check_circleStudy Completed

Neoplasms

Bayer Identifier:

16443

ClinicalTrials.gov Identifier:

NCT01976741

EudraCT Number:

2013-002155-15

EU CT Number:

Not Available
Dose escalation pan-FGFR (fibroblast growth factor receptor) inhibitor (Rogaratinib)

Trial 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.

Key Participants Requirements

Sex

Both

Age

18 - N/A
  • - 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

  • - 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

Trial summary

Enrollment Goal
168
Trial Dates
December 2013 - January 2020
Phase
Phase 1
Could I Receive a placebo
No
Products
Rogaratinib (BAY1163877)
Accepts Healthy Volunteer
No

Where to participate

StatusInstitutionLocation
Completed
Würzburg, 97080, Germany
Completed
Essen, 45147, Germany
Completed
Seoul, 03722, Korea, Republic Of
Completed
St. Gallen, 9007, Switzerland
Completed
Singapore, 119228, Singapore
Completed
Singapore, 169610, Singapore
Completed
Seoul, 03080, Korea, Republic Of
Completed
Barcelona, 08035, Spain
Completed
Köln, 50937, Germany
Completed
LYON CEDEX, 69008, France
Completed
Heidelberg, 69120, Germany
Completed
Magdeburg, 39120, Germany
Completed
Dresden, 01307, Germany
Withdrawn
Jena, 07740, Germany
Withdrawn
Lübeck, 23538, Germany
Completed
Chicago, 60611-2908, United States
Completed
CRETEIL, 94010, France
Completed
LILLE CEDEX, 59020, France
Completed
DIJON, 21079, France
Completed
Chicago, United States
Completed
Weiden, 92637, Germany
Completed
Tübingen, 72076, Germany
Completed
Hamburg, 20246, Germany
Withdrawn
Bochum, 44791, Germany
Completed
BESANCON, 25030, France
Completed
Madrid, 28034, Spain
Completed
Chur, 7000, Switzerland
Completed
Seoul, 135-710, Korea, Republic Of
Completed
Pittsburgh, 15232, United States
Completed
Madrid, 28041, Spain
Completed
Valencia, 46014, Spain
Completed
Genève, 1205, Switzerland
Withdrawn
Bern, 3010, Switzerland

Primary Outcome

  • Maximum tolerated dose (MTD), defined as maximum dose at which the incidence of Dose Limiting Toxicities (DLTs) during Cycle 1 is below 20%
    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.
    date_rangeTime Frame:
    Up to 21 days
  • Number of DLTs during Cycle 1
    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.
    date_rangeTime Frame:
    Up to 21 days
  • Cmax (maximum drug concentration in plasma) of BAY1163877 after single dose administration on Cycle 1, Day -3
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
  • Cmax (maximum drug concentration in plasma) of BAY1163877 after single dose administration on Cycle 1, Day 1
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
  • 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
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
  • 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
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
  • 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
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
  • 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
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
  • AUC (area under the plasma concentration vs time curve from zero to infinity) of BAY1163877 after single dose administration on Cycle 1, Day -3
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
  • AUC (area under the plasma concentration vs time curve from zero to infinity) of BAY1163877 after single dose administration on Cycle 1, 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 1. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
  • Cmax/D (maximum drug concentration in plasma divided by dose) of BAY1163877 after single dose administration on Cycle 1, Day -3
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
  • Cmax/D (maximum drug concentration in plasma divided by dose) of BAY1163877 after single dose administration on Cycle 1, Day 1
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
  • 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
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
  • 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
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
  • 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
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
  • 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
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
  • AUC/D (AUC divided by dose) of BAY1163877 after single dose administration on Cycle 1, Day -3
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day -2) and 48 hour(s) post-dose (Day -1)
  • AUC/D (AUC divided by dose) of BAY1163877 after single dose administration on Cycle 1, Day 1
    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.
    date_rangeTime Frame:
    pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 1) and 48 hour(s) post-dose (Day 2)
  • Cmax,md (Cmax after multiple-dose administration) of BAY1163877 on Cycle 1, Day 15
    Cmax,md (Cmax after multiple-dose administration) of BAY1163877. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    date_rangeTime Frame:
    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 on Cycle 1, Day 15
    Cmax/Dmd (Cmax divided by dose after multiple-dose administration) of BAY1163877. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    date_rangeTime Frame:
    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 on Cycle 1, Day 15
    AUC(0-12)md (AUC(0-12) after multiple-dose administration) of BAY1163877. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    date_rangeTime Frame:
    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 on Cycle 1, Day 15
    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.
    date_rangeTime Frame:
    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 on Cycle 1, Day 15
    AUC(0-tlast)md (AUC(0-tlast) after multiple dose administration) of BAY1163877. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    date_rangeTime Frame:
    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 on Cycle 1, Day 15
    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.
    date_rangeTime Frame:
    pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose
  • %AE,ur(0-12) (amount of drug excreted via urine during the collection interval 0 - 12 hours post administration) of BAY1163877
    %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.
    date_rangeTime Frame:
    On Cycle1, Day 1
  • %AE,ur(0-24) (amount of drug excreted via urine during the collection interval 0 - 24 hours post administration) of BAY1163877
    %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.
    date_rangeTime Frame:
    On Cycle1, Day 1
  • %AE,ur(12-24) (amount of drug excreted via urine during the collection interval 12 - 24 hours post administration) of BAY1163877
    %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.
    date_rangeTime Frame:
    On Cycle1, Day 1

