A Study Evaluating the Combination of Encorafenib and Cetuximab Versus Irinotecan/Cetuximab or Infusional 5-fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab in Chinese Patients With BRAF V600E Mutant Metastatic Colorectal Cancer. (NAUTICALCRC)

Pierre Fabre

Status and phase: Completed; Phase 2

Conditions: Metastatic Colorectal Cancer; BRAF V600E

Treatments: Drug: Encorafenib; Drug: Cetuximab; Drug: FOLFIRI

Study type: Interventional

Funder types: Industry

Identifiers

NCT05004350

W00090GE202

Details and patient eligibility

About

Encorafenib is currently being developed (with or without binimetinib), in combination with cetuximab, for the treatment of adult patients with B-RAF proto-oncogene, serine/threonine kinase V600E mutant (BRAF V600E) metastatic colorectal cancer (mCRC), who have received prior systemic therapy.

Enrollment: 107 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria for Molecular Prescreening:

The following inclusion criteria must be met for a participant to be eligible to undergo molecular tumor prescreening:

• Chinese male or female participant with age ≥18 years at the time of informed consent.
• Histologically- or cytologically-confirmed colorectal cancer (CRC) that is metastatic.
• Eligible to receive cetuximab per Chinese approved label with regard to tumor Rat Sarcoma Viral Oncogene Homologue (RAS) mutation status (i.e. approved for Rat Sarcoma Viral Oncogene Homologue Wild Type(RAS wt) status).
• Able to provide a sufficient amount of representative tumor specimen for central prospective laboratory testing of B-RAF Proto-oncogene, Serine/threonine Kinase (BRAF) mutation status and also retrospective RAS wt status and Microsatellite Instability (MSI) testing.

Inclusion Criteria for Treatment Period:

The following inclusion criteria must be met for a participant to be eligible for this study:

• Chinese male or female participant with age ≥18 years at time of informed consent.
• Histologically or cytologically confirmed CRC that is metastatic and unresectable at time of study entry (i.e. not suitable for complete surgical resection at screening).
• Presence of a BRAF V600E mutation in tumor tissue previously determined by a local assay at any time before screening or by the central laboratory.

NOTE: Other protocol defined Inclusion criteria may apply

Exclusion Criteria for Molecular Prescreening:

Participants meeting any of the following criteria are not eligible to undergo molecular tumor prescreening:

• Prior anti-Epidermal Growth Factor Receptor (anti-EGFR) treatment
• More than two prior regimens in the metastatic setting.
• Known contraindication to receive cetuximab or irinotecan at the planned dose according to the most recent cetuximab and irinotecan local label.
• Known history of Gilbert's syndrome or is known to have any of the following genotypes: uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*6/*6, UGT1A1*28/*28 or UGT1A1*6/*28.
• Leptomeningeal disease.

Exclusion Criteria for Treatment Period:

• Prior treatment with any Proto oncogene Serine/threonine-Protein Kinase (RAF) inhibitor, cetuximab, panitumumab or other EGFR inhibitors.
• Symptomatic brain metastasis.
• Leptomeningeal disease.
• Use of any herbal medications/supplements or any medications or foods that are moderate or strong inhibitors or inducers of cytochrome P450 (CYP)3A4/5 ≤1 week before the start of study intervention.
• Known history of acute or chronic pancreatitis within 6 months before the start of study intervention.

NOTE: Other protocol defined Exclusion criteria may apply

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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107 participants in 2 patient groups

Encorafenib and cetuximab

Experimental group

Description:

Safety Lead-in (SLI) phase: 28 day cycles of encorafenib once daily (QD) 300 mg (4 x 75 mg oral capsule) and cetuximab 400 mg/m² initial dose (120-minute infusion), then 250 mg/m² (60-minute infusion) thereafter once weekly Randomized (Phase II) phase: 28 day cycles of encorafenib once daily (QD) 300 mg (4 x 75 mg oral capsule) and cetuximab 400 mg/m² initial dose (120-minute infusion), then 250 mg/m² (60-minute infusion) thereafter once weekly

Treatment:

Drug: Cetuximab

Drug: Encorafenib

Irinotecan and cetuximab or FOLFIRI and cetuximab

Experimental group

Description:

Randomized (Phase II) phase: Either irinotecan and cetuximab or FOLFIRI and cetuximab in 28 day cycles. Irinotecan and cetuximab: * irinotecan 180 mg/m² (90-minute intravenous infusion or to study site standards) every 2 weeks and * cetuximab 400 mg/m² initial dose (120-minute intravenous infusion), then 250 mg/m² (60-minute infusion) thereafter once weekly OR FOLFIRI and cetuximab: * irinotecan 180 mg/m² (90-minute intravenous infusion or to study site standards) every 2 weeks * Folinic acid 400 mg/m² (120-minute infusion or to study site standards) or maximal dose tolerated in a prior regimen every 2 weeks * 5-FU 400 mg/m² initial dose bolus (not to exceed 15 minutes), then 1200 mg/m²/day × 2 days (total 2400 mg/m² over 46 to 48 hours) continuous infusion or maximal dose tolerated in a prior regimen every 2 weeks and * cetuximab 400 mg/m² initial dose (120-minute intravenous infusion), then 250 mg/m² (60-minute infusion) thereafter once weekly

Treatment:

Drug: FOLFIRI

Drug: Cetuximab

Drug: Encorafenib