Phase 1
N=168
Dose Escalation Pan-FGFR (Fibroblast Growth Factor Receptor) Inhibitor (Rogaratinib)
Neoplasms
Bottom Line
View on ClinicalTrials.gov: NCT01976741 ↗Enrolled (actual)
168
Serious AEs
57.1%
Results posted
Apr 2020
Primary outcome: Primary: Maximum Tolerated Dose (MTD), Defined as Maximum Dose at Which the Incidence of Dose Limiting Toxicities (DLTs) During Cycle 1 is Below 20% — 800 mg BID
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- Rogaratinib (BAY1163877) oral solution (Drug); Rogaratinib (BAY1163877) oral tablet (Drug); Rogaratinib (BAY1163877) 800 mg BID (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Bayer
- Primary completion
- Mar 2019
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Maximum Tolerated Dose (MTD), Defined as Maximum Dose at Which the Incidence of Dose Limiting Toxicities (DLTs) During Cycle 1 is Below 20% |
800 | — |
| PRIMARY Number of DLTs During Cycle 1 |
— | — |
| PRIMARY Cmax (Maximum Drug Concentration in Plasma) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3 |
2760; 11300 | — |
| PRIMARY Cmax (Maximum Drug Concentration in Plasma) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1 |
3640; 4360; 5630; 9480; 9060; 10200 | — |
| PRIMARY 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 |
15600; 71000 | — |
| PRIMARY 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 |
12100; 15300; 33200; 44000; 54300; 55700 | — |
| PRIMARY 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 |
20000; 99300 | — |
| PRIMARY 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 |
14200; 20100; 43800; 62000; 78000; 86600 | — |
| PRIMARY AUC (Area Under the Plasma Concentration vs Time Curve From Zero to Infinity) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3 |
20200; 102000 | — |
| PRIMARY AUC (Area Under the Plasma Concentration vs Time Curve From Zero to Infinity) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1 |
14300; 20700; 44300; 64000; 79800; 95400 | — |
| PRIMARY Cmax/D (Maximum Drug Concentration in Plasma Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3 |
0.0276; 0.0141 | — |
| PRIMARY Cmax/D (Maximum Drug Concentration in Plasma Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1 |
0.0728; 0.0436; 0.0282; 0.0237; 0.0151; 0.0127 | — |
| PRIMARY 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 |
0.156; 0.0888 | — |
| PRIMARY 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 |
0.242; 0.153; 0.166; 0.110; 0.0906; 0.0696 | — |
| PRIMARY 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 |
0.200; 0.124 | — |
| PRIMARY 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 |
0.283; 0.201; 0.219; 0.155; 0.130; 0.108 | — |
| PRIMARY AUC/D (AUC Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3 |
0.202; 0.127 | — |
| PRIMARY AUC/D (AUC Divided by Dose) of BAY1163877 After Single Dose Administration on Cycle 1, Day 1 |
0.286; 0.207; 0.221; 0.160; 0.133; 0.119 | — |
| PRIMARY Cmax,md (Cmax After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15 |
3940; 4870; 8320; 9490; 10500; 12400 | — |
| PRIMARY Cmax/Dmd (Cmax Divided by Dose After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15 |
0.0789; 0.0487; 0.0416; 0.0237; 0.0174; 0.0155 | — |
| PRIMARY AUC(0-12)md (AUC(0-12) After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15 |
13300; 21500; 41700; 61100; 73500; 90900 | — |
| PRIMARY AUC(0-12)/Dmd (AUC(0-12) Divided by Dose After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15 |
0.266; 0.215; 0.209; 0.153; 0.123; 0.114 | — |
| PRIMARY AUC(0-tlast)md (AUC(0-tlast) After Multiple Dose Administration) of BAY1163877 on Cycle 1, Day 15 |
12500; 21500; 39200; 60200; 72500; 89000 | — |
| PRIMARY AUC(0-tlast)/Dmd (AUC(0-tlast) Divided by Dose After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15 |
0.250; 0.215; 0.196; 0.151; 0.121; 0.111 | — |
| PRIMARY %AE,ur(0-12) (Amount of Drug Excreted Via Urine During the Collection Interval 0 - 12 Hours Post Administration) of BAY1163877 |
0.164 | — |
| PRIMARY %AE,ur(0-24) (Amount of Drug Excreted Via Urine During the Collection Interval 0 - 24 Hours Post Administration) of BAY1163877 |
0.180 | — |
| PRIMARY %AE,ur(12-24) (Amount of Drug Excreted Via Urine During the Collection Interval 12 - 24 Hours Post Administration) of BAY1163877 |
0.0224 | — |
| SECONDARY Response Rate as Defined by RECIST Version 1.1 Reported as Number of Participants With Different Response Type |
2; 1; 1; 1; 2; 0 | — |
| SECONDARY Progression-free Survival (PFS) |
45; 47; 105; 44; 84 | — |
| SECONDARY Time to Progression (TTP) |
45; 47; 105; 68; 85 | — |
| SECONDARY Duration of Response (DOR) |
522; 126; 105; 225 | — |
| SECONDARY Duration of Treatment (DOT) |
51; 82; 106; 49; 84 | — |
| SECONDARY Evaluation of Biomarker Status -Change in Serum FGF23 (Fibroblast Growth Factor 23) Levels From Baseline to C2D1 |
201.5; 149.9; 441.9; 528.0; 402.2; 517.7 | — |
| SECONDARY Evaluation of Pharmacodynamic Parameters (PD) - Change of Heart Rate (HR) From Baseline to End of Study |
8.22; 6.41; 6.40; 1.42; 6.27 | — |
| SECONDARY Evaluation of Pharmacodynamic Parameters (PD) - Change of Blood Pressure (BP) From Baseline to End of Study |
-1.33; -4.65; -2.56; -5.00; -1.83; -2.50 | — |
| SECONDARY Evaluation of Pharmacodynamic Parameters (PD) - Change of QT Intervals From Baseline up to Cycle 1, Day 15 |
0.60; 12.86; 7.82; 2.89; 6.41 | — |
| SECONDARY Evaluation of Relative Bioavailability of the Tablet Formulation in Comparison to the Solution Formulation of BAY1163877 |
0.9945; 0.9776; 0.6335 | — |
| SECONDARY 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 |
NA; 2.02; NA; NA; NA; NA | — |
| SECONDARY Tlast (Time of Last Plasma Concentration Above LLOQ) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3 and Cycle 1, Day 1 |
NA; 48.1; NA; NA; NA; NA | — |
| SECONDARY 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 |
NA; 8.15; NA; NA; NA; NA | — |
| SECONDARY Tmax,md (Time to Reach Maximum Drug Concentration in Plasma After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15 |
0.80; 1.08; 1.12; 2.08; 2.10; 2.56 | — |
| SECONDARY Tlast,md (Time of Last Plasma Concentration Above LLOQ After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15 |
9.80; 11.7; 11.6; 11.7; 11.6; 11.7 | — |
Summary
* 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.
Eligibility Criteria
Inclusion Criteria
- 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
Exclusion Criteria
- 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
Data sourced from ClinicalTrials.gov (NCT01976741). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.