Clinical Trials /

2-OHOA With RT and TMZ for Adults With Glioblastoma

NCT04250922

Description:

The proposed Phase IIB 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
Recruiting Status:

Recruiting

Phase:

Phase 2

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 + low-dose (3 g/day) 2-OHOA
TMZArm A: SoC + placebo for 2-OHOA

Purpose

The proposed Phase IIB 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, 3 parallel arms (1:1:1 ratio),
      adjuvant trial to assess the efficacy of two doses 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, low-dose 2-OHOA or
      high-dose 2-OHOA.

      The primary endpoint of the study is PFS. The study is planned to initially enrol 210
      patients and collect a total of 150 PFS events. One formal interim analysis will be performed
      by an independent statistical group and reviewed by an independent Data Monitoring Committee
      (iDMC) when 75 PFS events are observed. After reviewing the interim results, the iDMC will
      make recommendations regarding: the dose to take forward to the second part and the
      continuation of the trial overall.

      The interim dose selection will be made primarily based on the estimated hazard ratio (HR)
      for each dose over the placebo group, taking into consideration the totality of data
      including, safety, overall survival and subgroups. Patient enrolment to the dropped dose will
      be discontinued after the dose selection.

      At interim analysis, it will also be examined whether the molecular signature permits the
      identification of a subpopulation of patients who respond better to the treatment.

      Based on the data at interim analysis the sample size and events for the dose expansion part
      of the trial, will be re-estimated for the selected dose to ensure that the power is well
      maintained given the estimated treatment effect at interim analysis. The events/sample size
      increase will be based on the considerations of the success probability for the selected dose
      in the full population and the subpopulation. For this purpose, at interim analysis, the
      conditional power for the selected dose group in the full population will be computed. Based
      on the conditional power, the interim results will be classified into one of the following
      zones: promising, favourable, and unfavourable. If the interim results fall in the promising
      zone, then it is planned to increase the total number of events up to 225, i.e. 1.5 times the
      original planned 150 events. The total sample size will also be increased up to 273 to ensure
      that the desired number of events can be reached within a realistic time. If the interim
      results are favourable or unfavourable, the study size will remain as initially planned 150
      events, collected from 210 patients.

      Subjects enrolled after interim analysis will be randomized in a 1:1 ratio to the selected
      dose and control group.
    

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 + low-dose (3 g/day) 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 (low dose) 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 (low dose) 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
Arm C: SoC + high-dose (12 g/day) 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 (low dose) 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 C will receive 2-OHOA (high dose) 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 confirmation)

          5. Ability to swallow and retain oral medication

          6. Centrally obtained MGMT promoter methylation status

          7. Subjects who underwent total or partial/ incomplete resection

          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 < 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/mm3 or
             ≥1.5 x 109/L; Platelets ≥ 100,000/mm3 or ≥100 x 109/ 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 suitable for "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 or other intolerability to TMZ

          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 gastrointestinal events and gastroinflammatory
             pathologies

         13. Uncontrolled diabetes mellitus, with glycated haemoglobin (HbA1c) levels at the
             screening visit of ≥7.5%
      
Maximum Eligible Age:N/A
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
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Lipopharma Therapeutics SL

Trial Keywords

  • malignant

Last Updated

January 29, 2020