A Phase 2 Study of VS-7375 in Patients With KRAS G12D-Mutated Colorectal Cancer (TARGET-D 203)

A Phase 2, Open-label Study of VS-7375, an Oral KRAS G12D (ON/OFF) Inhibitor, With and Without an Anti-EGFR Antibody, and With an Anti-EGFR Antibody and Chemotherapy, in Patients With Metastatic KRAS G12D-Mutated Colorectal Adenocarcinoma (TARGET-D 203)

This study will assess the safety and efficacy of VS-7375 alone and in combination with cetuximab or panitumumab and cetuximab plus mFOLFOX in patients with metastatic KRAS G12D - mutated Colorectal Cancer

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: panitumumab; Drug: VS-7375; Drug: cetuximab; Drug: Cetuximab + mFOLFOX6

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Verastem Call Center; Phone Number: 7812924204; Email: VS-7375-203TrialSupport@verastem.com
• Study Contact Backup: Name: Luke Chung, MD; Email: VS-7375-203Medical@verastem.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histopathology confirmed metastatic CRC
• Measurable disease per RECIST 1.1
• Local testing confirmed KRAS G12D mutation (tissue required for confirmatory central testing)

• ECOG PS=0 or 1

  2L+ patients:

• Must have received at least 1 standard chemotherapy for metastatic colorectal adenocarcinoma
• Have documented disease progression during or following their most recent prior line of therapy

• Have either stable disease, partial response (PR), or complete response (CR) by RECIST v1.1 as the best overall response (BOR) during at least 1 prior systemic therapy.

  1L patients:

• Treatment-naïve or received no more than 1 cycle of standard systemic therapy for metastatic disease.

Exclusion Criteria:

• Have any other documented co-existing common RAS mutation(s)
• Prior anti-cancer Tx within 4 weeks or drug-specific timeline within first treatment dose, whichever shorter
• Major surgery within 4 weeks of first treatment dose
• Radiation therapy (RT) within 1 week of first treatment dose
• Receipt of prior direct RAS inhibitor
• Receipt of more than 1 investigational therapy
• Untreated or symptomatic CNS metastasis
• Receipt of strong CYP3A4 inhibitor/inducer or CYP3A4 sensitive substrates with narrow therapeutic index within 14 days or drug-specific timeline within first treatment dose, whichever is shorter
• Receipt of PPI or H2 blocker within 5 days
• Inability to swallow oral medication
• Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VS-7375 Monotherapy or Preferred Combination in 2L+ CRC; Participants randomized to a treatment in 2:1 ratio	Drug: panitumumab; Intravenous infusion; Drug: VS-7375; Taken by mouth; Drug: cetuximab; Intravenous infusion
Experimental: VS-7375 with chosen regimen in 2L+ CRC	Drug: panitumumab; Intravenous infusion; Drug: VS-7375; Taken by mouth; Drug: cetuximab; Intravenous infusion
Experimental: VS-7375 + cetuximab and mFOLFOX in 1L CRC	Drug: Cetuximab + mFOLFOX6; Intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed ORR by blinded independent central review (BICR) per RESIST v1.1 - 2L CRC only	Overall Response Rate per RECIST version 1.1, per blinded independent central review (BICR)	6 months
To characterize the safety and tolerability of VS-7375 monotherapy or in combination with cetuximab or panitumumab, administered on a daily oral schedule in participants with KRAS G12D-mutated 2L+ CRC	Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, and dose interruptions/reductions and discontinuations	6 months
To characterize the safety and tolerability of VS-7375 in combination with cetuximab + mFOLFOX, administered on a daily oral schedule in participants with KRAS G12D-mutated 1L CRC	Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, and dose interruptions/reductions and discontinuations	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Pharmacokinetics (PK) of VS-7375 and relevant metabolites, Cmax	Maximum concentration (Cmax)	20 weeks
Plasma Pharmacokinetics (PK) of VS-7375 and relevant metabolites, AUC	Area under plasma Concentration (AUC) 0 to t	20 weeks
To evaluate Pharmacodynamics (PD) and other relevant blood tumor markers specific to tumor type	CA19-9, CEA, CA-125	Up to 2.5 years
Confirmed ORR per RECIST v1.1 assessed by BICR (primary) and Investigator (secondary) assessments	To evaluate additional efficacy parameters of VS-7375 monotherapy and VS-7375 in combination with cetuximab or panitumumab or cetuximab + mFOLFOX, administered on a daily oral schedule in participants with KRAS G12D-mutated CRC	24 months
To assess the health-related quality of life and disease based on European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire Core module C30 (QLQ-C30)	The EORTC QLQ-C30 is a validated questionnaire to assess the quality of life of colorectal cancer patients	24 months
Time to next therapy	To assess the interval between initiation of study treatment and initiation of subsequent treatment	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Imaging of tumor metabolism changes in 2L monotherapy patients	To assess tumor metabolism dynamics on FDG-PET/CT	24 months

Collaborators and Investigators

• Sponsor: Verastem, Inc.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: June 15, 2026
• First Submitted That Met QC Criteria: June 15, 2026
• First Posted (Actual): June 22, 2026

Study Record Updates

• Last Update Posted (Actual): June 22, 2026
• Last Update Submitted That Met QC Criteria: June 15, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Panitumumab; Cetuximab
• Other Study ID Numbers: VS-7375-203; 2026-526473-42-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

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