Avutometinib and Cetuximab for the Treatment of Metastatic KRAS Mutated Colorectal Cancer

Inclusion Criteria

• Histologic Documentation: Participants must have metastatic colorectal adenocarcinoma with KRAS mutation, detected by any clinical laboratory improvement amendments (CLIA)-certified method (tumor or ct-DNA), for which curable treatment modalities are not an option. KRAS mutations: G12X, G13X, Q61X, A146X, codon 117, codon 12, 13 of exon 2 (G12D, G12V, G12C, G12A, G13D), codon 61 of exon 3 (Q61H, Q61L, Q61R) , codon 146 of exon 4 (A146T A146V) Please contact study chair for all other mutations that you feel may benefit from this treatment.
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be allowed. Of note, in the case when a baseline biopsy is done after scans are obtained, a lesion separate from one that is biopsied needs to be measurable per RECIST 1.1.
• Must have had progression of disease on 5-FU or capecitabine, oxaliplatin, irinotecan and bevacizumab therapy or must have a scientifically justifiable reason for not having had these therapies prior to trial. If high microsatellite instability (MSI-H), must have had recommended immunotherapy agent(s) i.e anti- programmed cell death-1 ligand (PD[L)]1) with or without anti-cytotoxic T-lymphocyte-associated antigen (4CTLA4) agents.
• No prior Lonsurf or regorafenib treatment is allowed
• No prior MEK inhibitor, anti-EGFR, KRAS, SOS1 and SHP2 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 last dose and male patients up to 90 days of the last dose.
• Age >= 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Absolute neutrophil count (ANC) >= 1,000/mm^3.
• Platelet count >= 100,000/mm^3.
• Hemoglobin >= 9 g/dL, no transfusion within 14 days of 1st dose.
• Creatinine =< 1.5 x upper limit of normal (ULN) or Calculated creatinine clearance >= 50 mL/min. * Note: Only if serum creatinine is >=1.5 times the ULN, a 24-H urine collection to calculate creatinine clearance by the Cockcroft-Gault formula must be performed.
• Total bilirubin =< 1.5 mg/dL x upper limit of normal (ULN).
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN).
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5.0 X ULN if hepatic metastases are present.
• Albumin >= 3g/dL.
• Creatine phosphokinase (CPK) =< 2.5 X upper limit of normal (ULN).
• International normalized ratio (INR) =< 1.5.
• Partial thromboplastin time (PTT) =< 1.5 X ULN in absence of anticoagulation or therapeutic levels in presence of anticoagulation.
• Left ventricular ejection fraction (LVEF) > 50% as determined by echocardiogram or multigated acquisition scan (MUGA).
• Baseline corrected QT (QTc) interval < 460ms for women and =< 450ms for men (CTCAE Grade 1) using Fridericia's QT correction formula. * NOTE: This criterion does not apply to subjects with a right or left bundle branch block.

Exclusion Criteria

• Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), myocardial infarction within the last 6 months, hemodynamically unstable arrhythmias, unstable angina or severe obstructive pulmonary disease or interstitial lung disease (ILD).
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For patients with a history of chronic hepatitis B virus infection, the hepatitis B virus (HBV) viral load must be undetectable on suppressive therapy, if indicated.
• Patients with a history of hepatitis C infection must have been treated and cured. For patients with hepatitis C virus (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 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.
• Not permitted, 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. Patients 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 (>180mgHg systolic or >130 mgHg diastolic pressures) may not receive cetuximab.
• History of QTc prolongation, Brugada syndrome, known history of QTc prolongation, or Torsades de Pointes are excluded.
• Known SARS-CoV2 infection within 28 days prior to first dose of therapy are excluded.
• History of Gilbert’s syndrome are excluded.
• History of recent rhabdomyolysis within last 3 months are excluded.
• Active skin disorder that has requested systemic therapy within past 12 months are excluded.
• Needing treatment with warfarin (low molecular weight heparin [LMWH] is permitted).
• History of neuromuscular disorders that are associated with elevated CPK (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) are excluded.
• 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
• Patients 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 are excluded.
• 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 investigator are excluded.
• Evidence of visible retinal pathology or retinal degenerative disease on screening ophthalmologic examination that places the participant at an unacceptable risk for ocular events are excluded. * Patients must not have history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes. * Patients must not have history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mmHg 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.
• Impairment of gastrointestinal function or gastrointestinal disease (e.g., active ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection) are excluded.
• Patients should not have history of bowel perforation or intestinal fistulas in the last 6 months.
• Current Grade 3 or higher neuropathy are excluded.
• Patients may not have had prior stem cell or solid organ transplantation.
• Women who are pregnant or breastfeeding are excluded.
• The patient has a 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
• Known or suspected allergy or hypersensitivity to avutometinib or any of the inactive ingredients which include, but is not limited to, hydroxypropylmethylcellulose, mannitol, magnesium stearate. If the patient has a 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 they must be excluded
• Chronic concomitant treatment with strong inhibitors of 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
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment
• Patients 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 avutometinib