Newly diagnosed primary glioblastoma multiforme (ndGBM) MedDRA version: 20.0 Level: PT Classification code 10018336 Term: Glioblastoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: 2-hydroxyoleic acid
Product Code: 2-OHOA
Pharmaceutical Form: Powder for oral suspension
INN or Proposed INN: 2-hydroxyoleic acid (sodium salt)
CAS Number: 1229114-68-4
Other descriptiv
Sponsors
Laminar Pharmaceuticals
Eligibility
Sex/Gender
All
Inclusion criteria
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) 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) > 40 % 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. Women must be: • Either of NOT childbearing potential: postmenopausal (= 60 years of age, or =65 years) yes F.1.3.1 Number of subjects for this age range 117
Exclusion criteria
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 a. Mean resting corrected QT interval (QTc) > 470 msec (for women) and > 450 ms (for men) obtained from 3 consecutive ECGs b. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (example, complete left bundle branch block, third degree heart block) c. 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 Additional information regarding concomitant medications. Based on data in vitro, 2-OHOA is a potent inhibitor of CYP2C9. Subjects on warfarin, phenytoin and various oral hypoglycaemics are excluded (see above). Where concomitant use of other products metabolized by CYP2C9 is unavoidable, caution must be exercised and subjects should be closely monitored as appropriate.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of 2-OHOA in combination with the standard of care (SoC) treatment of radiotherapy (RT) and TMZ, as assessed by: •Progression Free Survival (PFS) using the Response Assessment in Neuro-Oncology (RANO) criteria for conditional marketing authorization (CMA) application •Overall Survival (OS), for full marketing authorization (FMA) application. The detection of a large range of treatment effect (through sample size re-estimation) and the characterisation of an optional sub-group of responders (signature detection feature), are primary objectives integrated in the adaptive design of the study. ;Secondary Objective: •To evaluate clinical response: oChanges in neurological function, based on Neurologic Assessment in Neuro-Oncology (NANO) criteria •To evaluate additional measures of efficacy including: oTime to Progression (TTP) (as assessed using RANO criteria) •To evaluate Health-related Quality of Life (HRQoL) •To characterize the safety and tolerability of 2-OHOA in combination with RT and TMZ. •To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of 2-OHOA in combination with RT and TMZ. •To explore further the mechanism of action (MoA) of 2-OHOA. ;Primary end point(s): •PFS according to RANO criteria evaluated after 124 PFS events occur or 1.25 times the expected time to see that number of PFS events under observed accrual rate and powered effect size post-interim. Occurrence of disease progression to calculate PFS will be determined first by the investigator based on local evaluation of images and other clinical information. Progression will be confirmed by an adjudication/imaging committee. •Overall Survival evaluated after 124 OS events are observed or 1.25 * the expected time to see that number of OS events given the observed accrual rate and powered effect size post-interim. ;Timepoint(s) of evaluation of this end point: Assessed respectively after observing at least 124 Progression-Free Survival events | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Changes in neurological function, based on Neurologic Assessment in Neuro-Oncology (NANO) criteria • To evaluate additional measures of efficacy including: o Time to Progression (TTP) (as assessed using RANO criteria) • HRQoL assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, EORTC-QLQ C30, version 3.0 and brain cancer specific QLQ-BN20. • The incidence of adverse events (AEs) related to the 2-OHOA combination with RT and TMZ and according to NCI CTCAE, version 5.0. • Population pharmacokinetics will be evaluated in plasma samples collected according to a sparse sampling scheme. • Proteomic, genomic, lipidomic and transcriptomic biomarkers in blood and tumour tissue ;Timepoint(s) of evaluation of this end point: Each secondary endpoint will be tested in the order listed only after the superiority of dose selected (Arm B or C) compared to placebo (Arm A) with respect to the primary efficacy endpoints (PFS and OS) is established and all preceding secondary efficacy endpoints show statistically significant results | — |
Countries
France, Israel, Italy, Spain, United Kingdom
Contacts
Public ContactMiraj Murshed
SMS-oncology
Outcome results
None listed