Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy (MecMeth/ NOA-24)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rheinische Friedrich-Wilhelms-Universitaet Bonn

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Apr 2022 → ongoing

Decision date (initial)

2024-05-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-511264-89-00

EudraCT number

2021-000708-39

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Dose response, Safety

The primary objective of Phase I is to determine toxicity of meclofenamate sodium therapy in addition to standard temozolomide and, on this base, determine the daily meclofenamate sodium dose to be recommended for Phase II. In Phase II, the primary objective is efficacy of meclofenamate sodium therapy in addition to standard therapy.

Secondary objectives 1

1. To determine the efficacy of meclofenamate sodium therapy in addition to standard temozolomid throughout the trial. To assess the safety and tolerability of meclofenamate sodium therapy in addtion to standard temozolomid throughout the trial. To evaluate the clinical effect of meclofenamate sodium therapy in addition to temozolomide and the development of quality of life throughout the trial.

Conditions and MedDRA coding

Glioblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. 1. First relapse after first-line therapy with radiotherapy (RT) and alkylating chemotherapy, ≥ 3 months after last chemotherapy application and >6 months after end of RT. Drug therapy and/or radiotherapy for first relapse treatment not yet started.
2. 2. Tumor progression according to RANO criteria
3. 3. Written informed consent
4. 4. Cognitive state to understand rationale and necessity of study therapy and procedures
5. 5. MGMT promotor-methylated (MGMTmeth), IDH wildtype glioblastoma (GBM) or gliosarcoma confirmed with histology of the primary resection or, in phase II, last resection
6. 6. Age > 18 years
7. 7. Karnofsky performance score (KPS) ≥50%;
8. 8. Life expectancy > 6 months
9. 9. Adequate bone marrow reserve (WBC >3 G/nl, platelets >100 G/nl
10. 10. Adequate liver function (bilirubin <1.5 x ULN; ASAT /ALAT <3 x ULN, creat-inine < 1.5 x ULN
11. 11. Patient compliance that allows adequate follow up
12. 12. Male and female patients with reproductive potential must use an ap-proved contraceptive method during and for 3 months after the trial (Pearl index <1%)
13. 13. Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test (beta-HCG) must be obtained prior to treatment start
14. Addition criterion for Phase II only: 14. Resection at first relapse not yet performed; according to the local treating neurosurgeon and the documented decision of local neurooncological tu-mor board, reresection of the tumor is clinically indicated and can be safe-ly deferred until day 7-10 after initiation of MFA/TMZ therapy

