C4221015 - An open-label, multicenter, randomized phase 3 study of first-line encorafenib plus cetuximab with or without chemotherapy versus standard of care therapy with a safety lead-in of encorafenib and cetuximab plus chemotherapy in participants with metastatic BRAF V600E-mutant colorectal cancer (BREAKWATER)

Studio Clinico

Patologia: Tumori del colon retto

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: Sì

Fase di studio: III

Linee di trattamento: Prima linea

Criteri di inclusione: 

- Safety Lead-In = Male/female ≥ 18 years old
- Phase 3: Male/female ≥ 16 years old (where permitted locally)
- Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation
- Prior systemic treatment in metastatic setting
- SLI: 0-1 regimens
- Phase 3: None
- Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment
- Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in)
- ECOG PS 0-1
- Adequate organ function.

Criteri di esclusione: 

- Tumors that are locally confirmed or unknown MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition
- Active bacterial or viral infections in 2 weeks prior to starting dosing
- Symptomatic brain metastases.

Numero di pazienti previsti: 

52 (in Italia)

Schema di trattamento: 

Safety Lead-In (SLI) - Cohort 1
Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks Irinotecan 180 mg/m2 (90-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks
Safety Lead-In (SLI) - Cohort 2
Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120 minute IV infusion) every two weeks Oxaliplatin 85 mg/m2 (120-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks
Phase 3 Arm A
Encorafenib (300 mg QD) + cetuximab 500 mg/m2 (120-minute IV infusion Q2W).
Phase 3 Arm B
Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks Irinotecan 180 mg/m2 (90-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks -OR- Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120 minute IV infusion) every two weeks Oxaliplatin 85 mg/m2 (120-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks
Phase 3 Arm C (control Arm)
Every two weeks: Oxaliplatin 85 mg/m2 (120-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Every two weeks: Irinotecan 165 mg/m2 (90-minute IV infusion) Oxaliplatin 85 mg/m2 (120-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 2400 or 3200 mg/m2 continuous IV infusion over 46 48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Every two weeks: Irinotecan 180 mg/m2 (90-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Oxaliplatin 130 mg/m2 (120-minute IV infusion) every 3 weeks Capecitabine 1000 mg/m2 oral tablet twice daily on Days 1-14 Bevacizumab (optional; given per prescribing instructions)

Trattamento sperimentale: 

Safety Lead-in:
- Encorafenib + cetuximab + FOLFIRI
- Encorafenib + cetuximab + mFOLFOX6

Phase III:
Arm A: Encorafenib + cetuximab
Arm B: Encorafenib + cetuximab + mFOLFOX6
oppure
Encorafenib + cetuximab + FOLFIRI

Trattamento di controllo: 

Phase III:
- mFOLFOX6 ± bevacizumab
- FOLFIRI ± bevacizumab
- FOLFOXIRI ± bevacizumab or
- CAPOX ± bevacizumab.

Obiettivi primari dello studio: 

The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. Since encorafenib has not previously been combined with chemotherapy, the tolerability and PK of EC in combination with mFOLFOX6 and in combination with FOLFIRI will be evaluated in separate cohorts in the safety lead-in portion of the trial in order to identify which chemotherapy combination is to be used in the Phase 3 portion of the study.

Data di inizio dell'arruolamento: 06.01.2021

Data di fine dell'arruolamento: 22.01.2024

Centri partecipanti

Nord Italia

Sud Italia e isole

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2020-001288-99

Data di inserimento: 23.02.2022

Data di aggiornamento: 19.01.2023

Promotore

Pfizer

CRO

PPD

Principal Investigator ITALIA

Istituto Oncologico Veneto IRCCS, Padova

Riferimento: Dr.ssa Sara Lonardi

Telefono: 0498215910

Email: sara.lonardi@iov.veneto.it

Localita: Padova