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.
Exclusion Criteria for Phase 1b:
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.
