TTI-622 in Combination With Pembrolizumab for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma

PRIMARY OBJECTIVES: I. To determine the toxicities of maplirpacept (TTI-622) combined with pembrolizumab and to identify the recommended phase 2 dose (RP2D) of TTI-622, combined with pembrolizumab. (Safety run-in) II. To estimate preliminary efficacy of pembrolizumab in combination with TTI-622 as measured by overall response rate (ORR). (Phase 2). SECONDARY OBJECTIVE: I. To estimate efficacy of pembrolizumab in combination with TTI-622 as measured by duration of response (DOR), progression free survival (PFS), and overall survival (OS). CORRELATIVE OBJECTIVE: I. Correlation of biomarkers measured in serial peripheral blood samples and tumor tissues with clinical responses, which may include but are not limited to: SIRPalpha expression, monocyte/macrophage markers in tumor micro-environment, tumor infiltrating lymphocytes (TILs), PD-1/PDL-1 expression. OUTLINE: Patients are assigned to 1 of 2 arms. Patients enrolling after 8/16/2024 are assigned to Arm B. ARM A (CLOSED TO ACCRUAL AS OF 8/16/2024): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle and ontorpacept (TTI-621) IV over 60-120 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo positron emission tomography/computed tomography (PET/CT) scans or CT scans of the chest, abdomen, and pelvis prior to cycle 3 and every 4 cycles thereafter. If no disease progression after cycle 12, patients then receive pembrolizumab IV over 30 minutes on day 1 of each cycle and TTI-621 IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET/CT and/or CT and blood sample collection throughout the study. Patients may undergo biopsy on study. ARM B: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle and TTI-622 IV over 60-90 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET/CT scans or CT scans of the chest, abdomen, and pelvis prior to cycle 3 and every 4 cycles thereafter. If no disease progression after cycle 12, patients then receive pembrolizumab IV over 30 minutes on day 1 of each cycle and TTI-622 IV over 60-90 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET/CT and/or CT and blood sample collection throughout the study. Patients may undergo biopsy on study. After completion of the study treatment, patients are followed every 6 months for up to 2 years from registration.