Trial document




drksid header

  DRKS00025207

Trial Description

start of 1:1-Block title

Title

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

end of 1:1-Block title
start of 1:1-Block acronym

Trial Acronym

MecMeth

end of 1:1-Block acronym
start of 1:1-Block url

URL of the Trial

[---]*

end of 1:1-Block url
start of 1:1-Block public summary

Brief Summary in Lay Language

Glioblastoma (GBM) is the most frequent and malignant primary brain tumor. Survival, if tumor recurrence occurs, is very limited (mean 12 months). For this reason, there is a strong medical drive for improved and survival-prolonging second-line therapies. Preclinical studies have shown that meclofenamate (MFA), which was originally developed as a non-steroidal anti-rheumatic drug (NSAID), affects glioblastoma cells in that they show a better therapeutic response to the current standard therapy with temozolimide (TMZ). The MecMeth study is now bringing combined MFA/TMZ therapy into clinical application to patients with first relapse of a MGMT promotor-methylated glioblastoma. Phase I will aims at determining the optimal MFA dose for phase II, phase II ist searching for indiction of superior efficacy of the MFA/TMZ combination.

end of 1:1-Block public summary
start of 1:1-Block scientific synopsis

Brief Summary in Scientific Language

Glioblastoma (GBM) is the most frequent and malignant primary brain tumor. Even in the prognostically favourable MGMT-methylated subgroup treated with temozolomide (TMZ), survival after relapse is short (12 months). Thus, there is a high medical need for improved survival-prolonging second-line therapies. Preclinical results show that meclofenamate (MFA), originally developed as a nonsteroidal anti-inflammatory drug (NSAID), sensitizes GBM cells to TMZ-induced toxicity via inhibition of connexin43 and reduction of tumor microtubes. The MecMeth trial brings the concept of combined MFA/TMZ therapy to clinical application. Phase I (6-14 patients, 2 dose levels of MFA + standard dose TMZ) evaluates safety and feasibility and determines the dose for the randomized phase II (2 x 30 patients) with primary endpoint progression-free survival. If results of phase II provide indications for efficacy, further exploration in phase III and integration into medical practice could be envisioned.

end of 1:1-Block scientific synopsis
start of 1:1-Block forwarded Data

Do you plan to share individual participant data with other researchers?

Yes

end of 1:1-Block forwarded Data
start of 1:1-Block forwarded Data Content

Description IPD sharing plan:

Individual participant data will be available. Individual participant data (including data dictionaries) that underlie results concerning primary or secondary endpoints reported in a published scientific article will be shared on demand after deidentification. Furthermore, the following documents will be made available: Study Protocol, Statistical Analysis Plan, Informed Consent Form, Clinical Study Report.
The data will be shared beginning 6 months and ending 3 years following article publication.
Data are made available to researchers after a methodologically sound scientific proposal has been submitted to the Coordinating Investigator a steering committee consisting of the Coordinating Investigator, the representative of the Coordinating Investigator, and a SZB member has approved the proposal, and a data access agreement has been signed. Study protocol and the informed consent forms will be made available on demand or through the website of the Division of Clinical Neurooncology, University of Bonn, After 36 months the data will be available in our University’s data warehouse but without investigator support other than deposited metadata.

end of 1:1-Block forwarded Data Content
start of 1:1-Block organizational data

Organizational Data

  •   DRKS00025207
  •   2021/07/20
  •   2021/02/08
  •   yes
  •   Approved
  •   211/21-AMG-ff, Ethik-Kommission der Medizinischen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn
end of 1:1-Block organizational data
start of 1:n-Block secondary IDs

Secondary IDs

  •   2021-000708-39 
end of 1:n-Block secondary IDs
start of 1:N-Block indications

Health Condition or Problem studied

  •   C71 -  Malignant neoplasm of brain
end of 1:N-Block indications
start of 1:N-Block interventions

Interventions/Observational Groups

  •   Meclofenamate, oral administration, duration of treatment: 224 days or until tumor progression (what occurs first). Dosage 100mg - 400mg daily divided into two doses. Application additive to standard temozolomide dosing (TMZ 150-200 mg/m2/d days 1-5/28), 8 four weeks courses).
end of 1:N-Block interventions
start of 1:1-Block design

Characteristics

  •   Interventional
  •   [---]*
  •   Single arm study
  •   Open (masking not used)
  •   [---]*
  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   I-II
  •   Yes
end of 1:1-Block design
start of 1:1-Block primary endpoint

