Can a Triple-Drug cocktail outsmart Treatment-Resistant colorectal cancer?

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

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 \<1% per year when used consistently and correctly during the treatment period and for at least 180 days after the last study treatment. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical studies. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable hormonal contraceptives are limited to those which inhibit ovulation. * Progestogen- only contraceptive implant * Intrauterine hormone-releasing system * Intrauterine device (IUD) * Bilateral tubal occlusion * Vasectomized partner. A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. * Sexual abstinence. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. * Combined (estrogen- and progestogen- containing) hormonal contraception, including oral, intravaginal, transdermal, or injectable * Progestogen-only hormonal contraception, including oral or injectable 13. For men: Male participants with female partners of childbearing potential are eligible to participate if they agree to one of the following during the treatment period and for at least 180 days after the last dose of study treatment as defined below. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Men must also agree to refrain from donating sperm following during the treatment period and for at least 180 days after the last dose of study treatment. * Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent * Use a male condom plus partner use of a contraceptive method with a failure rate of \<1% per year as described in Inclusion Criteria #12 when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant. * Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration. Inclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: Cancer-related exclusion criteria: 1. Patients with known MSI-high status or known mismatch repair deficiency (dMMR) 2. Patients in whom both mismatch repair and microsatellite stability status are unknown 3. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to Cycle 1 Day 1. 4. Systemic anti-cancer therapy within 4 weeks of starting study treatment (6 weeks for mitomycin C or nitrosureas). If systemic anti-cancer therapy was given within 4 weeks, patient may be included if 5 times the elimination half-life of the drug has passed. 5. Malignancies other than CRC within 3 years prior to Cycle 1 Day 1 with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival \> 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent). 6. Prior radiation therapy within 14 days prior to study Cycle 1 Day 1 and/or persistence of radiation-related adverse effects. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. However, palliative radiation therapy (as long as it does not involve target lesions) is permitted on the study. 7. Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past. 8. Spinal cord compression not definitively treated with surgery and/or radiation. 9. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures. 10. Uncontrolled tumor related pain. Patients who require narcotic pain medication during screening should be on a stable dose regimen for seven days prior to Cycle 1 Day 1. Exclusion criteria related to study medication: 11. History of severe allergic, anaphylactic, or other hypersensitivity reactions to any of the study medications or their classes 12. History of red meat allergy or history of tick bite (these may increase the risk of a cetuximab infusion reaction). 13. Prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137). 14. Prior treatment with any anti-CD47 or anti-SIRPα drugs 15. Left-sided (at or distal to the splenic flexure) RAS/BRAF WT mCRC who are EGFR inhibitor naïve. 16. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to Cycle 1 Day 1. 17. History of hemolytic transfusion reaction. 18. History of non-infectious pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 19. Has an autoimmune disease that has required systemic treatment in the past 2 years with use of disease modifying agents, corticosteroids, or immunosuppressive drugs. Replacement therapy (eg; thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. 20. History of autoimmune hemolytic anemia or autoimmune thrombocytopenia Exclusion criteria based on organ function or medical history: 21. Any major surgery within 28 days prior to enrollment (does not include pre-treatment biopsy). 22. The patient has clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months or high risk of uncontrolled arrhythmia or uncontrolled cardiac insufficiency. 23. The patient has uncontrolled or poorly-controlled hypertension (\>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.