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

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.