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

NCT07778602 | Not Yet Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: IRB00574285
• Study Type: interventional
• Target: 22
• Locations: 2 countries
• Sites: 3

Brief Summary

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.

Conditions

MGMT-unmethylated Glioblastoma (GBM); IDH Wildtype Glioblastoma

Keywords

Glioblastoma; Newly Diagnosed; MGMT unmethylated; neoadjuvant; surgery; IDH Wildtype; WHO Grade 4

Outcome Measures

Primary Outcomes (2)

• Proportion of evaluable patients who complete at least 75% of the oral study drug intervention

  Feasibility of a pre-radiation (pre-RT) therapeutic treatment

  4 weeks

• Safety as assessed by Number of patients who experience grade 3 and Grade 4 adverse events

  Using CTCAE v6.0, toxicity will be assessed starting with C1D1 and continue until 4 weeks after the last dose of study drug (evaluated 16 weeks from start of treatment; total study period). Number of patients who experience grade 3 and Grade 4 events based on the 6.0 CTCAE Assessment tool.

  From start of treatment (day 0) up to 16 weeks post start of treatment

Secondary Outcomes (1)

• Radiographic response rate

  4 weeks

Study Arms (2)

Stage 1: Presumed GBM 1 cycle prior to radiation

EXPERIMENTAL

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)

Drug: avutometinib and defactinib for 3 weeks on/1 week off

Stage 2: MGMT-unmethylated GBM with Radiation

EXPERIMENTAL

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)

Drug: MGMT-unmethylated GBM with Radiation

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)

Also known as: pre-radiation

Stage 1: Presumed GBM 1 cycle prior to radiation

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).

Also known as: with radiation

Stage 2: MGMT-unmethylated GBM with Radiation

Eligibility Criteria

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

You may qualify if:

• Patient must be able to provide written informed consent.
• ≥ 18 years of age
• Likely high-grade glioma based on frozen pathology in patients with no prior diagnosis of a glioma or astrocytoma.
• Patient appropriate for standard therapy for high-grade glioma that includes 6 weeks of radiation.
• Patient is not deemed at a high risk of symptomatic progression within 4 weeks by the treating physician and investigator team.
• Karnofsky Performance Scale (KPS) ≥ 70%.
• Post-operative MRI completed with 72 hours of surgery that includes FLAIR sequences
• Measurable disease per RANO 2.0 enhancing criteria. Leptomeningeal disease not allowed.
• Patient is on a tapering dose of steroids anticipated to be on a total daily dose of dexamethasone \< 2 mg for at least 5 days by start of study intervention.
• Willing to submit archival tumor sample if available
• Adequate organ and marrow function defined as:
• Ability to swallow and retain orally administered medications (no liquid suspensions available).
• Female participants of childbearing potential must have a negative serum pregnancy test prior to study start.
• Male participants must also be documented to be surgically sterile or agree to use adequate contraception and not to donate sperm
• Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients with other malignancies must be disease-free for \> 2 years.

You may not qualify if:

• Any prior glioma or astrocytoma, or any prior cancer diagnosis resulting in irradiation of the skull or scalp
• Significant bi-hemispheric disease or midline shift observed on post-operative MRI likely to result in rapid clinical deterioration
• Those who have undergone diagnostic biopsy only for suspected primary brain cancer.
• Those who are on other investigational agents at the time of screening and including patients on carmustine and/or gamma tiles
• History of clinically significant ophthalmologic disorders
• Impairment in gastrointestinal function or disease that may significantly alter the absorption of oral study drug
• Clinically significant cardiovascular disease
• History of recent (≤ 90 days) thromboembolic or cerebrovascular event
• Known history of any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, and/or detectable virus.
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring antibiotics or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible.
• Patients may not take any of the listed contraindicated medications for 7 days prior to the start of study drug, with the exception of dexamethasone; see section 5.6 "concomitant therapy":
• Warfarin
• Strong CYP2C9 or CYP3A4 inhibitors or inducers
• P-glycoprotein inhibitors or inducers
• Patients may not be on H2 blocker or PPI (Proton pump inhibitors) for 2 days prior to start of study drug.

Sponsors & Collaborators

• Keep Punching Foundation: collaborator
• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead

Study Sites (3)

Emory University

Atlanta, Georgia, 30322, United States

Location

Johns Hopkins SKCCC

Baltimore, Maryland, 21287, United States

Location

Universidad Central del Caribe

Bayamón, 00960-6032, Puerto Rico

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

defactinib; Radiation

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Physical Phenomena

Study Officials

• Karisa C Schreck, MD, PhD

  Johns Hopkins University

  STUDY CHAIR

Central Study Contacts

Michaella Iacoboni, RN

CONTACT

410-955-8837; msheeh13@jhmi.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: First stage: All participants treated with 1 cycle of avutometinib/defactinib (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). After one cycle of drug, patients whose final pathology is GBM MGMT Methylated will come off study drug treatment at that time and proceed onto standard of care treatment Second stage: Patients whose final pathology is MGMT promoter unmethylated GBM will continue onto the second stage of treatment in this study and receive an additional 2 cycles of avutometinib/defactinib concurrently with radiation (without temozolomide).

Study Record Dates

• First Submitted: August 18, 2026
• First Posted: August 21, 2026
• Study Start (Estimated): November 10, 2026
• Primary Completion (Estimated): November 10, 2028
• Study Completion (Estimated): December 23, 2029
• Last Updated: August 26, 2026

Record last verified: 2026-08

Locations

PR (1); US (2)