HM95573 in Combination With Either Cobimetinib or Cetuximab in Patients With Locally Advanced or Metastatic Solid Tumors

\[Inclusion criteria\] 1. Signed Informed Consent Form 2. Age ≥ 19 years at time of signing Informed Consent Form 3. ECOG performance status of 0 or 1 4. Histologically or cytologically documented, locally advanced or metastatic solid tumors with RAS- or RAF-mutation for which standard therapy either does not exist or has proven ineffective or intolerable 5. Measurable disease per RECIST v1.1 6. Life expectancy ≥ 12 weeks 7. Adequate hematologic and end organ function, defined by the following laboratory results obtained within 2 weeks prior to the first dose of study-drug treatment: Absolute neutrophil count ≥ 1,500/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 9.0 g/dL (this criterion has to be met without transfusion within 2 weeks prior to laboratory test) Albumin ≥ 2.5 g/dL Total bilirubin ≤ 1.5 × ULN AST or ALT ≤ 3 × ULN, ALP ≤ 2.5 × 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 Serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min on the basis of the Cockroft-Gault glomerular filtration rate estimation PT/INR and PTT ≤ 1.5 × ULN 8. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use one highly effective form (defined as a failure rate of less than 1% per year) of contraception (e.g., surgical sterilization, birth control pills, or contraceptive hormone implants) and to continue use for the duration of the study. Additionally, female patients of childbearing potential should use pregnancy prevention measures for a minimum of 3 months following discontinuation of HM95573 in combination with either cobimetinib or cetuximab. 9. For male patients: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: For men with female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 3 months after the last dose of HM95573 in combination with either cobimetinib or cetuximab to avoid exposing the embryo. Men must refrain from donating sperm during this same period. The length of time that pregnancy preventative measures are used following discontinuation of drug may be adjusted based on the human pharmacokinetics. 10. Consent to provide archival tissue (either a paraffin-embedded tissue block or unstained slides) for testing with the FoundationOne panel to assess and confirm genetic alterations including, but not limited to, KRAS, NRAS, BRAF, EGFR and PI3K mutational status. 11. FDG-PET avid disease on baseline scan. Patients who are considered for enrollment into the cohort expansion (Stage 2) must meet all of the following additional eligibility criteria: 12. No more than five prior systemic therapies for locally advanced or metastatic cancer 13. For the expansion cohorts (except basket cohort in expansion cohort I, II): No prior therapy with a RAF, MEK or ERK inhibitor. No prior treatment with regorafenib in the CRC (KRAS G13D- and BRAF V600-mutant) expansion cohort II. No prior therapy with HM95573 or cobimetinib in the expansion cohort II. For Stage 1b and the expansion cohort III prior EGFR, RAF, MEK, ERK inhibitor is allowed. 14. Current cancer must be one of the following: * Expansion cohort I (HM95573 200 mg BID + cobimetinib 20 mg QD): * KRAS-mutant NSCLC * KRAS-mutant Pancreatic adenocarcinoma * RAS-mutant CRC * RAS- or RAF-mutant solid tumors (basket cohort; excludes KRAS-mutant NSCLC, KRAS-mutant pancreatic adenocarcinoma, and RAS-mutant CRC). A minimum of 10 melanoma patients will be enrolled. * Expansion cohort II (HM95573 300 mg BID + cobimetinib 20mg QOD (3 times a week: day 1, 3, 5, 8, 10, 12, 15, 17, 19 of 28 day cycle)): * KRAS G13D-mutant CRC * BRAF V600-mutant CRC * NRAS-mutant Melanoma * RAS- or RAF-mutant solid tumors (basket cohort: A minimum of 10 BRAF V600 melanoma will be enrolled) * BRAF Class II-mutant (including BRAF fusions) or Class IIImutant solid tumors * Stage 1b and Expansion cohort III (HM95573 selected dose from stage 1b + cetuximab): - BRAF V600-mutant CRC 15. At least one target lesion on CT must also be an FDG-PET avid region of interest which has a target-to-organ-background SUVmax (or similar radioactivity concentration measure) ratio of ≥ 2.0 and at least 15mm in longest diameter. 16. Consent to undergo pre- and post-treatment tumor biopsies for PD biomarker analysis is optional, provided sites of disease are easily and safely accessible. In the absence of easily and safely accessible sites of disease, patients may enroll without consenting to tumor biopsies (Stage 2). 