Exclusion criteria 17

1. 1. Indication for hematotoxicity in first-line therapy not allowing TMZ starting dose 150 mg/m2/d at the discretion of the investigator
2. 2. History of temozolomide-related liver toxicity > CTCAE5 grade 1 or skin toxicity > CTCAE5 grade 2 in first-line therapy
3. 3. History of gastrointestinal bleeding or gastroduodenal ulcer, active gastritis
4. 4. History of NSAID-related asthma, urticaria or allergic-type skin reactions
5. 5. Uncontrolled malignancy within the last 2 years
6. 6. History of confirmed or suspected hypersensitivity (delayed type and im-mediate type, inclusive of anaphylactic reaction) to any background/ standard TMZ drug product or one of its ingredients of the chosen prod-uct, or to cyclooxygenase inhibitors (“NSAIDs”), or to any ingredient of meclofenamate drug product
7. 7. History of other disease with poor prognosis
8. 8. History of severe coronary heart disease (esp. after coronary artery bypass graft or history of myocardial infarction)or severe heart failure
9. 9. Known HIV infection, active hepatitis B or C
10. 10. Breastfeeding or pregnant
11. 11. Unable to undergo contrast-enhanced MRI (i.e. contrast allergy, implants, etc
12. 12. Treatment in another clinical trial with therapeutic medical intervention or use of any other investigational agent during the trial or within the 30 days before enrollment
13. 13. Medication with a drug that is not allowed in conjunction with MFA intake and cannot be discontinued: i.e. lithium, methotrexate, etc
14. 14. Patients with active bleeding, bleeding diathesis, antiplatelet therapy or anticoagulant therapy except for the following anticoagulants which are permitted for low-dose thrombosis prophylaxis up to the dosage speci-fied here: unfractionated heparin 7,500 IU BID or 5,000 IU TID; low molecu-lar weight heparin e. g. enoxaparin 40 mg/d; fondaparinux 2.5 mg/d; danaparoid sodium 750 IU BID; argatroban IV route thrombin time < 70 s; dabigatran 110 mg BID; rivaroxaban 10 mg/d; edoxaban 30 mg/d; epixa-ban 2.5 mg BID This restriction is due to a potentially increased risk of GI ulcers with subsequent bleeding under MFA therapy. (Not applicable for Phase II)
15. 15. Patients with medically diagnosed hereditary Galactose Intolerance, com-plete lactase deficiency or confirmed Glucose-Galactose-Malabsorption
16. 16. Medical History of gastrointestinal Resection of any kind that may poten-tially alter the absorption of the investigational study drug, according to investigators judgement
17. 17. The presence of any other concomitant severe, progressive, or uncon-trolled renal, hepatic, hematological, endocrine, pulmonary, cardiac (in-cluding coronary artery bypass graft), or psychiatric disease, or signs and symptoms thereof, that may affect the subjects participation in the study, according to investigators judgement

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I: Incidence of dose-limiting toxicities (DLTs) during the first 8 weeks/56 days of MFA treatment.
2. Phase II: Progression-free survival (PFS) as measured from the day of randomization until diagnosis of progres-sive disease determined by MRI (RANO criteria) in the local center. In a sensitivity analysis, the PFS analysis does also include patients from phase I who received MFA at the same dose as applied in phase II (PFS measured from day of trial inclusion)

Secondary endpoints 8

1. Phase I: Progression-free survival (PFS) as measured from the inclusion into the trial until diagnosis of progressive disease determined by MRI (RANO criteria) in the local center.
2. Phase I: Analysis of PFS according to post hoc central refer-ence neuroradiological assessment
3. Phase I: Overall survival as measured from the day of inclusion into the trial
4. Phase I: •Assessment of safety beyond 8 weeks MFA treat-ment: Toxicity, i.e. continuous monitoring of AE/SAE/SUSARs
5. Phase II: Analysis of PFS according to post hoc central refer-ence neuroradiological assessment. PFS analysis including both patients from phase II and patients from phase I who received MFA at the same dose as applied in phase II (PFS measured from day of trial inclusion).
6. Phase II: Overall survival (OS) as measured from the day of randomization in phase II. A further sensitivity anal-ysis, will also include patients from phase I who re-ceived MFA at the same dose as applied in phase II. In these patients, OS starts from day of inclusion into the trial
7. Phase II: Assessment of safety: Toxcitiy, i.e. continuous moni-toring of AE/SAE/SUSARs until 3 days after end of therapy
8. Phase II: Karnofsky performance score (KPS), Quality of life (QoL) throughout the trial and Mini Mental state ex-amination (MMSE).

Investigational products

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

Test 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rheinische Friedrich-Wilhelms-Universitaet Bonn

Sponsor organisation

Rheinische Friedrich-Wilhelms-Universitaet Bonn

Address

Venusberg-Campus 1, Venusberg Venusberg

City

Bonn

Postcode

53127

Country

Germany

Scientific contact point

Organisation

Rheinische Friedrich-Wilhelms-Universitaet Bonn

Contact name

Prof. Dr. Ulrich Herrlinger

Public contact point

Organisation

Rheinische Friedrich-Wilhelms-Universitaet Bonn

Contact name

Prof. Dr. Ulrich Herrlinger

Locations

1 EU/EEA country · 15 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 12 files

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

Application history

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