Phase 1b/2 Study of Rogaratinib (BAY1163877) in Combination With Atezolizumab in Urothelial Carcinoma

Study Overview
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Brief Summary
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FORT-2 is designed to evaluate safety, efficacy, RP2D and PK of rogaratinib in combination with atezolizumab in patients with untreated FGFR-positive urothelial carcinoma. The study originally comprised two separate parts: Phase 1b (Part A) and Phase 2 (Part B). The study parts differ in design, objectives, and treatment. The primary objectives of this Phase 1b study (Part A) are to determine the safety, tolerability, RP2D and pharmacokinetics of rogaratinib in combination with atezolizumab in these patients. The primary objective of the Part B is to compare progression-free survival (PFS) according to RECIST v1.1 of rogaratinib in combination with atezolizumab over placebo in combination with atezolizumab in untreated patients with FGFR-positive locally advanced or metastatic urothelial carcinoma. Of note, patients who participate in Part A are not allowed to participate in Part B. Part B will be initiated once the data from Part A supports continuation of the study, even if this occurs prior to primary completion of Part A. The sponsor may decide not to continue the study as a whole after completion of Part A if the data do not support further development. Part B of the study will no longer be conducted.

Official Title
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An International, Multicenter, Phase 1b/2 Study of Rogaratinib (BAY1163877) in Combination With Atezolizumab as First-line Treatment in Cisplatin-ineligible Patients With FGFR-positive Locally Advanced or Metastatic Urothelial Carcinoma

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: Rogaratinib (BAY1163877)
* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Existence of archival or fresh tumor biopsy specimen for FGFR1/3 mRNA expression testing High FGFR1 or 3 mRNA expression levels (RNAscope score of 3+ or 4+) in archival or fresh tumor biopsy specimen Documented locally advanced (T4, any N; or any T, N2-3) or metastatic urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra, meeting all of the following criteria: No prior systemic treatment for locally advanced or metastatic urothelial carcinoma. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval > 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment-naïve in the metastatic setting. Prior local intra-vesical chemotherapy or prior local immunotherapy is allowed if completed at least 4 weeks before the first study drug administration. Regionally available standard of care options must be considered for all patients. Ineligibility for cisplatin-based chemotherapy as defined by any one of the following criteria: Impaired renal function (GFR > 30 but < 60 mL/min/1.73 m2) according to the modification of diet in renal disease (MDRD) abbreviated formula A Hearing loss (measured by audiometry) of > 25 dB at two contiguous test frequencies in at least one ear. Grade ≥ 2 peripheral neuropathy (i.e. sensory alteration or paresthesia including tingling) Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1. Exclusion criteria: Active symptomatic or untreated brain metastases as determined by CT or MRI evaluation during screening and prior radiographic assessment. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, granulomatosis with polyangiitis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. History or current condition of an uncontrolled cardiovascular disease including any of the following conditions: Congestive heart failure (CHF) NYHA Class 2 or greater, unstable angina (symptoms of angina at rest) or New-onset angina (within last 3 months before the first study drug administration) Myocardial infarction (MI) within past 6 months before the first study drug administration Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or known left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate. Current diagnosis of any retinal disorders including retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion. Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia). Concomitant therapies that are known to increase serum calcium or phosphate levels (i.e. antacids, phosphate-containing laxatives oral/rectal, potassium phosphate) and that cannot be discontinued or switched to a different medication before the first study drug administration Treatment with systemic corticosteroids or other systemic immunosuppressant medications within 2 weeks before the first study drug administration, or anticipated requirement for systemic immunosuppressive medications during the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rogaratinib + Atezolizumab in Part A<br>Part A: Part A is conducted in patients who are cisplatin-ineligible and have had no prior systemic treatment for locally advanced or metastatic disease. Patients will receive rogaratinib plus atezolizumab combination treatment. | Drug: Rogaratinib (BAY1163877)<br>* Part A:Rogaratinib will be administered orally until disease progression, unacceptable toxicity or consent withdrawal. The starting dose of 800 mg b.i.d. will be confirmed using a dose selection design.<br>Drug: Atezolizumab<br>* Part A: A fixed dose of 1200 mg atezolizumab will be administered through intravenous (i.v.) infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity or consent withdrawal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Dose-limiting toxicities(DLTs) in Part A | A DLT is defined as any of the hematological, non-hematological or other TEAEs occurring during Cycle 1 and regarded by the investigators and/or sponsor to be related to rogaratinib or atezolizumab. The CTCAE v 4.03 will be used to assess toxicities / adverse events. | Up to 21 days | 
| Number of participants with treatment-emergent adverse events (TEAEs) in Part A | Part A | Up to 30 days after the last dose of rogaratinib or 90 days after the last atezolizumab administration, whichever comes later | 
| Number of participants with drug-related TEAEs in Part A | Part A | Up to 30 days after the last dose of rogaratinib or 90 days after the last atezolizumab administration, whichever comes later | 
| Number of participants with treatment-emergent serious adverse events(TESAEs) in Part A | Part A | Up to 30 days after the last dose of rogaratinib or 90 days after the last atezolizumab administration, whichever comes later | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate(ORR) in Part A | Part A:Objective response rate (ORR) is defined as the percentage of patients with complete response (CR) or partial response (PR). Patients for whom best overall tumor response is not CR or PR, as well as patients without any post-baseline tumor assessment will be considered non-responders. For all patients, the best overall tumor response will be determined locally by investigators using the RECIST criteria (v1.1). | Up to 5 months | 
| Maximal plasma concentration (Cmax) of rogaratinib in Part A | Part A | At cycle 1 Day 1 | 
| Area under the curve(0-8) (AUC(0-8)) of rogaratinib in Part A | Part A | At cycle 1 Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally advanced or metastatic urothelial carcinoma, Bladder cancer, Checkpoint inhibition, FGFR inhibition