⁃ Patients must meet all of the inclusion criteria to be eligible:

• Provision of signed Informed Consent prior to any screening procedures being performed.

∙ Non-English speaking patients 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 systemic chemotherapy):

∙ Cohort A: KRAS, NRAS, EGFR ectodomain, BRAF V600E wild-type status

‣ BRAF expansion Cohort: BRAF V600E mutation must be present

• 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:

• a. Cohort A: anti-EGFR therapy (cetuximab or panitumumab) setting for at least 16 weeks with either CR or PR as best response, prior to progression b. BRAF expansion Cohort: BRAF therapy (not including regorafenib) and anti-EGFR therapy (cetuximab or panitumumab)

• ECOG performance status ≤ 1.

• Patients 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).

• Patients 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

⁃ i. Note: Patients who have a total bilirubin level \> 1.5 x ULN will be allowed if their indirect bilirubin level is ≤ 1.5 x ULN.

⁃ ii. Note: Participants with hyperbilirubinemia due to non-hepatic cause (eg, hemolysis, hematoma) may be enrolled following discussion and agreement with the principle investigator.

⁃ Adequate renal function: either serum creatinine ≤ 1.5 x ULN, or calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 50mL/min at screening are acceptable.

⁃ QTc interval ≤ 480 ms (preferably the mean from triplicate ECGs)

⁃ Able to take oral medications.

⁃ Because the teratogenicity of cetuximab is not known, the patient, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods). Female patients 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.

⁃ Patients 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 Principle Investigator.