A Phase 1 Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 250
- 试验地点
- 19
- 主要终点
- Parts 1 and 2: Number of Patients With Adverse Events (AE) and Serious Adverse Events (SAE)
研究概览
简要总结
This is a Phase 1, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antineoplastic activity of avapritinib (formerly BLU-285), administered orally (PO), in adult patients with unresectable GIST or other relapsed or refractory solid tumors. The study consists of 2 parts, a dose-escalation part (Part 1) and an expansion part (Part 2).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •For Part 1: Histologically- or cytologically-confirmed diagnosis of unresectable GIST or another advanced solid tumor. Patients with unresectable GIST must have disease that has progressed following imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib or an experimental kinase-inhibitor agent, or disease with a D842 mutation in the PDGFRα gene. Patients with an advanced solid tumor other than GIST must have relapsed or refractory disease without an available effective therapy.
- •OR For Part 2:
- •Group 1: Patients must have a confirmed diagnosis of unresectable GIST that has progressed following imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib, or an experimental kinase-inhibitor agent, and the patient does not have a D842V mutation in PDGFRα.
- •Group 2: Patients must have a confirmed diagnosis of unresectable GIST with a D842V mutation in the PDGFRα gene. The PDGFRα mutation will be identified by local or central assessment, either in an archival tissue sample or a new tumor biopsy obtained prior to treatment with avapritinib.
- •Group 3: Patients must have a confirmed diagnosis of unresectable GIST that has progressed and/or patients must have experienced intolerance to imatinib and not received additional kinase-inhibitor therapy. Patients must not have a known D842V mutation in PDGFRα.
- •Groups 1, 2 and 3: At least 1 measurable lesion defined by mRECIST 1.1 for patients with GIST.
- •Groups 1 and 2: A tumor sample (archival tissue or a new tumor biopsy) has been submitted for mutational testing.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
排除标准
- •QT interval corrected using Fridericia's formula (QTcF) >450 milliseconds
- •Platelet count <90,000/mL
- •Absolute neutrophil count <1000/mL
- •Hemoglobin <9 g/dL
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 x the upper limit of normal (ULN) if no hepatic metastases are present; >5 × ULN if hepatic metastases are present
- •Total bilirubin >1.5 × ULN; >3 × ULN with direct bilirubin, >1.5 × ULN in the presence of Gilbert's Disease
- •Estimated (Cockroft-Gault formula) or measured creatinine clearance <40 mL/min Brain malignancy or metastases to the brain
- •History of a seizure disorder or requirement for anti-seizure medication
- •Group 3: Patients known to be KIT wild type.
研究组 & 干预措施
Part 1 Avapritinib (formerly BLU-285) 30 mg QD
Part 1: Patients received a starting dose of 30 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued.
Patients received avapritinib in continuous 28 day cycles until discontinuation.
干预措施: Avapritinib (Drug)
Part 1 Avapritinib (formerly BLU-285) 60 mg QD
Part 1: Patients received a starting dose of 60 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued.
Patients received avapritinib in continuous 28 day cycles until discontinuation.
干预措施: Avapritinib (Drug)
Part 1 Avapritinib (formerly BLU-285) 90 mg QD
Part 1: Patients received a starting dose of 90 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued.
Patients received avapritinib in continuous 28 day cycles until discontinuation.
干预措施: Avapritinib (Drug)
Part 1 Avapritinib (formerly BLU-285) 135 mg QD
Part 1: Patients received a starting dose of 135 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued.
Patients received avapritinib in continuous 28 day cycles until discontinuation.
干预措施: Avapritinib (Drug)
Part 1 Avapritinib (formerly BLU-285) 200 mg QD
Part 1: Patients received a starting dose of 200 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued.
Patients received avapritinib in continuous 28 day cycles until discontinuation. .
干预措施: Avapritinib (Drug)
Part 1 Avapritinib (formerly BLU-285) 300 mg QD
Part 1: Patients received a starting dose of 300 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued.
Patients received avapritinib in continuous 28 day cycles until discontinuation. Patients that received at least one dose of avapritinib were included in the Part 2 analysis.
干预措施: Avapritinib (Drug)
Part 1 Avapritinib (formerly BLU-285) 400 mg QD
Part 1: Patients received a starting dose of 400 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued.
