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Glioblastoma Multiforme (GBM)Phase 1/25G-RUBYNCT06630260

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

A Phase 1/2 study testing Avutometinib, Defactinib and Temozolomide in people with Glioblastoma Multiforme (GBM) and Glioblastoma Multiform (Grade IV Astrocytoma), run by Institute of Cancer Research, United Kingdom at 3 sites in United Kingdom.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 16 years and older
What is being tested?
Avutometinib, Defactinib and Temozolomide
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
182 participants
Where
3 sitesUnited Kingdom
Study dates
15 Nov 2024to 30 Sep 2030
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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.
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  • 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.
  • 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.
  • 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)
  • 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.

Who cannot join

  • 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.
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  • Patients with carcinomatous meningitis, leptomeningeal spread of tumour, spread of tumour to the brain stem or spinal cord.
  • Has evidence of recent intratumoural or peritumoural haemorrhage on baseline MRI. Patients with radiological findings that are stable on at least 2 consecutive MRI scans at least 3 weeks apart will be eligible.
  • History of clinically relevant bleeding disorders, including significant GI bleeding within last 6 months.
  • History of arterial thromboembolism.
  • Recent (within 3 months) deep vein thrombosis or pulmonary embolism or another significant thromboembolism. Venous port of catheter thrombosis or superficial thrombosis are not considered significant. Patients with prior thrombosis (> 3 months ago) on stable anticoagulation are permitted to be enrolled. Patients on Warfarin will need to be converted onto low-molecular weight-based heparin therapy.
  • History of clinically significant cardiac disorders:
  • Myocardial infarction, or New York Heart Association Class II to IV congestive heart failure, within 6 months of the first dose of study drug
  • Concurrent and clinically significant abnormalities on ECG at Screening, including a corrected QT interval (QTcF >460ms).
  • History of malabsorption syndrome or other conditions that may interfere with enteral absorption. Patients with a history of or active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis). Patients with acute or chronic pancreatitis. History of gastrointestinal perforation or fistulae. Patients with known Gilbert's syndrome will be excluded from this study.
  • Concurrent ocular disorders:
  • Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes
  • Patient with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO.
  • Patients with a history of corneal erosion (instability of corneal epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions.
  • Has urine protein > 1g/24 hours. Participants with >1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria.
  • Has significant lung disease including pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, active tuberculosis, or history of opportunistic infections (including PCP or CMV pneumonia).
  • Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
  • Steroid requirement for neurological symptom control of > 3mg Dexamethasone per day (patients will allowed to enrol if they have been on a stable dose of steroids of equivalent or less than 3mg Dexamethasone for at least 5 days prior to Day 1 of Cycle 1).
  • Has received a live vaccine within 30 days of planned start of study therapy. Note: inactive vaccines including COVID vaccines are allowed prior to 1 week of Day 1 of Cycle 1).
  • Current active concurrent malignancy. Cancer survivors who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease recurrence for three years or more and are deemed at negligible risk of recurrence will be eligible.
  • Is a participant or plans to participate on another interventional clinical trial while taking part in this Phase 1 study. Participation in an observational trial would be acceptable.
  • Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with study interventions within 14 days prior to the first dose of study intervention and during the course of therapy, including:
  • Strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactions with both avutometinib and defactinib.
  • Strong CYP2C9 inhibitors or inducers, due to potential drug-drug interactions with defactinib. Not applicable if and when patients randomized to avutometinib monotherapy.
  • Strong P-glycoprotein (P-gp) inhibitors or inducers, due to potential drug-drug interactions with both avutometinib and defactinib.
  • Strong breast cancer resistance protein (BCRP) inhibitors or inducers, due to potential drug-drug interactions with avutometinib.
  • Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of defactinib.
  • Any other condition which in the investigator's opinion would not make the patient a good candidate for the clinical trial.

Trial locations and contacts

3 sites in 1 country. Contact the study team or a site near you to ask about taking part.

5G Team contact

+44 (0)2034376003

5G-enquiries@icr.ac.uk

United Kingdom3 sites, 3 recruiting

  • Cambridge University Hospitals

    Cambridge, CB2 0QQ

    Mareike Thompson, MD, +44 (0)12 2358 6705, mareike.thompson3@nhs.net

    Recruiting

  • The Royal Marsden Hospital - Drug Development Unit

    Sutton, SM2 5PT

    Juanita Lopez, MD, PhD, +44 (0)20 86613539, juanita.lopez@icr.ac.uk

    Recruiting

  • The Royal Marsden Hospital - Neuro-Oncology Unit

    Sutton, SM2 5PT

    Liam Welsh, MD, +44 (0)20 8661 3826, Liam.Welsh@rmh.nhs.uk

    Recruiting

Other trials in United Kingdom

About this study

Official title: A Phase 1/2 Trial of the Doublet Combination of Avutometinib and Defactinib and as a Triplet in Combination With Temozolomide in Patients With High Grade Malignant Brain Tumours Within the 5G Platform

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.

Read the 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.

Being tested
Avutometinib, Defactinib, Temozolomide
Medical subject headings
Glioblastoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AvutometinibDrug

    Also called VS-6766

    Supplied as 0.8mg capsules.

  • DefactinibDrug

    Supplied as 200mg tablets.

  • TemozolomideDrug

    Also called Temodal

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

Study groups in NCT06630260
Study groupRoleWhat they receive
Phase 1bExperimentalThe 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.
Receives: Drug: Avutometinib; Drug: Defactinib
Phase 2ExperimentalThe 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).
Receives: Drug: Avutometinib; Drug: Defactinib; Drug: Temozolomide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 12 months

  2. 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)

    Measured: 12 months

  3. 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

    Measured: 9 months

Secondary outcomes (6)

  1. 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.

    Measured: 12 months

  2. 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

    Measured: 9 months

  3. 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)

    Measured: 9 months

  4. 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

    Measured: 9 months

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

    PFS6, defined as the percentage of patients who remained free of disease progression 6 months from study enrolment

    Measured: 9 months

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

    OS12, defined as the percentage of patients who remained free of death at 12 months from study enrolment

    Measured: 9 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Oct 2024
  2. Study start15 Nov 2024
  3. Primary completion30 Sep 2029 (estimated)
  4. Study completion30 Sep 2030 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Health services research
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
182 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06630260
Sponsor's protocol ID
CCR5812
Acronym
5G-RUBY
Status last verified
Jan 2026
First submitted
3 Oct 2024
Last updated
21 Jan 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Avutometinib, Defactinib and Temozolomide in people with Glioblastoma Multiforme (GBM) and Glioblastoma Multiform (Grade IV Astrocytoma), run by Institute of Cancer Research, United Kingdom at 3 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 21 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact 5G Team (+44 (0)2034376003, 5G-enquiries@icr.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase 1b - To evaluate the safety and tolerability of investigational agent in patients with malignant brain tumours (time frame: 12 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06630260.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jan 2026.

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