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.
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 Response Assessment in
Neuro-Oncology (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): ≥ 10.0 g/dL Absolute neutrophil count: ≥ 1.5 x 10^9/L Platelet
count: ≥ 75 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: ≤ 1.5
x ULN; subjects with Gilbert's syndrome can enrol if conjugated bilirubin is within
normal limits.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): < 3 x ULN
Albumin: ≥ 28 g/L Creatinine: <1.5 x ULN and creatinine clearance > 45 ml/min as
measured or calculated based on Cockcroft-Gault formula 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, or urine,
pregnancy test at screening and within 72 hours of the first dose of study treatment
and must agree to further serum or urine pregnancy tests during the study.
12. A participant must be either of the following: a. not of childbearing potential, b.
of child-bearing potential and practicing true abstinence during the entire period
of the study, including up to 6 months after the last dose of the study treatment is
given, or c. of childbearing potential and practicing 2 methods of contraception,
including 1 highly effective user independent method and a second method, to avoid
impregnating a partner or becoming pregnant, respectively. A participant must agree
to continue contraception throughout the study, and for at least 6 months after the
last dose of study treatment.
Please, refer to section 4.1 of CTFG guidance "Recommendations related to
contraception and pregnancy testing in clinical trials" and to section 9.6 of the
Master Protocol for further details.
Note: If the childbearing potential changes after start of the study (eg,
participant of childbearing potential who is not heterosexually active becomes
active, premenarchal participant experiences menarche) the participant must begin
birth control, as described above.
13. A participant must agree not to donate eggs (ova, oocytes) for the purposes of
assisted reproduction during the study and for 6 months after receiving the last
dose of study treatment.
14. A participant must wear a condom when engaging in any activity that allows for
passage of ejaculate to another person during the study and for 6 months after
receiving the last dose of study treatment. A participant who is sexually active
with a partner of childbearing potential must agree to use a condom with spermicidal
foam/gel/film/cream/suppository and their partner must also be practicing a highly
effective method of contraception (ie, established use of oral, injected, or
implanted hormonal methods of contraception; placement of an intrauterine device
[IUD] or intrauterine hormone-releasing system [IUS]). If the participant is
vasectomized, they must still use a condom (with or without spermicide) for
prevention of passage of exposure through ejaculation, but their partner is not
required to use contraception.
15. A participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum of 6 months after receiving the last dose of study
treatment.
16. A participant must be willing and able to adhere to the lifestyle restrictions
specified in this protocol.
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
EGFR-targeting therapy is not permitted. Prior use of any other immune-modulatory
investigational agent must be discussed with sponsor team and CI.
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
gastrointestinal (GI) bleeding within last 6 months.
7. Participant has active cardiovascular disease including, but not limited to:
- - A medical history of deep venous thrombosis or pulmonary embolism within 1
month prior to first dose of study drug or any of the following within 6 months
prior to first dose of study drug: myocardial infarction, unstable angina,
stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or
any acute coronary syndrome.
Clinically non-significant thrombosis such as
non-obstructive catheter-associated thrombus, incidental or asymptomatic
pulmonary embolism, are not exclusionary. Patients on Warfarin will need to be
converted onto low-molecular weight-based heparin therapy.
- - Participant has a significant genetic predisposition to venous thromboembolic
(VTE) events such as Factor V Leiden.
- - Participant has a prior history of VTE and is not on appropriate therapeutic
anticoagulation as per National Comprehensive Cancer Network (NCCN) or local
guidelines.
- - Uncontrolled (persistent) hypertension: systolic blood pressure > 160 mm Hg;
diastolic blood pressure > 100 mm Hg.
- - Congestive heart failure (CHF), defined as New York Heart Association (NYHA)
class III-IV or hospitalization for CHF (any NYHA class) within 6 months of
first dose of the study drug.
- - Concurrent and clinically significant abnormalities on ECG at Screening,
including a corrected QT interval (QTcF > 460ms).
8. 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 GI perforation or fistulae.
9. Has urine protein > 1g/24 hours. Participants with > 1+ on urine dipstick testing
will undergo 24-hour urine collection for quantitative assessment of proteinuria.
10. Has significant lung disease including pneumonitis, interstitial lung disease
(including drug-induced or radiation ILD/pneumonitis), idiopathic pulmonary
fibrosis, cystic fibrosis, active tuberculosis, or history of opportunistic
infections (including PCP or Cytomegalovirus (CMV) pneumonia).
11. Participant is serologically positive for hepatitis B surface antigen (HbsAg), Note:
participants with a prior history of hepatitis B virus (HBV) demonstrated by
positive hepatitis B core antibody are eligible if they have at Screening 1) a
negative HBsAg and 2) a HBV DNA (viral load) below the lower limit of
quantification, per local testing. Subjects with a positive HBsAg due to recent
vaccination are eligible if HBV DNA (viral load) is below the lower limit of
quantification, per local testing.
12. Participant is serologically positive for hepatitis C antibody. Note: participants
with a prior history of hepatitis C virus (HCV), who have completed antiviral
treatment and have subsequently documented HCV RNA below the lower limit of
quantification per local testing are eligible.
13. Participant has other clinically active infectious liver disease.
14. Participant is positive for human immunodeficiency virus (HIV), with 1 or more of
the following:
- - Receiving antiretroviral therapy (ART) that may interfere with study treatment
(consult sponsor for review of medication prior to enrolment).
- - CD4 count < 350 at screening.
- - AIDS-defining opportunistic infection within 6 months of start of screening.
- - Not agreeing to start ART and be on ART > 4 weeks plus having HIV viral load <
400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV
controlled).
15. Participant has an uncontrolled illness, including but not limited to:
- - Ongoing or active infection (includes infection requiring treatment with
antimicrobial therapy [participants will be required to complete antibiotics 1
week prior to starting study treatment] or diagnosed or suspected viral
infection.
- - active bleeding diathesis.
- - Impaired oxygenation requiring continuous oxygen supplementation.
- - Psychiatric illness, social situation, or any other circumstances that would
limit compliance with study requirements.
- - Any ophthalmologic condition that is clinically unstable.
16. 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).
17. 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).
18. Concurrent or prior malignancy other than the disease under study. The following
exceptions require consultation with the Chief Investigator:
1. Non-muscle invasive bladder cancer (NMIBC) treated within the last 24 months
that is considered completely cured.
2. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that
is completely cured.
3. Non-invasive cervical cancer treated within the last 24 months that is
considered completely cured.
19. 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.
20. A participant has major surgery excluding placement of vascular access or tumour
biopsy, or had significant traumatic injury within 4 weeks before first dose of
study drug or minor surgery within 2 weeks, or will not have fully recovered from
surgery, or has surgery planned during the time the participant is expected to
participate in the study. Note: Participants with planned surgical procedures to be
conducted under local anaesthesia may participate.
21. A participant has palliative radiotherapy within 1 week of the firs dose of study
drug,
22. Any other condition which in the investigator's opinion would not make the patient a
good candidate for the clinical trial.
