Study of Rogaratinib (BAY1163877) vs Chemotherapy in Patients With FGFR (Fibroblast Growth Factor Receptor)-Positive Locally Advanced or Metastatic Urothelial Carcinoma (FORT-1)

• ClinicalTrials.gov Identifier: NCT03410693
• Recruitment Status: Completed
• First Posted: January 25, 2018
• Results First Posted: December 29, 2021
• Last Update Posted: September 28, 2022
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: January 19, 2018
• First Posted Date: January 25, 2018
• Results First Submitted Date: October 13, 2021
• Results First Posted Date: December 29, 2021
• Last Update Posted Date: September 28, 2022
• Actual Study Start Date: May 31, 2018
• Actual Primary Completion Date: October 27, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 30, 2021)

Objective Response Rate (ORR) - Central Assessment [ Time Frame: From start of treatment up to end of active follow-up, approximately 29 months ]

ORR is defined as the percentage of participants with complete response (CR) or partial response (PR). participants for whom overall best response is not CR or PR, as well as participants without any post-baseline tumor assessment will be considered non-responders.

Original Primary Outcome Measures (submitted: January 19, 2018)

Overall Survival [ Time Frame: Up to 45 months ]

Defined as the time (days) 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.

Current Secondary Outcome Measures (submitted: November 30, 2021)

• Disease-control Rate (DCR) - Central Assessment [ Time Frame: From start of treatment till end of active follow-up, approximately 29 months ]
  DCR was defined as the percentage of participants whose overall best response was not a progressive disease (i.e., CR, PR, stable disease [SD] or Non CR/Non PD).
• Progression-free Survival (PFS) - Central Assessment [ Time Frame: From start of treatment till end of active follow-up, approximately 29 months ]
  Progression free survival (PFS) was defined as the time (days) from randomization to date of first observed disease progression (radiological or clinical assessment or both) or death due to any cause (if death occurred before progression was documented).
• Duration of Response (DOR) - Central Assessment [ Time Frame: From start of treatment till end of active follow-up, approximately 29 months ]
  DOR (for patients with PR and CR only) was defined as the time from the first documented objective response of PR or CR, whichever was noted earlier, to disease progression (including symptomatic deterioration) or death, whichever was earlier
• Number of Participants With Treatment Emergent Adverse Events [ Time Frame: From start of treatment up to 30 days after the last administration of study treatment, approximately 29 months ]
  A treatment-emergent event was defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of study treatment

Original Secondary Outcome Measures (submitted: January 19, 2018)

• Progression-free survival (PFS) [ Time Frame: Up to 45 months ]
  Defined as the time (days) from randomization to date of first observed disease progression (radiological or clinical assessment) or death due to any cause, if death occurs before progression is documented. 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.
• Objective response rate (ORR) [ Time Frame: Up to 45 months ]
  Defined as the percentage of patients with complete response (CR) or partial Response (PR). Patients for whom overall best response is not CR or PR, as well as patients without any post-baseline tumor assessment will be considered non-responders.
• Disease-control rate (DCR) [ Time Frame: Up to 45 months ]
  Defined as the percentage of patients, whose overall best response was not progressive disease [PD] (i.e. CR, PR, Stable Disease [SD] or Non CR/Non PD). Tumor assessments with SD as response, that is performed prematurely after randomization of the patient (i.e. substantially earlier than the first planned radiological tumor assessment at 6 weeks), will not be taken into account.
• Duration of response (DOR) [ Time Frame: Up to 45 months ]
  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.
• Incidence of Adverse Events as a measure of safety and tolerability [ Time Frame: Up to 45 months ]

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

Descriptive Information

• Brief Title: Study of Rogaratinib (BAY1163877) vs Chemotherapy in Patients With FGFR (Fibroblast Growth Factor Receptor)-Positive Locally Advanced or Metastatic Urothelial Carcinoma
• Official Title: A Randomized, Open Label, Multicenter Phase 2/3 Study to Evaluate the Efficacy and Safety of Rogaratinib (BAY1163877) Compared to Chemotherapy in Patients With FGFR-positive Locally Advanced or Metastatic Urothelial Carcinoma Who Have Received Prior Platinum-containing Chemotherapy

Brief Summary

This is a randomized, open-label, multicenter Phase 2/3 study to evaluate the efficacy and safety of rogaratinib (BAY 1163877) compared to chemotherapy in patients with FGFR-positive locally advanced or metastatic urothelial carcinoma who have received prior platinum-containing chemotherapy.

The primary objective is to demonstrate the superiority of rogaratinib over chemotherapy in terms of objective response rate (before: overall survivial) of urothelial carcinoma patients with FGFR positive tumors.

At randomization, patients will have locally advanced or metastatic urothelial carcinoma and have received at least one prior platinum-containing chemotherapy regimen. Only patients with FGFR1 or 3 positive tumors can be randomized into the study. Archival tumor tissue is adequate for testing of FGFR1 and 3 mRNA expressions, which will be determined centrally using an RNA in situ hybridization (RNA-ISH) test. Approximately 42 % of UC patients with locally advanced or metastatic UC are identified as FGFR-positive by the RNA-ISH cut-off applied.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Transitional Cell

Intervention

• Drug: Rogaratinib (BAY1163877)
  Rogaratinib administered as oral (p.o.) tablets twice daily (b.i.d.) continuously
• Drug: Chemotherapy
  Chemotherapy as taxane (docetaxel or paclitaxel) or vinflunine administered through intravenous (i.v.) infusion every 3 weeks (on day 1 of a 21-day cycle) The choice of the chemotherapy is at the discretion of the investigator, taking into consideration the status of the authorization or treatment guidelines in the given country.

