A Phase I/II, Multicenter, Open-label Study of Oral FGF401 in Adult Patients With Hepatocellular Carcinoma or Solid Malignancies Characterized by Positive FGFR4 and KLB Expression
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 172
- 试验地点
- 4
- 主要终点
- Overall Response Rate (ORR) Based on Local Assessment: Group 3 (Phase II Only)
研究概览
简要总结
Estimate the maximum tolerated dose and/or recommended phase II dose and efficacy of FGF401 as single agent and in combination with PDR001 in patients with hepatocellular carcinoma and as single agent in patients with other solid malignancies based on RECIST 1.1.
详细描述
The primary objectives of this study were in 2 parts: Phase l & Phase II.
The study included different periods starting by molecular pre-screening (applicable for all subjects enrolled under protocol versions 00 to 03, or applicable only for Phase I and Group 3 in Phase II of FGF401 single agent, for subjects enrolled under protocol version 04), Screening, Treatment, End of Treatment, Disease progression follow-up (if applicable), Safety follow-up and then ended by survival follow-up period
In the Phase I part, subjects with HCC or other advanced solid tumors characterized by positive FGFR4 and KLB expression were enrolled and treated with FGF401 as a single agent or in combination with PDR001. Subjects in this phase were dosed under fasted or fed conditions.
In the Phase 2 part, subjects with advanced HCC or other solid tumors bearing positive FGFR4 and KLB expression were enrolled into three groups (Group 1: HCC subjects from Asian countries; Group 2: HCC subjects from non-Asian countries; Group 3: Subjects with other solid malignancies regardless of geography) to assess the preliminary anti-tumor activity of FGF401 in Phase ll. This Phase II part investigated the anti-tumor activity of FGF401 single agent and in combination with PDR001.
Each group within the Phase II dose expansion part targeted a different number of subjects. Group 1 and Group 2 planned to enroll around 40 subjects each and Group 3 planned to enroll approximately 20 subjects. Subjects in this phase were dosed under fasted conditions.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •ECOG Performance Status ≤ 1
- •Presence of at least one measurable lesion according to RECIST v1.
- •c-i) FGF401 single agent-Phase I and Phase II, Group 3: Patients with HCC or advanced solid tumors, who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists. c-ii) FGF401 single agent-Phase II, Groups 1 and 2: HCC patients previously treated with sorafenib for advanced HCC with documented disease progression during or after discontinuation of sorafenib treatment, or intolerance to sorafenib treatment c-iii) FGF401 in combination with PDR001:Advanced HCC patients who have received up to 2 previous lines of systemic treatment and one treatment must have included sorafenib with documented disease progression during or after discontinuation of sorafenib treatment, or intolerance to sorafenib treatment
排除标准
- •Previous treatment with a selective FGF19-FGFR4 targeted therapy and/or pan-FGFR inhibitor.
- •Symptomatic CNS metastases which are neurologically unstable or requiring increasing doses of steroids to control their CNS disease.
- •Patient having out of range laboratory values defined as:
- •Hematology Hemoglobin ≤ 9 g/dL (SI Units: 90 g/L) Platelet count < 75000/mm3 Absolute neutrophil count (ANC) < 1500/mm3
- •Chemistry Total bilirubin ≥ 2 mg/dL AST and/or ALT > 3 x ULN Serum creatinine > 1.5 x ULN and/or creatinine clearance ≤ 45 mL/min
- •Coagulation: PT > 4 seconds more than ULN or INR > 1.7
- •Pregnant or nursing (lactating) women.
