Phase 1/2 Study of TAS-120 in Patients With Advanced Solid Tumors Harboring FGF/FGFR Aberrations
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 407
- 试验地点
- 58
- 主要终点
- Phase 1: Dose Escalation-Maximum Tolerated Dose (MTD)
研究概览
简要总结
This is an open-label, nonrandomized, Phase 1/2 study for the fibroblast growth factor receptor (FGFR) inhibitor futibatinib (TAS-120). The purpose of the study is to evaluate the safety, tolerability, pharmacokinetic, pharmacodynamic, and anti-tumor activity of futibatinib in patients with advanced solid tumors with and without genomic FGF/FGFR abnormalities. The study will be conducted in 3 parts:
- Dose escalation portion to determine the -Maximum Tolerated Dose and/ or Recommended Phase 2 Dose of futibatinib.
- Phase 1 expansion portion to further evaluate the safety and efficacy of futibatinib in patients with tumors harboring FGF/FGFR aberrations, including patients with cholangiocarcinoma (CCA), primary central nervous system tumors, urothelial carcinoma, breast cancer, gastric cancer.
- Phase 2 study portion to confirm objective response rate of futibatinib in intrahepatic CCA patients with tumors harboring FGFR2 gene rearrangements (incl fusions).
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
- •Provide written informed consent
- •Age ≥ 18 years of age
- •Has histologically or cytologically confirmed, locally advanced or metastatic cancer
- •The following specific criteria for each study portion
- •Phase 1 (Dose Escalation):
- •Patients with any type of solid tumor
- •Disease progression following standard therapies or intolerant to prior standard therapies
- •Phase 1 (Dose Expansion)
- •Have at least one FGF/FGFR aberration
- •Disease progression following standard therapies or were intolerant to prior standard therapies (including prior FGFR inhibitors).
- •Have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1, 2009) for advanced solid tumors or Response Assessment in Neuro-Oncology criteria (2010) for brain tumors.
- •Patients with any of the following tumor types
- •Patients with intrahepatic or extrahepatic CCA harboring FGFR2 gene fusions or other FGFR2 aberrations
- •Patients with primary CNS tumors
- •Patients with advanced urothelial carcinoma with FGFR3 fusions or FGFR3 activating mutations
- •Patients with breast cancer or gastric cancer
- •Patients with other solid tumor types harboring FGFR gene fusions or activating mutations
- •Patients with solid tumor types and other FGF/FGFR alterations not listed above
- •Patients with iCCA and FGFR2 gene rearrangements (incl fusions)
- •Have been treated with at least one prior systemic gemcitabine and platinum-based chemotherapy
- •Must have documentation of radiographic progression of disease
- •No prior FGFR inhibitor
- •Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1, 2009)
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Adequate organ function.
排除标准
- •History and/or current evidence of clinically significant non-tumor related alteration of calcium-phosphorus homeostasis.
- •History and/or current evidence of clinically significant ectopic mineralization/calcification.
- •History and/or current evidence of clinically significant retinal disorder
- •A serious illness or medical condition(s)
- •Pregnant or breast-feeding female
研究组 & 干预措施
Phase 1: Dose Escalation: QOD Dosing: 8 mg
Participants with or without fibroblast growth factor [FGF]/fibroblast growth factor receptor [FGFR] gene abnormalities received orally TAS-120 8 milligrams (mg) orally every other day (QOD; Monday, Wednesday and Friday of each week) in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QOD Dosing: 16 mg
Participants with or without FGF/FGFR gene abnormalities received orally TAS-120 16 mg orally QOD (Monday, Wednesday and Friday of each week) in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QOD Dosing: 24 mg
Participants with or without FGF/FGFR gene abnormalities received orally TAS-120 24 mg orally QOD (Monday, Wednesday and Friday of each week) in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QOD Dosing: 36 mg
Participants with or without FGF/FGFR gene abnormalities received orally TAS-120 36 mg orally QOD (Monday, Wednesday and Friday of each week) in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QOD Dosing: 56 mg
Participants with FGF/FGFR gene abnormalities received orally TAS-120 56 mg orally QOD (Monday, Wednesday and Friday of each week) in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QOD Dosing: 80 mg
Participants with FGF/FGFR gene abnormalities received orally TAS-120 80 mg orally QOD (Monday, Wednesday and Friday of each week) in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QOD Dosing: 120 mg
Participants with FGF/FGFR gene abnormalities received orally TAS-120 120 mg orally QOD (Monday, Wednesday and Friday of each week) in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QOD Dosing: 160 mg
Participants with FGF/FGFR gene abnormalities received orally TAS-120 160 mg orally QOD (Monday, Wednesday and Friday of each week) in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QOD Dosing: 200 mg
