase 2 Cohorts: Immune-Related Progression-Free Survival (irPFS)(From the start of treatment to the time of first documented progression, or death (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 2 prOVCA: Change From Baseline in Tumor Markers at Day 1 of Cycle 1, 2, 3, 4, 5, 6, 7, Day 8, 15 of Cycle 1 and Treatment Discontinuation(Baseline, Day 1 of Cycle 1, 2, 3, 4, 5, 6, 7, Day 8, 15 of Cycle 1 and Treatment discontinuation (before 13.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Accumulation Ratio (R) for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870)(Pre dose of ARRY-382 (120 minutes prior to administration),1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) after administration of ARRY-382 on Day 1 of Cycle 1 and 2)
- Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Shift in Thyroid Panel Severity From Baseline Grade to Post Baseline Grades(Baseline, 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Clinically Significant Urinalysis Finding(First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months))
- Phase 1b, Part A and Phase 2 Cohorts: Plasma Concentration Versus Time Profile of ARRY-382(Pre dose of ARRY-382 (120 minutes prior to administration): on Day 15 of Cycle 1, on Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9 , 10; 1 hour(hr) (±5 min), 2 hours(hrs) (±10 min), 4 hrs (±20 min) and 8 hrs (±30 min) post dose of ARRY-382 on Day 1 of Cycle 1, 2)
- Phase 1b, Part A and Phase 2 Cohorts: Plasma Concentration Versus Time Profile of Metabolite AR00469100(Pre dose of ARRY-382 (120 minutes prior to administration): on Day 15 of Cycle 1, on Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9 , 10; 1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) post dose of ARRY-382 on Day 1 of Cycle 1, 2)
- Phase 1b, Part A and Phase 2 Cohorts: Maximum Observed Plasma Concentration (Cmax) for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870)(Pre dose of ARRY-382 (120 minutes prior to administration), 1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) after administration of ARRY-382 on Day 1 of Cycle 1 and 2)
- Phase 1b, Part A and Phase 2 Cohorts: Metabolite-to-Parent Ratio (MR) for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870)(Pre dose of ARRY-382 (120 minutes prior to administration),1 hrs (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) after administration of ARRY-382 on Day 1 of Cycle 1 and 2)