Trabectedin for Recurrent Grade II/III Meningioma

This is a randomized open label multicenter comparative phase II trial. The objective of the study is to investigate whether trabectedin demonstrates sufficient antitumor activity against recurrent grade II or III to justify further investigation in phase III or as adjuvant therapy for newly diagnosed disease after resection and radiotherapy.

Patient selection criteria

• Age 18 or older
• Histological diagnosis of World Health Organization (WHO) grade II (chordoid meningioma, clear cell meningioma, atypical meningioma) or WHO grade III (papillary meningioma, rhabdoid meningioma, anaplastic/malignant meningioma) according to WHO 2007 classification.
• Radiologically documented progression of any existing tumor (growth > 25% in the last year) or appearance of new lesions (including intra- and extracranial manifestations)
• No more option for local therapy (resection or radiotherapy) after maximal feasible surgery and radiotherapy
• No prior systemic anti-neoplastic therapy for meningioma
• Measurable disease (10 x10 mm) on cranial MRI no more than 2 weeks prior to randomization.
• WHO performance status 0-2
• Adequate liver, renal and hematological function within 4 weeks prior to randomization, defined as:

• Neutrophils ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL or hemoglobin ≥ 5.6 mmol/L, platelets ≥ 100 x 109/L
• Total Bilirubin ≤ 1 x Upper Limit of Normal (ULN), serum glutamate pyruvate transaminase(SGPT)/ Alanine Aminotransferase (ALT) and serum glutamate oxaloacetate transaminase (SGOT)/ Aspartate Aminotransferase (AST) ≤ 2.5 x ULN
• Alkaline phosphatase ≤ 2.5 x ULN; if alkaline phosphatase > 2.5 ULN, Alkaline Phosphatase (ALP) hepatic isoenzyme and/or 5-nucleotidase and/or gamma glutamyltransferase (GGT) must be within the normal range
• Albumin ≥ 30 g/L
• Serum creatinine ≤ 1.5 x ULN
• Creatinine clearance > 30 ml/min as calculated by Cockcroft and Gault formula (see Appendix E)
• Creatine phosphokinase (CPK) ≤ 2.5 x ULN
• Normal cardiac function (LVEF assessed by Multigated radionuclide angiography (MUGA) or Echocardiogram (ECHO) within normal range of the institution), normal 12 lead ECG (without clinically significant abnormalities). The following unstable cardiac conditions are not allowed:

• Congestive heart failure
• Angina pectoris
• Myocardial infarction within 1 year before registration/randomization
• Uncontrolled arterial hypertension defined as blood pressure ≥ 150/100 mm Hg despite optimal medical therapy
• Arrhythmias clinically significant
• Life expectancy of at least 9 weeks
• No history of any other invasive malignancy within the last 5 years (except adequately treated non-melanoma skin cancer, clinically localized and very low risk prostate cancer, and adequately treated cervical intraepithelial neoplasia)
• No serious illness or medical conditions, specifically: active infectious process; chronic active liver disease, including chronic hepatitis B, C or cirrhosis
• No concomitant use of any other investigational agent or phenytoin
• Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 72 hours prior to the first dose of study treatment. Women of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months after the last study treatment. Men who are fertile must use effective contraception during treatment with trabectedin and for 5 months thereafter. A highly effective method of birth control is defined as one that results in low failure rate, i.e. less than 1% per year, when used consistently and correctly.
• Female subjects who are breastfeeding should discontinue nursing prior to the first dose of study treatment and until 3 months after the last study treatment.
• No known MRI or CT, including contrast media, contraindications
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Patients with a buffer range from the normal values of +/- 5 % for hematology and +/- 10% for biochemistry are acceptable. A maximum of +/- 2 days for timelines may be acceptable
• Before patient randomization, written informed consent must be given according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)/ Good Clinical Practice (GCP), and national/local regulations.