Multicenter Phase 2 study to evaluate the efficacy and safety of Cetuximab in combination with Encorafenib plus Binimetinib as induction treatment in BRAF (V600E) mutated MSS, initially resectable or potentially resectable advanced colorectal cancer: CEBBRA study.

Prior treatment

• Previous administration with an investigational drug within 28 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (wichever is longer).
• Known contraindication to receiving cetuximab including hypersensitivity or toxicity that would suggest an inability to tolerate maximun cetuximab dose of 500 mg/m^2.
• Evidence of active and uncontrolled bacterial or viral infection, with certain exceptions, as noted below, for chronic infection with HIV, hepatitis B or hepatitis C (please see below), within 2 weeks prior to start os study treatment.
• Full dose radiotherapy <28 days prior to the start of study treatment. Short course radiotherapy for local control of primary tumor or other palliative indication is allowed.
• Residual CTCAE≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy.
• Previous treatment with any selective BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib, XL281/BMS-908662) and/or any selective MEK inhibitor prior to screening.
• Use of any prohibited medication (including herbal medication), supplement or food that is a moderate or strong inhibitor or inducer of CYP3A4/5 ≤1 week prior to the start of study intervention.
• Major surgery (e.g., inpatient procedure with regional or general anesthesia) or completion of radiation therapy ≤4 weeks prior to the start of study treatment.
• History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medication or surgery) ≤ 12 months prior to the start of study treatment.
• Prior systemic regimen in first line treatment for metastatic CRC in patients with the following exceptions: Patients with resected (R0 or R1 resections) metastasis of CRC treated with or without adjuvant or neoadjuvant chemotherapy (+/- antiEGFR or bevacizumab) that relapsed, would be eligible if the time from the last dose of chemotherapy or the surgery (the later) to the initiation of the treatment of the study were longer than 28 days.
• Prior chemotherapy for stage II/III CRC, with the following exceptions: Patients with previous adjuvant or neoadjuvant chemotherapy for resected St II/III CRC that relapsed, would be eligible if the time from the last dose of chemotherapy or the surgery (the later) to the initiation of the treatment of the study were longer than 28 days.

Other illness

• Leptomeningeal disease or brain metastases.
• Concurrent or previous other malignancy within 3 years of study entry, except curatively treated basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix. Bowen´s disease or prostate cancer with a Gleason score ≤6. Participants with other curatively treated malignancies with low risk of recurrence not listed may also be considered eligible after review and approval by the medical monitor.
• Impaired gastrointestinal function (e.g., uncontrolled nausea, vomiting or diarrhea malabsorption syndrome, small bowel resection) or disease wich may significantly alter the absorption of oral study intervention or recent changes in bowel function suggesting current or impending bowel obstruction.
• Evidence of active non-infectious pneumonitis.

Lab values

• Any medical or psychiatric condition including recent (within the past year) or current suicidal ideation/behaviour or laboratory abnormality that may increase the risk of study participation or, in the investigator´s judgment, make the participant inappropiate for the study.
• Participants with known positive for HIV are ineligible unless they meet all of the folllowing: a. A stable regimen of highly active anti-retroviral therapy that is not contraindicated. b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections. c. A CD4 count ≥250 cells/mcL. and an undetectable HIV viral load on standard PCR-based tests.
• Know active hepatitis B or hepatitis C infection a. Active HBV is defined as any of the following: i. HBsAg (+), HBV DNA >200 IU/ml (105 copies/mL); ii. HBsAg (+), HBV DNA ≤200 IU/mL and persistent or intermittent elevation of ALT/AST and/or liver biopsy showing chronic hepatitis with moderate or severe necroinflammation. Note: Participants who are HBsAg (-), HBcAb (+) are elegible and should be monitored/treated as per local standard of care. b. Active HCV is defined as: i. HCV antibody positive; AND. ii. Presence of HCV RNA.
• Clinically significant cardiovascular diseases, including any of the following: a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤6 months prior to the start of study treatment Congetive heart failure requiring treatment (New York Heart Association Grade ≥2). b. History or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventicular tachycardia). c. History of thromboembolic or cerebrovascular events ≤12 weeks prior to the start of the study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e., massive or sub-massive) deepd vein thrombosis or pulmonary emboli. Note 1: Participants with either deep vein thrombosis or pulmonary emboli that do not result in hemodynamic instability are allowed to enroll as long as they have been on a stable dose of anticoagulants for al least 4 weeks. Note 2: Participants with thromboembolic events related to indwelling catheters (including PCC lines) or other procedures may be enrolled. d. Triplicate average QTcF interval ≥480 ms or a history of prolonged QT syndrome. e. Congenital LQTS.

Age

• Male or female of childbearing age who do not agree with taking highly effective contraceptive precautions, (for definition, please refer to Appendix 15) or abstinence during the course of the study and for 6 months after the last administration os study drug for women and men.

Other

• Known sensitivity or contraindication to any component of study intervention or their excipients al the planned doses.
• Pregnant, or is breastfeeding (lactating).
• Patients with known ulcerative keratitis.
• Known RAS-mutant colorectal adenocarcinoma.

• Male or female participant age ≥ 18 years at the time of informed consent.
• Adequate bone marrow function characterired by the following at screening: a. ANC ≥1.5 x 10^9/L. b. Platelets ≥ 100 x 10^9/L. c. Hemoglobin ≥ 9.0 g/dL (with or without blood transfusions).
• Adequate hepatic and renal function characterized by the following at screening: a. Serum total bilirubin ≤1.5 x ULN. Note 1: Total bilirubin >1.5 x ULN is allowed if direct (conjugated) ≤1.5 x ULN and indirect (unconjugated) bilirubin is ≤4.25 x ULN. Note 2: Participants with hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the medical monitor. b. ALT and AST ≤2.5 x ULN, or ≤5 x ULN in the presence of liver metastases. c. Adequate renal function defined by an estimated creatinine clearance ≥50 mL/min according to the Cockcroft Gault formula or by 24-hour urine collection for creatinine clearance, or according to local institutional standar method.
• Able to swallow, retain, and absorb oral medications.
• Capable of giving signed informed consent/assent.
• Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory test, lifestyle considerations, and other study procedures.
• Participants with histologically or cytologically confirmed colorectal adenocarcinoma.
• Presence of a BRAF V600E mutation confirmed as per standard of care according to international guidelines at any time prior to Screening.
• Microsatellite stable (MSS) or Mismatch-Repair proficient (pMMR) disease confirmation assessed by local PCR or immunohistochemistry (ICH)
• Participants with CRC who have one of these criteria: a. Locally advanced colorectal cancer with initially unresectable but potentially resectable disease according to the local Multidisciplinary Tumour Board (MTB). b. Oligometastatic colorectal cancer (possible metastasis sites: liver, lung, lymph nodes and peritoneum) with: i. Initially resectable disease according to the local MTB or ii. Initially unresectable but potentially resectable disease according to the local MTB. c. c. Stage II-IV colorectal cancer relapsed after previous R0 or R1 resection and neoadjuvant and/or adjuvant chemotherapy, if the shorter time from the resection or from the end of the adjuvant chemotherapy to the initiation of the treatment of the study is longer than 28 days. This relapse (locoregional and/or systemic) should be initially resectable or initially unresectable but potentially resectable according to the local MTB.
• ECOG performance status of 0 or 1
• Measurable or evaluable disease as assessed by investigator, according to RECIST v 1.1