Participants with FGF/FGFR gene abnormalities received orally TAS-120 200 mg orally QOD (Monday, Wednesday and Friday of each week) in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QD Dosing: 4 mg
Participants with or without FGF/FGFR gene abnormalities received a dose between 4 mg orally once daily (QD) in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QD Dosing: 8 mg
Participants with or without FGF/FGFR gene abnormalities received a dose between 8 mg orally QD in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QD Dosing: 16 mg
Participants with or without FGF/FGFR gene abnormalities received a dose between 16 mg orally QD in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QD Dosing: 20 mg
Participants with or without FGF/FGFR gene abnormalities received a dose between 20 mg orally QD in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Escalation: QD Dosing: 24 mg
Participants with or without FGF/FGFR gene abnormalities received a dose between 24 mg orally QD in a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Expansion Cohort 1
Participants with intra-hepatic or extrahepatic cholangiocarcinoma (iCCA or eCCA) harboring FGFR2 gene fusions or rearrangements and who were treated or not treated with prior FGFR inhibitors received TAS-120 20 mg tablets orally QD in each of 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Expansion: Cohort 2
Participants with primary central nervous system (CNS) tumors harboring FGFR gene fusions or FGFR1 activating mutations received TAS-120 20 mg tablets orally QD in each of 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Expansion: Cohort 3
Participants with advanced urothelial carcinoma harboring FGFR3 gene fusions or FGFR3 activating mutations received TAS-120 20 mg tablets orally QD in each of 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Expansion: Cohort 4
Participants with breast or gastric cancer with harboring FGFR2 amplification received TAS-120 20 mg tablets orally QD in each of 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1:Dose Expansion: Cohort 5
Participants with tumor types harboring FGFR gene fusions or activating mutations received TAS-120 20 mg tablets orally QD in each of 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Expansion: Cohort 6
Participants who were not included in Cohorts 1 to 5 received TAS-120 20 mg tablets orally QD in each of 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Expansion: Sub-cohort 1
Participants with iCCA who were enrolled prior to the confirmation of the recommended Phase 2 dose (RP2D) received TAS-120 16 mg tablets orally QD in each of 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 1: Dose Expansion: Sub-cohort 2
Participants with other tumor types who were enrolled prior to the confirmation of the RP2D received TAS-120 16 mg tablets orally QD in each of 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
Phase 2
Participants with iCCA with tumors harboring FGFR2 gene rearrangements received TAS-120 20 mg tablets orally QD in each of 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or death.
干预措施: Futibatinib (Drug)
结局指标
主要结局
Phase 1: Dose Escalation-Maximum Tolerated Dose (MTD)
时间窗: Cycle 1 (21-day cycle)
MTD:Highest dose level at which \<33% of participants experience dose-limiting toxicity (DLT) during Cycle1. DLT: \>=Grade(G)3: - nonhematologic toxicity, - nausea/vomiting lasting \>48hrs(uncontrolled by aggressive antiemetic), - diarrhea lasting \>48hrs (unresponsive to antidiarrheal drug); G4 neutropenia lasting \>7days; Febrile neutropenia (ANC\<1000/mm\^3 with body temperature=\>38.3°C/sustained temperature \>=38°C for \>1hr; Thrombocytopenia G4/G3 with bleeding, required blood transfusion; Corneal disorder worsened by 1 grade or more; Increased phosphorus: \>=9mg/dL or \>=7mg/dL lasting for \>=7days or phosphate lowering therapy\[PLT\] for 7days); Creatinine increase (\>1.5×upper limit of normal \[ULN\]) lasting for \>=7 days associated with serum phosphorus \>5.5 mg/dL(PLT=7days)/calcium×phosphorus \>55 mg/dL(PLT=7days); Hypercalcemia G2 for \>7days or G3; Ectopic de novo calcification in soft tissues; \>G2 DLT: prevented Cycle 1 completion, inability to start Cycle 2 within 2 weeks of schedule.
Phase 1: Dose Expansion: Percentage of Participants With Objective Response
时间窗: Up to approximately 50.5 months (through cut-off date 29-May-2021) for Cohorts 1 to 6; up to approximately 27.5 months (through cut-off date 30-Jun-2019) for pooled sub-cohorts
Objective response was defined as proportion of participants who had achieved best overall response of partial response (PR) or complete response (CR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The CR was defined as a disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must had reduction in short axis to \<10 millimeters (mm) and PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions. For Cohorts 1 to 6: Objective response was based on Independent Review Committee (IRC) and for pooled Sub-cohort: Objective response was based on investigator review.
