Study of Evorpacept (ALX148) With Cetuximab and Pembrolizumab for Refractory Microsatellite Stable Metastatic Colorectal Cancer

This Phase 2 clinical study will evaluate evorpacept (ALX148) in combination with cetuximab and pembrolizumab for refractory microsatellite stable metastatic colorectal cancer

Inclusion Criteria: To be eligible to participate in this study, an individual must meet all of the following criteria at screening (any assessments included in the Schedule of Events \[Section 1.3\] on Cycle 1 Day 1 must also continue to be met for the patient to remain eligible): 1. Provision to sign and date the consent form. 2. Able to comply with all study procedures and be available for the duration of the study in the Investigator's judgment. 3. Age ≥ 18 years on the day of signing informed consent 4. If in Cohort A, the patient must state willingness to undergo pre- and post-treatment biopsies. According to the Investigator's judgement, the planned biopsies should not expose the patient to substantially increased risk of complications. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Histologically confirmed unresectable metastatic colorectal adenocarcinoma. * All primary tumor locations are allowed * Measurement of EGFR expression by immunohistochemistry is not required 7. Progression on at least two prior lines of therapy for unresectable metastatic colorectal adenocarcinoma. * A patient who progressed on a single line of therapy including a fluoropyrimidine, oxaliplatin, and irinotecan for unresectable metastatic colorectal adenocarcinoma (e.g., FOLFIRINOX or FOLFOXIRI) is eligible. * Previous administration of anti-EGFR drugs does not impact eligibility, except as listed in Exclusion Criterion #15. 8. Microsatellite stable or proficient mismatch repair status documented (only one of these criteria is needed, however if one criterion is met and one is not met then the patient is excluded) 9. Measurable disease, according to RECIST v1.1. Previously irradiated lesions are not considered measurable unless progression has been documented in the lesion. Note that lesions intended to be biopsied should not be target lesions. 10. Adequate hematologic and end organ function, defined by the following laboratory results: * ANC ≥ 1.5 × 109/L * Platelet count ≥ 100 × 109/L * Hemoglobin ≥ 9 g/dL without transfusion in the previous week * Serum bilirubin ≤ 1.5 x the upper limit of normal (ULN); patients with known Gilbert's disease may have a bilirubin ≤ 3.0 ×ULN * AST, ALT, and alkaline phosphatase (ALP) ≤ 3 × ULN with the following exceptions: * Patients with documented liver metastases: AST and/or ALT ≤ 5 ×ULN * Patients with documented liver or bone metastases: ALP ≤ 5×ULN * Creatinine clearance ≥ 50 mL/min as calculated using the Cockcroft-Gault formula or measured using a 24-hour urine collection * International normalized ratio (INR) OR prothrombin time (PT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as INR or PT is within expected or therapeutic range of intended use of anticoagulants * Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as aPTT is within expected or therapeutic range of intended use of anticoagulants 11. QTcF interval of ≤480 msec (Based upon value from the screening ECG). 12. Serum pregnancy test (for females of childbearing potential) negative at screening and at C1D1. A woman is considered fertile (woman of childbearing potential, "WOCBP") following menarche and until becoming post-menopausal unless permanently sterile. Women in the following categories are not considered WOCBP: * Premenarchal * Premenopauseal female with one of the following: documented hysterectomy, documented bilateral salpingectomy, documented bilateral oophorectomy (note: documentation can come from the site personnel's review of the participant's medical records, medical examination, or medical history interview) * Postmenopausal female. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required. Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment. Female participants of childbearing potential are eligible to participate if they agree to correctly use one of the following forms of highly effective method of contraception with a failure rate of \180 mmHg systolic or \> 130 mmHg diastolic). 24. Life expectancy of \< 12 weeks. 25. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 26. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 27. Pregnant or lactating or intending to become pregnant during the study. 28. AEs due to prior cancer therapies that have not returned to ≤Grade 1 or baseline. Participants with endocrine-related AEs Grade ≤2 that are now controlled with treatment/hormonal therapy are eligible. Exclusion criteria based on infectious diseases: 29. Active infection requiring IV antibiotics at screening. 30. Patients with active hepatitis B (chronic or acute). Active hepatitis B infection is defined as having a positive hepatitis B surface antigen \[HBsAg\] test at screening. Patients with a cleared hepatitis B infection (as defined by the presence of hepatitis B core antibody \[anti-HBc\], absence of HBsAg, and negative HBV DNA) are eligible. 31. Patients with active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 32. Known HIV infection. 33. Recent COVID-19 diagnosis (symptomatic or asymptomatic). To become eligible (following symptomatic infection), the patient must not have fever for 24 hours (without using medicine to reduce fever), other symptoms have improved, and at least 10 days have passed since onset of symptoms. To become eligible (following asymptomatic infection, ie positive test only), at least 10 days have passed since the positive test. In either case, a repeat COVID-19 test is not required. Likewise, a persistently positive test (if obtained) does not continue to exclude the patient should the other criteria be satisfied. 34. Influenza vaccination should be given during influenza season. Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 30 days prior to Cycle 1 Day 1 or at any time during the study and for at least 5 months after the last dose of study drug.