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
As a result of the little benefit obtained from standard treatments and the poor prognosis of these patients, the BRAF-V600E mutant MSS aCRC represents an unmet medical need requiring clinical research. The combination of encorafenib, cetuximab and binimetinib as second- or third-line treatment for mCRC resulted in significantly better outcomes than standard therapy in a phase 3 clinical trial, which also revealed treatment safety and tolerability to be acceptable. Compared to the control group (cetuximab and irinotecan or cetuximab and FOLFIRI), the triplet therapy cohort showed higher median overall survival (9.3 vs. 5.9 months) and response rates (26.8% vs. 1.8%). Grade 3 adverse events occurred in 65.8% and 64.2% of patients for triple-therapy and control groups, respectively. Based on these results, the investigators speculated that the combination of encorafenib, cetuximab and binimetinib could be used as induction therapy to improve treatment outcomes in BRAF-V600E-mutated MSS aCRC locally advanced initially unresectable but potentially resectable; initially resectable or initially unresectable but potentially resectable oligometastatic disease; and in patients with stage II-IV who have relapsed after chemotherapy (neo and/or adjuvant) or surgery, if the shorter time after resection or from treatment end to relapse is longer than 6 months.
• 1\. Male or female participants age ≥18 years at the time of informed consent. 2. Capable of giving signed informed consent/assent. 3. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
• 4\. Participants with histologically or cytologically confirmed colorectal adenocarcinoma.
• 5\. Presence of a BRAF V600E mutation confirmed as per standard of care according to international guidelines at any time prior to Screening.
• 6\. Microsatellite stable (MSS) or Mismatch-Repair proficient (pMMR) disease confirmation assessed by local PCR or immunohistochemistry (IHC).
• 7\. Participants with CRC who have one of these criteria:
⁃ Locally advanced colorectal cancer with initially unresectable but potentially resectable disease according to the local Multidisciplinary Tumour Board (MTB).
⁃ 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. Stage II-IV colorectal cancer treated with previous neoadjuvant and/or adjuvant chemotherapy, for R0, if the shorter time from the resection or from the end of the adjuvant treatment to the relapse of colorectal cancer (possible metastasis sites: liver, lung, lymph nodes and peritoneum) is longer than 6 months. This relapse (locoregional and/or systemic) should be initially resectable or initially unresectable but potentially resectable disease according to the local MTB 8. ECOG performance status of 0 or 1. 9. Measurable or evaluable disease as assessed by investigator, according to RECIST v1.1.
• 10\. Adequate bone marrow function characterized by the following at screening:
⁃ ANC ≥1.5 × 109/L
⁃ Platelets ≥100 × 109/L
⁃ Hemoglobin ≥9.0 g/dL (with or without blood transfusions). 11. Adequate hepatic and renal function characterized by the following at screening:
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‣ 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.
⁃ ALT and AST ≤2.5 × ULN, or ≤5 × ULN in the presence of liver metastases.
⁃ 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 standard method.
‣ 12\. Able to swallow, retain, and absorb oral medications.