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

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

Status

Terminated

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03123055

Acronym

FIERCE-22

Enrollment

Registered

2017-04-21

Start date

2017-04-20

Completion date

2019-12-01

Last updated

2020-03-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

Keywords

Urothelial Cell Carcinoma, UCC, bladder cancer, B-701, FGFR3, invasive bladder cancer, Transitional Cell Carcinoma, TCC, second line therapy, monoclonal antibody, combination therapy, Phase 1b, pembrolizumab, checkpoint inhibitor, Phase 2, Urothelial Carcinoma, Vofatamab

Brief summary

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

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.

Interventions

DRUGB-701

B-701 (vofatamab) is a human IgG1 monoclonal antibody that is highly specific for the FGFR3 receptor.

DRUGPembrolizumab

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.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

B-701 (vofatamab) as monotherapy for first 2 weeks followed by B-701 (vofatamab) in combination with pembrolizumab thereafter.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

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.

Design outcomes

Primary

Measure	Time frame	Description
Efficacy of B-701 (Vofatamab) Plus Pembrolizumab Measured by ORR	2 years	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).
Number of Subjects Experiencing Adverse Events (AEs and SAEs)	2.5 years	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.
Number of Participants With Dose Limiting Toxicities Within a Period of 35 Days	1 year	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.

Secondary

Measure	Time frame	Description
Efficacy of B-701 (Vofatamab) in Combination With Pembrolizumab as Measured by DCR	2 years	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.
Efficacy of B-701 (Vofatamab) in Combination With Pembrolizumab as Measured by OS	2.5 years	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)
Change in Subject Reported Quality of Life	2 years	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).
Efficacy of B-701 (Vofatamab) in Combination With Pembrolizumab as Measured by PFS	2 years	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.
Assessment of Changes in Biomarkers Induced by B-701 (Vofatamab)	2.5 years	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.
Efficacy of B-701 (Vofatamab) in Combination With Pembrolizumab as Measured by DOR	2 years	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).

Other

Measure	Time frame	Description
PK Analysis of B-701 (Vofatamab)	2 years	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.
Immunogenicity of B-701 (Vofatamab)	2 years	Determine the immunogenicity of B-701 as measured by anti-B-701 antibody titers at several time points throughout the study.

Countries

Belgium, Denmark, France, Germany, Hungary, Italy, Moldova, Netherlands, Poland, Russia, Serbia, South Korea, Spain, Sweden, Turkey (Türkiye), Ukraine, United States

Participant flow

Participants by arm

Arm	Count
Phase 2 B-701 (vofatamab, 25 mg/kg plus pembrolizumab (200 mg) will be administered by IV infusion on Cycle 1 Day 1 once every 3 weeks.	28
Total	28

Baseline characteristics

Characteristic	Phase 2
Age, Continuous	61.5 years
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	1 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	27 Participants
Sex: Female, Male Female	11 Participants
Sex: Female, Male Male	17 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	12 / 28
other Total, other adverse events	28 / 28
serious Total, serious adverse events	13 / 28

Outcome results

Primary

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).

Time frame: 2 years

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
B-701 (Vofatamab) Plus Pembrolizumab	Efficacy of B-701 (Vofatamab) Plus Pembrolizumab Measured by ORR	9 Participants

Primary

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.

Time frame: 1 year

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
B-701 (Vofatamab) Plus Pembrolizumab	Number of Participants With Dose Limiting Toxicities Within a Period of 35 Days	0 Participants

Primary

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.

Time frame: 2.5 years

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
B-701 (Vofatamab) Plus Pembrolizumab	Number of Subjects Experiencing Adverse Events (AEs and SAEs)	28 Participants

Secondary

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.

Time frame: 2.5 years