This study is an open-label, Phase 1, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) profiles of a novel fragment crystallizable (Fc)-engineered immunoglobulin G1 anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) human monoclonal antibody (botensilimab) monotherapy and in combination with an anti-programmed cell death protein-1 (PD-1) antibody (balstilimab), and to assess the maximum tolerated dose (MTD) in participants with advanced solid tumors. This study will also determine the recommended phase 2 dose (RP2D) of botensilimab monotherapy and in combination with balstilimab.
This Phase 1 study will enroll up to approximately 550 evaluable adult participants with refractory, advanced cancer (solid tumors). The study will consist of a 3+3 dose escalation. Different dose levels of botensilimab, both monotherapy and in combination with balstilimab, will be evaluated in individual cohorts based upon dose. Each participant will remain in the cohort of the dose level and schedule assigned at study entry. Participants can be replaced for any reason other than a dose-limiting toxicity (DLT). Participants will receive treatment for ≤ 2 years or until progressive disease, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal of trial occurs. Additionally, the study is intended to further explore the safety, PK, PD, and clinical activity in selected cancer types at dose levels (botensilimab monotherapy and combination therapy with balstilimab) determined as potentially effective. Indications of interest include, but are not limited to, non-small-cell lung cancer, melanoma, endometrial cancer, ovarian cancer, angiosarcoma, colorectal cancer without liver metastases, prostate cancer, and fibrolamellar carcinoma.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
499
An Fc-engineered anti-CTLA-4 monoclonal antibody
A fully human monoclonal anti-PD-1 antibody
HonorHealth Research Institute
Scottsdale, Arizona, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
The Angeles Clinic & Research Institute, a Cedars-Sinai Affiliate
Los Angeles, California, United States
University of Southern California Norris Comprehensive Cancer Center
Los Angeles, California, United States
UCLA Santa Monica Hematology Oncology
Los Angeles, California, United States
Saint John's Cancer Institute
Santa Monica, California, United States
University of Colorado
Aurora, Colorado, United States
Yale Cancer Center
New Haven, Connecticut, United States
University of Miami Sylvester Comprehensive Cancer Center
Miami, Florida, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
...and 8 more locations
Incidence Of Treatment-emergent Adverse Events (TEAEs)
TEAEs will include adverse events of special interest, immune-related adverse events, and adverse drug reactions, according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
Time frame: First dose through 90 days following last study dose (up to 2 years)
DLT Of Botensilimab
DLTs will include any Grade 2 or greater drug related toxicity for all dose groups, according to NCI CTCAE version 5.0 and protocol specifications.
Time frame: First 28 days of treatment
RP2D Of Botensilimab
MTD based on DLT occurrence at DLT period (28 days after first dose) and all TEAEs seen through 90 days following last study dose.
Time frame: First dose through 90 days following last study dose
Objective Response Rate (ORR) According To Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
Confirmed ORR will be in the analysis population.
Time frame: First dose through up to 2 years
ORR According to Prostate Cancer Working Group 3 (PCWG3)
Confirmed ORR will be in the analysis population.
Time frame: First dose through up to 2 years
Duration Of Response (DOR) According To RECIST 1.1
Time frame: From first dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment) (up to 2 years)
DOR According to PCWG3
Time frame: From first dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment) (up to 2 years)
Disease Control Rate (DCR) According To RECIST 1.1
DCR will include complete response, partial response, and stable disease.
Time frame: First study dose through 24 weeks
DCR According to PCWG3
DCR will include complete response, partial response, and stable disease.
Time frame: First study dose through 24 weeks
Progression-free Survival (PFS) According To RECIST 1.1
PFS time will be assessed.
Time frame: First study dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment) (up to 2 years)
PFS According to PCWG3
PFS time will be assessed.
Time frame: First study dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment) (up to 2 years)
Overall Survival Time
Duration of survival will be assessed.
Time frame: First study dose through up to 3 years
Maximum Drug Concentration At Steady-state (Cmax-ss)
Serum botensilimab concentrations measured throughout the study
Time frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years)
Minimum Drug Concentration At Steady-state (Cmin-ss)
Serum botensilimab concentration measured throughout the study
Time frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years)
Area Under The Drug Concentration-time Curve Within Time Span t1 To t2 At Steady-state (AUC(t1-t2)-ss)
Serum botensilimab concentrations measured throughout the study
Time frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years)
Area Under The Drug Concentration-time Curve From Time Zero To Infinity [AUC(0-∞)]
Serum botensilimab concentrations measured throughout the study
Time frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years)
Terminal Elimination Rate Constant (λz)
Serum botensilimab concentrations measured throughout the study
Time frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years)
Terminal Elimination Half-life (t1/2)
Serum botensilimab concentrations measured throughout the study
Time frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years)
Systemic Clearance (CL)
Serum botensilimab concentrations measured throughout the study
Time frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years)
Volume Of Distribution (Vd)
Serum botensilimab concentrations measured throughout the study
Time frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years)
Anti-drug Antibodies (ADAs)
Serum botensilimab ADAs measured throughout the study
Time frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years)
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