The purpose of this clinical trial is to evaluate the safety and tolerability of avutometinib and defactinib and to determine the preliminary antitumour activity of avutometinib and defactinib administered at the recommended Phase 2 dose (RP2D). In the Phase 1b of this study parallel biomarker defined arms will be opened, initially in the relapsed GMB setting, enrolling 12 patients onto each arm. These patients will be treated with avutometinib and defactinib double therapy. Avutometinib will be administered orally at 3.2mg twice a week (e.g., on Monday / Thursday or Tuesday / Friday) with or without a meal. The total weekly dose of avutometinib is 6.4mg. Defactinib will be administered orally, at 200mg, twice a day within 30 min after a meal. The total daily dose of defactinib is 400mg.
Once a treatment in any biomarker arm has met the "GO" decision (≥3 successes/12 patients) for relapsed GBM in Phase 1b, that arm can progress to Phase 2. The primary objective of Phase 2 is to determine the antitumour activity of investigational agents administered at the RP2D in patients with molecularly defined malignant brain tumours.
Glioblastoma, IDH-wildtype Grade 4
Astrocytoma, IDH-mutant, Grade 4 (lower Grade 2/3 are not included)
Diffuse hemispheric glioma, H3 G34 mutant Grade 4
Patients for Phase 1 will need to have consented to the Minderoo Precision Brain Tumour Programme and have available whole genome, and transcriptome data available.
16 years or over
Life expectancy of at least 12 weeks.
World Health Organisation (WHO) performance status of 0-1
Neurologically stable (e.g., without a progression of neurological symptoms or requiring escalating doses of systemic steroid therapy within the last week)
Parallel
Avutometinib
DrugSupplied as 0.8mg capsules.
Defactinib
DrugSupplied as 200mg tablets.
Temozolomide
DrugTemozolomide will be supplied as 5, 20, 100, 140, 180 or 250 mg hard capsules.
Phase 1b - To evaluate the safety and tolerability of investigational agent in patients with malignant brain tumours
To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0
Phase 1b - To determine the preliminary antitumour activity of the investigational agent administered at the RP2D in patients with molecularly defined malignant brain tumours
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)
Phase 2 - To determine the antitumour activity of investigational agent administered at the RP2D in patients with molecularly defined malignant brain tumours
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
Phase 1b - To identify molecular determinants of response and antitumour activity of the investigational agent in patients with molecularly selected brain tumours
Determine biomarkers of response, including but not limited to genomic, transcriptomic or immunological signatures from responders and non-responders.
Phase 2 - To identify molecular determinants of response and antitumour activity of the investigational agent in patients with molecularly selected brain tumours
Determine biomarkers of response, including but not limited to genomic, transcriptomic or immunological signatures from responders and non-responders from archival tumour samples
Phase 2 - To assess changes in Quality of Life over time
Global changes over time in health-related quality of life (HRQOL) as assessed by the EORTC QLQ C30 and EORTC QLQ BN20 (Baseline, end of C1, C3D1)
Phase 2 - To assess safety and tolerability of combination with TMZ when given as standard of care maintenance therapy
To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0
Exploratory objective - To determine mechanisms of resistance to the investigational agent in patients with malignant brain tumours
Correlate antitumour activity of the investigational agent with the detection of putative predictive biomarkers of response and resistance in archival tumours, patient derived cells lines and plasma samples banked as part of the Minderoo Precision Brain Tumour Programme.
Exploratory objective - To assess putative predictive biomarkers of the investigational agent in patients with malignant brain tumours
Correlate treatment response with co-segregating mutational landscapes and identify mechanism of precision drug resistance e.g., on target vs off target, on pathway.
Exploratory objective - To identify putative precision therapy combinations with the potential for additive benefit
Plan rational combination therapies based on these results.
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Institute of Cancer Research, United Kingdom
Lead sponsor
Minderoo Foundation
Collaborator
Verastem, Inc.
Collaborator
Royal Marsden NHS Foundation Trust
Collaborator
Cambridge University Hospitals NHS Foundation Trust
Collaborator
Cancer Research UK
Collaborator
University of Cambridge
Collaborator
