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

Urothelial Carcinoma Clinical Trial

— FORT-2  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03473756
• Other study ID #: 19131
• Secondary ID: 2017-001483-38
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: May 15, 2018
• Est. completion date: August 30, 2024

Study information

• Verified date: May 2024
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 37
• Est. completion date: August 30, 2024
• Est. primary completion date: July 16, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Transitional Cell
• Urothelial Carcinoma

Intervention

Drug:
• Rogaratinib (BAY1163877)
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.
• Atezolizumab
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.

Locations

Country	Name	City	State
Austria	Ordensklinikum Linz GmbH Elisabethinen	Linz	Oberösterreich
Austria	Uniklinikum Salzburg - Landeskrankenhaus	Salzburg
Austria	Krankenhaus der Barmherzigen Brüder	Wien
Austria	Universitätsklinikum AKH Wien	Wien
France	Institut Bergonié - Unicancer Nouvelle Aquitaine	Bordeaux Cedex
France	Centre Oscar Lambret - Lille	Lille Cedex
France	Institut de Cancérologie de l'Ouest - Saint Herblain	Nantes
Germany	Universitätsklinikum Essen	Essen	Nordrhein-Westfalen
Germany	Universitätsklinikum Köln	Köln	Nordrhein-Westfalen
Germany	Universitätsmedizin der Johannes Gutenberg Universität Mainz	Mainz	Rheinland-Pfalz
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	Lombardia
Italy	IRCCS Istituto Europeo di Oncologia s.r.l. (IEO)	Milano	Lombardia
Italy	A.O.U. di Modena - Policlinico	Modena	Emilia-Romagna
Italy	Istituto Oncologico Veneto IRCCS (IOV)	Padova	Veneto
Italy	A.O.U.I. Verona	Verona	Veneto
Japan	National Cancer Center Hospital East	Kashiwa	Chiba
Japan	The Cancer Institute Hospital of JFCR	Koto-ku	Tokyo
Japan	National Hospital Organization Shikoku Cancer Center	Matsuyama	Ehime
Japan	University of Tsukuba Hospital	Tsukuba	Ibaraki
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Spain	Ciutat Sanitaria i Universitaria de la Vall d'Hebron	Barcelona
Spain	Hospital Clínic i Provincial de Barcelona	Barcelona
Spain	Hospital Ramón y Cajal | Oncología	Madrid
Spain	Hospital General Universitario de Valencia	Valencia
United States	Comprehensive Cancer Center	Chicago	Illinois
United States	Barbara Ann Karmanos Cancer Institute - Detroit	Detroit	Michigan
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	University of Arizona Cancer Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Austria,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	Maximal plasma concentration (Cmax) of rogaratinib in Part A	Part A	At cycle 1 Day 1
Secondary	Area under the curve(0-8) (AUC(0-8)) of rogaratinib in Part A	Part A	At cycle 1 Day 1