mRNA FGF receptor 1 and 3 positive locally advanced or metastatic urothelial carcinoma progressed after prior platinum-containing chemotherapy MedDRA version: 20.0 Level: LLT Classification code 10064467 Term: Urothelial carcinoma System Organ Class: 100000004864
Conditions
Interventions
Product Name: BAY 1163877 hydrochloride coated tablet 200 mg
Product Code: BAY 1163877 hydrochloride coated tablet 200 mg
Pharmaceutical Form: Coated tablet
INN or Proposed INN: ROGARATINIB
Current S
Sponsors
Bayer AG, D-51368 Leverkusen, Germany
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Existence of archival or fresh biopsy for FGFR testing. FGFR testing of patients will be performed at the investigators’ discretion up to a max. of 90 days prior to start of screening (signing of informed consent for study treatment eligibility). Investigators should ensure all patients will be eligible in terms of disease status and lines of treatment within this timeframe. If the patient is positive for FGFR 1 and/or 3 and is unable start screening by 90 days after FGFR testing, the patient may still be considered for screening after discussion with the sponsor’s designated medical representative and approval by the sponsor Male or female patients = 18 years of age (at least age of legal maturity). Documented urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra, meeting all of the following criteria: Histologically or cytologically confirmed. Patients with mixed histologies are required to have a dominant transitional cell pattern. Locally advanced (T4b, any N; or any T, N 2-3) or metastatic disease (any T, any N and M1). Locally advanced bladder cancer must be unresectable i.e. invading the pelvic or abdominal wall (stage T4b) or presenting with bulky nodal disease (N2-3). ECOG Performance Status of 0 or 1. Disease progression during or following treatment with at least one platinum-containing regimen (patients should have been treated for at least 2 cycles). In patients who received prior adjuvant/neoadjuvant platinum-containing chemotherapy, progression had to occur within 12 months of treatment. High FGFR1 or 3 mRNA expression levels (RNAscope score of 3+ or 4+; measurement is part of this protocol) in archival or fresh tumor biopsy specimen. At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) in contrast enhanced (unless contraindicated) CT or MRI. Adequate laboratory and organ function: Absolute neutrophil count (ANC) = 1,500/mm3 Platelet count = 100,000/mm3 Hemoglobin = 9.0 g/dL (without transfusion or erythropoietin within 4 weeks before randomization). Total bilirubin = 1.5 times the upper limit of normal (ULN). Known Gilbert syndrome is allowed if total bilirubin is = 3 x ULN. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 x ULN (= 5 x ULN for patients with liver involvement of their cancer). Alkaline phosphatase limit = 2.5 x ULN (= 5 x ULN for patients with liver and bone involvement of their cancer). Lipase < 2 x ULN Glomerular filtration rate (GFR) = 30 mL/min/1.73 m2 according to Modification of Diet in Renal Disease (MDRD) abbreviated formula. International normalized ratio (INR) = 1.5 ? ULN, and partial thromboplastin time (PTT) or activated PTT (aPTT) = 1.5 ? ULN. Patients being treated with anticoagulant, e.g. warfarin or heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR is stable based on a pre-dose measurement as defined by the local standard of care. Women of childbearing potential (WOCBP) and fertile men must agree to use adequate contraception when sexually active from signing of the ICF for study treatment eligibility until at least 12 weeks after the last study drug administration. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth contro
Exclusion criteria
Exclusion criteria: Previous or concurrent cancer except: cervical carcinoma in situ treated basal-cell or squamous cell skin carcinoma any cancer curatively treated > 3 years before randomization ocuratively treated incidental prostate cancer (T1/T2a) Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has no radiological evidence of tumor growth and is clinically stable with respect to the tumor at randomization. Also the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies). Known human immunodeficiency virus (HIV) infection. Renal dialysis. Any malabsorption condition. Breast-feeding. Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies) or with taxanes or vinflunine. More than two prior lines of systemic anti-cancer therapy for urothelial carcinoma. Ongoing or previous anti-cancer treatment within 4 weeks before randomization: Patients who have received prior treatment with anti-CTLA-4 may be enrolled provided at least 5 half-lives (approximately 75 days) have elapsed before randomization. Prior cancer vaccines and cellular immunotherapy are permitted. Previous radiotherapy is acceptable under the following conditions: Therapeutic radiotherapy = 3 weeks before the baseline tumor scan. Palliative radiotherapy for bone metastases or soft tissue lesions is allowed and should be completed >7 days prior to baseline tumor scan. Lesions at the site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease. Anti-cancer therapy is defined as any agent or combination of agents with clinically proven anti-tumor activity administered by any route with the purpose of affecting the malignancy, either directly or indirectly, including palliative and therapeutic endpoints. Use of strong inhibitors and inducers of CYP3A4 (see Appendix 16.1) should have been stopped 2 weeks before randomization. Concomitant therapies that are known to increase serum calcium or phosphate levels and cannot be discontinued or switched to a different medication before randomization. