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

This phase II trial tests the safety, side effects, and best dose of TTI-621 (closed to enrollment) or TTI-622 in combination with pembrolizumab in treating patients with diffuse large B-cell lymphoma that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). TTI-621 and TTI-622 are called fusion proteins. A fusion protein includes two specialized proteins that are joined together. In TTI-621 and TTI-622, one of the proteins binds with other proteins found on the surface of certain cells that are part of the immune system. The other protein targets and blocks a protein called CD47. CD47 is present on cancer cells and is used by those cells to hide from the body's immune system. By blocking CD47, TTI-621 and TTI-622 may help the immune system find and destroy cancer cells. Pembrolizumab is a monoclonal antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1) that works by helping the body\'s immune system attack the cancer and may interfere with the ability of cancer cells to grow and spread. Giving TTI-621 (closed to enrollment) or TTI-622 in combination with pembrolizumab may kill more cancer cells in patients with 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.