An Open Label, Non-randomized, Phase I Dose Escalation Study to Characterize Safety, Tolerability, Pharmacokinetics and Maximum Tolerated Dose of BAY1163877 in Subjects With Refractory, Locally Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Bayer
- 入组人数
- 168
- 主要终点
- Number of DLTs During Cycle 1
研究概览
简要总结
- This was the first study where BAY1163877 was given to humans. Impact of the study was to evaluate if patients with advanced solid cancers show advanced clinical benefit under the treatment with the pan FGFR inhibitor. Patients (all comers) received the study drug treatment in a dose-escalation scheme (no placebo group) to determine the safety, tolerability and maximum tolerated dose (MTD) of BAY1163877. The relative bioavailability of liquid service formulation and tablets was determined.
- After the MTD was defined patients with solid tumors (all comers), lung cancer (lung adenocarcinoma & squamous non-small cell lung cancer), head and neck cancer or bladder cancer was enrolled according to their FGFR expression profile (biomarker stratification).
- The study also assessed the pharmacokinetics, biomarker status, pharmacodynamic parameters and tumor response of BAY1163877.
- BAY1163877 was given twice daily as oral application. Treatment was stopped if the tumor continued to grow, if side effects, which the patient cannot tolerate, occurred or if the patient decided to exit treatment.
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
- •For dose escalation: Participants with any type of solid tumor (all comer) were eligible for dose escalation and dose expansion at MTD in Part 1; Participants enrolled for dose expansion (MTD expansion cohort "all comer") were stratified according to high fibroblast growth factor receptor (FGFR) expression levels / FGFR mutation using archival or fresh tumor biopsy material
- •For expansion cohorts: Participants were eligible for Part 2 only if they have histological or cytological confirmed squamous non-small cell lung cancer (sqNSCLC), lung adenocarcinoma, head and neck cancer or bladder cancer (BC). All participants in Part 2 were stratified according to high FGFR expression levels FGFR mutation using archival or fresh tumor biopsy specimen. BC participants with low overall FGFR expression levels could be included if activating FGFR3 (FGFR tyrosine kinases 3) mutations were confirmed
- •Participants must have measurable disease (Response evaluation criteria in solid tumors (RECIST 1.1))
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 2
- •Bone marrow, liver and renal functions as assessed by adequate laboratory methods to be conducted within 7 days prior to starting study Treatment
- •Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m^2 according to the modified diet in renal disease (MDRD) abbreviated formula
排除标准
- •Previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors or FGFR-specific antibodies)
- •Concomitant therapies that cannot be discontinued or switched to a different medication prior to study entry that are known to increase serum phosphate levels are not permitted within 4 weeks prior to start of study treatment)
- •Anticancer chemotherapy or immunotherapy during the study or within 5-halflives prior to start of study treatment. Mitomycin C, nitrosoureas or monoclonal antibodies with anticancer activity (e.g. bevacizumab or cetuximab etc.) should not be given within 6 weeks before starting to receive study treatment or within 6 weeks of pre-treatment biopsy for biomarker (p-ERK1/2) studies
研究组 & 干预措施
Rogaratinib total dose escalation
Participants with any type of solid tumor received escalating doses of Rogaratinib oral solution or tablet. The actual dose-escalation cohorts were 100 mg (50 mg BID), 200 mg (100 mg BID), 400 mg (200 mg BID), 800 mg (400 mg BID), 1200 mg (600 mg BID), and 1600 mg (800 mg BID). The participants in the 100 mg and 200 mg dose-escalation cohorts received oral solution and the participants in all the subsequent dose-escalation cohorts received tablet. And as an exception, on C1D-3 in the 200 mg dose-escalation cohort, the participants received tablet instead of oral solution.
干预措施: Rogaratinib (BAY1163877) oral solution (Drug)
Rogaratinib total dose escalation
Participants with any type of solid tumor received escalating doses of Rogaratinib oral solution or tablet. The actual dose-escalation cohorts were 100 mg (50 mg BID), 200 mg (100 mg BID), 400 mg (200 mg BID), 800 mg (400 mg BID), 1200 mg (600 mg BID), and 1600 mg (800 mg BID). The participants in the 100 mg and 200 mg dose-escalation cohorts received oral solution and the participants in all the subsequent dose-escalation cohorts received tablet. And as an exception, on C1D-3 in the 200 mg dose-escalation cohort, the participants received tablet instead of oral solution.
干预措施: Rogaratinib (BAY1163877) oral tablet (Drug)
Rogaratinib dose expansion (All Comers)
Participants with cancer types other than bladder cancer (BC), squamous cell carcinoma of the head and neck (SCCHN), and squamous non-small cell lung cancer (sqNSCLC) received 800 mg Rogaratinib oral tablet b.i.d.
(1600 mg/day) in 21-days cycles.