Study Arms

• Experimental: Rogaratinib

  Rogaratinib treatment study arm, comprising

  1. Pre-treatment period, including FGFR testing and screening,
  2. Treatment period, and
  3. Follow-up period, including active follow-up and long-term follow-up. Patients will be considered "on study" during the pre-treatment, treatment and active followup periods. During the long-term follow-up period the patients will be considered "off study".
  Intervention: Drug: Rogaratinib (BAY1163877)
• Active Comparator: Chemotherapy

  Chemotherapy treatment study arm, comprising

  1. Pre-treatment period, including FGFR testing and screening,
  2. Treatment period, and
  3. Follow-up period, including active follow-up and long-term follow-up. Patients will be considered "on study" during the pre-treatment, treatment and active followup periods. During the long-term follow-up period the patients will be considered "off study".
  Intervention: Drug: Chemotherapy

Publications *

• Sternberg CN, Petrylak DP, Bellmunt J, Nishiyama H, Necchi A, Gurney H, Lee JL, van der Heijden MS, Rosenbaum E, Penel N, Pang ST, Li JR, Garcia Del Muro X, Joly F, Papai Z, Bao W, Ellinghaus P, Lu C, Sierecki M, Coppieters S, Nakajima K, Ishida TC, Quinn DI. FORT-1: Phase II/III Study of Rogaratinib Versus Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on FGFR1/3 mRNA Expression. J Clin Oncol. 2023 Jan 20;41(3):629-639. doi: 10.1200/JCO.21.02303. Epub 2022 Oct 14.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 13, 2021): 175
• Original Estimated Enrollment (submitted: January 19, 2018): 400
• Actual Study Completion Date: October 27, 2020
• Actual Primary Completion Date: October 27, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Existence of archival or fresh biopsy for FGFR testing. Mandatory FGFR testing of patients will be performed prior to start of screening. The timing of the FGFR test is at the discretion of the investigator. Investigators should ensure all patients will be eligible in terms of disease status and lines of treatment.

• Documented urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra meeting all of the following criteria

  • Histologically confirmed (Patients with mixed histologies are required to have a dominant transitional cell pattern.)
  • Locally advanced (T4, any N; or any T, N 2-3) or metastatic disease (any T, any N and M1). Locally advanced bladder cancer must be unresectable i.e. invading the pelvic or abdominal wall (stage T4b) or presenting with bulky nodal disease (N2-3).
• ECOG (Eastern Cooperative Oncology Group) Performance Status of 0 or 1
• Disease progression during or following treatment with at least one platinum-containing regimen (patients should have been treated for at least 2 cycles). In patients who received prior adjuvant/ neoadjuvant platinum-containing chemotherapy, progression had to occur within 12 months of treatment.
• High FGFR1 or 3 mRNA expression levels in archival or fresh tumor biopsy specimen quantified as outlined in the lab manual
• At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) in contrast enhanced (unless contraindicated) CT or MRI

Exclusion Criteria:

• Previous or concurrent cancer except

  • cervical carcinoma in situ
  • treated basal-cell or squamous cell skin carcinoma
  • any cancer curatively treated > 3 years before randomization
  • curatively treated incidental prostate cancer (T1/T2a)
• Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies) or with taxanes or vinflunine
• More than two prior lines of systemic anti-cancer therapy for urothelial carcinoma given for advanced unresectable/ metastatic disease
• Ongoing or previous anti-cancer treatment within 4 weeks before randomization.
• Unresolved toxicity higher than National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE v.4.03) Grade 1 attributed to any prior therapy/ procedure excluding alopecia, anemia and/ or hypothyroidism

• History or current condition of an uncontrolled cardiovascular disease including any of the following conditions:

  • Congestive heart failure (CHF) NYHA (New York Heart Association) > Class 2
  • Unstable angina (symptoms of angina at rest) or new-onset angina (within last 3 months before randomization)
  • Myocardial infarction (MI) within past 6 months before randomization
  • Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with arrhythmia under control with anti-arrhythmic therapy such as beta-blockers or digoxin are eligible.
• Arterial or venous thrombotic events or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before randomization
• Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia)
• Current diagnosis of any retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion
• Any hemorrhage / bleeding event ≥ CTCAE v.4.03 Grade 3 within 4 weeks before randomization

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: Australia, Austria, Belgium, Canada, China, Czechia, Denmark, Finland, France, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Portugal, Russian Federation, Singapore, Slovakia, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
• Removed Location Countries: Brazil

Administrative Information

• NCT Number: NCT03410693
• Other Study ID Numbers: 17403; 2016-004340-11 ( 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: Not Provided
• Current Responsible Party: Bayer
• Original Responsible Party: Same as current
• Current Study Sponsor: Bayer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: September 2022