An efficacy and safety study of 2-OHOA in patients with glioblastoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Laminar Pharmaceuticals S.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Sep 2019 → ongoing

Decision date (initial)

2024-03-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Laminar Pharmaceuticals - Spain · European Commission (Horizon 2020 programme) - Belgium

External identifiers

EU CT number

2024-511542-39-00

EudraCT number

2018-000365-37

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Pharmacodynamic

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.
• Overall Survival (OS). The detection of a large range of treatment effect (through sample size re-estimation) is primary objectives integrated in the adaptive design of the study.

Secondary objectives 1

1. • To evaluate clinical response: o Changes in neurological function, based on Neurologic Assessment in Neuro-Oncology (NANO) criteria • To evaluate additional measures of efficacy including: o Time to Progression (TTP) (as assessed using RANO criteria) • To evaluate Health-related Quality of Life (HRQoL) • To characterize the safety and tolerability of 2-OHOA in combination with RT and TMZ. • To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of 2-OHOA in combination with RT and TMZ. • To explore further the mechanism of action (MoA) of 2-OHOA.

Conditions and MedDRA coding

Newly diagnosed primary glioblastoma multiforme (ndGBM)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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) 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. 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 (in Germany, patients who use an efficient method of hormonal contraception during the study period must continue to use this for minimum of six months after their last dose of temozolomide) 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 (if any/where applicable) 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

1. 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 postsurgery 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 a. Mean resting corrected QT interval (QTc) > 470 msec (for women) and > 450 ms (for men) obtained from 3 consecutive ECGs b. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (example, complete left bundle branch block, third degree heart block) c. 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 Additional information regarding concomitant medications. Based on data in vitro, 2-OHOA is a potent inhibitor of CYP2C9. Subjects on warfarin, phenytoin and various oral hypoglycaemics are excluded (see above). Where concomitant use of other products metabolized by CYP2C9 is unavoidable, caution must be exercised and subjects should be closely monitored as appropriate.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • PFS according to RANO criteria evaluated after at least 66 PFS events occur. Occurrence of disease progression to calculate PFS will be determined first by the investigator based on local evaluation of images and other clinical information. Progression will be confirmed by an adjudication/imaging committee. • Overall Survival evaluated after at least 90 OS events are observed.

Secondary endpoints 1

1. • Changes in neurological function, based on Neurologic Assessment in Neuro-Oncology (NANO) criteria • To evaluate additional measures of efficacy including: o Time to Progression (TTP) (as assessed using RANO criteria) • 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. • Please refer to protocol for full list

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Laminar Pharmaceuticals S.A.

Sponsor organisation

Laminar Pharmaceuticals S.A.

Address

Block A Planta 1 Pureta 3 Edificio Naorte 4, Carretera De Valldemossa Km 7 Parcbit Carretera De Valldemossa Km 7 Parcbit

City

Palma

Postcode

07121

Country

Spain

Scientific contact point

Organisation

Laminar Pharmaceuticals S.A.

Contact name

Chief of Clinical Operations

Public contact point

Organisation

Laminar Pharmaceuticals S.A.

Contact name

Clinical Development Department

Third parties 5

Locations

3 EU/EEA countries · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications