Diffuse Hemispheric Glioma, H3 G34-Mutant, Glioblastoma Multiforme (GBM), Glioblastoma Multiform (Grade IV Astrocytoma), Malignant Primary Gliomas
Conditions
Brief summary
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.
Detailed description
The clinical trial will be divided into two parts: Phase 1b (proof of concept of hypothesis-driven biomarker-guided therapies) and Phase 2 (preliminary efficacy testing). This is a study within Minderoo 5G: A Next Generation AGile Genomically Guided Glioma Modular Platform for proof-of-concept molecular hypothesis testing in patients with high grade malignant brain tumours. 5G-RUBY is a Bayesian multi-centre, multi-arm, open-label, adaptive, seamless Phase 1/2 trial of doublet combination of avutometinib and defactinib and triplet combination with temozolomide for patients with malignant brain tumours. 5G-RUBY will recruit patients with glioblastoma (GBM) into two molecularly-defined biomarker arms of patients who have tumours that harbour: * Hyperactivating BRAF mutations or fusions predicted to be pathogenic by COSMIC * NF1 loss Each biomarker arm, within Phase 1, will have robust GO/ADAPT decision points, reviewed by the Safety Review Committee (SRC) to allow for both agility and clear direction for next steps. A 2-stage Bayesian adaptive design will be performed to assess preliminary efficacy. 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 with a total weekly dose of 6.4mg, and defactinib with a total daily dose of 400mg. Phase 2 efficacy testing will be undertaken in the front line adjuvant MRD setting. This can be either as double combination or in triple combination with temozolomide (concomitantly, or sequentially) depending on emerging data. Further details will be provided at once the SRC has assessed data from Phase 1 and formally opened Phase 2.
Interventions
DRUGAvutometinib
Supplied as 0.8mg capsules.
DRUGDefactinib
Supplied as 200mg tablets.
DRUGTemozolomide
Temozolomide will be supplied as 5, 20, 100, 140, 180 or 250 mg hard capsules.
Sponsors
Institute of Cancer Research, United Kingdom
Minderoo Foundation
Verastem, Inc.
Royal Marsden NHS Foundation Trust
Cambridge University Hospitals NHS Foundation Trust
Cancer Research UK
University of Cambridge
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for Phase 1b: 1. Patients with histologically confirmed advanced WHO Stage IV glioblastoma (per fourth edition 2016). Per the new 2021 fifth edition of WHO Classification of Tumours of the Central Nervous System, this will include: * 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 with any other CNS tumours will only be eligible for defined Phase 2 biomarker arms once a Phase 1b GO decision has been met. Specific eligibility criteria for these tumours will be defined following an amendment. 2. 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. 3. Patients for the relapsed cohorts will be eligible at first relapse following completion of optimal surgery, and Stupp based adjuvant chemo-radiotherapy (or equivalent). They will need to have measurable disease per RANO or evaluable disease. 4. Patients for the front line minimal residual disease (mrd) cohort will be eligible following completion of optimal surgery and Stupp based adjuvant chemoradiotherapy as long as they meet all other inclusion/
Exclusion criteria
. 5. 16 years or over 6. Life expectancy of at least 12 weeks. 7. World Health Organisation (WHO) performance status of 0-1 8. Neurologically stable (e.g., without a progression of neurological symptoms or requiring escalating doses of systemic steroid therapy within the last week) 9. Written (signed or dated) informed consent and be capable of co-operating with treatment and follow up 10. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week prior to the first dose of either IMP Haemoglobin (Hb): ≥ 9.0 g/dL; Absolute neutrophil count: ≥1.5 x 10\^9/L; Platelet count: ≥100 x 10\^9/L; Coagulation: INR \<1.5 and APTT \<1.5x if not anticoagulated, INR stable \> 7 days within intended therapeutic range if anticoagulated; Bilirubin: Within institution normal ranges; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): \<3 x ULN; Albumin: ≥ 28 g/dL; Creatinine: \<1.5 x ULN; Sodium: ≥130 mmol/L; Potassium, Calcium, Magnesium, phosphate: Within institution normal ranges (replacement is permitted); Urinary protein: \< 1+ on dipstick. 11. Female patients with reproductive potential must have a negative serum pregnancy test within 14 days prior to start of trial. 12. Men and women of childbearing potential must agree to comply with the use of a highly effective method of contraception to avoid impregnating a partner or becoming pregnant, respectively, during the study, and for at least 150 days after the last dose of either investigational drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b - To evaluate the safety and tolerability of investigational agent in patients with malignant brain tumours | 12 months | 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 | 12 months | 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 | 9 months | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b - To identify molecular determinants of response and antitumour activity of the investigational agent in patients with molecularly selected brain tumours | 12 months | 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 | 9 months | 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 | 9 months | 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 | 9 months | To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0 |
Countries
United Kingdom
Contacts
CONTACT5G Team
STUDY_DIRECTORJuanita Lopez, MD, PhD
National Health Service, UK
Outcome results
None listed