Clinical trial NCT03473756: Phase 1b/2 Study of Rogaratinib (BAY1163877) in Combination With Atezolizumab in Urothelial Carcinoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Urothelial Carcinoma
Keywords: Locally advanced or metastatic urothelial carcinoma
Bladder cancer
Checkpoint inhibition
FGFR inhibition
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2018-03-22
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Dose-limiting Toxicities(DLTs)
timeFrame: Up to 21 days
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: up to 90 days after the last study medication intake, an average of 60 days
measure: Number of Participants With Drug-related TEAEs
timeFrame: up to 90 days after the last study medication intake, an average of 60 days
measure: Number of Participants With Treatment-emergent Serious Adverse Events(TESAEs)
timeFrame: up to 90 days after the last study medication intake, an average of 60 days
Secondary outcomes:
measure: Objective Response Rate(ORR)
timeFrame: Up to 5 months
measure: Maximal Plasma Concentration (Cmax) of Rogaratinib
timeFrame: At cycle 1 Day 1
measure: Area Under the Rogaratinib Concentration Versus Time Curve (AUC)
timeFrame: At cycle 1 Day 1, 0-t(last)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Chicago
country: United States
facility: UChicago Medicine Comprehensive Cancer Center - Hyde Park
state: Illinois
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute - Detroit Headquarters
state: Michigan
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH Elisabethinen
state: Oberösterreich
city: Vienna
country: Austria
facility: Krankenhaus der Barmherzigen Brüder
state: Wien
city: Salzburg
country: Austria
facility: Uniklinikum Salzburg - Landeskrankenhaus
city: Wien
country: Austria
facility: Universitätsklinikum AKH Wien
city: Bordeaux Cedex
country: France
facility: Institut Bergonie - Unicancer Nouvelle Aquitaine
city: Lille Cedex
country: France
facility: Centre Oscar Lambret - Lille
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest - Saint Herblain
city: Essen
country: Germany
facility: Universitätsklinikum Essen
state: Nordrhein-Westfalen
city: Köln
country: Germany
facility: Universitätsklinikum Köln
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg Universität Mainz
state: Rheinland-Pfalz
city: Modena
country: Italy
facility: Azienda Ospedaliero Universitaria di Modena
state: Emilia-Romagna
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: Lombardia
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia s.r.l - Sviluppo di nuovi farmaci per Terapie Innovative
state: Lombardia
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
state: Veneto
city: Verona
country: Italy
facility: A.O.U.I. Verona
state: Veneto
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Matsuyama
country: Japan
facility: National Hospital Organization Shikoku Cancer Center
state: Ehime
city: Tsukuba
country: Japan
facility: University of Tsukuba Hospital
state: Ibaraki
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital of JFCR
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Barcelona
country: Spain
facility: Ciutat Sanitaria i Universitaria de la Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial de Barcelona
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal | Oncología
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
Study officials:
References:
citation: Grunewald S, Politz O, Bender S, Heroult M, Lustig K, Thuss U, Kneip C, Kopitz C, Zopf D, Collin MP, Boemer U, Ince S, Ellinghaus P, Mumberg D, Hess-Stumpp H, Ziegelbauer K. Rogaratinib: A potent and selective pan-FGFR inhibitor with broad antitumor activity in FGFR-overexpressing preclinical cancer models. Int J Cancer. 2019 Sep 1;145(5):1346-1357. doi: 10.1002/ijc.32224. Epub 2019 Mar 13.