Trial Title:
5G-RUBY: Avutometinib and Defactinib in Malignant Brain Tumours
NCT ID:
NCT06630260
Condition:
Glioblastoma Multiforme (GBM)
Glioblastoma Multiform (Grade IV Astrocytoma)
Diffuse Hemispheric Glioma, H3 G34-Mutant
Malignant Primary Gliomas
Conditions: Official terms:
Glioblastoma
Glioma
Brain Neoplasms
Astrocytoma
Temozolomide
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Health Services Research
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Avutometinib
Description:
Supplied as 0.8mg capsules.
Arm group label:
Phase 1b
Arm group label:
Phase 2
Other name:
VS-6766
Intervention type:
Drug
Intervention name:
Defactinib
Description:
Supplied as 200mg tablets.
Arm group label:
Phase 1b
Arm group label:
Phase 2
Intervention type:
Drug
Intervention name:
Temozolomide
Description:
Temozolomide will be supplied as 5, 20, 100, 140, 180 or 250 mg hard capsules.
Arm group label:
Phase 2
Other name:
Temodal
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
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.
Exclusion Criteria Phase 2
1. 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.
2. 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.
3. Ongoing Grade 2 or greater toxicities from pre-existing conditions or from previous
treatments.
4. Patients with carcinomatous meningitis, leptomeningeal spread of tumour, spread of
tumour to the brain stem or spinal cord.
5. 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.
6. History of clinically relevant bleeding disorders, including significant GI bleeding
within last 6 months.
7. History of arterial thromboembolism.
8. 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.
9. 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).
10. 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.
11. Concurrent ocular disorders:
1. Patients with history of glaucoma, history of retinal vein occlusion (RVO),
predisposing factors for RVO, including uncontrolled hypertension, uncontrolled
diabetes
2. 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.
3. 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.
12. Has urine protein > 1g/24 hours. Participants with >1+ on urine dipstick testing
will undergo 24-hour urine collection for quantitative assessment of proteinuria.
13. 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).
14. Known to be serologically positive for hepatitis B, hepatitis C or human
immunodeficiency virus (HIV).
15. 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).
16. 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).
17. 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.
18. 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.
19. 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:
1. Strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactions
with both avutometinib and defactinib.
2. Strong CYP2C9 inhibitors or inducers, due to potential drug-drug interactions
with defactinib. Not applicable if and when patients randomized to avutometinib
monotherapy.
3. Strong P-glycoprotein (P-gp) inhibitors or inducers, due to potential drug-drug
interactions with both avutometinib and defactinib.
4. Strong breast cancer resistance protein (BCRP) inhibitors or inducers, due to
potential drug-drug interactions with avutometinib.
20. 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.
21. Any other condition which in the investigator's opinion would not make the patient a
good candidate for the clinical trial.
Gender:
All
Minimum age:
16 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Cambridge University Hospitals
Address:
City:
Cambridge
Zip:
CB2 0QQ
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Mareike Thompson, MD
Phone:
+44 (0)12 2358 6705
Email:
mareike.thompson3@nhs.net
Facility:
Name:
The Royal Marsden Hospital - Drug Development Unit
Address:
City:
Sutton
Zip:
SM2 5PT
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Juanita Lopez, MD, PhD
Phone:
+44 (0)20 86613539
Email:
juanita.lopez@icr.ac.uk
Facility:
Name:
The Royal Marsden Hospital - Neuro-Oncology Unit
Address:
City:
Sutton
Zip:
SM2 5PT
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Liam Welsh, MD
Phone:
+44 (0)20 8661 3826
Email:
Liam.Welsh@rmh.nhs.uk
Start date:
November 4, 2024
Completion date:
September 30, 2030
Lead sponsor:
Agency:
Institute of Cancer Research, United Kingdom
Agency class:
Other
Collaborator:
Agency:
Minderoo Foundation
Agency class:
Other
Collaborator:
Agency:
Verastem, Inc.
Agency class:
Industry
Collaborator:
Agency:
Royal Marsden NHS Foundation Trust
Agency class:
Other
Collaborator:
Agency:
Cambridge University Hospitals NHS Foundation Trust
Agency class:
Other
Collaborator:
Agency:
Cancer Research UK
Agency class:
Other
Collaborator:
Agency:
University of Cambridge
Agency class:
Other
Source:
Institute of Cancer Research, United Kingdom
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06630260