17. Willingness to take prophylactic antibiotics and topical steroids for the management of skin toxicity unless otherwise contraindicated for patient in Stage 1b and Expansion cohort III. \[Exclusion criteria\] Patients who meet any of the following criteria will be excluded from study entry: 1. History of prior significant toxicity from another RAF, MEK, ERK, or EGFR inhibitor requiring discontinuation of treatment 2. History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration. Patients will be excluded from study participation if they currently are known to have any of the following risk factors for RVO: * Grade ≥ 2 or symptomatic hyperglycemia (fasting) * Grade ≥ 2 uncontrolled hypertension (patients with a history of hypertension controlled with anti-hypertensive medication to Grade ≤ 1 are eligible) 3. History of glaucoma 4. Allergy or hypersensitivity to components of the cobimetinib, cetuximab or HM95573 formulation 5. Palliative radiotherapy within 2 weeks prior to first dose of study-drug treatment in Cycle 1 6. Experimental therapy within 4 weeks prior to first dose of study-drug treatment in Cycle 1 7. Major surgical procedure or significant traumatic injury within 4 weeks prior to the first dose of study-drug treatment in Cycle 1, or anticipation of the need for major surgery during the course of study treatment 8. Anti-cancer therapy within 28 days prior to the first dose of study-drug treatment in Cycle 1. Exceptions include a washout period of at least five half-lives for anti-PD1 or anti-PDL1 antibodies and ipilimumab during Stage I dose escalation and at least three halflives for anti-PD1 or anti-PDL1 antibodies and ipilimumab during Stage II expansion phase, a washout of 6 weeks for nitrosoureas or mitomycin C, or 14 days for hormonal therapy or kinase inhibitors. (upon discussion with the Medical Monitor, fewer than stated wash-out period may be allowed provided that the patient has adequately recovered from any clinically relevant toxicity). 9. Current Grade \> 1 toxicity (except alopecia and anorexia) from prior therapy or Grade \> 1 neuropathy from any cause 10. Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease, ongoing or active infection) 11. History of clinically significant cardiac dysfunction, including the following: Current uncontrolled Grade ≥ 2 hypertension or unstable angina 12. History of symptomatic congestive heart failure of New York Heart Association class III or IV or serious cardiac arrhythmia requiring treatment, with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia 13. History of myocardial infarction within 6 months prior to the first dose of study-drug treatment in Cycle 1 14. History of bradyarrhythmias, bradycardia or heart block or baseline HR \< 55bpm 15. History of congenital long QT syndrome or QTcF \> 440 msec 16. LVEF (as measured by echocardiography \[ECHO\] or multi-plegated acquisition scan \[MUGA\]) \< 50% or below the lower limit of normal (LLN; whichever is lower) 17. Inability or unwillingness to swallow pills 18. History of malabsorption or other condition that would interfere with enteral absorption 19. Clinically significant history of liver disease (including cirrhosis), current alcohol abuse, or current known active infection with HIV, hepatitis B virus, or hepatitis C virus 20. Any hemorrhage or bleeding event CTCAE Grade 3 or higher within 28 days of Cycle 1, Day 1 21. Patients receiving therapeutic anticoagulation or thrombolytic anticoagulants. Use of low molecular weight heparin and low dose aspirin are allowed. 22. Active autoimmune disease 23. Uncontrolled ascites requiring weekly large volume paracentesis for 3 consecutive weeks prior to enrollment 24. Pregnancy, lactation, or breastfeeding 25. Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms \- Patients with a history of adequately treated brain metastases are eligible. Adequately treated brain metastases are defined as those having no ongoing requirement for medical therapy to control symptoms, and no evidence of progression or hemorrhage for ≥ 2 months after radiation treatment (such as whole brain radiotherapy or radiosurgery \[Gamma Knife, linear accelerator, or equivalent\]) and/or ≥ 3 months after surgical treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging \[MRI\] or CT scan) during the screening period. Any medical therapy for brain metastases (e.g., steroids or seizure medications) must have been discontinued without the subsequent appearance of symptoms for ≥ 4 weeks before the first dose of study-drug treatment in Cycle 1. 26. Inability to comply with study and follow-up procedures 27. No other history of or ongoing malignancy that would potentially interfere with the interpretation of the pharmacodynamics (PD) or efficacy assays 28. Need to take a concomitant medication, dietary supplement, or food that is prohibited during the study 29. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).