Clinical Trials /

2-OHOA With RT and TMZ for Adults With Glioblastoma

NCT04250922

Description:

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.

Related Conditions:
  • Glioblastoma
  • Glioblastoma, IDH-Wildtype
Recruiting Status:

Active, not recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 2-OHOA With RT and TMZ for Adults With Glioblastoma
  • Official Title: A Randomized, Double-blind, Placebo-controlled Adjuvant Trial in Newly Diagnosed Primary Glioblastoma Subjects to Assess the Efficacy and Safety of 2-hydroxyoleic Acid (2-OHOA) in Combination With Radiotherapy and Temozolomide Standard of Care Treatment.

Clinical Trial IDs

  • ORG STUDY ID: MIN-003-1806
  • NCT ID: NCT04250922

Conditions

  • Primary Glioblastoma
  • Glioblastoma Multiforme

Interventions

DrugSynonymsArms
2-OHOAArm B: SoC + 12 g/day of 2-OHOA
TMZArm A: SoC + placebo for 2-OHOA

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: SoC + placebo for 2-OHOAPlacebo ComparatorChemoradiation 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.
  • TMZ
Arm B: SoC + 12 g/day of 2-OHOAExperimentalChemoradiation 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.
  • 2-OHOA
  • TMZ

Eligibility 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.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To evaluate the efficacy of 2-OHOA in combination with the standard of care (SoC) treatment of radiotherapy (RT) and TMZ.
Time Frame:Assessed after observing at least 124 PFS events
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:To evaluate clinical response
Time Frame:Baseline and Post-baseline: day 1 of each odd cycle of maintenance/monotherapy phase and at progression
Safety Issue:
Description:Changes in neurological function, based on Neurologic Assessment in Neuro-Oncology (NANO) criteria
Measure:To evaluate additional measures of efficacy
Time Frame:Baseline and Post-baseline: day 1 of each odd cycle of maintenance/monotherapy phase and at progression
Safety Issue:
Description:Time to Progression (TTP) (as assessed using RANO criteria)
Measure:To characterize the pharmacokinetics (PK) parameters
Time Frame:At week 3 and 5 (day in both cases) of chemo-radiotherapy phase and at day 1 and 15 of cycle 1 of the maintenance phase
Safety Issue:
Description:Blood samples for determination of plasma concentrations of 2-OHOA in combination with RT and/or TMZ. Maximum Plasma Concentration [Cmax]
Measure:To characterize the pharmacokinetics (PK) parameters
Time Frame:At week 3 and 5 (day in both cases) of chemo-radiotherapy phase and at day 1 and 15 of cycle 1 of the maintenance phase
Safety Issue:
Description:Blood samples for determination of plasma concentrations of 2-OHOA in combination with RT and/or TMZ. Lowest plasma concentration reached before the next dose is administered (Trough)
Measure:To characterize the pharmacokinetics (PK) parameters
Time Frame:At week 3 and 5 (day in both cases) of chemo-radiotherapy phase and at day 1 and 15 of cycle 1 of the maintenance phase
Safety Issue:
Description:Blood samples for determination of plasma concentrations of 2-OHOA in combination with RT and/or TMZ. Area Under the plasma concentration-time Curve (AUC)
Measure:To evaluate Health-related Quality of Life (HRQoL)
Time Frame:Baseline and Post-baseline: day 1 of each odd cycle of maintenance/monotherapy phase and at progression
Safety Issue:
Description: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 QLQ-C30 is a 30-item patient self-report questionnaire composed of both multi-item and single scales, including five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/HRQoL scale, and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). Subjects rate items on a four-point scale, with 1 as "not at all" and 4 as "very much". The QLQ-C30 was developed and validated for use in a cancer patient population, and its reliability and validity is highly consistent across different language-cultural groups.
Measure:To evaluate Health-related Quality of Life (HRQoL)
Time Frame:Baseline and Post-baseline: day 1 of each odd cycle of maintenance/monotherapy phase and at progression
Safety Issue:
Description: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 QLQ-BN20 is a 20-item patient self-report questionnaire that was developed specifically as a module for subjects with brain cancer. It consists of four domain scores, including future uncertainty, visual disorder, motor dysfunction, and communication deficit, as well as seven individual symptom items (headache, seizures, drowsiness, hair loss, itching, difficulty with bladder control, and weakness of both legs). Subjects rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A retrospective validation study has been conducted confirming its psychometric validity.
Measure:To evaluate Health-related Quality of Life (HRQoL)
Time Frame:Baseline and Post-baseline: day 1 of each odd cycle of maintenance/monotherapy phase and at progression
Safety Issue:
Description: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 EORTC QLQ-C30/BN20 as outlined in SoA. These assessments should be completed prior to study drug administration and any other study procedures being performed at these visits, and prior to discussing with the subject that their disease has progressed.

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Laminar Pharmaceuticals

Trial Keywords

  • malignant

Last Updated

December 16, 2020