Primary Outcome

- Phase I: Incidence of dose-limiting toxicities (DLTs) during the first 8 weeks/56 days of MFA treatment.
- Phase II: Progression-free survival (PFS) as measured from the day of randomization until diagnosis of progressive 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)

end of 1:1-Block primary endpoint
start of 1:1-Block secondary endpoint

Secondary Outcome

- 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; Overall survival as measured from the day of inclusion into the trial; Assessment of safety beyond 8 weeks MFA treatment: Toxicity, i.e. continuous monitoring of AE/SAE/SUSARs; Karnofsky performance score (KPS) and Quality of life (QoL) throughout the trial
- Phase II: Analysis of PFS according to post hoc central reference 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); Overall survival (OS) as measured from the day of randomization in phase II. A further sensitivity analysis, will also include patients from phase I who received MFA at the same dose as applied in phase II. In these patients, OS starts from day of inclusion into the trial; Assessment of safety: continuous monitoring of AE/SAE/SUSARs until 30 days after end of therapy; Karnofsky performance score (KPS) and Quality of life (QoL) throughout the trial

end of 1:1-Block secondary endpoint
start of 1:n-Block recruitment countries

Countries of Recruitment

  •   Germany
end of 1:n-Block recruitment countries
start of 1:n-Block recruitment locations

Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
end of 1:n-Block recruitment locations
start of 1:1-Block recruitment

Recruitment

  •   Actual
  •   2022/04/11
  •   72
  •   Multicenter trial
  •   National
end of 1:1-Block recruitment
start of 1:1-Block inclusion criteria

Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
end of 1:1-Block inclusion criteria
start of 1:1-Block inclusion criteria add

Additional Inclusion Criteria

For Phase I and II
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. 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 confirmed with histology of the primary 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 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 deferred until day 7-10 after initiation of MFA/TMZ therapy.

end of 1:1-Block inclusion criteria add
start of 1:1-Block exclusion criteria

Exclusion Criteria

For Phase I and II
1. Indication for hematotoxicity in first-line therapy not allowing TMZ starting dose 150 mg/m2/d
2. 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. Severe coronary heart disease (esp. after coronary artery bypass graft or history of myocardial infarction), 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 investigational 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 discontinued: 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 thrombin time < 70 s; vitamin-K-antagonist INR < 1.8; dabigatran 150 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

end of 1:1-Block exclusion criteria
start of 1:n-Block addresses

Addresses

  • start of 1:1-Block address primary-sponsor
    • Medizinische Fakultät der Universität BonnRheinische Friedrich-Wilhelms Universität Bonn
    • Mr.  Prof. Dr.  Bernd  Weber 
    • Venusberg-Campus 1
    • 53127  Bonn
    • Germany
    end of 1:1-Block address primary-sponsor
    start of 1:1-Block address contact primary-sponsor
    end of 1:1-Block address contact primary-sponsor
  • start of 1:1-Block address scientific-contact
    • Klinik für Neurologie und Zentrum für Integrierte OnkologieUniversität Bonn
    • Mr.  Prof. Dr. med.  Ulrich  Herrlinger 
    • Venusberg-Campus 1
    • 53127  Bonn
    • Germany
    end of 1:1-Block address scientific-contact
    start of 1:1-Block address contact scientific-contact
    end of 1:1-Block address contact scientific-contact
  • start of 1:1-Block address public-contact
    • Klinik für Neurologie und Zentrum für Integrierte OnkologieUniversität Bonn
    • Mr.  Prof. Dr. med.  Ulrich  Herrlinger 
    • Venusberg-Campus 1
    • 53127  Bonn
    • Germany
    end of 1:1-Block address public-contact
    start of 1:1-Block address contact public-contact
    end of 1:1-Block address contact public-contact
end of 1:n-Block addresses
start of 1:n-Block material support

Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bundesministerium für Bildung und Forschung Dienstsitz Bonn
    • Heinemannstr. 2
    • 53175  Bonn
    • Germany
    end of 1:1-Block address materialSupport
    start of 1:1-Block address contact materialSupport
    end of 1:1-Block address contact materialSupport
end of 1:n-Block material support
start of 1:1-Block state

Status

  •   Recruiting ongoing
  •   [---]*
  •   [---]*
  •   [---]*
  •   [---]*
  •   [---]*
end of 1:1-Block state
start of 1:n-Block publications

Trial Publications, Results and other Documents

  • [---]*
end of 1:n-Block publications
* This entry means the parameter is not applicable or has not been set.