Study of Petosemtamab Plus Chemotherapy Versus Cetuximab Plus Chemotherapy in RAS and BRAF Wild-type, Unresectable or Metastatic, Left-sided Colorectal Cancer

A Randomized, Open-label, Phase 3 Trial of Petosemtamab in Combination With mFOLFOX6 or FOLFIRI Versus Cetuximab in Combination With mFOLFOX6 or FOLFIRI as First-line Treatment for Participants With RAS and BRAF Wild-type, Unresectable or Metastatic, Left-sided Colorectal Cancer

The purpose of this trial is to evaluate how well petosemtamab in combination with chemotherapy works against colorectal cancer located on the left side of the colon that cannot be safely removed by surgery or has spread to other parts of the body.

Participants will receive either petosemtamab + doctor's choice of chemotherapy (mFOLFOX6 or FOLFIRI) or standard-of-care cetuximab + doctor's choice of chemotherapy (mFOLFOX6 or FOLFIRI). No participants will be given placebo.

The treatment duration will be different for every participant. If a participant's cancer stays the same or gets better, and there are not any serious problems, participants can keep getting study treatment for as long as the study is open.

Participants will be asked to attend 2 visits at the study clinic for each cycle (duration of cycle is 4 weeks). During visits, there will be various tests (such as blood draws) and procedures (such as imaging) to monitor whether the study treatment is safe and effective. The overall study duration (including screening, treatment, and follow-up) will be different for every participant.

Study Overview

• Status: Not yet recruiting
• Conditions: Left-sided Colorectal Cancer
• Intervention / Treatment: Drug: Petosemtamab; Drug: FOLFIRI; Drug: mFOLFOX6; Drug: Cetuximab

Detailed Description

This Phase 3, randomized, open-label, global trial is designed to assess the efficacy and safety of petosemtamab plus investigator's choice (IC) chemotherapy (fluorouracil + leucovorin (calcium folinate) + oxaliplatin [mFOLFOX6] or fluorouracil + leucovorin (calcium folinate) + irinotecan [FOLFIRI]) versus standard of care (SOC) (ie, cetuximab + IC chemotherapy [mFOLFOX6 or FOLFIRI]) as 1L therapy in participants with unresectable or metastatic left-sided colorectal cancer.

• Study Type: Interventional
• Enrollment (Estimated): 960
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Genmab Trial Information; Phone Number: +4570202728; Email: clinicaltrials@genmab.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Histologically or cytologically confirmed left-sided colorectal adenocarcinoma that is unresectable or metastatic.
• Must have documented KRAS and NRAS wild type (wt) colorectal cancer (CRC), as determined by medical record of results from local testing or as assessed by central testing. Local testing must have been conducted in accordance with local guidelines using an Food and Drug Administration (FDA)-approved test or a laboratory-developed test that is validated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (sites in the United States) or an accredited local laboratory (sites outside of the United States). Next-generation sequencing (NGS)-based test results from tumor tissue are required for determining eligibility. Polymerase chain reaction (PCR)-based tests, sanger sequencing, or pyrosequencing test results are not allowed.
• Has not received any prior systemic therapy for unresectable or metastatic CRC.
• Must be eligible for treatment with mFOLFOX6 (if assigned to receive mFOLFOX6) or FOLFIRI (if assigned to receive FOLFIRI) according to local regulatory approvals and SOC guidelines.

Key Exclusion Criteria:

• BRAF mutation, and/or microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) and/or protocol specified tumor status as documented by local test results in the medical record or from central testing or known documented activating HRAS mutation identified prior to enrollment from local testing results in the medical record, if available.
• Prior exposure to any agents that target epidermal growth factor receptor (EGFR) (including but not limited to protein products, monoclonal antibodies, tyrosine kinase inhibitors, or antisense oligonucleotide therapy).
• Known complete dihydropyrimidine dehydrogenase (DPD) deficiency or known homozygous/compound heterozygous dihydropyrimidine dehydrogenase gene (DPYD) variants associated with complete loss of DPD activity. Testing for DPD deficiency should be performed per local guidelines.
• For a participant who is to receive FOLFIRI: known to be homozygous for the UGT1A1*28 or *6 alleles or compound or double heterozygous for the UGT1A1*28 and *6 alleles. Testing for UGT1A1 should be done in accordance with local guidelines.
• Participants with non-colorectal adenocarcinomatous disease.

Note: Other protocol-defined Inclusion and Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Petosemtamab + IC Chemotherapy; Participants will receive petosemtamab and IC chemotherapy (mFOLFOX6 or FOLFIRI).	Drug: Petosemtamab; Intravenous infusion; Drug: FOLFIRI; Fluorouracil + leucovorin (calcium folinate) + irinotecan via intravenous infusion.; Drug: mFOLFOX6; Fluorouracil + leucovorin (calcium folinate) + oxaliplatin via intravenous infusion.
Active Comparator: Cetuximab + IC Chemotherapy; Participants will receive cetuximab + IC chemotherapy (mFOLFOX6 or FOLFIRI).	Drug: FOLFIRI; Fluorouracil + leucovorin (calcium folinate) + irinotecan via intravenous infusion.; Drug: mFOLFOX6; Fluorouracil + leucovorin (calcium folinate) + oxaliplatin via intravenous infusion.; Drug: Cetuximab; Intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Assessed by Blinded Independent Central Review (BICR)	Up to approximately 35 months
Objective Response Rate (ORR) per RECIST v1.1 as Assessed by BICR	Up to approximately 35 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall Survival (OS)	Up to approximately 62 months
Duration of Response (DOR) per RECIST v1.1 as Assessed by BICR	Up to approximately 62 months
Disease Control Rate (DCR) per RECIST v1.1 as Assessed by BICR	Up to approximately 62 months
Progression-free Survival after First Subsequent Therapy (PFS2)	Up to approximately 62 months
Curative Resection (R0) Rate	Up to approximately 62 months
Number of Participants with Adverse Events (AEs)	Up to approximately 62 months
Change from Baseline in Symptoms and Functioning, as Measured by European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-life Questionnaire (QLQ)-F17	Baseline up to approximately 62 months
Change from Baseline in Symptoms and Functioning, as Measured by EORTC QLQ-CR29	Baseline up to approximately 62 months
Time to Worsening in Symptoms and Functioning, as Measured by EORTC QLQ-F17	Up to approximately 62 months
Time to Worsening in Symptoms and Functioning, as Measured by EORTC QLQ-CR29	Up to approximately 62 months
Overall Side Effect Burden, as Measured by EORTC Item 168	Up to approximately 62 months

Collaborators and Investigators

• Sponsor: Genmab
• Investigators: Study Director: Study Official, Genmab

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): September 1, 2031

Study Registration Dates

• First Submitted: July 9, 2026
• First Submitted That Met QC Criteria: July 9, 2026
• First Posted (Actual): July 14, 2026

Study Record Updates

• Last Update Posted (Actual): July 14, 2026
• Last Update Submitted That Met QC Criteria: July 9, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cetuximab; IFL protocol
• Other Study ID Numbers: GCT1158-08; 2026-525883-17 (Other Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No