Ivonescimab and ADG126, Alone, and in Combination With Leucovorin and Fluorouracil or FOLFIRI Regimen for the Treatment of Microsatellite Stable Advanced/Metastatic Colorectal Cancer

PRIMARY OBJECTIVES: I. Determine the recommended phase II dose of muzastotug (ADG126) and ivonescimab (Arm A) in advanced/metastatic MSS colorectal cancer without liver metastatic disease. II. Determine the recommended phase II dose of ADG126 and ivonescimab with fluorouracil (5-FU)/leucovorin (LV) (Arm B) in advanced/metastatic MSS colorectal cancer. III. Determine the recommended phase II dose of ADG126 and ivonescimab with leucovorin, fluorouracil, and irinotecan (FOLFIRI) (Arm C) in advanced/metastatic MSS colorectal cancer. SECONDARY OBJECTIVES: I. Describe the safety of giving ADG126 with ivonescimab, and in combination with 5-FU/LV, and in combination with FOLFIRI in MSS advanced/metastatic colorectal cancer. II. Describe the overall response rate (ORR) as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for the three treatment arms individually. III. Describe the duration of response (DoR), progression free survival (PFS), and overall survival (OS) of each of the three treatment arms. IV. Assess ADG126 pharmacokinetics (PK) through sparse sampling at different doses of ADG126 on study and in combination with ivonescimab, 5-FU/LV, or FOLFIRI. EXPLORATORY OBJECTIVE: I. Explore the dynamics of immune cells in relation to clinical outcome by treatment arm, which include the data from immunophenotyping, cytokine analysis and ribonucleic acid (RNA) sequencing of peripheral blood and buffy coat at baseline, 4 weeks, and 8 weeks, and every subsequent 8 weeks until progression. OUTLINE: This is a dose-escalation study of muzastotug in combination with ivonescimab, leucovorin, fluorouracil, and irinotecan. Patients are assigned to 1 of 3 arms. ARM A: Patients receive muzastotug intravenously (IV) over 60-90 minutes on day 1 of each cycle and ivonescimab IV over 60 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 6 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI), and collection of blood samples throughout the study. ARM B: Patients receive muzastotug IV over 60-90 minutes on day 1 of each cycle, ivonescimab IV over 60 minutes on days 1, 15, and 29 of each cycle, leucovorin IV over 2 hours on days 1, 15, and 29 of each cycle, and fluorouracil IV continuously over 46 hours on days 1, 15, and 29 of each cycle. Cycles repeat every 6 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI, and collection of blood samples throughout the study. ARM C: Patients receive muzastotug IV over 60-90 minutes on day 1 of each cycle, ivonescimab IV over 60 minutes on days 1, 15, and 29 of each cycle, leucovorin IV over 2 hours on days 1, 15, and 29 of each cycle, fluorouracil IV continuously over 46 hours on days 1, 15, and 29 of each cycle, and irinotecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 6 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI, and collection of blood samples throughout the study. After completion of study treatment, patients are followed for 30 days, every 3 months until disease progression (if applicable) for 2 years and/or after disease progression periodically for survival.