2-OHOA With RT and TMZ for Adults With Glioblastoma (CLINGLIO)

• ClinicalTrials.gov Identifier: NCT04250922
• Recruitment Status: Active, not recruiting
• First Posted: January 31, 2020
• Last Update Posted: December 16, 2020
• Sponsor: Laminar Pharmaceuticals
• Collaborators: Specialized Medical Services (SMS)-Oncology BV; Northern Institute for Cancer Research, Newcastle; Theradis pharma; LIPODOM THERAPEUTICS
• Information provided by (Responsible Party): Laminar Pharmaceuticals

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Primary Glioblastoma; Glioblastoma Multiforme	Drug: 2-OHOA; Drug: TMZ; Radiation: RT	Phase 2; Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

This is a randomized, double-blind, placebo-controlled, 2 parallel arms (1:1), adjuvant trial to assess the efficacy of 2-OHOA vs placebo in patients with ndGBM. The 2 arms are: Arm A: SoC + placebo for 2-OHOA; Arm B: SoC + 12g/day of 2-OHOA

Treatment consists of 3 phases:

1. Chemoradiotherapy (6 to 7 weeks)

   • RT in daily fractions of 2Gy, 5 days per week (60Gy)
   • TMZ 75mg/m2 daily (maximum of 49 days)
   • Placebo or 2-OHOA for 4 weeks (from week 3 to week 6, both inclusive) -Washout period (4 weeks)

2. Maintenance (4-week cycles, maximum of 6 cycles)

   • Placebo/2-OHOA daily in the first 3 weeks of each cycle, followed by 7 days washout
   • TMZ 150-200mg/m2 daily in the first 5 days of each cycle
3. Monotherapy: 4-week cycles until disease progression, unacceptable toxicity or lack of clinical benefit Placebo/2-OHOA daily in the first 3 weeks of each cycle followed by 7 days washout

• Masking: Triple (Participant, Care Provider, Investigator)

Masking Description

At the Screening Visit, the IRT will assign a unique number to the subject. The site will use the IRT to receive drug kit numbers and a unique randomization number.

Subjects will be randomized to Arm A or B in a 1:1 ratio. Drug kit numbers and treatment content will be assigned according to a list generated before the start of the study. At interim, the IRT vendor will transfer the list of attribution to the iSCs. After the final lock, the list of attribution will be transmitted to the company involved in analysis. The IRT vendor will be in charge of the stock management/logistics in each site and shipments. Upon receipt of study drug, the study site will acknowledge receipt in the IRT system.

The investigators, the study site personnel and subject will remain blinded to throughout the course of the study. The IRT will provide access to for a subject in case of medical emergency. If sponsor/clinical team should break the blind, the reason will be documented on the eCRF.

• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: December 1, 2019
• Estimated Primary Completion Date: April 30, 2022
• Estimated Study Completion Date: October 30, 2023

Arms and Interventions

Arm	Intervention/treatment
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.	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).
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.	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).

Outcome Measures

Primary Outcome Measures :

1. 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 ]

   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.

2. 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 OS events ]

   To evaluate the efficacy of 2-OHOA in combination with the standard of care (SoC) treatment of radiotherapy (RT) and TMZ, as assessed by

   - Overall Survival (OS), for full marketing authorization (FMA) application.

Secondary Outcome Measures :

1. To evaluate clinical response [ Time Frame: Baseline and Post-baseline: day 1 of each odd cycle of maintenance/monotherapy phase and at progression ]
   Changes in neurological function, based on Neurologic Assessment in Neuro-Oncology (NANO) criteria
2. 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 ]
   Time to Progression (TTP) (as assessed using RANO criteria)
3. 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 ]

   Blood samples for determination of plasma concentrations of 2-OHOA in combination with RT and/or TMZ.

   Maximum Plasma Concentration [Cmax]

4. 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 ]

   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)

5. 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 ]

   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)

6. 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 ]

   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.

7. 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 ]

   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.

8. 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 ]

   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

France

Institut Cancerologie de L'Ouest (ICO)

Angers, France

Gustave Roussy University Hospital

Rennes, France

Institut universitaire du cancer

Toulouse, France

Israel

Reaserch Fund of the Hadassah Medical Organization

Jerusalem, Israel

Italy

Istituto Nazionale Neurologico Carlo Besta

Milan, Italy

Istituto Nazionale Tumori "Regina Elena"

Roma, Italy

University of Turin

Turin, Italy

Spain

Hospital Universitari i Politécnic La Fe.

Valencia, Comunidad Valenciana, Spain, 46026

Hospital Clinic

Barcelona, Spain

Hospital del Mar

Barcelona, Spain

Hospital Vall d'Hebron

Barcelona, Spain

Hospital Universitario 12 De Octubre

Madrid, Spain

Hospital Parc Tauli

Sabadell, Spain

United Kingdom

Freeman Hospital's Northern Centre of Cancer Care

Newcastle, Newcastle Upon Tyne, United Kingdom, NE7 7DN

Cambridge university hospital

Cambridge, United Kingdom

The Royal Marsden Hospital

London, United Kingdom

Sponsors and Collaborators

Laminar Pharmaceuticals

Specialized Medical Services (SMS)-Oncology BV

Northern Institute for Cancer Research, Newcastle

Theradis pharma

LIPODOM THERAPEUTICS

More Information

• Responsible Party: Laminar Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04250922
• Other Study ID Numbers: MIN-003-1806
• First Posted: January 31, 2020
• Last Update Posted: December 16, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Laminar Pharmaceuticals:

malignant

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue