This is a phase 0/I exploratory study. Patients at first or second recurrence of glioblastoma will be enrolled. The study will be divided into two cohorts: Cohort A (safety cohort) and Cohort B (surgical patient cohort). Cohort A: Eligible patients will be sequentially enrolled to receive intravenous domvanalimab combined with zimberelimab (N=6). Domvanalimab will be given at a dose of 10 mg/kg and zimberelimab will be given at a dose of 240 mg (flat). The dosing was determined in a separate study in solid tumors; this cohort will confirm the safety of the dosing schedule in patients with brain tumors. Cohort B: Expansion surgical cohort. The purpose of cohort B is to provide an additional safety evaluation of domvanalimab + zimberelimab as well as tissue and blood for exploratory ancillary studies investigating the effects of domvanalimab + zimberelimab in the tumor and tumor microenvironment. A total of 46 patients will be enrolled in this cohort.
This is a phase 0/I exploratory study. Patients at first or second recurrence of glioblastoma will be enrolled. The study will be divided into two cohorts: Cohort A (safety cohort) and Cohort B (surgical patient cohort). Cohort A: Eligible patients will be sequentially enrolled to receive intravenous domvanalimab combined with zimberelimab (N=6). Domvanalimab will be given at a dose of 10 mg/kg and zimberelimab will be given at a dose of 240 mg (flat). The dosing was determined in a separate study in solid tumors; this cohort will confirm the safety of the dosing schedule in patients with brain tumors. Cohort B: Expansion surgical cohort. The purpose of cohort B is to provide an additional safety evaluation of domvanalimab + zimberelimab as well as tissue and blood for exploratory ancillary studies investigating the effects of domvanalimab + zimberelimab in the tumor and tumor microenvironment. A total of 46 patients will be enrolled in this cohort. Following completion of cohort A, patients who are candidates for surgical resection for management of tumor progression (i.e. need for diagnostic confirmation or tumor debulking) will be enrolled prior to surgical resection, and initiate study treatment approximately two weeks prior to the resection. Patients will be randomized to one of the four treatment arms and initiate treatment prior to surgery, according to treatment assignment. The pre-surgical dose (neoadjuvant treatment) will be double-blinded, to minimize dropouts. A total of 10 patients will be allocated to each one of the following groups in a blinded fashion, approximately two weeks before surgery: * B1 (N=10): domvanalimab single agent (10 mg/kg) + placebo * B2 (N=10): zimberelimab single agent (240 mg) + placebo * B3 (N=10): domvanalimab (10 mg/kg) +zimberelimab (240 mg) * B4 (N=10): Two placebo infusions Two to six weeks, following surgery, all patients (N=46) will be re-screened and if still eligible will initiate treatment with the combination of domvanalimab and zimberelimab.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
46
Zimberelimab (AB122) is a fully human immunoglobulin G4 (hIgG4) monoclonal antibody (mAb) that targets PD-1.
Domvanalimab (AB 154) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets TIGIT.
Saline placebo comparator for pre-surgery treatment in cohort B4
University of California San Francisco
San Francisco, California, United States
Yale University
New Haven, Connecticut, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] associated with the combination AB122 and AB154 in patients with recurrent glioblastoma
Adverse events will be listed individually by patient and treatment group. The number of patients experiencing each adverse event will be summarized by organ and grade. The number and percentage of patients with adverse events in the different categories will be summarized by treatment group.
Time frame: through study completion, an average of 2 years
Single cell RNA sequencing of tumor and blood after exposure to AB154 with and without AB122
Pharmacodynamic effects of each pre-surgery treatment will be evaluated with single-cell RNA sequencing of tumor and blood to determine effects of each intervention on the immune response.
Time frame: through study completion, an average of 2 years
Tregs and CD8 T cells ratio by immunofluorescence
Resected tumors in cohorts B1 to 4 will be analyzed utilizing immunofluorescence for the ratio between Tregs and CD8 T cells, calculated by counting cells that are positive for a FoxP3 or a CD8 staining.
Time frame: through study completion, an average of 2 years
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