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

Pfizer

Status and phase: Active, not recruiting; Phase 3

Conditions: Neoplasms

Treatments: Drug: Cetuximab; Drug: Oxaliplatin; Drug: Leucovorin; Drug: Irinotecan; Drug: Capecitabine; Drug: 5-FU; Drug: Bevacizumab; Drug: Encorafenib

Study type: Interventional

Funder types: Industry

Identifiers

NCT04607421

C4221015

BREAKWATER (Other Identifier)

2023-509405-77-00 (Registry Identifier)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 816 patients

Sex: All

Ages: 16+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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

Exclusion criteria

• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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816 participants in 7 patient groups

Safety Lead-in Cohort 1

Experimental group

Description:

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

Treatment:

Drug: Encorafenib

Drug: 5-FU

Drug: Leucovorin

Drug: Irinotecan

Drug: Cetuximab

Safety Lead-in Cohort 2

Experimental group

Description:

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

Treatment:

Drug: Encorafenib

Drug: 5-FU

Drug: Leucovorin

Drug: Oxaliplatin

Drug: Cetuximab

Phase 3 Arm A

Experimental group

Description:

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

Treatment:

Drug: Encorafenib

Drug: Cetuximab

Phase 3 Arm B

Experimental group

Description:

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

Treatment:

Drug: Encorafenib

Drug: 5-FU

Drug: Leucovorin

Drug: Oxaliplatin

Drug: Cetuximab

Phase 3 Arm C

Active Comparator group

Description:

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)

Treatment:

Drug: Bevacizumab

Drug: 5-FU

Drug: Capecitabine

Drug: Leucovorin

Drug: Irinotecan

Drug: Oxaliplatin

Cohort 3 Arm D

Experimental group

Description:

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

Treatment:

Drug: Encorafenib

Drug: 5-FU

Drug: Leucovorin

Drug: Irinotecan

Drug: Cetuximab

Cohort 3 Arm E

Active Comparator group

Description:

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)

Treatment:

Drug: Bevacizumab

Drug: 5-FU

Drug: Leucovorin

Drug: Irinotecan