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

• ClinicalTrials.gov Identifier: NCT03473756
• Recruitment Status: Active, not recruiting
• First Posted: March 22, 2018
• Last Update Posted: May 6, 2022
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: March 16, 2018
• First Posted Date: March 22, 2018
• Last Update Posted Date: May 6, 2022
• Actual Study Start Date: May 15, 2018
• Actual Primary Completion Date: July 16, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 6, 2022)

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

Original Primary Outcome Measures (submitted: March 21, 2018)

• Progression Free Survival(PFS) [ Time Frame: Up to 25 months ]
  Part B Progression-free survival (PFS) is defined as the time (days) from randomization to date of first observed disease progression (radiological or clinical, whichever is earlier) or death due to any cause, if death occurs before progression is documented. The actual date that the tumor scan was performed will be used for this calculation. If a tumor assessment is performed over more than one day (e.g. scans for chest and abdomen done on different days for the same evaluation), the earliest date will be used for the calculation of PFS. For patients without documented radiological or clinical progression or death at the time of analysis, PFS will be censored at the last actual visit date of tumor evaluation. The primary analysis of PFS will be based on assessment by independent central review.
• Number of subjects with Dose-limiting toxicities(DLTs) in Part A [ Time Frame: 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 [ Time Frame: Up to 5 months ]
  Part A
• Number of subjects with drug-related TEAEs in Part A [ Time Frame: Up to 5 months ]
  Part A
• Number of subjects with treatment-emergent serious adverse events(TESAEs) in Part A [ Time Frame: Up to 5 months ]
  Part A

Current Secondary Outcome Measures (submitted: April 6, 2022)

• Objective Response Rate(ORR) in Part A [ Time Frame: 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 [ Time Frame: At cycle 1 Day 1 ]
  Part A
• Area under the curve(0-8) (AUC(0-8)) of rogaratinib in Part A [ Time Frame: At cycle 1 Day 1 ]
  Part A

Original Secondary Outcome Measures (submitted: March 21, 2018)

• Objective Response Rate(ORR) in Part A [ Time Frame: 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).
• Disease Control Rate(DCR) in Part B [ Time Frame: Up to 25 months ]
  Part B:Disease control rate (DCR) is defined as the percentage of patients, whose overall best response was not progressive disease (i.e. CR, PR, SD or Non CR/Non PD).
• Duration of Response(DOR) in Part B [ Time Frame: Up to 25 months ]
  Part B:Duration of response (DOR) (for PR and CR) is defined as the time from the first documented objective response of PR or CR, whichever is noted earlier, to disease progression or death (if death occurs before progression is documented). DOR will be defined for responders only, i.e. patients with a CR or PR.
• Overall Survival(OS) in Part B [ Time Frame: Up to 25 months ]
  Part B:Overall survival (OS) is defined as the time from randomization to death due to any cause. Patients alive at the date of data cut-off for analysis will be censored at the last date known to be alive.
• Maximal plasma concentration (Cmax) of rogaratinib in Part A [ Time Frame: At cycle 1 Day 1 ]
  Part A
• Area under the curve(0-8) (AUC(0-8)) of rogaratinib in Part A [ Time Frame: At cycle 1 Day 1 ]
  Part A
• Objective Response Rate (ORR) in Part B [ Time Frame: Up to 25 months ]
• Concentrations for rogaratinib in Part B [ Time Frame: Cycle 1 Day 1(C1D1), C2D1, C3D1, C4D1, C5D1 ]
  Part B
• Concentrations for atezolizumab in Part B [ Time Frame: C1D1, C1D15 ]
  Part B
• Number of subjects with treatment-emergent adverse events (TEAEs) in Part B [ Time Frame: Up to 25 months ]
  Part B
• Number of subjects with drug-related TEAEs in Part B [ Time Frame: Up to 25 months ]
  Part B
• Number of subjects with treatment-emergent serious adverse events(TESAEs) in Part B [ Time Frame: Up to 25 months ]
  Part B
• Number of subjects with significant change in vital signs, physical finding and clinical laboratory results [ Time Frame: Up to 25 months ]
  Part B

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description:

Part A is open-label.

Primary Purpose: Treatment

• Condition: 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.
• 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.

Study Arms

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.

Interventions:

• Drug: Rogaratinib (BAY1163877)
• Drug: Atezolizumab

• Publications *: Grünewald S, Politz O, Bender S, Héroult 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 6, 2022): 37
• Original Estimated Enrollment (submitted: March 21, 2018): 190
• Estimated Study Completion Date: December 23, 2022
• Actual Primary Completion Date: July 16, 2021 (Final data collection date for primary outcome measure)

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.

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, France, Germany, Italy, Japan, Korea, Republic of, Spain, United States

Administrative Information

• NCT Number: NCT03473756
• Other Study ID Numbers: 19131; 2017-001483-38 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: Availability of this study's data will be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.

• Responsible Party: Bayer
• Study Sponsor: Bayer
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Bayer
• Verification Date: May 2022