Phase 2: Percentage of Participants With Objective Response
时间窗: Up to approximately 37.5 months (through cut-off date 29-May-2021)
Objective response was defined as proportion of participants who had achieved best overall response of PR or CR per RECIST v1.1. CR was defined as a disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must had reduction in short axis to \<10 mm and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. The Phase 2 evaluation of objective response was based on central independent CT/MRI image assessment.
Phase 1: Dose Escalation-Recommended Phase 2 Dose (RP2D) of TAS-120
时间窗: Cycle 1 (21-day cycle)
RP2D was MTD or less. MTD: Highest dose level at which \<33% of participants experience DLT) during Cycle1. DLT: \>=Grade(G)3: - nonhematologic toxicity, - nausea/vomiting lasting \>48hrs(uncontrolled by aggressive antiemetic), - diarrhea lasting \>48hrs (unresponsive to antidiarrheal drug); G4 neutropenia lasting \>7days; Febrile neutropenia (ANC\<1000/mm\^3 with body temperature=\>38.3°C/sustained temperature \>=38°C for \>1hr; Thrombocytopenia G4/G3 with bleeding, required blood transfusion; Corneal disorder worsened by 1 grade or more; Increased phosphorus: \>=9mg/dL or \>=7mg/dL lasting for \>=7days or phosphate lowering therapy\[PLT\] for 7days); Creatinine increase (\>1.5×upper limit of normal \[ULN\]) lasting for \>=7 days associated with serum phosphorus \>5.5 mg/dL(PLT=7days)/calcium×phosphorus \>55 mg/dL(PLT=7days); Hypercalcemia G2 for \>7days or G3; Ectopic de novo calcification in soft tissues; \>G2 DLT: prevented Cycle 1 completion, inability to start Cycle 2 within 2 weeks of schedule.
次要结局
- Phase 1: Dose Expansion: Duration of Response (DOR)(Up to approximately 50.5 months (through cut-off date 29-May-2021) for Cohorts 1 to 6; up to approximately 27.5 months (through cut-off date 30-Jun-2019) for pooled sub-cohorts)
- Phase 2: Duration of Response (DOR)(Up to approximately 37.5 months (through cut-off date 29-May-2021))
- Phase 2: Progression-free Survival (PFS)(Up to approximately 37.5 months (through cut-off date 29-May-2021))
- Phase 1: Dose Expansion: Disease Control Rate (DCR)(Up to approximately 50.5 months (through cut-off date 29-May-2021) for Cohorts 1 to 6; up to approximately 27.5 months (through cut-off date 30-Jun-2019) for pooled sub-cohort)
- Phase 2: Disease Control Rate (DCR)(Up to approximately 37.5 months (through cut-off date 29-May-2021))
- Phase 1: Dose Expansion: Progression-free Survival (PFS)(up to approximately 27.5 months (through cut-off date 30-Jun-2019))
- Phase 2: Overall Survival (OS)(Up to approximately 37.5 months (through cut-off date 29-May-2021))
- Phase 2: European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Questionnaire: Mobility Scores at Specified Visits(Baseline, Cycle 2, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40 and end of treatment (i.e., Cycle 43 [30 months]))
- Phase 2: European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Questionnaire: Self-care Scores at Specified Visits(Baseline, Cycle 2, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40 and end of treatment (i.e., Cycle 43 [30 months]))
- Phase 2: European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Questionnaire: Usual Activities Scores at Specified Visits(Baseline, Cycle 2, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40 and end of treatment (i.e., Cycle 43 [30 months]))
- Phase 2: European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Questionnaire: Pain/Discomfort Scores at Specified Visits(Baseline, Cycle 2, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40 and end of treatment (i.e., Cycle 43 [30 months]))
- Phase 2: European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Questionnaire: Anxiety/Depression Scores at Specified Visits(Baseline, Cycle 2, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40 and end of treatment (i.e., Cycle 43 [30 months]))
- Phase 2: Change From Baseline in EQ-5D-3L Visual Analogue Scale (VAS) at Specified Visits(Baseline, Cycle 2, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40 and end of treatment (i.e., Cycle 43 [30 months]))
- Phase 2:Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status Score at Specified Timepoints(Baseline, Cycle 2, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40 and end of treatment (i.e., Cycle 43 [30 months]))
- Phase 1: Dose Expansion: Number of Participants With Any Adverse Events (AEs) and Any Serious AEs (SAEs)(From the first dose up to approximately 50.5 months (through cut-off date 29-May-2021))
- Phase 2: Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs)(From the first dose up to approximately 37.5 months (through cut-off date 29-May-2021))
- Phase 1: Dose Expansion: Overall Survival (OS)(up to approximately 27.5 months (through cut-off date 30-Jun-2019))