Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
avutometinib · 4 trials · 10 indications
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.
Confirmed overall response rate per RECIST 1.1
Confirmed overall response rate per RECIST 1.1
Confirmed overall response rate per RECIST 1.1
Confirmed ORR defined according to RECIST 1.1
To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0
Antitumour activity will be defined on the basis of the following outcomes. If any of the following occur, patients will be considered to have clinically benefitted: For relapsed GBM: Achievement of overall response of CR or PR per Response Assessment in Neuro-Oncology (RANO) within 6 months or Free of disease progression or death at 6 months For front line unmethylated GBM (MRD): • Progression-free survival (PFS)
Antitumour activity will be defined on the basis of the following outcomes: Progression-free survival (PFS), defined as the time from enrolment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RANO Overall survival (OS), defined as the time from enrolment to death from any cause
Defactinib concentration will be measured in a sample of the glioblastoma, brain around the glioblastoma, and in a serum sample from each subject receiving Defactinib. Descriptive statistics, such as mean and standard deviation, will be generated with these results. Concentration will be compared between dose levels within study drug using two-sample t-tests or non-parametric equivalents such as Mann Whitney U tests.
VS-6766 concentration will be measured in a sample of the glioblastoma, brain around the glioblastoma, and in a serum sample from each subject receiving VS-6766. Descriptive statistics, such as mean and standard deviation, will be generated with these results. Concentration will be compared between dose levels within study drug using two-sample t-tests or non-parametric equivalents such as Mann Whitney U tests.
Will be assessed by quantification of the recognized side effects of this agent including fatigue, nausea, diarrhea, vomiting, hyperbilirubinemia, decreased appetite, peripheral edema, dizziness, and headache and by monitoring for new or undescribed adverse events. Summary statistics will include frequencies and percentages of adverse events.
Will be assessed by quantification of the recognized side effects of this agent including rash, creatine phosphokinase elevation, visual disturbances, hypoalbuminemia, and fatigue and by monitoring for new or undescribed adverse events. Summary statistics will include frequencies and percentages of adverse events.
| Arm | Type | Description |
|---|---|---|
| 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 |
| Part A | EXPERIMENTAL | To determine the optimal regimen, either avutometinib(VS-6766) monotherapy or avutometinib (VS-6766) in combination with defactinib, for subsequent evaluation for efficacy in the Expansion Phase (Part B) |
| Part B | EXPERIMENTAL | To determine the efficacy of the optimal regimen identified from Part A |
| Part C: | EXPERIMENTAL | To evaluate additional efficacy parameters for the optimal regimen identified in Part A. |
| Part D | EXPERIMENTAL | To evaluate additional efficacy parameters for a lower dose of avutometinib in combination with defactinib |
| Phase 1b | EXPERIMENTAL | The Phase 1b will evaluate the safety and tolerability of combination of avutometinib and defactinib and determine its preliminary antitumour activity when administered at the recommended Phase 2 dose (RP2D) in patients with molecularly defined malignant brain tumours. |
| Phase 2 | EXPERIMENTAL | The Phase 2 part of the study will determine the antitumour activity of investigational agents administered at the RP2D in patients with molecularly defined malignant brain tumours. Avutometinib and defactinib may be administered in combination with temozolomide (TMZ). |
| Arm I (Defactinib) | EXPERIMENTAL | Patients receive 1 dose of defactinib PO while on study, prior to planned tumor resection. Patients undergo blood collection and donate resected tumor tissue while on study. |
| Arm II (Avutometinib) | EXPERIMENTAL | Patients receive 1 dose of avutometinib PO while on study, prior to planned tumor resection. Patients undergo blood collection and donate resected tumor tissue while on study. |
| Name | Type | Description |
|---|---|---|
| Avutometinib | DRUG | 3.2mg orally |
| Defactinib | DRUG | 200 mg orally |
| avutometinib (VS-6766) | DRUG | avutometinib (VS-6766) monotherapy |
| avutometinib (VS-6766) and defactinib | DRUG | avutometinib (VS-6766) and defactinib combination |
| Temozolomide | DRUG | Temozolomide will be supplied as 5, 20, 100, 140, 180 or 250 mg hard capsules. |
| Biospecimen Collection | PROCEDURE | Undergo blood and tissue sample collection |
Inclusion Criteria: 1. 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. 2. Prior therapy w...