Description:
- 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.
Title
- Brief Title: Dose Escalation Pan-FGFR (Fibroblast Growth Factor Receptor) Inhibitor (Rogaratinib)
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
16443
- SECONDARY ID:
2013-002155-15
- NCT ID:
NCT01976741
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| Rogaratinib (BAY1163877) oral solution | | Rogaratinib total dose escalation |
| Rogaratinib (BAY1163877) oral tablet | | Rogaratinib total dose escalation |
| Rogaratinib (BAY1163877) 800 mg BID | | Rogaratinib dose expansion (All Comers) |
Purpose
- 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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Rogaratinib total dose escalation | Experimental | 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. | - Rogaratinib (BAY1163877) oral solution
- Rogaratinib (BAY1163877) oral tablet
|
| Rogaratinib dose expansion (All Comers) | Experimental | 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. | - Rogaratinib (BAY1163877) 800 mg BID
|
| Rogaratinib dose expansion (BC) | Experimental | Participants with bladder cancer (BC) received 800 mg Rogaratinib oral tablet b.i.d. (1600 mg/day) in 21-days cycles. | - Rogaratinib (BAY1163877) 800 mg BID
|
| Rogaratinib dose expansion (SCCHN) | Experimental | 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. | - Rogaratinib (BAY1163877) 800 mg BID
|
| Rogaratinib dose expansion (sqNSCLC) | Experimental | 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. | - Rogaratinib (BAY1163877) 800 mg BID
|
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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Maximum Tolerated Dose (MTD), Defined as Maximum Dose at Which the Incidence of Dose Limiting Toxicities (DLTs) During Cycle 1 is Below 20% |
| Time Frame: | Up to 21 days |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Response Rate as Defined by RECIST Version 1.1 Reported as Number of Participants With Different Response Type |
| Time Frame: | Up to 2 years |
| Safety Issue: | |
| Description: | Response as defined by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1: complete response (CR: disappearance of all target lesions), partial response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as the reference the baseline sum of diameters), stable disease (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference, the smallest sum of diameters while in the trial), progressive disease (PD: at least a 20% increase in the sum of diameters of the target lesions, taking as a references the smallest sum on study). |
| Measure: | Progression-free Survival (PFS) |
| Time Frame: | Up to 2 years |
| Safety Issue: | |
| Description: | PFS was defined as the time (days) from the date of the first dose of study drug to the date of the first observed disease progression (radiological or clinical) or death due to any cause, if death occurred before progression was documented. PFS for participants without tumor progression at the time of analysis was censored at their last date of tumor evaluation. |
| Measure: | Time to Progression (TTP) |
| Time Frame: | Up to 2 years |
| Safety Issue: | |
| Description: | TTP was defined as the time from start of study treatment until first observed disease progression (radiological or clinical). Progression is defined using RECIST v1.0, as at least a 20% increase in the sum of diameters of the target lesions, taking as a references the smallest sum on study. |
| Measure: | Duration of Response (DOR) |
| Time Frame: | Up to 2 years |
| Safety Issue: | |
| Description: | DOR (for partial and complete response (PR/CR)) was defined as the time (days) from the first documented objective response of PR or CR, whichever was noted earlier, to disease progression or death (if death occurred before progression was documented). DOR was calculated for responders only, i.e. participants with complete or partial response. Therefore, the dose escalation group is not displayed. |
| Measure: | Duration of Treatment (DOT) |
| Time Frame: | Up to 2 years |
| Safety Issue: | |
| Description: | |
| Measure: | Evaluation of Biomarker Status -Change in Serum FGF23 (Fibroblast Growth Factor 23) Levels From Baseline to C2D1 |
| Time Frame: | From baseline to C2D1 |
| Safety Issue: | |
| Description: | Change in serum FGF23 levels from baseline to C2D1 was reported as ratio to baseline (%). |
| Measure: | Evaluation of Pharmacodynamic Parameters (PD) - Change of Heart Rate (HR) From Baseline to End of Study |
| Time Frame: | From baseline up to 2 years |
| Safety Issue: | |
| Description: | |
| Measure: | Evaluation of Pharmacodynamic Parameters (PD) - Change of Blood Pressure (BP) From Baseline to End of Study |
| Time Frame: | From baseline up to 2 years |
| Safety Issue: | |
| Description: | |
| Measure: | Evaluation of Pharmacodynamic Parameters (PD) - Change of QT Intervals From Baseline up to Cycle 1, Day 15 |
| Time Frame: | From baseline up to Cycle 1, Day 15 |
| Safety Issue: | |
| Description: | |
| Measure: | Evaluation of Relative Bioavailability of the Tablet Formulation in Comparison to the Solution Formulation of BAY1163877 |
| Time Frame: | On Cycle 1, Day -3 and Cycle 1, Day 1 |
| Safety Issue: | |
| Description: | In order to evaluate the relative bioavailability of the tablet formulation, tablet Cmax/D, AUC(0-tlast)/D, and AUC/D on Cycle 1, Day -3 were compared to solution Cmax/D, AUC(0-tlast)/D, AUC/D on Cycle 1, Day 1 for all analytes. The logarithms of the PK parameters were analyzed using analysis of variance (ANOVA) including participant and formulation effects. Based on these analyses, point estimates (LS-means) and exploratory 90% confidence intervals for the ratios (tablet/solution) of Cmax/D, AUC(0- tlast)/D, and AUC/D were calculated by re-transformation of the logarithmic data using the intra-individual standard deviation of the ANOVA. |
| Measure: | 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 |
| Time Frame: | pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) post-dose |
| Safety Issue: | |
| Description: | 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. Median and full range were reported. |
| Measure: | Tlast (Time of Last Plasma Concentration Above LLOQ) of BAY1163877 After Single Dose Administration on Cycle 1, Day -3 and Cycle 1, Day 1 |
| Time Frame: | pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) post-dose |
| Safety Issue: | |
| Description: | Tlast (time of last plasma concentration above LLOQ) of BAY1163877 after single dose administration on Cycle 1, Day -3 and Cycle 1, Day 1. Median and full range were reported. |
| Measure: | 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 |
| Time Frame: | pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hour(s) post-dose |
| Safety Issue: | |
| Description: | 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. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Measure: | Tmax,md (Time to Reach Maximum Drug Concentration in Plasma After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15 |
| Time Frame: | pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose |
| Safety Issue: | |
| Description: | Tmax,md (time to reach maximum drug concentration in plasma after multiple-dose administration) of BAY1163877. Median and full range were reported. |
| Measure: | Tlast,md (Time of Last Plasma Concentration Above LLOQ After Multiple-dose Administration) of BAY1163877 on Cycle 1, Day 15 |
| Time Frame: | pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose |
| Safety Issue: | |
| Description: | Tlast,md (time of last plasma concentration above LLOQ after multiple-dose administration) of BAY1163877. Median and full range were reported. |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Bayer |
Trial Keywords
- Phase I
- Dose escalation
- refractory, locally advanced or metastatic solid tumor
- Bladder cancer
- squamous non-small cell lung cancer
- pan-FGFR inhibitor
- lung adenocarcinoma
- head and neck cancer
Last Updated
May 6, 2021
