New combo therapy targets tough 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: * Must be able to show documentation of disease: Participants must have metastatic colorectal adenocarcinoma with kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, detected by any Clinical Laboratory Improvement Amendments-certified method (tumor or ct-DNA), for which curable treatment modalities are not an option. * Participants with the following KRAS mutations can be included in the study. These eligible KRAS mutations will be confirmed by the Study Chair, Dr. Shergill. Please contact Dr. Shergill for all other mutations that you feel may benefit from this treatment. * Must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1). * Must have had progression of disease on 5-FU or capecitabine, oxaliplatin, irinotecan and bevacizumab therapy or any other approved anti-VEGF therapy or must have a scientifically justifiable reason for not having had these therapies prior to trial. If participant has high levels of MicroSatellite Instability (MSI-H), they must have had recommended immunotherapy agent(s) i.e anti- programmed death ligand 1 (L)1 with or without anti-CTLA4 agents. * No prior Lonsurf or regorafenib treatment is allowed. * Must have not had any treatment with prior MEK (mitogen-activated protein kinase kinase) inhibitor, anti-EGFR (antineoplastic epidermal growth factor receptor), KRAS, SOS1 ( Son of sevenless 1) and SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) inhibitor therapy. * Participants should not have had chemotherapy, radiotherapy, or major surgery within 2 weeks prior to entering the study. * Participants should not be receiving any other study agents concurrently with the study drugs. * Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 days prior to registration is required. Negative serum pregnancy test is required for all female patients of child bearing potential within 7 days of cycle 1 day. All patients should agree to use highly effective method of contraceptive: female patient up to 2 months after 30 days of the last dose and male pts up to 90 days of the last dose. * Must be 18 years old or older. * Must have Eastern Cooperative Oncology Group Performance status of 0-1 * Must meet required clinical laboratory values set by study doctor to show participant's health and organ function meets requirements to be in study. * Must have adequate cardiac function as clinically confirmed by study doctor. * Participants with human immunodeficiency virus (HIV)-infected who are on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. * For participants with a history of chronic hepatitis B virus infection, the hepatitis B virus (HBV) viral load must be undetectable on suppressive therapy, if indicated. * Participants with a history of hepatitis C (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. * Participants with known untreated Central Nervous System (CNS) metastases are excluded. Patients with a history of CNS metastases are permitted to enroll if they have been treated, and systemic steroids have been tapered to physiologic doses (10 milligrams (mg) or less of prednisone or equivalent), and CNS disease has been stable for a minimum of one month on imaging and clinically. Exceptions for participants with asymptomatic sub-centimeter metastases that, in the opinion of the treating investigator, do not require intervention may be possible following discussion and agreement with the overall Study Chair. Exclusion criteria: * Participants with uncontrolled intercurrent illness including, but not limited to: ongoing or active infection requiring systemic treatment, symptomatic congestive heart failure, cardiac arrhythmia, psychiatric illness/social situations that would limit compliance with study requirements, hypertension, defined as systolic blood pressure \> 160 mmHg despite medical management, myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting \< 12 months prior to screening. * Participants with clinically relevant coronary artery disease or history of myocardial infarction in last 12 months or high risk of uncontrolled arrhythmia or uncontrolled cardiac insufficiency, or those with uncontrolled or poorly controlled hypertension (\>180 millimeters of mercury (mmHg) systolic or \>130 mmHG diastolic pressures) may not receive cetuximab. * Participants with history of corrected QT interval (QTc) prolongation, Brugada syndrome, known history of QTc prolongation, or Torsades de Pointes. * Participants with known COVID-19 infection within 28 days prior to first dose of therapy are excluded. History of Gilbert's syndrome. * Participants with history of recent rhabdomyolysis within last 3 months. * Participants with active skin disorder that has requested systemic therapy within past 12 months. * Participants with a history of neuromuscular disorders that are associated with elevated creatine phosphokinase (CPK) (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). * History of other malignancy which could affect compliance with the protocol or interpretation of results. * History of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are allowed. Subjects with a malignancy that has been treated with curative intent will also be allowed if the malignancy has been in remission without treatment for ≥ 2 years prior to Cycle 1, Day 1. Subjects with localized prostate cancer that has been treated with curative intent will be allowed. * Participants planning to embark on a new strenuous exercise regimen after the first dose of study treatment (e.g. running or bicycling \> 10 mph) due to risk of CPK elevation. * Participants with history of a malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may interfere with the absorption of oral study medication in the opinion of the treating study doctor. * Participants with evidence of visible retinal pathology or retinal degenerative disease on screening ophthalmologic examination that places the participant at an unacceptable risk for ocular events. Related to their vision and eye health, patients must also: * Not have history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes. * Not have history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO * Patients must not have history of corneal erosion (instability of corneal epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. * Patients must not have history of retinal degenerative disease. * Patient must not have presence of neurosensory retinal detachment, or neovascular macular degeneration on screening ophthalmologic exam. * Patients with Impairment of gastrointestinal function or gastrointestinal disease (e.g., active ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection) are excluded. * Participants should not have history of bowel perforation or intestinal fistulas in the last 6 months. * Participants with current Grade 3 or higher neuropathy are excluded. * No prior allogeneic stem cell or solid organ transplantation. Patients may not have had prior stem cell or solid organ transplantation. Women who are pregnant or breastfeeding are excluded. * 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. * The participant is on any medications that conflict with the drugs administered in study. * Participants with known or suspected allergy or hypersensitivity to VS-6766 or any of the inactive ingredients which include, but is not limited to, hydroxypropylmethylcellulose, mannitol, magnesium stearate. * If the participant has a history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab, or if the participant had red meat allergy/tick bite history they must be excluded. * Chronic concomitant treatment with strong inhibitors of Cytochrome P450 3A4 (CYP3A4) is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study. See Section 8.1.9 for more information. * Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment. * Participants must avoid grapefruit, grapefruit juice, St. John's Wort and other medications (with or without prescriptions), supplements, herbal remedies or foods that are strong inhibitors or inducers of CYP3A4 while on VS-6766.