A Study of B-701 in Combination With Pembrolizumab in Treatment of Locally Advanced or Metastatic Urothelial Cell Carcinoma (FIERCE-22)

A Multi-Center, Open-Label Phase 1b/2 Study of a Novel FGFR3 Inhibitor (B-701) Combined With Pembrolizumab in Subjects With Locally Advanced or Metastatic Urothelial Carcinoma Who Have Progressed Following Platinum-based Chemotherapy

This is a Phase 1b/2 multi-center, open-label study to establish the initial safety and to determine a recommended Phase 2 dose of B-701 in combination with pembrolizumab, and to determine safety, tolerability and efficacy of B-701 (vofatamab) plus pembrolizumab in the treatment of subjects with locally advanced or metastatic UCC, who have progressed following platinum-based chemotherapy and who have not received prior immune checkpoint inhibitor therapy.

Study Overview

• Status: Terminated
• Conditions: Urinary Bladder Disease; Locally Advanced or Metastatic Urothelial Cell Carcinoma; Urological Diseases
• Intervention / Treatment: Drug: B-701; Drug: Pembrolizumab

Detailed Description

This is a Phase 1b/2 multi-center, open-label study to determine the safety, tolerability, and efficacy of B-701 (vofatamab) plus pembrolizumab in the treatment of subjects with locally advanced or metastatic UCC, who have progressed following platinum-based chemotherapy and who have not received prior immune checkpoint inhibitor or FGFR inhibitor-targeted therapy. The study consists of 2 parts: a Phase 1b lead-in phase enrolling 6 to 18 subjects and a Phase 2 dose expansion phase enrolling up to a total of 74 subjects.

Subjects who discontinue B-701 (vofatamab) may continue on study and receive pembrolizumab alone until disease progression, death, withdrawal of patient consent, or study termination. Subjects who discontinue pembrolizumab may continue on study and receive B-701 (vofatamab) alone until disease progression, death, withdrawal of patient consent, or study termination.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1000
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Yvoir, Belgium, 5530
    • Research team
• Denmark
  • Copenhagen, Denmark, 2100
    • Research team
• France
  • Bordeaux, France, 33076
    • Research Site
  • Dijon, France, 21000
    • Research Site
• Germany
  • Dresden, Germany, 01307
    • Research Site
  • Frankfurt, Germany, 60488
    • Research Site
  • Heidelberg, Germany, 69120
    • Research Site
  • Kassel, Germany, 34125
    • Research Site
  • Munich, Germany, 81377
    • Research Site
  • Münster, Germany, 48149
    • Research Site
• Hungary
  • Budapest, Hungary, 1122
    • Research Site
• Italy
  • Milano, Italy, 20141
    • Research Site
  • Milano, Italy, 20133
    • Research Site
• Korea, Republic of
  • Gwangju, Korea, Republic of, 61469
    • Research Site
  • Seongnam-si, Korea, Republic of, 13620
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, 2025
    • Research Site
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Research Site
• Poland
  • Katowice, Poland, 40-514
    • Research Site
  • Warsaw, Poland, 02-781
    • Research Site
  • Warsaw, Poland, 02-567
    • Research Site
  • Wieliszew, Poland, 05-135
    • Research Site
  • Wroclaw, Poland, 53-413
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 125284
    • Research Site
  • Saint Petersburg, Russian Federation, 197758
    • Research Site
  • Ufa, Russian Federation, 450000
    • Research team
• Serbia
  • Belgrade, Serbia, 11000
    • Research Site
  • Belgrade, Serbia, 11070
    • Research Site
  • Kragujevac, Serbia, 34000
    • Research Site
  • Niš, Serbia, 18000
    • Research Site
  • Sremska Kamenica, Serbia, 21204
    • Research Site
• Spain
  • Barcelona, Spain, 08035
    • Research Site
  • Barcelona, Spain, 08036
    • Research Site
  • Madrid, Spain, 28034
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • CA
    • Madrid, CA, Spain, 28050
      • Research Site
• Sweden
  • Uppsala, Sweden, 75185
    • Research Site
• Turkey
  • Ankara, Turkey, 06100
    • Research Site
  • Antalya, Turkey, 07059
    • Research Site
• Ukraine
  • Dnipropetrovs'k, Ukraine, 49102
    • Research Site
  • Kiew, Ukraine, 03022
    • Research Site
• United States
  • California
    • Greenbrae, California, United States, 94904
      • Research Site
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Research Site
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Research Site
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

1. Have locally advanced (on TNM staging: T4b and any N, or any T and N2-3) or metastatic transitional cell carcinoma of the urothelium, including of the urinary bladder, urethra, ureter, and/or renal pelvis. The diagnosis must be histologically or cytologically confirmed.
2. Have progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
3. Have available archival tumor or be willing to undergo diagnostic biopsy at screening. Sample must be of suitable quality and quantity to satisfy group assignment and biomarker endpoints.
4. Have measurable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.

