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

Prior treatment

• Indication for hematotoxicity in first-line therapy not allowing TMZ starting dose 150 mg/m2/d at the discretion of the investigator
• 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
• Medication with a drug that is not allowed in conjunction with MFA intake and cannot be discontinued: i.e. lithium, methotrexate, etc
• 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

Other illness

• Unable to undergo contrast-enhanced MRI (i.e. contrast allergy, implants, etc
• Medical History of gastrointestinal Resection of any kind that may poten-tially alter the absorption of the investigational study drug, according to investigators judgement
• History of temozolomide-related liver toxicity > CTCAE5 grade 1 or skin toxicity > CTCAE5 grade 2 in first-line therapy
• History of gastrointestinal bleeding or gastroduodenal ulcer, active gastritis
• History of NSAID-related asthma, urticaria or allergic-type skin reactions
• Uncontrolled malignancy within the last 2 years
• 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
• History of other disease with poor prognosis
• History of severe coronary heart disease (esp. after coronary artery bypass graft or history of myocardial infarction)or severe heart failure
• Known HIV infection, active hepatitis B or C

Lab values

• 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)
• Patients with medically diagnosed hereditary Galactose Intolerance, com-plete lactase deficiency or confirmed Glucose-Galactose-Malabsorption

Other

• Breastfeeding or pregnant

• 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.
• Adequate liver function (bilirubin <1.5 x ULN; ASAT /ALAT <3 x ULN, creat-inine < 1.5 x ULN
• Patient compliance that allows adequate follow up
• 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%)
• Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test (beta-HCG) must be obtained prior to treatment start
  • 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
• Tumor progression according to RANO criteria
• Written informed consent
• Cognitive state to understand rationale and necessity of study therapy and procedures
• MGMT promotor-methylated (MGMTmeth), IDH wildtype glioblastoma (GBM) or gliosarcoma confirmed with histology of the primary resection or, in phase II, last resection
• Age > 18 years
• Karnofsky performance score (KPS) ≥50%;
• Life expectancy > 6 months
• Adequate bone marrow reserve (WBC >3 G/nl, platelets >100 G/nl