This is a randomized, double-blind, placebo-controlled, 2 parallel arms (1:1 ratio), adjuvant
trial to assess the efficacy of 2-hydroxyoleic acid (2-OHOA) versus placebo in patients with
newly diagnosed, IDH wildtype, GBM. In all arms, patients will receive the SoC and will be
randomized to receive either placebo or 2-OHOA dose.
The primary endpoint of the study is PFS. The study is planned to initially enrol 180
patients and collect a total of 124 PFS events. After 62 events for PFS are observed, a
formal interim analysis will be performed and the data reviewed by an Independent Data
Monitoring Committee (IDMC) or may be activated by the IDMC 12 months after the inclusion of
the last patient if follow up is sufficient to identify an overall PFS or OS significant
deviation from the literature. After reviewing the interim results, the iDMC will make
recommendations regarding: the sample size and the continuation of the trial overall.
At interim analysis, if molecular data permit to identify a subpopulation of patients who
respond better to the combination treatment, this signature will be applied to the patients
entering in the second stage of the trial and the treatment effect will be estimated in the
corresponding subgroup (Adaptive signaturedesign according to Freidlin and Simon, Clin Cancer
Res 2005).
Further, the sample size and events will be re-estimated to ensure that the statistical power
is maintained given the estimated treatment effect at interim analysis. The events/sample
size increase will be based on the considerations of the success probability in the full
population and the subpopulation.
For that purpose, based on the conditional power, the interim results will be classified into
the following zones: favourable, unfavourable or promising with a planned enrolment of 60
additional patients or 114 additional patients.
If the interim results fall in the promising zone, then it is planned to increase the total
number of events both for PFS and OS by up to 50%, with up to 186 events for PFS and up to
186 events for OS. The total sample size will also be increased to up to 234 patients to
ensure the desired number of events within a realistic time. If the interim results are
favourable or unfavourable, the study size will remain as initially planned with 124 events
for PFS and for OS, collected from 180 patients. Depending on prevalence and strength of
treatment effect in the subpopulation, it may also be decided to enlarge the subpopulation
beyond those to be expected by prevalence in the second cohort, up to a maximum of 275
patients.
Inclusion criteria:
1. Written informed consent, signed and dated
2. Subjects who are able to understand and follow instructions during the trial
3. Age ≥18 and ≤75
4. Subjects with newly histologically confirmed intracranial malignant glioma
(glioblastoma WHO Grade IV) that is IDH1 wildtype (local assessment) and who are
scheduled to receive chemo-radiotherapy with temozolomide
5. Ability to swallow and retain oral medication
6. Centrally obtained MGMT promoter methylation status
7. Subjects who underwent total or partial / incomplete resection and with the
appropriate quantity of tumour tissue releasable for eligibility and signature
assessments
8. Karnofsky Performance Score (KPS) > 50 %
9. Female subjects with a childbearing potential must have a negative pregnancy test
within one week before inclusion in the trial. Those female and male subjects admitted
in the study must use a reliable method of contraception, for female subjects during
the study period up until 32 days after last study treatment and for male subjects up
until 92 days after last study administration.
Women must be:
- Either of NOT childbearing potential: postmenopausal (≥ 60 years of age, or < 60
years of age and amenorrhoea for 12 months in the absence of chemotherapy,
tamoxifen, toremifene, or ovarian suppression with follicle-stimulating hormone
(FSH) above 40 U/L and oestradiol below 30 ng/L, or if taking tamoxifen or
toremifene, and age < 60 years, then FSH and oestradiol in the postmenopausal
range), permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral
salpingectomy), or otherwise incapable of pregnancy
- Or of childbearing potential and practicing a highly effective method of birth
control consistent with local regulations regarding the use of birth control
methods for subjects participating in clinical studies: e.g., established use of
oral, injected or implanted hormonal methods of contraception; placement of an
intrauterine device or intrauterine system; male partner sterilization (the
vasectomized partner should be the sole partner for that subject).
10. A man who is sexually active and has not had a vasectomy must agree to use a barrier
method of birth control e.g., either condom or partner with occlusive cap (diaphragm
or cervical/vault caps).
11. Adequate bone marrow function including: Absolute neutrophil count (ANC) ≥1,500/mm^3
or ≥1.5 x 10^9/L; Platelets ≥ 100,000/mm3 or ≥100 x10^9/L; Haemoglobin ≥ 9 g/dL (may
have been transfused).
12. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit
of normal range (ULN), an aspartate aminotransferase (AST), level ≤ 2.5 × ULN, and an
alanine aminotransferase (ALT) level ≤ 2.5 × ULN or, for subjects with documented
metastatic disease to the liver, AST and ALT levels ≤ 5 × ULN. Subjects with
documented Gilbert disease are allowed if total bilirubin ≤ 3 x ULN
13. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min
according to the Cockcroft-Gault formula
Exclusion Criteria:
1. Known hypersensitivity to any component of the investigational product.
2. Any other investigational drug within the preceding 30 days. Prior, concomitant, or
planned concomitant treatment with anti-neoplastic aim including (but not limited) to
NovoTumor Treatment Fields (Novo TTF), bevacizumab, intratumoural or intracavitary
anti-neoplastic therapy (e.g Gliadel wafers), or other experimental therapeutics
intended to treat the tumour.
3. Subjects who underwent "only biopsy" resection
4. Anticancer therapy within 4 weeks of study entry (6 weeks for mitomycin and
nitrosoureas)
5. Other major surgery within the preceding 30 days
6. Allergy, hypersensitivity or other intolerability to temozolomide and its excipients,
patients with hypersensitivity to dacarbazine and patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption.
7. Unable to undergo MRI
8. Presenting with diffuse midline gliomas or multifocal GBM (distant from the flare or
contralateral) or rapid progression between early post-surgery MRI and
pre-radiotherapy MRI
9. Uncontrolled or significant cardiovascular disease
10. A history of uncontrolled hyperlipidaemia and/or the need for concurrent lipid
lowering therapy
11. Need for warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride, glipizide,
glyburide or nateglanide)
12. Past medical history of uncontrolled clinically significant active or chronic
gastrointestinal disorders (for example, Crohn's disease, celiac disease, untreated
stomach ulcers, etc) and gastro-inflammatory pathologies
13. Uncontrolled diabetes mellitus, with glycated haemoglobin (HbA1c) levels at the
screening visit of ≥7.5%
14. Cardiac disease, defined specifically as either
1. Mean resting corrected QT interval (QTc) > 470 msec (for women) and > 450 ms (for
men) obtained from 3 consecutive ECGs
2. Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG (example, complete left bundle branch block, third degree heart
block)
3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, potential for Torsades de Pointes,
congenital long QT syndrome, family history of long QT syndrome or unexplained
sudden death under 40 years of age
15. Previous malignancies within the last three years other than ndGBM, except
successfully treated squamous cell carcinoma of the skin, superficial bladder cancer,
and in situ carcinoma of the cervix.