Phase II Study of ctDNA-guided Encorafenib Plus Cetuximab Retreatment in Patients BRAF V600E Mutated mCRC

NCT06578559 | Active Not Recruiting Phase 2

• 1 other identifier: BRICKET
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 13

Brief Summary

The aim of this study is to evaluate the activity, in terms of best response according to RECIST criteria 1.1 as assessed by the local investigator, of the ctDNA-guided retreatment with encorafenib plus cetuximab in BRAFV600E mutated mCRC patients experiencing benefit from previous exposure to encorafenib plus cetuximab (+/- chemotherapy) and with BRAFV600E mutated, KRAS, NRAS and MAP2K1 wild-type and MET not amplified status on ctDNA at the time of study entry.

Conditions

Colorectal Cancer

Keywords

ctDNA; Encorafenib; Cetuximab; rechallenge; retreatment; BRAF V600E

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  The percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria. The determination of clinical response will be based on investigator-reported measurements. Responses will be evaluated with a total body computed tomography (CT) scan every 8 weeks.

  8 months after the enrollment of the last patient.

Secondary Outcomes (12)

• Progression Free Survival (PFS)

  8 months after the enrollment of the last patient.

• Overall Survival (OS)

  8 months after the enrollment of the last patient.

• Overall Toxicity Rate

  8 months after the enrollment of the last patient.

• Grade 3/4 Toxicity Rate

  8 months after the enrollment of the last patient.

• Early Objective Response Rate (EORR)

  8 months after the enrollment of the last patient.

Study Arms (1)

Encorafenib + Cetuximab

EXPERIMENTAL

Drug: Cetuximab; Drug: Encorafenib

Interventions

Cetuximab DRUG

500 mg/sqm intravenous infusion over 120-minute at cycle 1 (if well tolerated, it is administered over 90 minutes at second administration, and over 60 minutes by the third administration) every 14 days.

Encorafenib + Cetuximab

Encorafenib DRUG

300 mg once daily (four 75 mg oral capsules).

Encorafenib + Cetuximab

Eligibility Criteria

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

You may qualify if:

• histologically proven diagnosis of colorectal adenocarcinoma;
• age ≥ 18 years;
• ECOG Performance status ≤ 1;
• BRAFV600E mutated status of primary colorectal cancer and/or related metastasis, by local laboratory assessment according to standard procedures by means of molecular assay on genomic DNA;
• Metastatic disease with at least one measurable lesion according to RECIST 1.1. criteria;
• previous treatment with encorafenib plus cetuximab with or without chemotherapy (i.e., ±FOLFOX/FOLFIRI) in any line, producing a RECIST 1.1 complete/partial response or disease stabilisation, with a PFS of this treatment lasting at least 6 months;
• documentation of RECIST 1.1 disease progression during or after the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy;
• one intervening line of treatment not including any BRAF and EGFR inhibitor, between the end of first exposure to encorafenib plus cetuximab ± chemotherapy and the time of screening;
• at least 4 months elapsed between the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy and the retreatment with encorafenib plus cetuximab;
• previous treatment with immune checkpoint inhibitors (anti-PD-1/PD-L1 alone or in combination with anti-CTLA-4 agent), in the case of MSI-H or dMMR mCRC;
• availability of blood sample for ctDNA analysis within 28 days prior enrolment;
• BRAFV600E mutated status of ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health);
• KRAS, NRAS, MAP2K1 wild-type status and MET not amplified status in ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health);
• Availability of archival tumour tissue (primary tumour and/or metastases) for biomarker analysis;
• neutrophils \>1.5 x 109/L, Platelets \>100 x 109/L, Hgb \>9 g/dl. Transfusions will be permitted provided the patient has not received more than two units red blood cells in the prior 4 weeks to achieve this criterion.

You may not qualify if:

• Known hypersensitivity or contraindications to trial drugs or any component of the trial drugs;
• discontinuation of previous treatment with encorafenib and/or cetuximab with or without chemotherapy due to encorafenib- and/or cetuximab-related adverse events;
• symptomatic brain metastases or spinal cord compression. Notes: Patients previously treated or untreated for these conditions who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases or spinal cord compression must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging \[MRI\] or computed tomography \[CT\]) demonstrating no current evidence of progressive brain metastases or spinal cord compression at screening;
• leptomeningeal disease;
• other co-existing malignancies or malignancies diagnosed within the last 5 years except for adequately treated localised basal and squamous cell carcinoma or cervical cancer in situ;
• treatment with any investigational drug within 30 days prior to enrolment or two investigational agent half-lives (whichever is longer);
• Impaired gastrointestinal function (i.e., uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, small bowel resection) or disease which may significantly alter the absorption of oral study intervention or recent changes in bowel function suggesting current or impending bowel obstruction;
• use of any herbal medications/supplements or any medications or foods that are moderate or strong inhibitors or inducers of CYP3A4/5 ≤1 week prior to the start of treatment;
• diagnosis of interstitial pneumonitis or pulmonary fibrosis;
• known history of acute or chronic pancreatitis within 6 months prior to the start of the treatment;
• history of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to first dose;
• impaired hepatic function, defined as Child-Pugh class B or C;
• clinically significant cardiovascular diseases, including any of the following:
• history of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤6 months prior to registration;
• congestive heart failure requiring treatment (New York Heart Association Class II and above);

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest: lead
• Merck Sharp & Dohme LLC: collaborator
• Pierre Fabre Laboratories: collaborator

Study Sites (13)

L'Azienda Ospedaliero Universitaria di Cagliari

Monserrato, CA, 09042, Italy

Location

Istituto Romagnolo Per Lo Studio Dei Tumori "Dino Amadori" Irccs Irst

Meldola, FC, 47014, Italy

Location

Fondazione Casa Sollievo Della Sofferenza - Irccs

San Giovanni Rotondo, FG, 71013, Italy

Location

Pia Fondazione di Culto e di Religione Cardinale G. Panico

Tricase, LE, 73039, Italy

Location

IRCCS Istituto Nazionale dei Tumori di Milano

Milan, MI, 20133, Italy

Location

Istituto Oncologico Veneto Irccs

Padua, PD, 35128, Italy

Location

Azienda Ospedaliero-Universitaria Pisana

Pisa, PI, 56126, Italy

Location

Nuovo Ospedale di Prato S. STEFANO

Prato, PO, 59100, Italy

Location

AUSL Romagna

Ravenna, RA, 48121, Italy

Location

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Roma, RM, 00168, Italy

Location

A.O.U. Citta Della Salute E Della Scienza Di Torino Presidio Molinette

Turin, TO, 10126, Italy

Location

Azienda Sanitaria Universitaria Friuli Centrale

Udine, UD, 33100, Italy

Location

Azienda Ospedaliera Universitaria degli Studi di Campania L. Vanvitelli

Naples, 80131, Italy

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Cetuximab; encorafenib

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

• Carlotta Antoniotti, MD, PhD

  Department of Translational Research and New Technologies in Medicine and Surgery - University of Pisa

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2024
• First Posted: August 29, 2024
• Study Start: July 23, 2024
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: January 5, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

IT (13)