干预措施: Rogaratinib (BAY1163877) 800 mg BID (Drug)
Rogaratinib dose expansion (BC)
Participants with bladder cancer (BC) received 800 mg Rogaratinib oral tablet b.i.d. (1600 mg/day) in 21-days cycles.
干预措施: Rogaratinib (BAY1163877) 800 mg BID (Drug)
Rogaratinib dose expansion (SCCHN)
Participants with squamous cell carcinoma of the head and neck (SCCHN) received 800 mg Rogaratinib oral tablet b.i.d. (1600 mg/day) in 21-days cycles.
干预措施: Rogaratinib (BAY1163877) 800 mg BID (Drug)
Rogaratinib dose expansion (sqNSCLC)
Participants with squamous non-small cell lung cancer (sqNSCLC) received 800 mg Rogaratinib oral tablet b.i.d. (1600 mg/day) in 21-days cycles.
干预措施: Rogaratinib (BAY1163877) 800 mg BID (Drug)
结局指标
主要结局
Number of DLTs During Cycle 1
时间窗: Up to 21 days
DLT was defined as any of the pre-defined adverse events occurring during Cycle 1 of a dose level and regarded by the investigators and/or sponsor to be related to the investigational drug.
AUC(0-tlast) (Area Under the Plasma Concentration vs Time Curve From Time Zero to the Last Data Point > LLOQ [Lower Limit of Quantification]) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
Area under the plasma concentration vs time curve from time zero to the last data point \> LLOQ \[lower limit of quantification\] (AUC(0-tlast)) of BAY1163877 after single dose administration on Cycle 1, Day -3. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC (Area Under the Plasma Concentration vs Time Curve From Zero to Infinity) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
Area under the plasma concentration vs time curve from zero to infinity (AUC) of BAY1163877 after single dose administration on Cycle 1, Day 1. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC(0-tlast)/D (Area Under the Plasma Concentration vs Time Curve From Time Zero to the Last Data Point > LLOQ Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
Area under the plasma concentration vs time curve from time zero to the last data point \> LLOQ divided by dose (AUC(0-tlast)/D) of BAY1163877 after single dose administration on Cycle 1, Day 1. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC/D (AUC Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
AUC divided by dose (AUC/D) of BAY1163877 after single dose administration on Cycle 1, Day 1. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Maximum Tolerated Dose (MTD), Defined as Maximum Dose at Which the Incidence of Dose Limiting Toxicities (DLTs) During Cycle 1 is Below 20%
时间窗: Up to 21 days
The MTD was defined as maximum dose at which the incidence of Dose Limiting Toxicities (DLTs) during Cycle 1 is below 20%. DLT was defined as any of the pre-defined adverse events occurring during Cycle 1 of a dose level and regarded by the investigators and/or sponsor to be related to the investigational drug. BID=twice daily.
Cmax (Maximum Drug Concentration in Plasma) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
Maximum drug concentration in plasma (Cmax) of BAY1163877 after single dose administration on Cycle 1, Day -3. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Cmax (Maximum Drug Concentration in Plasma) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
Maximum drug concentration in plasma (Cmax) of BAY1163877 after single dose administration on Cycle 1, Day 1. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC(0-12)/D (Area Under the Plasma Concentration vs Time Curve From Time Zero to 12 Hours Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
Area under the plasma concentration vs time curve from time zero to 12 hours divided by dose (AUC(0-12)/D) of BAY1163877 after single dose administration on Cycle 1, Day -3. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC(0-12)/D (Area Under the Plasma Concentration vs Time Curve From Time Zero to 12 Hours Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
Area under the plasma concentration vs time curve from time zero to 12 hours divided by dose (AUC(0-12)/D) of BAY1163877 after single dose administration on Cycle 1, Day 1. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC/D (AUC Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
AUC divided by dose (AUC/D) of BAY1163877 after single dose administration on Cycle 1, Day -3. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC(0-12)md (AUC(0-12) After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15
时间窗: pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose
AUC(0-12)md (AUC(0-12) after multiple-dose administration) of BAY1163877. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC(0-12)/Dmd (AUC(0-12) Divided by Dose After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15
时间窗: pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose
AUC(0-12)/Dmd (AUC(0-12) divided by dose after multiple-dose administration) of BAY1163877. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC(0-12) (Area Under the Plasma Concentration vs Time Curve From Time Zero to 12 Hours) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
Area under the plasma concentration vs time curve from time zero to 12 hours (AUC(0-12)) of BAY1163877 after single dose administration on Cycle 1, Day -3. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC(0-12) (Area Under the Plasma Concentration vs Time Curve From Time Zero to 12 Hours) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
Area under the plasma concentration vs time curve from time zero to 12 hours (AUC(0-12)) of BAY1163877 after single dose administration on Cycle 1, Day 1. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC(0-tlast) (Area Under the Plasma Concentration vs Time Curve From Time Zero to the Last Data Point > LLOQ [Lower Limit of Quantification]) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
