Avutometinib and Defactinib in Diffuse Gastric Cancer

NCT06487221 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: AAAV0009
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine if the combination study treatment with avutometinib and defactinib will prolong life in participants, is effective in decreasing the size of the tumor(s), and if it is safe in subjects with diffuse-type stomach cancer.

Conditions

Gastric Cancer; Stomach Cancer

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS) Rate

  To determine the efficacy of combination defactinib and avutometinib in patients with metastatic diffuse gastric cancer (DGC) as measured by 6-month progression-free survival (PFS) rate. PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.

  6 months

Secondary Outcomes (5)

• Overall Response Rate (ORR)

  6 months

• Median Progression-Free Survival

  24 months

• Median Overall Survival (OS)

  Up to 5 years

• Disease Control Rate (DCR)

  24 months

• Duration of response (DOR)

  24 months

Study Arms (1)

Avutometinib & Defactinib

EXPERIMENTAL

Avutometinib: Study participants will receive Avutometinib 3.2mg orally two times per week for three weeks in a row followed by one week of rest Defactinib: Study participants will receive Defactinib 200mg twice daily for three weeks in a row followed by one week of rest

Drug: Avutometinib; Drug: Defactinib

Interventions

Avutometinib DRUG

3.2mg orally

Also known as: VS6766

Avutometinib & Defactinib

Defactinib DRUG

200 mg orally

Also known as: VS-6063

Avutometinib & Defactinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologic or cytologic evidence of gastric/gastroesophageal junction carcinoma, classified as diffuse type, poorly cohesive, signet ring cell, or mixed type. Patients with known pathogenic CDH1 and/or RHOA mutations will be allowed regardless of histology.
• Prior therapy with at least one line of therapy for unresectable/metastatic disease, which must include platinum and fluoropyrimidine.
• ECOG performance status of 0 or 1
• Age ≥ 18 years
• Adequate organ function, defined by the following laboratory parameters:
• a. Adequate hematologic function, including hemoglobin \[Hb\] ≥ 9.0 g/dL; platelets ≥ 100,000/mm3; and absolute neutrophil count \[ANC\] ≥ 1500/mm3. If a red blood cell transfusion or erythropoiesis-stimulating agent has been administered the Hb must remain stable and ≥ 9 g/dL for at least 1 week prior to first dose of study intervention.
• (i) Subjects with Hgb ≥ 8.5 g/dL and \<9.0 g/dL are eligible if there is no history of significant cardiovascular risk features as per the investigator (i.e., prior myocardial infarction) b. Adequate hepatic function: (i) total bilirubin ≤ 1.5 × upper limit of normal \[ULN\] for the institution; patients with Gilbert syndrome may enroll if total bilirubin is \< 3.0 mg/dL (51 μmol/L); (ii) alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
• ≤ 2.5 × ULN (or \< 5 x ULN in patients with liver metastases). c. Adequate renal function with creatinine clearance rate of ≥ 50 mL/min, as calculated by the Cockcroft-Gault formula d. International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation.
• e. Albumin ≥ 3.0 g/dL (451 μmol/L). f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN. g. Adequate cardiac function with left ventricular ejection fraction ≥ 55% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
• Disease that can be evaluated radiographically, which can be measurable disease or non-measurable disease per RECIST 1.1. All radiology studies must be performed within 28 days prior to start of study-directed therapy.
• Tumor that is amenable to fresh biopsy, which may include malignant ascites that is amenable for paracentesis.
• Baseline QTc interval \< 460 ms for females and ≤ 450 ms for males (average of triplicate readings) using Fredericia's QT correction formula. NOTE: This criterion does not apply to subjects with a right or left bundle branch block.
• Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v 5.0. Exceptions include alopecia and peripheral neuropathy grade ≤ 2. Subjects with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval from the principal investigator.
• The effects of the study drugs on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (see Section 7.6 for Contraception Guidance) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after the last dose of the study drug.
• Ability to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• Systemic anti-cancer therapy within 3 weeks of the first dose of study therapy, or within 5 half-lives of the previous drug, whichever is shorter.
• Patients currently receiving any other investigational agent.
• Subjects may not have had a history of malignancy other that esophagogastric cancer within two years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year overall survival \>90%) such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer.
• Major surgery within 4 weeks or palliative radiotherapy within 1 week of the first dose of study therapy.
• Treatment with warfarin. Subjects on warfarin for DVT/PE can be converted to low- molecular-weight heparin (LMWH).
• History of treatment with a direct and specific inhibitor of FAK, MEK, or KRAS.
• Patients who had exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with avutometinib and/or defactinib within 14 days prior to the first dose of study intervention and during the course of therapy, including:
• Strong CYP3A4 inhibitors or inducers.
• Strong CYP2C9 inhibitors or inducers.
• Strong P-glycoprotein (P-gp) inhibitors or inducers
• Strong breast cancer resistance protein (BCRP) inhibitors or inducers
• Symptomatic brain metastases requiring steroids or other local interventions. Subjects with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks prior to first dose of study therapy, and are neurologically stable.
• Known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection that is active and/or requires therapy. HIV patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the investigational agents.
• Active skin disorder that has required systemic therapy within the past 1 year.
• History of rhabdomyolysis.

Sponsors & Collaborators

• Ryan H. Moy, MD, PhD: lead
• Verastem, Inc.: collaborator

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

RECRUITING

MeSH Terms

Conditions

Stomach Neoplasms

Interventions

defactinib

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Study Officials

• Ryan Moy, MD, PhD

  Columbia University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Research Nurse Navigator

CONTACT

212-342-5162; cancerclinicaltrials@cumc.columbia.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: June 26, 2024
• First Posted: July 5, 2024
• Study Start: October 28, 2024
• Primary Completion (Estimated): November 30, 2028
• Study Completion (Estimated): May 30, 2029
• Last Updated: November 4, 2025

Record last verified: 2025-10

Locations

US (1)