Bevacizumab Plus encoRAfenib-cetuximab in BRAF-V600E Mutated Metastatic Colorectal Cancer, a Phase II Study With a Safety lead-in Cohort, the BRAVE Trial
The BRAVE is a phase II clinical trial aimed at evaluating the efficacy of the combination therapy of encorafenib, cetuximab, and bevacizumab in patients with metastatic colorectal cancer (CRC) harboring the BRAF-V600E mutation. This mutation is present in about 8-10% of CRC cases and is associated with poor prognosis and limited treatment options. The rationale behind this trial stems from preclinical studies suggesting that the overexpression and activation of vascular endothelial growth factor A (VEGFA) may contribute to resistance to BRAF inhibitors (BRAFi) in CRC. Thus, the trial hypothesizes that adding bevacizumab, an anti-angiogenic agent targeting VEGFA, to the combination of encorafenib and cetuximab may delay acquired resistance, leading to improved progression-free survival. The primary objective of the BRAVE is to evaluate the antitumor activity of the encorafenib-cetuximab-bevacizumab combination in patients who have experienced disease progression after one or two chemotherapy regimens for BRAF V600E-mutant metastatic CRC. This activity will be assessed based on the confirmed progression-free survival rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.
• Provision of signed and dated informed consent form.
• Age ≥18 years at time of informed consent.
• Histologically- or cytologically-confirmed mCRC that is metastatic.
• Presence of BRAF V600E mutation in tumor tissue previously determined according to the guidelines of each center, any time point before the enrollment in the study.
• Microsatellite stability must be confirmed according to the guidelines of each center, any time point before the enrollment in the study.
• Eligible to receive cetuximab per locally approved label with regard to tumor RAS status, any time point before the enrollment in the study.
• Progression of disease after 1 or 2 prior regimens in the metastatic setting.
• Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1.
• ECOG PS of 0 or 1.
• Adequate bone marrow function characterized by the following at screening:
‣ Absolute neutrophil count (ANC) ≥1.5 x 109/L
⁃ Platelets ≥100 x 109/L
⁃ Hemoglobin ≥9.0 g/dL (with or without blood transfusions).
• Adequate hepatic and renal function characterized by the following at screening:
‣ Serum total bilirubin ≤1.5 x upper limit of normal (ULN) and \<2 mg/dL. Note: 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: Participants with hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the Sponsor medical monitor.
⁃ Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤2.5 x ULN, or ≤5 x 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.
⁃ Protein \< 2+ on dipstick urinalysis or ≤ 1.0 g in a 24-hour urine collection. All patients with ≥2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection for protein.
⁃ Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits.
∙ Note: Replacement treatment to achieve adequate electrolytes will be allowed.
• Adequate cardiac function characterized by the following at screening:
• a.Mean triplicate QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤480 msec.
• Able to take oral medications.
• Highly effective contraception for both male and female subjects if the risk of conceptions exists during and at least up to 6 months after the last medication. See 10.4. Appendix 4.