Area under the plasma concentration vs time curve from time zero to the last data point \> LLOQ \[lower limit of quantification\] (AUC(0-tlast)) of BAY1163877 after single dose administration on Cycle 1, Day 1. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC (Area Under the Plasma Concentration vs Time Curve From Zero to Infinity) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
Area under the plasma concentration vs time curve from zero to infinity (AUC) of BAY1163877 after single dose administration on Cycle 1, Day -3. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Cmax/D (Maximum Drug Concentration in Plasma Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
Maximum drug concentration in plasma divided by dose (Cmax/D) of BAY1163877 after single dose administration on Cycle 1, Day -3. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Cmax/D (Maximum Drug Concentration in Plasma Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
Maximum drug concentration in plasma divided by dose (Cmax/D) of BAY1163877 after single dose administration on Cycle 1, Day 1. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Cmax,md (Cmax After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15
时间窗: pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose
Cmax,md (Cmax after multiple-dose administration) of BAY1163877. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Cmax/Dmd (Cmax Divided by Dose After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15
时间窗: pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose
Cmax/Dmd (Cmax divided by dose after multiple-dose administration) of BAY1163877. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC(0-tlast)md (AUC(0-tlast) After Multiple Dose Administration) of BAY1163877 on Cycle 1, Day 15
时间窗: pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose
AUC(0-tlast)md (AUC(0-tlast) after multiple dose administration) of BAY1163877. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
%AE,ur(0-12) (Amount of Drug Excreted Via Urine During the Collection Interval 0 - 12 Hours Post Administration) of BAY1163877
时间窗: On Cycle1, Day 1
%AE,ur(0-12) (amount of drug excreted via urine during the collection interval 0 - 12 hours post administration, also expressed as percent of dose administered) of BAY1163877.
AUC(0-tlast)/D (Area Under the Plasma Concentration vs Time Curve From Time Zero to the Last Data Point > LLOQ Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3
时间窗: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
Area under the plasma concentration vs time curve from time zero to the last data point \> LLOQ divided by dose (AUC(0-tlast)/D) of BAY1163877 after single dose administration on Cycle 1, Day -3. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
AUC(0-tlast)/Dmd (AUC(0-tlast) Divided by Dose After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15
时间窗: pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose
AUC(0-tlast)/Dmd (AUC(0-tlast) divided by dose after multiple-dose administration) of BAY1163877. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
%AE,ur(0-24) (Amount of Drug Excreted Via Urine During the Collection Interval 0 - 24 Hours Post Administration) of BAY1163877
时间窗: On Cycle1, Day 1
%AE,ur(0-24) (amount of drug excreted via urine during the collection interval 0 - 24 hours post administration, also expressed as percent of dose administered) of BAY1163877.
%AE,ur(12-24) (Amount of Drug Excreted Via Urine During the Collection Interval 12 - 24 Hours Post Administration) of BAY1163877
时间窗: On Cycle1, Day 1
%AE,ur(12-24) (amount of drug excreted via urine during the collection interval 12 - 24 hours post administration, also expressed as percent of dose administered) of BAY1163877.
次要结局
- Duration of Response (DOR)(Up to 2 years)
- Duration of Treatment (DOT)(Up to 2 years)
- Evaluation of Relative Bioavailability of the Tablet Formulation in Comparison to the Solution Formulation of BAY1163877(On Cycle 1, Day -3 and Cycle 1, Day 1)
- Tlast,md (Time of Last Plasma Concentration Above LLOQ After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15(pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose)
- Time to Progression (TTP)(Up to 2 years)
- Evaluation of Biomarker Status -Change in Serum FGF23 (Fibroblast Growth Factor 23) Levels From Baseline to C2D1(From baseline to C2D1)
- Tmax (Time to Reach Maximum Drug Concentration in Plasma) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3 and Cycle 1, Day 1(pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) post-dose)
- Tlast (Time of Last Plasma Concentration Above LLOQ) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3 and Cycle 1, Day 1(pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) post-dose)
- T1/2 (Half-life Associated With the Terminal Slope) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3 and Cycle 1, Day 1(pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) post-dose)
- Tmax,md (Time to Reach Maximum Drug Concentration in Plasma After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15(pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose)
- Response Rate as Defined by RECIST Version 1.1 Reported as Number of Participants With Different Response Type(Up to 2 years)
- Progression-free Survival (PFS)(Up to 2 years)
- Evaluation of Pharmacodynamic Parameters (PD) - Change of Heart Rate (HR) From Baseline to End of Study(From baseline up to 2 years)
- Evaluation of Pharmacodynamic Parameters (PD) - Change of Blood Pressure (BP) From Baseline to End of Study(From baseline up to 2 years)
- Evaluation of Pharmacodynamic Parameters (PD) - Change of QT Intervals From Baseline up to Cycle 1, Day 15(From baseline up to Cycle 1, Day 15)