2-OHOA With RT and TMZ for Adults With Glioblastoma

Study Purpose

The proposed Phase IIB/III randomized, double-blind, placebo-controlled trial in subjects with newly diagnosed primary glioblastoma multiforme (ndGBM) aims to compare the efficacy and safety of 2-OHOA versus placebo, given with standard of care (SoC) therapy of radiation therapy plus temozolomide (TMZ), followed by an adjuvant treatment of 6 month period of TMZ and then 2-OHOA or placebo in monotherapy.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years - 75 Years
Gender All
More Inclusion & Exclusion 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) 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.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT04250922
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 2/Phase 3
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Laminar Pharmaceuticals
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

N/A
Principal Investigator Affiliation N/A
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Industry, Other
Overall Status Recruiting
Countries France, Israel, Italy, Spain, United Kingdom
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Primary Glioblastoma, Glioblastoma Multiforme
Additional Details

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.

Arms & Interventions

Arms

Placebo Comparator: Arm A: SoC + placebo for 2-OHOA

Chemoradiation Phase: all subjects undergo focal RT, with a treatment given 5 days per week over ~6 weeks (no more than 7 weeks). TMZ will be administered at 75 mg/m2 orally, once daily, continuously throughout the RT for a maximum of 49 days. Subjects in Arm A will receive placebo every day from Day 1 of week 3 to the end of this Phase. The start of the first cycle during the Maintenance (Adjuvant) Phase will be scheduled ~28 days (and never more than 42 days) after the last day of chemoradiation. During the Maintenance Phase, subjects will receive oral TMZ 150-200 mg/m2 once daily on Days 1-5 of each 28-day cycle for 6 cycles. Subjects in Arm A will receive placebo every day during the first 3 weeks of each 28-day cycle and until progression. Patients will continue with Placebo after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression, unacceptable toxicity or refusal to continue study treatment.

Experimental: Arm B: SoC + 12 g/day of 2-OHOA

Chemoradiation Phase: all subjects undergo focal RT, with a treatment given 5 days per week over ~6 weeks (no more than 7 weeks). TMZ will be administered at 75 mg/m2 orally, once daily, continuously throughout the RT for a maximum of 49 days. Subjects in Arm B will receive 2-OHOA every day from Day 1 of week 3 to the end of this Phase. The start of the first cycle during the Maintenance Phase will be scheduled ~28 days (and never more than 42 days) after the last day of chemoradiation. During the Maintenance Phase, subjects will receive oral TMZ 150-200 mg/m2 once daily on Days 1-5 of each 28-day cycle for 6 cycles. Subjects in Arm B will receive 2-OHOA during the Maintenance Phase. Patients will continue to be administered with 2-OHOA after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression, unacceptable toxicity or refusal to continue study treatment.

Interventions

Drug: - 2-OHOA

Subjects in Arm B will receive orally 2-OHOA during the Chemoradiation Phase. Subjects in Arm B will receive 2-OHOA orally during the Maintenance (Adjuvant) Phase. Patients will continue to be administered with 2-OHOA/Placebo after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression as defined by RANO criteria, unacceptable toxicity, or refusal to continue study treatment.

Drug: - TMZ

TMZ will be administered at 75 mg/m2, orally, once daily, continuously from Day 1 of radiotherapy to the last day of radiation for a maximum of 49 days. During the Maintenance (Adjuvant) Phase, all subjects will receive oral TMZ 150 - 200 mg/m2 once daily on Days 1 - 5 of each 28-day cycle for 6 cycles.

Radiation: - RT

During the Chemoradiation Phase, all subjects will undergo focal RT, with one treatment given daily 5 days per week over approximately 6 weeks (and no more than 7 weeks).

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

Institut Cancerologie de L'Ouest (ICO), Angers, France

Status

Recruiting

Address

Institut Cancerologie de L'Ouest (ICO)

Angers, ,

Gustave Roussy University Hospital, Rennes, France

Status

Not yet recruiting

Address

Gustave Roussy University Hospital

Rennes, ,

Institut universitaire du cancer, Toulouse, France

Status

Recruiting

Address

Institut universitaire du cancer

Toulouse, ,

Jerusalem, Israel

Status

Recruiting

Address

Reaserch Fund of the Hadassah Medical Organization

Jerusalem, ,

Milan, Italy

Status

Recruiting

Address

Istituto Nazionale Neurologico Carlo Besta

Milan, ,

Istituto Nazionale Tumori "Regina Elena", Roma, Italy

Status

Not yet recruiting

Address

Istituto Nazionale Tumori "Regina Elena"

Roma, ,

University of Turin, Turin, Italy

Status

Recruiting

Address

University of Turin

Turin, ,

Valencia, Comunidad Valenciana, Spain

Status

Not yet recruiting

Address

Hospital Universitari i Politécnic La Fe.

Valencia, Comunidad Valenciana, 46026

Hospital Clinic, Barcelona, Spain

Status

Not yet recruiting

Address

Hospital Clinic

Barcelona, ,

Hospital del Mar, Barcelona, Spain

Status

Recruiting

Address

Hospital del Mar

Barcelona, ,

Hospital Vall d'Hebron, Barcelona, Spain

Status

Not yet recruiting

Address

Hospital Vall d'Hebron

Barcelona, ,

Hospital Universitario 12 De Octubre, Madrid, Spain

Status

Not yet recruiting

Address

Hospital Universitario 12 De Octubre

Madrid, ,

Hospital Parc Tauli, Sabadell, Spain

Status

Not yet recruiting

Address

Hospital Parc Tauli

Sabadell, ,

Newcastle, Newcastle Upon Tyne, United Kingdom

Status

Not yet recruiting

Address

Freeman Hospital's Northern Centre of Cancer Care

Newcastle, Newcastle Upon Tyne, NE7 7DN

Cambridge university hospital, Cambridge, United Kingdom

Status

Not yet recruiting

Address

Cambridge university hospital

Cambridge, ,

The Royal Marsden Hospital, London, United Kingdom

Status

Not yet recruiting

Address

The Royal Marsden Hospital

London, ,

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