NCT04607421|Active Not RecruitingPhase 3DMCFDA Drug

A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer

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

Pfizer ClinicalTrials.gov

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3 other identifiers

C42210152023-509405-77-00BREAKWATER

Study Type

interventional

Target

831

Locations

29 countries

Sites

268

Timeline

RegisteredOct 2020

StartedDec 2020

CompletionDec 2027

Brief Summary

The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that:

has spread to other parts of the body (metastatic);
has a certain type of abnormal gene called "BRAF"; and
has not received prior treatment. Participants in this study will receive one of the following study treatments:
Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic.
Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home.
Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home. This study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone. The study team will monitor how each participant responds to the study treatment for up to about 3 years.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Strong global presence with extensive site network

Enrollment

831

participants targeted

Target at P75+ for phase_3

Timeline

20mo left

Started Dec 2020

Longer than P75 for phase_3

Geographic Reach

29 countries

268 active sites

Status

active not recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

7 years study duration

Study Progress77%

Dec 2020Dec 2027

First Submitted

Initial submission to the registry

October 5, 2020

Completed

24 days until next milestone

First Posted

Study publicly available on registry

October 29, 2020

Completed

2 months until next milestone

Study Start

First participant enrolled

December 21, 2020

Completed

5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 8, 2025

Completed

2.1 years until next milestone

Study Completion

Last participant's last visit for all outcomes

December 28, 2027

Expected

Last Updated

August 14, 2025

Status Verified

August 1, 2025

Enrollment Period

5 years

First QC Date

October 5, 2020

Last Update Submit

August 12, 2025

Conditions

Neoplasms

Keywords

Colorectal cancerColon cancerRectal cancerColorectal NeoplasmsIntestinal cancerIntestinal NeoplasmsGastrointestinal cancerGastrointestinal NeoplasmsDigestive system cancerDigestive System NeoplasmsDigestive System DiseasesGastrointestinal DiseasesColonic DiseasesIntestinal DiseasesRectal DiseasesBREAKWATER Study

Outcome Measures

Primary Outcomes (4)

Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs)
Incidence of dose limiting toxicity defined as any adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies occurring during the first 28 days of treatment
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Phase 3: Progression free survival, by blinded independent review
Progression free survival, defined as the time from the date of randomization to the earliest documented disease progression or death due to any cause: encorafenib and cetuximab + mFOLFOX6 (Arm B) vs the Control Arm (Arm C)
Duration of Phase 3, approximately 36 months
Phase 3: Objective response rate by blinded independent review
Objective response defined as complete response (CR), or partial response (PR) according to RECIST v1.1 based on BICR assessment, from the date of randomization until the date of the first documentation of progression of disease (PD)
Duration of Phase 3, approximately 23 months
Cohort 3: Objective response rate by blinded independent review
Defined as CR, or PR according to RECIST v1.1 based on BICR assessment, from the date of randomization until the date of the first documentation of PD, death or start of new anticancer therapy
Duration of Cohort 3, approximately 15 months.

Secondary Outcomes (44)

Safety Lead-in: Incidence of adverse events
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Incidence of dose interruptions, dose modifications and discontinuations due to adverse events
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Overall response rate by investigator
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Duration of response by Investigator
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
+39 more secondary outcomes

Study Arms (7)

Safety Lead-in Cohort 1

EXPERIMENTAL

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

Drug: EncorafenibDrug: CetuximabDrug: IrinotecanDrug: LeucovorinDrug: 5-FU

Safety Lead-in Cohort 2

EXPERIMENTAL

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

Drug: EncorafenibDrug: CetuximabDrug: OxaliplatinDrug: LeucovorinDrug: 5-FU

Phase 3 Arm A

EXPERIMENTAL

Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks

Drug: EncorafenibDrug: Cetuximab

Phase 3 Arm B

EXPERIMENTAL

Drug: EncorafenibDrug: CetuximabDrug: OxaliplatinDrug: LeucovorinDrug: 5-FU

Phase 3 Arm C

ACTIVE COMPARATOR

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- 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)

Drug: OxaliplatinDrug: IrinotecanDrug: LeucovorinDrug: 5-FUDrug: CapecitabineDrug: Bevacizumab

Cohort 3 Arm D

EXPERIMENTAL

Drug: EncorafenibDrug: CetuximabDrug: IrinotecanDrug: LeucovorinDrug: 5-FU

Cohort 3 Arm E

ACTIVE COMPARATOR

Irinotecan 180 mg/m2 (90-minute IV infusion) every 2 weeks, Leucovorin 400 mg/m2 (120-minute IV infusion) every 2 weeks, 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks, Bevacizumab (optional; given per prescribing instructions)

Drug: IrinotecanDrug: LeucovorinDrug: 5-FUDrug: Bevacizumab

Interventions

EncorafenibDRUG

75 mg capsules

Also known as: Braftovi, PF-07263896, LGX818, ONO-7702

Cohort 3 Arm DPhase 3 Arm APhase 3 Arm BSafety Lead-in Cohort 1Safety Lead-in Cohort 2

CetuximabDRUG

Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial

Also known as: Erbitux

Cohort 3 Arm DPhase 3 Arm APhase 3 Arm BSafety Lead-in Cohort 1Safety Lead-in Cohort 2

OxaliplatinDRUG

Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial

Also known as: Eloxatin

Phase 3 Arm BPhase 3 Arm CSafety Lead-in Cohort 2

IrinotecanDRUG

Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial

Also known as: Campostar

Cohort 3 Arm DCohort 3 Arm EPhase 3 Arm CSafety Lead-in Cohort 1

LeucovorinDRUG

Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial

Also known as: Wellcovorin, Fusilev, Khapzory

Cohort 3 Arm DCohort 3 Arm EPhase 3 Arm BPhase 3 Arm CSafety Lead-in Cohort 1Safety Lead-in Cohort 2

5-FUDRUG

Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial

Also known as: Fluorouracil

Cohort 3 Arm DCohort 3 Arm EPhase 3 Arm BPhase 3 Arm CSafety Lead-in Cohort 1Safety Lead-in Cohort 2

CapecitabineDRUG

150 mg or 500 mg Tablet

Also known as: Xeloda

Phase 3 Arm C

BevacizumabDRUG

Optional Injection for intravenous use 100 mg/vial or 400 mg/vial

Also known as: Zirabev

Cohort 3 Arm EPhase 3 Arm C

Eligibility Criteria

Age16 Years+

Sexall

Healthy VolunteersNo

Age GroupsChild (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

Safety Lead-In = Male/female ≥ 18 years old
Phase 3 and Cohort 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: 0-1 regimens for Safety Lead In; none for Phase 3 and Cohort 3. (Note: Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis \< 6 month from end of adj/neoadjuvant treatment )
Measurable disease (Phase 3 and Cohort 3)/ Measurable or evaluable disease (Safety Lead-in)
ECOG PS 0-1
Adequate organ function

You may not qualify if:

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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Pfizerlead
Ono Pharmaceutical Co. Ltdcollaborator
Merck KGaA, Darmstadt, Germanycollaborator
Eli Lilly and Companycollaborator

Study Sites (268)

Mayo Clinic Hospital

Phoenix, Arizona, 85054, United States

Location

Mayo Clinic in Arizona - Scottsdale

Scottsdale, Arizona, 85259, United States

Location

Keck Hospital of USC