Open-label Phase 2 Study of Avutometinib (RAF/MEK Clamp) in Combination With Defactinib (FAK Inhibitor) and Cetuximab in Patients With Unresectable, Anti-EGFR-Refractory Advanced Colorectal Cancer

To learn if avutometinib in combination with defactinib and cetuximab can help to control unresectable, anti-EGFR-refractory, advanced colorectal cancer.

Inclusion Criteria: • Provision of signed Informed Consent prior to any screening procedures being performed. * Non-English speaking participants will be eligible for participation with involvement of the MD Anderson Language Assistance department in the informed consent process (per MD Anderson SOP 04\_Informed Consent Process). * Individuals lacking the ability, based on reasonable medical judgment, to understand and appreciate the nature and consequences of participation in this study will not be eligible for participation. * Age ≥ 18 years at the time of informed consent. * Histologically (or cytologically) confirmed diagnosis of adenocarcinoma of the colon or rectum, with clinical confirmation of unresectable and/or metastatic disease that is measurable according to RECIST1.1 criteria. * Mutation status at the time of colorectal cancer diagnosis performed on tumor tissue or circulating tumor DNA (prior to any anti-EGFR directed therapy): * KRAS, NRAS, EGFR ectodomain, BRAF V600E wild-type status * Prior treatment with at least one systemic chemotherapy regimen for mCRC, or recurrence/progression with development of unresectable or metastatic disease within 6 months of adjuvant chemotherapy for resected colorectal cancer. * Prior treatment with: * anti-EGFR therapy (cetuximab or panitumumab) setting for at least 16 weeks with either CR or PR as best response, prior to progression • ECOG performance status ≤ 1. • Participants who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to day 1 of study. A washout period of at least 21 days is required between last chemotherapy dose and day 1 of study (provided the patient did not receive radiotherapy). • Participants who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 7 days is required between end of radiotherapy and day 1 of study. • Adequate hematologic status: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; Hemoglobin (Hgb) ≥ 9 g/dL with or without transfusions; Platelets (PLT) ≥ 100 x 109/L without transfusions • Adequate liver function: * ALT and AST ≤3 × ULN, or ≤5 × ULN in the presence of liver metastases * Total bilirubin ≤ 1.5 × ULN and \< 1.5 mg/dL * Note: Participants with hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the principal investigator. • Adequate renal function: Serum Creatinine ≤ 1.5 x ULN, or calculated creatinine clearance (measured via 24-hour urine collection) ≥ 40 mL/min at screening * QTc interval ≤ 480 ms (preferably the mean from triplicate ECGs) * Able to take oral medications. * Because the teratogenicity of cetuximab is not known, the participant, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods). Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment * Willing and able to participate in the trial and comply with all trial requirements. * Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational agent may be included after consultation with the medical monitor. Exclusion Criteria: 1. History of grade 3 or 4 allergic reaction or intolerability attributed to cetuximab or panitumumab. 2. History of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab, or if the patient had red meat allergy/tick bite history. 3. Previously exposed to ERK1/2, MEK or BRAF inhibitor 4. Any known symptomatic brain metastasis 5. Note: Participants previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Known brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging \[MRI\] or computed tomography \[CT\]) demonstrating no current evidence of progressive brain metastases at screening. 6. Known leptomeningeal disease 7. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR). 8. Previous or concurrent malignancy within 3 years of study entry, with the following exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy; other solid tumors treated curatively without evidence of recurrence for at least 3 years prior to study entry. 9. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: 1\. History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) \