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results. Major surgery, or significant trauma within 4 weeks before randomization (central line surgery is not considered major surgery). Unresolved toxicity higher than National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE v.4.03) Grade 1 attributed to any prior therapy/procedure excluding alopecia, anemia and/or hypothyroidism. History or current condition of an uncontrolled cardiovascular disease including any of the following conditions: Congestive heart failure (CHF) NYHA > Class 2. Unstable angina (symptoms of angina at rest) or new-onset angina (within last 3 months before randomization). Myocardial infarction (MI) within past 6 months before randomization. Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with arrhythmia under control with anti-arrhythmic therapy such as beta-blockers or digoxin are eligible. Arterial or venous thrombotic events or embolic events such as cerebrovascular accident (including
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary objective of this trial is to demonstrate the superiority of rogaratinib over chemotherapy in terms of prolonging overall survival of urothelial carcinoma patients with FGFR positive tumors. The objective for the Phase 2 part of the study is to demonstrate the efficacy of rogaratinib over chemotherapy in terms of objective response rate of urothelial carcinoma patients with FGFR positive tumors.;Secondary Objective: Secondary objective of this trial is to evaluate additional efficacy including the following variables: Progression-free survival (PFS) Objective response rate (ORR) Disease control rate (DCR) Duration of response (DOR) and to evaluate the safety of rogaratinib (adverse events) Tertiary objectives are: Patient-reported outcome (PRO) Evaluate biomarkers to investigate the drug (i.e. mode-of-action-related) Pharmacokinetics effect and/or safety) and/or the pathomechanism of the disease. Pharmacokinetics;Primary end point(s): Overall survival is the primary efficacy variable. The primary efficacy variable is overall survival (OS). OS data will be considered mature and the final OS analysis (i.e. primary completion) will be performed when approximately a total of 232 PIK3CA and RAS WT patients have died, in accordance with the power calculations specified for the full analysis set (FAS). For the primary efficacy variable of overall survival, a hierarchical fixed-sequence procedure based on stratified log-rank test controlling type I error at a level of 0.025 (one-sided) will be conducted for the WT population first (step 1). A full alpha of 0.025 (one-sided) will be passed on to OS in all study population and some selected secondary endpoints (step 2), if and only if the null hypothesis of OS for WT population is rejected.in the following sequence: step 1) WT population; step 2) all study population. Step 2 will be tested if and only if the null hypothesis of step 1) is rejected. Details on controlling family-wise type I error with | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy variables include PFS, ORR, DCR and DOR based on independent central review assessments. Secondary efficacy variables including progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and duration of response (DOR) (see Section 9.4 for definitions) will be analyzed based on final database when approximately a total of 232 PIK3CA and RAS WT patients have died. The formal testing procedure controlling family-wise type I error of 0.025 as one-sided for PFS and ORR in WT and all study population will be specified in a separate Statistical Analysis Plan (SAP) document. Further analysis details with respect to PFS, ORR, DCR and DOR are summarized below. For analyses of PFS, in both populations, the two treatment arms will be compared using a log-rank test stratified by the same stratification factors as used in the analyses of the primary variable, based on independent central review assessments. The hazard ratio (rogaratinib / chemotherapy) and 95% confidence interval will be provided. KM estimates and KM curves will also be presented for each treatment arm. The KM estimates at time points such as 2 months, 4 months etc. together with corresponding 95% confidence intervals as well as the differences of these estimates between the rogaratinib arm and the chemotherapy arm will also be calculated. ORR as well as DCR will be compared between treatment arms using the Cochran-Mantel-Haenszel (CMH) test adjusting for the same stratification factors as used in the analyses of the primary variable, based on independent central review assessments for both populations. Estimates and 95% confidence intervals will be computed for each treatment arm. The differences in ORR and DCR between the rogaratinib and chemotherapy arms and the corresponding 95% confidence intervals will also be calculated. For both populations, summary statistics will be displayed for all best response categories: CR, PR, SD, N | — |
Countries
Australia, Austria, Belgium, Brazil, Canada, China, Czech Republic, Denmark, Finland, France, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Korea, Democratic People's Republic of, Netherlands, Poland, Portugal, Russian Federation, Singapore, Slovakia, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Contacts
Public ContactBayer Clinical Trials Contact
Bayer AG
Outcome results
None listed