A Phase 2 Study of VS-7375 in Patients With KRAS G12D-Mutated Colorectal Cancer

• VS-7375 (Drug): Taken by mouth
• cetuximab (Drug): Intravenous infusion
• panitumumab (Drug): Intravenous infusion
• Cetuximab + mFOLFOX6 (Drug): Intravenous infusion

Primary outcomes

• Confirmed ORR by blinded independent central review (BICR) per RESIST v1.1 - 2L CRC only [6 months]: Overall Response Rate per RECIST version 1.1, per blinded independent central review (BICR)
• 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 [6 months]: Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, and dose interruptions/reductions and discontinuations
• 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 [6 months]: Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, and dose interruptions/reductions and discontinuations

Secondary outcomes

• Confirmed ORR per RECIST v1.1 assessed by BICR (primary) and Investigator (secondary) assessments [24 months]: 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
• Plasma Pharmacokinetics (PK) of VS-7375 and relevant metabolites, Cmax [20 weeks]: Maximum concentration (Cmax)
• Plasma Pharmacokinetics (PK) of VS-7375 and relevant metabolites, AUC [20 weeks]: Area under plasma Concentration (AUC) 0 to t
• To evaluate Pharmacodynamics (PD) and other relevant blood tumor markers specific to tumor type [Up to 2.5 years]: CA19-9, CEA, CA-125
• 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) [24 months]: The EORTC QLQ-C30 is a validated questionnaire to assess the quality of life of colorectal cancer patients
• Time to next therapy [24 months]: To assess the interval between initiation of study treatment and initiation of subsequent treatment

Other outcomes

• Imaging of tumor metabolism changes in 2L monotherapy patients [24 months]: To assess tumor metabolism dynamics on FDG-PET/CT

Sex: All, ages: 18 Years to any

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