Combination Therapy for BRAF-V600E Metastatic CRCm

NCT06411600 | Recruiting Phase 2

• 1 other identifier: VHIO23001
• Study Type: interventional
• Target: 94
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Colorectal Cancer

Keywords

Encorafenib; Cetuximab; Bevacizumab

Outcome Measures

Primary Outcomes (1)

• Progression-Free Survival (PFS)

  PFS will be evaluated by local radiologist/investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). It refers to the duration from the start of treatment until disease progression or death due to any cause.

  Until disease progression, typically within a follow-up period of approximately 5 years.

Secondary Outcomes (5)

• Objective Response Rate (ORR)

  Throughout the study duration, that it will take 5 years

• Duration of Response (DOR)

  Until disease progression, typically within a follow-up period of approximately 5 years.

• Disease Control Rate (DCR)

  Throughout the study duration, that it will take 5 years

• Electrocardiogram (ECG) Changes

  During treatment (until disease progression) and up to 30 ± 2 days after the last dose.

• Incidence and Severity of Adverse Events

  Until disease progression, typically within a follow-up period of approximately 5 years.

Study Arms (2)

Experimental arm

EXPERIMENTAL

The experimental arm in the BRAVE protocol involves the administration of a combination therapy consisting of encorafenib, cetuximab, and bevacizumab. This arm is designed to evaluate the efficacy and safety of this combination in patients with metastatic colorectal cancer harboring the BRAF-V600E mutation who have experienced disease progression after one or two prior chemotherapy regimens. The primary objective is to assess the antitumor activity of the combination therapy, with secondary objectives including safety and tolerability assessments, as well as evaluations of progression-free survival, overall survival, and patient-reported outcomes.

Drug: Encorafenib; Drug: Cetuximab; Drug: Bevacizumab

Control arm

ACTIVE COMPARATOR

The control arm in the BRAVE protocol involves standard-of-care treatment, which may include various chemotherapy regimens or targeted therapies typically used for metastatic colorectal cancer. In this arm, patients receive the standard treatment without the addition of encorafenib, cetuximab, or bevacizumab. The purpose of the control arm is to provide a reference point for comparing the efficacy and safety of the experimental combination therapy. Patients in this arm may also undergo similar assessments for tumor response, survival outcomes, and adverse events to facilitate comparison with the experimental arm.

Drug: Bevacizumab

Interventions

Encorafenib DRUG

Encorafenib is administered orally at a daily dose of 300 mg, typically in the form of four 75 mg capsules taken together.

Experimental arm

Cetuximab DRUG

Cetuximab is administered intravenously every two weeks at a dose of 500 mg/m².

Experimental arm

Bevacizumab DRUG

Bevacizumab is administered intravenously every two weeks at a dose of 5 mg/kg.

Control arm; Experimental arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Treatment with another investigational drug or participation in another investigational study at enrolment or within 30 days prior to enrolment.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study.
• Prior history of hypertensive crisis or hypertensive encephalopathy.
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1.
• Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence of therapeutic anticoagulation).
• Patients with history of pulmonary hemorrhage/hemoptysis (\>1/2 teaspoon red blood) within 6 months prior to Cycle 1, Day 1.
• Known history of acute or chronic pancreatitis.
• Tumors with microsatellite instability or mismatch repair deficiency.
• History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention. (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months before the enrollment in the study.
• Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
• History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft \[CABG\], coronary angioplasty or stenting) ≤ 6 months prior to start of study treatment.
• Symptomatic congestive heart failure (i.e., Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality ≤ 6 months prior to start of study treatment, except atrial fibrillation and paroxysmal supraventricular tachycardia.
• Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
• Impaired hepatic function, defined as Child-Pugh class B or C.
• Known history of human immunodeficiency virus (HIV), active hepatitis B virus (HBV) infection or active hepatitis C virus (HCV) infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients with past exposure to HBV are also eligible for the study provided they are negative for HBV DNA.

Sponsors & Collaborators

• Vall d'Hebron Institute of Oncology: lead

Study Sites (1)

Vall d'Hebron Hospital

Barcelona, 08035, Spain

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

encorafenib; Cetuximab; Bevacizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Elena Elez, MD PhD

  Vall d'Hebron Institute of Oncology

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Elena Elez, MD PhD

CONTACT

+34 932744350; meelez@vhio.net

Susana Muñoz

CONTACT

smunoz@vhio.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 24, 2024
• First Posted: May 13, 2024
• Study Start: May 17, 2024
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2029
• Last Updated: November 8, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)