- •Other protocol-defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Phase I: FGF401 80 mg fasted
Participants received single agent FGF401 80 mg while fasted
干预措施: FGF401 (Drug)
Phase I: FGF401 50 mg fasted
Participants received single agent FGF401 50 mg while fasted
干预措施: FGF401 (Drug)
Phase I: FGF401 80 mg fed
Participants received single agent FGF401 80 mg while fed
干预措施: FGF401 (Drug)
Phase I: FGF401 120 mg fasted
Participants received single agent FGF401 120 mg while fasted
干预措施: FGF401 (Drug)
Phase I: FGF401 120 mg fed
Participants received single agent FGF401 120 mg while fed
干预措施: FGF401 (Drug)
Phase I: FGF401 150 mg fasted
Participants received single agent FGF401 150 mg while fasted
干预措施: FGF401 (Drug)
Phase I: FGF401 80 mg + PDR001 300 mg
Participants received FGF401 80 mg in combination with PDR001 300 mg while fasted
干预措施: FGF401 (Drug)
Phase I: FGF401 80 mg + PDR001 300 mg
Participants received FGF401 80 mg in combination with PDR001 300 mg while fasted
干预措施: PDR001 (Biological)
Phase I: FGF401 120 mg + PDR001 300 mg
Participants received FGF401 120 mg in combination with PDR001 300 mg while fasted
干预措施: FGF401 (Drug)
Phase I: FGF401 120 mg + PDR001 300 mg
Participants received FGF401 120 mg in combination with PDR001 300 mg while fasted
干预措施: PDR001 (Biological)
Phase II: Group 1 - FGF401 120 mg QD
Group 1 was comprised of HCC participants from Asian countries who received single agent FGF401 120 mg QD while fasted
干预措施: FGF401 (Drug)
Phase II: Group 2 - FGF401 120 mg QD
Group 2 was comprised of HCC participants from non-Asian countries who took single agent FGF401 120 mg QD while fasted
干预措施: FGF401 (Drug)
Phase II: Group 3 - FGF401 120 mg QD
Group 3 was comprised of participants with other solid malignancies regardless of geography who took single agent FGF401 120 mg QD while fasted
干预措施: FGF401 (Drug)
结局指标
主要结局
Overall Response Rate (ORR) Based on Local Assessment: Group 3 (Phase II Only)
时间窗: approx. 4.5 years
ORR is defined as the percentage of patients with a best overall response of CR or PR (RECIST v1.1). FGF401 single agent-Phase II part - Group 3 (non-HCC, other solid tumors).
Time to Progression (TTP): Group 1 & Group 2 (Phase II Only)
时间窗: approx. 4.5 years
TTP is defined as the date of start treatment to the date of event defined as the first documented progression or death due to underlying cancer. Method used was Kaplan-Meier analysis. Group 1: HCC subjects form Asian countries; Group 2: HCC subjects form non-Asian countries
Number of Participants With Dose-limiting Toxicity (DLT): Phase I Only
时间窗: Cycle 1 (C1) (21 days) for FGF401 single agent, Cycle 1 and Cycle 2 (C2) (42 days) for FGF401 and PDR001 combination
A dose-limiting toxicity was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the evaluation period of DLTs and met any of the criteria listed. The estimation of the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of the treatment was based upon the estimation of the probability of DLT during the evaluation period for subjects in the dose determining set (DDS). A subject with multiple occurrences of a DLT under one treatment is counted only once in the AE category for that treatment. A subject with multiple DLTs within a primary system organ class is counted only once in the total row.
次要结局
- Best Overall Response (BOR) by Investigator Assessment: Phase I and Phase II(approx. 4.5 years)
- Overall Response Rate (ORR) by Investigator Assessment Phase I and FGF401 Single Agent Phase II Groups 1 & 2(approx. 4.5 years)
- Time to Progression (TTP) in Participants Dosed With Single Agent FGF401 120 mg (Fasted & Fed) & With Combination FGF401 120 mg + PDR001 300 mg Q3W (Phase I)(approx. 4.5 years)
- AUCinf, AUClast & AUCtau of FGF401: Phase I(C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), C1D8 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), and C2D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h))
- Progression-free Survival (PFS) - FGF401 Single Agent Phase II: Group 3(4.5 years)
- Presence and/or Concentration of Anti-PDR001 Antibodies(Day 1 of Cycle 1 to 6, approx. 10 months after C1D1 and 150-day safety follow up (FU))
- Cmax of FGF401: Phase I(C1D1 (0 hour (h), 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), C1D8 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), and C2D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h))
- Cmax of FGF401 in Combination With PDR001: Phase I(C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h))
- Overall Survival (OS) in Participants Dosed With Single Agent FGF401 120 mg (Fasted & Fed) and in Participants Dosed With Combination FGF401 120 mg and PDR001 300 mg Q3W (Phase I & II)(start of treatment to death, up to about 53 months)
- Cmax of PDR001 in Combination With FGF401: Phase I(After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days)
- T1/2 of PDR001: Phase I(After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days)
- AUCinf, AUClast & AUCtau of FGF401 in Combination With PDR001: Phase I(C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h))
- Disease Control Rate (DCR) by Local Investigator Assessment Phase I and FGF401 Single Agent Phase II Groups 1, 2 & 3(approx. 4.5 years)
- AUClast and AUCtau of PDR001 in Combination of FGF401: Phase I(After the first dosing sample collection was at: C1D1 0hr , C1D1 1hr, C1D8 168hr, C1D15 336hr, C2D1 504hr; each cycle is 21 days)
- T1/2 of FGF401: Phase I(C1D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), C1D8 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h), and C2D1 (0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h))