This study will evaluate the safety, tolerability, and pharmacokinetics of BLYG8824A and will make a preliminary assessment of the anti-tumor activity of BLYG8824A in patients with locally advanced or metastatic colorectal cancer.

Inclusion Criteria:

• ECOG performance status of 0 or 1
• Life expectancy of at least 12 weeks
• Histologically or cytologically documented invasive CRC: incurable, unresectable, locally advanced or metastatic CRC previously treated with multimodality therapy or mCRC
• Locally advanced or metastatic CRC that has relapsed or is refractory to established therapies
• Prior disease progression (or intolerance) following oxaliplatin, irinotecan, fluoropyrimidines, and anti-EGFR monoclonal antibodies
• An archival tissue specimen or fresh baseline biopsy (when archival is not available) is required for enrollment into the study
• Measurable disease, according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Non-measurable evaluable disease is acceptable for dose-escalation.
• Adequate hematologic and end organ function
• Acute, clinically significant treatment-related toxicity from prior therapy resolved to Grade ≤ 1 prior to study entry

Expansion Cohort-Specific Inclusion Criteria

• MSS or MSI-L disease as determined by polymerase chain reaction (PCR) and/or IHC
• Measurable disease by RECIST v1.1 with at least one measurable target lesion in the expansion cohort
• Progression must have occurred during or after most recent treatment for locally advanced or metastatic colorectal cancer
• For patients enrolled in either a dedicated biopsy cohort or other expansion cohorts where biopsy is clinically feasible, willingness to consent to mandatory fresh pretreatment and on-treatment biopsies of safely accessible tumor lesions

Exclusion Criteria:

• Pregnant or breastfeeding, or intending to become pregnant during the study or within 4 months after the final dose of BLYG8824A
• Significant cardiopulmonary dysfunction
• Known clinically significant liver disease
• Positive serologic or PCR test results for acute or chronic HBV infection
• Acute or chronic HCV infection
• HIV seropositivity
• Poorly controlled Type 2 diabetes mellitus
• Current treatment with medications that are well known to prolong the QT interval
• Primary CNS malignancy, untreated CNS metastases, or active CNS metastases
• Leptomeningeal disease
• Spinal cord compression that has not been definitively treated with surgery and/or radiation
• History of autoimmune disease
• Prior allogeneic stem cell or solid organ transplantation

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