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

Sponsor

Bayer (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03473756

Collaborator

(none)

Enrollment

Locations

Arm

67.3

Anticipated Duration (Months)

1.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Urothelial Carcinoma	Drug: Rogaratinib (BAY1163877) Drug: Atezolizumab	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

37 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Masking Description:

Part A is open-label.

Primary Purpose:

Treatment

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

Actual Study Start Date :

May 15, 2018

Actual Primary Completion Date :

Jul 16, 2021

Anticipated Study Completion Date :

Dec 22, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rogaratinib + Atezolizumab in Part A 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) 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. Drug: 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.

Arm

Intervention/Treatment

Experimental: Rogaratinib + Atezolizumab in Part A

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)

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.

Drug: 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.

Outcome Measures

Primary Outcome Measures

Number of subjects with Dose-limiting toxicities(DLTs) in Part A [Up to 21 days]
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.
Number of subjects with treatment-emergent adverse events (TEAEs) in Part A [Up to 5 months]
Part A
Number of subjects with drug-related TEAEs in Part A [Up to 5 months]
Part A
Number of subjects with treatment-emergent serious adverse events(TESAEs) in Part A [Up to 5 months]
Part A

Secondary Outcome Measures

Objective Response Rate(ORR) in Part A [Up to 5 months]
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).
Maximal plasma concentration (Cmax) of rogaratinib in Part A [At cycle 1 Day 1]
Part A
Area under the curve(0-8) (AUC(0-8)) of rogaratinib in Part A [At cycle 1 Day 1]
Part A

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Exlusion 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona Cancer Center	Tucson	Arizona	United States	85724
2	Comprehensive Cancer Center	Chicago	Illinois	United States	60637
3	Barbara Ann Karmanos Cancer Institute - Detroit	Detroit	Michigan	United States	48201
4	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
5	Ordensklinikum Linz GmbH Elisabethinen	Linz	Oberösterreich	Austria	4020
6	Uniklinikum Salzburg - Landeskrankenhaus	Salzburg		Austria	5020
7	Krankenhaus der Barmherzigen Brüder	Wien		Austria	1020
8	Universitätsklinikum AKH Wien	Wien		Austria	1090
9	Institut Bergonié - Unicancer Nouvelle Aquitaine	Bordeaux Cedex		France	33076
10	Centre Oscar Lambret - Lille	Lille Cedex		France	59020
11	Institut de Cancérologie de l'Ouest - Saint Herblain	Nantes		France	44805
12	Universitätsklinikum Essen	Essen	Nordrhein-Westfalen	Germany	45122
13	Universitätsklinikum Köln	Köln	Nordrhein-Westfalen	Germany	50937
14	Universitätsmedizin der Johannes Gutenberg Universität Mainz	Mainz	Rheinland-Pfalz	Germany	55131
15	A.O.U. di Modena - Policlinico	Modena	Emilia-Romagna	Italy	41124
16	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	Lombardia	Italy	20133
17	IRCCS Istituto Europeo di Oncologia s.r.l. (IEO)	Milano	Lombardia	Italy	20141
18	Istituto Oncologico Veneto IRCCS (IOV)	Padova	Veneto	Italy	35128
19	A.O.U.I. Verona	Verona	Veneto	Italy	37134
20	National Cancer Center Hospital East	Kashiwa	Chiba	Japan	277-8577
21	National Hospital Organization Shikoku Cancer Center	Matsuyama	Ehime	Japan	791-0280
22	University of Tsukuba Hospital	Tsukuba	Ibaraki	Japan	305-8576
23	The Cancer Institute Hospital of JFCR	Koto-ku	Tokyo	Japan	135-8550
24	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
25	Asan Medical Center	Seoul		Korea, Republic of	05505
26	Samsung Medical Center	Seoul		Korea, Republic of	06351
27	Ciutat Sanitària i Universitaria de la Vall d'Hebron	Barcelona		Spain	08035
28	Hospital Clínic i Provincial de Barcelona	Barcelona		Spain	08036
29	Hospital Ramón y Cajal \| Oncología	Madrid		Spain	28034
30	Hospital General Universitario de Valencia	Valencia		Spain	46014