Trabectedin for Recurrent Grade II/III Meningioma

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to collect data on activity, toxicity and quality of life of trabectedin therapy in patients with recurrent high-grade meningioma.

Detailed Description
-----------------
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.

Official Title
-----------------
Trabectedin for Recurrent Grade II or III Meningioma: a Randomized Phase II Study of the EORTC Brain Tumor Group

Conditions
-----------------
Recurrent High Grade Meningioma

Intervention / Treatment
-----------------
* Drug: Trabectedin
* Other: Local standard of care


Participation Criteria
=================
Eligibility Criteria
-----------------
Patient selection criteria Age 18 or older Histological diagnosis of 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 ULN, SGPT/ALT and SGOT/AST ≤ 2.5 x ULN Alkaline phosphatase ≤ 2.5 x ULN; if alkaline phosphatase > 2.5 ULN, ALP hepatic isoenzyme and/or 5-nucleotidase and/or gamma glutyamyltransferase (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 MUGA or 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, clinicaly 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 ICH/GCP, and national/local regulations.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trabectedin<br>Patient will be treated with trabectedin | Drug: Trabectedin<br>* Trabectedin will be given as a 24-hour infusion every 3 weeks at a starting dose of 1.5 mg/m2 body surface area (BSA), until one of the treatment withdrawal criteria has been met.<br>* Other names: Yondelis;|
| Other: Local standard of care<br>Treatment in the control arm is left to the discretion of the investigator, according to the local standard of care. | Other: Local standard of care<br>* Left to the discretion of the investigator<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) |  | From the date of randomization until the date of first objective progression or the date of patient's death whichever occurs first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival at 6 months (PFS-6), median PFS (mPFS) |  | From the date of randomization until the date of first objective progression or the date of patient's death whichever occurs first | 
| Best overall response (BOR). Objective response (CR/PR), rate and median duration. Complete response (CR), rate and median duration. |  | From the date of randomization until disease progression | 
| Overall survival (OS), OS probability at 6 (OS6) and 12 months (OS12), median OS (mOS) |  | From the date of randomization up to the date of death, up to 12 months | 
| Safety (CTCAE v.4.0) |  | From randomization up to 30 days after administration of the last dose of protocol treatment or until the start of a new antitumor therapy, whichever occurs first. | 
| Health-related Quality of life (HRQol) |  | Untill six months after randomization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Grade 2 Chordoid meningioma, Grade 2 Clear cell meningioma, Grade 2 Atypical meningioma, Grade 3 Papillary meningioma, Grade 3 Rhabdoid meningioma, Grade 3 Anaplastic meningioma, Grade 3 Malignant meningioma