Title
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)

Description
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)

Objective
Primary
(Parts A and B):
-To evaluate the anti-tumor efficacy of 900 mg VS 7375 monotherapy administered on a daily oral schedule and 900 mg VS-7375 combination therapy with intravenous (IV) cetuximab or panitumumab, in participants with metastatic KRAS G12D-mutated colorectal adenocarcinoma (CRC).
-To characterize the safety and tolerability of VS-7375 monotherapy administered on a daily oral schedule and VS-7375 combination therapy with IV cetuximab or panitumumab in participants with metastatic KRAS G12D-mutated CRC.

(Part C):
To characterize the safety, tolerability, and AE profile of VS-7375 administered on a daily oral schedule in combination with IV cetuximab and IV mFOLFOX6 in participants with metastatic KRAS G12D-mutated CRC.

Secondary
(Parts A and B):
To evaluate additional efficacy parameters of VS-7375 monotherapy administered on a daily oral schedule and VS-7375 combination therapy with IV cetuximab or panitumumab in participants with metastatic KRAS G12D-mutated CRC.

(Part C):
To determine the efficacy of VS-7375 administered on a daily oral schedule in combination with IV cetuximab and IV mFOLFOX6 in participants with metastatic KRAS G12D-mutated CRC.

(All Parts):
To continue to evaluate the PK of VS-7375 in participants with metastatic KRAS G12D-mutated CRC.

Treatment 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

Key Eligibility 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.

Applicable Disease Sites
Colon and Rectum

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital