2-OHOA With RT and TMZ for Adults With Glioblastoma

  • STATUS
    Recruiting
  • End date
    Oct 30, 2023
  • participants needed
    180
  • sponsor
    Laminar Pharmaceuticals
Updated on 25 July 2021
neutrophil count
temozolomide
malignant glioma
tamoxifen
renal function test

Summary

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.

Description

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.

Details
Condition Glioblastoma Multiforme, Primary Glioblastoma, glioblastoma
Treatment TMZ, RT, 2-OHOA
Clinical Study IdentifierNCT04250922
SponsorLaminar Pharmaceuticals
Last Modified on25 July 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Written informed consent, signed and dated
Subjects who are able to understand and follow instructions during the trial
Age 18 and 75
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
Ability to swallow and retain oral medication
Centrally obtained MGMT promoter methylation status
Subjects who underwent total or partial / incomplete resection and with the appropriate quantity of tumour tissue releasable for eligibility and signature assessments
Karnofsky Performance Score (KPS) > 50 %
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

Known hypersensitivity to any component of the investigational product
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
Subjects who underwent "only biopsy" resection
Anticancer therapy within 4 weeks of study entry (6 weeks for mitomycin and nitrosoureas)
Other major surgery within the preceding 30 days
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
Unable to undergo MRI
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
Uncontrolled or significant cardiovascular disease
A history of uncontrolled hyperlipidaemia and/or the need for concurrent lipid lowering therapy
Need for warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride, glipizide, glyburide or nateglanide)
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
Uncontrolled diabetes mellitus, with glycated haemoglobin (HbA1c) levels at the screening visit of 7.5%
Cardiac disease, defined specifically as either
Mean resting corrected QT interval (QTc) > 470 msec (for women) and > 450 ms (for men) obtained from 3 consecutive ECGs
Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (example, complete left bundle branch block, third degree heart block)
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
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
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