Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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.
Patients with a presumptive diagnosis of high-grade glioma based on frozen pathology and measurable (by RANO2.0 2D criteria) residual enhancing disease on post-operative MRI will be screened and consented within 2 weeks of surgery. All participants will start treatment within 2 weeks of surgery and receive study drug for one cycle at the FDA-approved dose (avutometinib 3.2 mg orally twice weekly and defactinib 200 mg orally twice a day; 3 wks on/1 wk off). Co-primary endpoint for all participants will be safety of the study intervention in this population and feasibility of receiving study dru…
Inclusion Criteria: * 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 p…
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)
Patients whose final pathology is MGMT promoter unmethylated GBM will receive an additional 2 cycles of avutometinib/defactinib concurrently with radiation (without temozolomide).