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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Locally Advanced or Metastatic Urothelial Cell Carcinoma, Urinary Bladder Disease, Urological Diseases

Intervention / Treatment
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* Drug: B-701
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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. Have progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 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. Have measurable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1. Key Exclusion Criteria: 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. 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. 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. Primary central nervous system (CNS) malignancy or CNS metastases. History of clinically significant coagulation or platelet disorder in the past 12 months.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: B-701 (vofatamab) as monotherapy for first 2 weeks followed by B-701 (vofatamab) in combination with pembrolizumab thereafter.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: B-701 (vofatamab)<br>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<br>* B-701 (vofatamab) is a human IgG1 monoclonal antibody that is highly specific for the FGFR3 receptor.<br>* Other names: Vofatamab;|
| Experimental: B-701 (vofatamab) plus pembrolizumab<br>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<br>* B-701 (vofatamab) is a human IgG1 monoclonal antibody that is highly specific for the FGFR3 receptor.<br>* Other names: Vofatamab;Drug: Pembrolizumab<br>* 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.<br>* Other names: Keytruda;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transitional Cell Carcinoma, Urothelial Cell Carcinoma, UCC, bladder cancer, B-701, FGFR3, invasive bladder cancer, TCC, second line therapy, monoclonal antibody, combination therapy, Phase 1b, pembrolizumab, checkpoint inhibitor, Phase 2, Urothelial Carcinoma, Vofatamab