Key Exclusion Criteria:

1. Participants with a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on the Screening chest CT scan.
2. Prior therapy with an anti-programmed cell death 1 (PD-1) or anti-PD-Ligand 1 agent, or with an agent directed to another co-inhibitory T-cell receptor or FGFR inhibitor.
3. Patients with autoimmune disease or medical conditions that required systemic corticosteroids (> 10 mg/day prednisone or its equivalent) or other immunosuppressive medications or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment. Note: Replacement therapy (e.g. physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
4. Primary central nervous system (CNS) malignancy or CNS metastases.
5. History of clinically significant coagulation or platelet disorder in the past 12 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: B-701 (vofatamab); B-701 (vofatamab, 25 mg/kg) will be administered via IV infusion on Cycle 0 Day 1 for a single 14-day cycle.	Drug: B-701; B-701 (vofatamab) is a human IgG1 monoclonal antibody that is highly specific for the FGFR3 receptor.; Other Names: MFGR1877S; Vofatamab
Experimental: B-701 (vofatamab) plus pembrolizumab; B-701 (vofatamab, 25 mg/kg [or the recommended Phase 2 dose if different than 25 mg/kg]) plus pembrolizumab (200 mg) will be administered by IV infusion on Cycle 1 Day 1 once every 3 weeks.	Drug: B-701; B-701 (vofatamab) is a human IgG1 monoclonal antibody that is highly specific for the FGFR3 receptor.; Other Names: MFGR1877S; Vofatamab; Drug: Pembrolizumab; Pembrolizumab is a humanized antibody used in cancer immunotherapy. Pembrolizumab targets and blocks a protein called PD-1 on the surface of certain immune cells called T-cells. Blocking PD-1 triggers the T-cells to find and kill cancer cells.; Other Names: Keytruda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities Within a Period of 35 Days	Number of Participants with Dose Limiting Toxicities within a period of 35 days will be analyzed reviewing the aggregate of adverse events (AEs) and serious adverse events (SAEs) by the B-701 program Safety Oversight Committee and will result in a recommended Phase 2 dose. Six subjects at a time are enrolled and observed for 35 days after the initial dose. If 2 or more subjects experience a DLT that dose will be declared intolerable and de-escalation of the dose will occur.	1 year
Number of Subjects Experiencing Adverse Events (AEs and SAEs)	Evaluate the safety and tolerability of B-701 (vofatamab) plus pembrolizumab in subjects with UCC as assessed by number of subjects experiencing adverse events (AEs and SAEs), physical examination findings, laboratory test results, and vital signs over time. This outcome is measured by a safety monitoring committee who regularly met and reviewed aggregate trends of reports AEs, lab ranges, physical exams etc. and determined if the drug was safe to continue.	2.5 years
Efficacy of B-701 (Vofatamab) Plus Pembrolizumab Measured by ORR	Evaluate the efficacy of B-701 (vofatamab) plus pembrolizumab in subjects with UCC as measured by objective response rate (ORR) by RECIST 1.1. ORR is defined as the percentage of subjects who have baseline measurable disease and who achieve a best response of either complete response (CR) or partial response (PR).	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of Changes in Biomarkers Induced by B-701 (Vofatamab)	Whole blood (PBMCs), serum, and plasma samples for biomarker analyses will be obtained prior to infusion of B-701 at pre-defined visit days. The effects of B-701 on the downstream signaling of the FGFR3 pathway, tumor sub-type and on the immune surveillance of UCC tumors will be monitored using techniques that include gene expression profiling (such as whole transcriptome RNAseq), sequencing of T-cell receptors, and immunohistochemistry.	2.5 years
Efficacy of B-701 (Vofatamab) in Combination With Pembrolizumab as Measured by DOR	Evaluate the efficacy of B-701 (vofatamab) in combination with pembrolizumab in the treatment of subjects with UCC as measured by duration of objective response (DOR), defined as the time from first occurrence of a documented, objective response until the time of relapse or death from any cause (RECIST 1.1).	2 years
Efficacy of B-701 (Vofatamab) in Combination With Pembrolizumab as Measured by DCR	Evaluate the efficacy of B-701 in combination with pembrolizumab in the treatment of subjects with UCC as measured by disease control rate (DCR), defined as the percentage of subjects who achieve either complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST 1.1.	2 years
Efficacy of B-701 (Vofatamab) in Combination With Pembrolizumab as Measured by PFS	Evaluate the efficacy of B-701 (vofatamab) in combination with pembrolizumab in the treatment of subjects with UCC as measured by progression-free survival (PFS), defined as the time from a first study treatment dose to first occurrence of disease progression (per RECIST 1.1) or death from any cause, whichever occurs first.	2 years
Efficacy of B-701 (Vofatamab) in Combination With Pembrolizumab as Measured by OS	Evaluate the efficacy of B-701 (vofatamab) in combination with pembrolizumab in the treatment of subjects with UCC as measured by overall survival (OS), defined as the time from first study drug administration to death from any cause (RECIST 1.1)	2.5 years
Change in Subject Reported Quality of Life	Evaluate the efficacy of B-701 (vofatamab) in combination with pembrolizumab in the treatment of subjects with UCC as measured by the change over time in subject reported quality of life as measured by the European Organization for Research and Treatment Quality of Life Questionnaire (EORTC QLQ-C30).	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK Analysis of B-701 (Vofatamab)	PK will be analyzed by measuring B-701 C(trough) levels. B-701 C(trough) levels then will be summarized over time throughout the study and will be compared to predicted B-701 C(trough) levels, whose prediction is based on data observed in previous studies with B-701.	2 years
Immunogenicity of B-701 (Vofatamab)	Determine the immunogenicity of B-701 as measured by anti-B-701 antibody titers at several time points throughout the study.	2 years

Collaborators and Investigators

• Sponsor: Rainier Therapeutics
• Investigators: Study Chair: Rainier Therapeutics, Rainier Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2017
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: April 11, 2017
• First Submitted That Met QC Criteria: April 20, 2017
• First Posted (Actual): April 21, 2017

Study Record Updates

• Last Update Posted (Actual): March 18, 2020
• Last Update Submitted That Met QC Criteria: March 11, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Urothelial Carcinoma; monoclonal antibody; bladder cancer; combination therapy; second line therapy; pembrolizumab; Phase 1b; TCC; checkpoint inhibitor; Phase 2; FGFR3; Transitional Cell Carcinoma; Urothelial Cell Carcinoma; UCC; B-701; invasive bladder cancer; Vofatamab
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Urologic Diseases; Urinary Bladder Diseases; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: B-701-U22; 2017-001292-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No