Clinical Trials Register

Summary
EudraCT Number:	2021-000708-39
Sponsor's Protocol Code Number:	NEU-201901
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-05-17
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2021-000708-39

A.3

Full title of the trial

Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy

Phase I/II Studie zur Anwendung von Meclofenamate bei Glioblastom-Rezidiv mit methylierten MGMT-Promotor unter Zweitlinien Temozolomid Therapie

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy

Phase I/II Studie zur Anwendung von Meclofenamate bei Glioblastom-Rezidiv mit methylierten MGMT-Promotor unter Zweitlinien Temozolomid Therapie

A.3.2

Name or abbreviated title of the trial where available

MecMeth/ NOA-24

A.4.1

Sponsor's protocol code number

NEU-201901

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Rheinische Friedrich-Wilhelms-Universität Bonn
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bundesministerium für Bildung und Forschung
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Studienzentrale Studienzentrum Bonn (SZB)
B.5.2	Functional name of contact point	Corinna Reineke
B.5.3	Address:
B.5.3.1	Street Address	Venusberg-Campus 1
B.5.3.2	Town/ city	Bonn
B.5.3.3	Post code	53127
B.5.3.4	Country	Germany
B.5.4	Telephone number	004922828713939
B.5.5	Fax number	004922828716039
B.5.6	E-mail	corinna.reineke@ukbonn.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Meclofenamate sodium
D.2.1.1.2	Name of the Marketing Authorisation holder	Mylan Pharmaceuticals Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MECLOFENAMATE SODIUM
D.3.9.1	CAS number	6385-02-0
D.3.9.4	EV Substance Code	SUB03106MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Meclofenamate sodium
D.2.1.1.2	Name of the Marketing Authorisation holder	Mylan Pharmaceuticals Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MECLOFENAMATE SODIUM
D.3.9.1	CAS number	6385-02-0
D.3.9.4	EV Substance Code	SUB03106MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Adult patients with IDHwt, MGMT promotor methylated glioblastoma at first relapse

E.1.1.1

Medical condition in easily understood language

Adult Glioblastoma patients at first relapse

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10018336
E.1.2	Term	Glioblastoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

To determine the efficacy of meclofenamate sodium therapy in addition to standard temozolomide throughout the trial.
To assess the safety and tolerability of meclofenamate sodium therapy in addition to standard temozolomide 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.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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 radiothera-py for first relapse treatment not yet started.
2. Tumor progression according to RANO criteria
3. Written informed consent
4. Cognitive state to understand rationale and necessity of study therapy and procedures
5. MGMT promotor-methylated (MGMTmeth), IDH wildtype glioblastoma (GBM) or gliosarcoma con-firmed with histology of the primary resection or, in phase II, last resection
6. age > 18 years
7. Karnofsky performance score (KPS) ≥60%;
8. Life expectancy > 6 months
9. Adequate bone marrow reserve (WBC >3 G/nl, platelets >100 G/nl)
10. Adequate liver function (bilirubin <1.5 x ULN; ASAT /ALAT <3 x ULN, creatinine < 1.5 x ULN)
11. Patient compliance and geographic proximity that allow adequate follow up
12. Male and female patients with reproductive potential must use an approved contraceptive method during and for 3 months after the trial (Pearl index <1%)
13. Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test (beta-HCG) must be obtained prior to treatment start
Additional inclusion criterion ONLY for phase I:
14. Resection at first relapse not yet performed; according to the local treating neurosurgeon and the documented decision of local neurooncological tumor board, reresection of the tumor is clinically indicated and can be safely de-ferred until day 7-10 after initiation of MFA/TMZ therapy.

E.4

Principal exclusion criteria

1. Indication for hematotoxicity in first-line therapy not allowing TMZ starting dose 150 mg/m2/d
2. History of skin or liver toxicity >CTCAE5 grade 1 in first-line therapy
3. History of gastrointestinal bleeding or gastroduodenal ulcer, active gastritis
4. History of asthma, urticaria or allergic-type skin reactions to NSAID
5. Prior malignancy other than glioma
6. History of confirmed or suspected hypersensitivity (delayed type and immediate type, inclusive of anaphylactic reaction) to any background/ standard TMZ drug product or one of its ingredients of the chosen product, or to cyclooxygenase inhibitors (“NSAIDs”), or to any ingredient of meclofenamate drug product
7. History of disease with poor prognosis
8. History of severe coronary heart disease (esp. after coronary artery bypass graft or history of myocardial infarction) or severe heart failure
9. Known HIV infection, active hepatitis B or C
10. Breastfeeding or pregnant
11. Unable to undergo contrast-enhanced MRI (i.e. contrast allergy, implants, etc).
12. Treatment in another clinical trial with therapeutic medical intervention or use of any other investiga-tional agent during the trial or within the 30 days before enrollment
13. Medication with a drug that is not allowed in conjunction with MFA intake and cannot be discontin-ued: i.e. lithium, methotrexate, etc.
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 specified here: unfractionated heparin 7,500 IU BID or 5,000 IU TID; low molecular weight heparin e. g. enoxa-parin 40 mg/d; fondaparinux 2.5 mg/d; danaparoid sodium 750 IU BID; argatroban IV route throm-bin time < 70 s; dabigatran 110 mg BID; rivaroxaban 10 mg/d; edoxaban 30 mg/d; epixaban 2.5 mg BID This restriction is due to a potentially increased risk of GI ulcers with subsequent bleeding under MFA therapy
15. Patients with medically diagnosed hereditary Galactose Intolerance, complete lactase deficiency or confirmed Glucose-Galactose-Malabsortion
16. Medical History of gastrointestinal Resection of any kind that may potentially alter the absorption of the investigational study drug, according to investigators judgement
17. The presence of any other concomitant severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac (including 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

E.5 End points

E.5.1

Primary end point(s)

Incidence of dose-limiting toxicities (DLTs, Phase I) and Progression-free survival (PFS, Phase II)

E.5.1.1

Timepoint(s) of evaluation of this end point

After 56 days of meclofenamate sodium treatment (DLT incidence) and at diagnosis of progressive disease determined by MRI (RANO criteria) in the local center (PFS).

E.5.2

Secondary end point(s)

Phase I: Progression-free survival (PFS); Overall survival (OS); Assessment of safety beyond 8 weeks MFA treatment: Toxicity, i.e. continuous monitoring of AE/SAE/SUSARs; Karnofsky performance score (KPS), Quality of life (QoL) and Mini-Mental-status examination (MMSE).
Phase II: PFS according to post hoc central reference neuroradiological assessment; OS; Assessment of safety: Toxicity, i.e. continuous monitoring of AE/SAE/SUSARs; KPS, QoL and MMSE.

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase I: PFS is measured at diagnosis of progressive disease determined by MRI (RANO criteria) in the local center and according to post hoc central reference neuroradiological assessment; OS is measured from the day of inclusion into the trial; Safety is measured until 3 days after end of therapy; KPS, QoL and MMSE are measured throughout the trial.
Phase II: PFS is measured post hoc at the central reference neuroradiological assessment; OS is measured from the day of randomization in phase II; Safety is measured until 3 days after end of therapy; KPS, QoL and MMSE are measured throughout the trial.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

consecutive Phase I/II

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard treatment

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The specialists at the neuro-oncology center where the study treatment (and usually also the pre-treatment) was carried out will care for the patient. In case of progression under or after MFA therapy or standard TMZ therapy alone, a proposal for the type of further treatment is decided in the Neurooncology Tumor Board of the treating Center for Neurooncology.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-07-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-07-16

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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