Safety and Feasibility of First-line Avutometinib and Defactinib in Patients With Newly Diagnosed High-grade Gliomas

Conditions

• IDH Wildtype Glioblastoma
• MGMT-unmethylated Glioblastoma (GBM)

Eligibility Criteria

Sex

ALL

Age

18 Years - N/A

Healthy Volunteers

Not accepted

Interventions

• avutometinib and defactinib for 3 weeks on/1 week off — DRUG
  avutometinib 3.2 mg orally twice weekly and defactinib 200 mg orally twice a day for 3 weeks on/1 week off (one cycle = 4 weeks total)
• MGMT-unmethylated GBM with Radiation — DRUG
  Patients whose final pathology is MGMT promoter unmethylated GBM will receive an additional 2 cycles of avutometinib/defactinib concurrently with radiation (without temozolomide).

Study Details

This clinical trial is designed with two treatment stages: Stage 1: one cycle of study drug treatment prior to initiation of first-line standard radiation in all study participants. Stage 2: two additional cycles of study drug treatment (8 weeks total) concomitantly with standard of care radiation (\~6 weeks) for participants with pathology-confirmed MGMT (enzyme O-6-methylguanine-DNA methyltransferase) unmethylated GBM only. The co-primary endpoints of the study are 1) feasibility of completing Stage 1 of treatment prior to radiation in all study participants and starting radiation within 6 weeks, and 2) safety of study drug across both treatment parts. The investigators will additionally evaluate the radiographic response rate after the first cycle of drug in all patients based upon RANO 2.0 (Response Assessment in Neuro-Oncology) criteria as well as safety of study drug in all patients (secondary endpoints). Exploratory endpoints will include characterization of ERK (extracellular signal-regulated kinase) and FAK (Focal adhesion kinase) dependence in pre-treatment tissue (by immunohistochemistry and/or 'omics) and correlation of expression and co-mutations with response and survival. A total of up to 22 evaluable patients can be enrolled in this study. Evaluable patients are those who have received at least one dose of study drug treatment. Patients who do not start drug will be replaced, up to a total of 28 patients.

Key Dates

First listed

Aug 21, 2026

Start date

Nov 10, 2026

Status verified

Aug 2026

Primary completion

Nov 10, 2028

Completion

Dec 23, 2029

Study Design

Enrollment

22 participants (estimated)

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Arms

• Experimental: Stage 1: Presumed GBM 1 cycle prior to radiation
  1 cycle of avutometinib 3.2 mg orally twice weekly and defactinib 200 mg orally twice a day) for 3 weeks on/1 week off during the pre-radiation window (one cycle = 4 weeks total)
• Experimental: Stage 2: MGMT-unmethylated GBM with Radiation
  2 additional cycles of 3.2 mg orally twice weekly and defactinib 200 mg orally twice a day for 3 weeks on/1 week off during radiation (one cycle = 4 weeks total)

Primary Outcome Measure

Proportion of evaluable patients who complete at least 75% of the oral study drug intervention [ Time Frame: 4 weeks ]

Central Contacts

• Karisa C Schreck, MD, PhD
  410-955-8837
  [email protected]

Locations (2)

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