Secondary Outcome

  • Response Rate as Defined by RECIST Version 1.1 Reported as Number of Participants With Different Response Type
    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).
    date_rangeTime Frame:
    Up to 2 years
  • Progression-free survival (PFS)
    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.
    date_rangeTime Frame:
    Up to 2 years
  • Time to progression (TTP)
    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.
    date_rangeTime Frame:
    Up to 2 years
  • Duration of response (DOR)
    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.
    date_rangeTime Frame:
    Up to 2 years
  • Duration of treatment (DOT)
    date_rangeTime Frame:
    Up to 2 years
  • Evaluation of biomarker status –change in serum FGF23 (Fibroblast Growth Factor 23) levels from baseline to C2D1
    Change in serum FGF23 levels from baseline to C2D1 was reported as ratio to baseline (%).
    date_rangeTime Frame:
    From baseline to C2D1
  • Evaluation of Pharmacodynamic Parameters (PD) – change of heart rate (HR) from baseline to end of study
    date_rangeTime Frame:
    From baseline up to 2 years
  • Evaluation of Pharmacodynamic Parameters (PD) – change of blood pressure (BP) from baseline to end of study
    date_rangeTime Frame:
    From baseline up to 2 years
  • Evaluation of Pharmacodynamic Parameters (PD) - Change of QT Intervals From Baseline up to Cycle 1, Day 15
    date_rangeTime Frame:
    From baseline up to Cycle 1, Day 15
  • Evaluation of relative bioavailability of the tablet formulation in comparison to the solution formulation of BAY1163877
    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.
    date_rangeTime Frame:
    On Cycle 1, Day -3 and Cycle 1, Day 1
  • 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
    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.
    date_rangeTime Frame:
    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
    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.
    date_rangeTime Frame:
    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
    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.
    date_rangeTime Frame:
    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
    Tmax,md (time to reach maximum drug concentration in plasma after multiple-dose administration) of BAY1163877. Median and full range were reported.
    date_rangeTime Frame:
    pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose
  • Tlast,md (time of last plasma concentration above LLOQ after multiple-dose administration) of BAY1163877 on Cycle 1, Day 15
    Tlast,md (time of last plasma concentration above LLOQ after multiple-dose administration) of BAY1163877. Median and full range were reported.
    date_rangeTime Frame:
    pre-dose (before morning dose), and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose

Trial design

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
Trial Type
Interventional
Intervention Type
Drug
Trial Purpose
Treatment
Allocation
Non-randomized
Blinding
Open Label
Assignment
Single Group Assignment
Trial Arms
5