Patients received avapritinib in continuous 28 day cycles until discontinuation.
Patients that received at least one dose of avapritinib were included in the Part 2 analysis.
干预措施: Avapritinib (Drug)
Part 1 Avapritinib (formerly BLU-285) 600 mg QD
Part 1: Patients received a starting dose of 600 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued.
Patients received avapritinib in continuous 28 day cycles until discontinuation.
干预措施: Avapritinib (Drug)
Part 1 and Part 2 Avapritinib (formerly BLU-285) 300 mg or 400 mg QD
Part 1 and Part 2: Patients enrolled in Part 1 and Part 2 at a starting dose of 300 or 400 mg QD were included in the Part1/Part 2 safety and efficacy analysis.
Patients received avapritinib in continuous 28 day cycles until discontinuation.
干预措施: Avapritinib (Drug)
结局指标
主要结局
Parts 1 and 2: Number of Patients With Adverse Events (AE) and Serious Adverse Events (SAE)
时间窗: AEs were collected from the start of study drug until 30 days after the last dose, SAEs were collected from the date of the informed consent signature until 30 days after the last dose of study drug, up to 5 years
The overall safety profile of the drug was assessed by reviewing the number of patients with AEs, SAEs and other events. There was no formal statistical analysis. Safety assessments continued for the duration of treatment.
Part 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Avapritinib
时间窗: Cycle 1 (28 days) of treatment
Patients with event(s) of dose-limiting toxicity
Part 2: Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1
时间窗: Tumor assessments were performed at screening, Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter up to approximately 4 years. Each cycle is 28 days.
To evaluate objective response rate (ORR) determined by central radiology assessment per mRECIST, version 1.1 in patients with advanced GIST treated with avapritinib. A complete response per modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) is defined as complete disappearance of all target lesions. A partial response is defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Overall Response (OR) = CR + PR
次要结局
- Maximum Plasma Drug Concentration (Cmax)(Cycle 1 Day 1)
- Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose at Steady State (C24,ss)(Cycle 1 Day 15)
- Apparent Volume of Distribution, Unadjusted for Bioavailability (Vz/F)(Cycle 1 Day 1)
- Time of Maximal Concentration (Tmax) at Steady State(Cycle 1 Day 15)
- Progression-free Survival Per mRECIST Version 1.1(Tumor assessments were performed at screening, Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter up to approximately 4 years. Each cycle is 28 days.)
- Apparent Oral Clearance at Steady State, Unadjusted for Bioavailability (CLss/F)(Cycle 1 Day 15)
- Time to Maximum Plasma Drug Concentration (Tmax)(Cycle 1 Day 1)
- Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC 0-24)(Cycle 1 Day 1)
- Terminal Elimination Half-life (t1/2)(Cycle 1 Day 1)
- Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Steady Sate (AUC0-τ,ss) (τ=24 h)(Cycle 1 Day 15)
- Response Rate Determined by Central Radiology Assessment Per Choi Criteria(Tumor assessments were performed at screening, Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter up to approximately 4 years. Each cycle is 28 days.)
- Apparent Oral Clearance Unadjusted for Bioavailability (CL/F)(Cycle 1 Day 1)
- Maximum Plasma Drug Concentration (Cmax) at Steady State(Cycle 1 Day 15)
- Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose (C24)(Cycle 1 Day 1)
- KIT, PDGFRA, and Other Cancer-relevant Mutations Present in Tumor Tissue at Baseline and EOT(Baseline and end of treatment)
- Clinical Benefit Rate Determined by Central Radiology Assessment Per mRECIST, Version 1.1(Tumor assessments were performed at screening, Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter up to approximately 4 years. Each cycle is 28 days.)
- Change From Baseline in Levels of KIT and PDGFRα Mutant Allele Fractions in Peripheral Blood(Baseline and End of treatment)
- Duration of Response Determined by Central Radiology Assessment Per mRECIST, Version 1.1(Tumor assessments were performed at screening, Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter up to approximately 4 years. Each cycle is 28 days.)
- Median PFS on Last Prior Anti-cancer Therapy(Historical data collected at enrollment, all available data on prior therapy was collected)