A Phase II Trial of Avutometinib in Combination With Defactinib in Metastatic Diffuse Gastric Cancer
Overview
- Phase
- Phase 2
- Intervention
- Avutometinib
- Conditions
- Gastric Cancer
- Sponsor
- Ryan H. Moy, MD, PhD
- Enrollment
- 27
- Locations
- 1
- Primary Endpoint
- Progression-free survival (PFS) Rate
- Status
- Recruiting
- Last Updated
- 5 months ago
Overview
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.
Detailed Description
There are two main types of stomach cancer based on the appearance under the microscope: intestinal-type and diffuse-type. Some stomach cancers also have a mix of intestinal-type and diffuse-type (mixed type). The participants are being invited to take part in this research study due to having been diagnosed with stomach cancer that has spread to other parts of the body and/or cannot be surgically removed, has diffuse-type or mixed type cells or has gene changes that are associated with diffuse-type stomach cancers (such as mutations in the genes called CDH1 or RHOA), and have already been treated with chemotherapy and the disease is now growing. Defactinib is an oral drug that inhibits the protein focal adhesion kinase (FAK), which has been shown to promote growth of gastric cancer. Avutometinib (also known as VS-6766) is an oral drug that blocks an important signaling pathway in cancer cells known as the MAP kinase pathway. Avutometinib inhibits two proteins in the MAPK kinase pathway, RAF and MEK. The purpose of this study is to determine if the combination study treatment with defactinib and avutometinib is effective in improving the length of time after the start of treatment in which a participant is alive and their cancer does not grow or spread.
Investigators
Ryan H. Moy, MD, PhD
Assistant Professor of Medicine
Columbia University
Eligibility Criteria
Inclusion Criteria
- •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/mm
- •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.
Exclusion Criteria
- •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
Arms & Interventions
Avutometinib & Defactinib
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
Intervention: Avutometinib
Avutometinib & Defactinib
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
Intervention: Defactinib
Outcomes
Primary Outcomes
Progression-free survival (PFS) Rate
Time Frame: 6 months
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.
Secondary Outcomes
- 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)