5G-RUBY: Avutometinib and Defactinib in Malignant Brain Tumours

NCT06630260 | Recruiting Phase 1

• 1 other identifier: CCR5812
• Study Type: interventional
• Target: 182
• Locations: 1 country
• Sites: 3

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.

Conditions

Malignant Primary Gliomas; Diffuse Hemispheric Glioma, H3 G34-Mutant; Glioblastoma Multiforme (GBM); Glioblastoma Multiform (Grade IV Astrocytoma)

Outcome Measures

Primary Outcomes (3)

• 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

  12 months

• 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)

  12 months

• 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

  9 months

Secondary Outcomes (6)

• Phase 1b - To identify molecular determinants of response and antitumour activity of the investigational agent in patients with molecularly selected brain tumours

  12 months

• Phase 2 - To identify molecular determinants of response and antitumour activity of the investigational agent in patients with molecularly selected brain tumours

  9 months

• Phase 2 - To assess changes in Quality of Life over time

  9 months

• Phase 2 - To assess safety and tolerability of combination with TMZ when given as standard of care maintenance therapy

  9 months

• Phase 2 - To assess changes in Quality of Life over time

  9 months

Other Outcomes (3)

• Exploratory objective - To determine mechanisms of resistance to the investigational agent in patients with malignant brain tumours

  12 months

• Exploratory objective - To assess putative predictive biomarkers of the investigational agent in patients with malignant brain tumours

  12 months

• Exploratory objective - To identify putative precision therapy combinations with the potential for additive benefit

  12 months

Study Arms (2)

Phase 1b

EXPERIMENTAL

The Phase 1b will evaluate the safety and tolerability of combination of avutometinib and defactinib and determine its preliminary antitumour activity when administered at the recommended Phase 2 dose (RP2D) in patients with molecularly defined malignant brain tumours.

Drug: Avutometinib; Drug: Defactinib

Phase 2

EXPERIMENTAL

The Phase 2 part of the study will determine the antitumour activity of investigational agents administered at the RP2D in patients with molecularly defined malignant brain tumours. Avutometinib and defactinib may be administered in combination with temozolomide (TMZ).

Drug: Avutometinib; Drug: Defactinib; Drug: Temozolomide

Interventions

Avutometinib DRUG

Supplied as 0.8mg capsules.

Also known as: VS-6766

Phase 1b; Phase 2

Defactinib DRUG

Supplied as 200mg tablets.

Phase 1b; Phase 2

Temozolomide DRUG

Temozolomide will be supplied as 5, 20, 100, 140, 180 or 250 mg hard capsules.

Also known as: Temodal

Phase 2

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.

You may not qualify if:

• 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)
• Written (signed or dated) informed consent and be capable of co-operating with treatment and follow up
• 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.
• Female patients with reproductive potential must have a negative serum pregnancy test within 14 days prior to start of trial.
• 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.
• Receipt of treatment before the first dose of study drug (Cycle 1 Day 1) within an interval shorter than the following, as applicable:
• Cytotoxic chemotherapy during the prior 2 weeks or 6 weeks for nitrosoureas
• Bevacizumab during the prior 6 weeks
• Five half-lives of any small molecule investigational or licensed medicinal product.
• Prior immune checkpoint inhibitor therapy or vaccine therapy is not permitted. Prior use of any other immune-modulatory investigational agent must be discussed with sponsor team and CI. Prior use of BRAF or MEK inhibitors is not permitted.
• Ongoing Grade 2 or greater toxicities from pre-existing conditions or from previous treatments.

Sponsors & Collaborators

• Minderoo Foundation: collaborator
• Verastem, Inc.: collaborator
• Cambridge University Hospitals NHS Foundation Trust: collaborator
• Cancer Research UK: collaborator
• University of Cambridge: collaborator
• Institute of Cancer Research, United Kingdom: lead
• Royal Marsden NHS Foundation Trust: collaborator

Study Sites (3)

Cambridge University Hospitals

Cambridge, CB2 0QQ, United Kingdom

RECRUITING

The Royal Marsden Hospital - Drug Development Unit

Sutton, SM2 5PT, United Kingdom

RECRUITING

The Royal Marsden Hospital - Neuro-Oncology Unit

Sutton, SM2 5PT, United Kingdom

RECRUITING

MeSH Terms

Conditions

Glioblastoma

Interventions

defactinib; Temozolomide

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)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Juanita Lopez, MD, PhD

  National Health Service, UK

  STUDY DIRECTOR

Central Study Contacts

5G Team

CONTACT

+44 (0)2034376003; 5G-enquiries@icr.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 3, 2024
• First Posted: October 8, 2024
• Study Start: November 15, 2024
• Primary Completion (Estimated): September 30, 2029
• Study Completion (Estimated): September 30, 2030
• Last Updated: January 21, 2026

Record last verified: 2026-01

Locations

GB (3)