E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent high-grade meningioma |
|
E.1.1.1 | Medical condition in easily understood language |
Recurrent high-grade meningioma |
|
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 | 19.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10027191 |
E.1.2 | Term | Meningioma |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The aim of this randomized phase II study is to collect data on activity, safety and quality of life of trabectedin therapy in patients with recurrent high-grade meningioma. |
|
E.2.2 | Secondary objectives of the trial |
The aim of this randomized phase II study is to collect data on activity, safety and quality of life of trabectedin therapy in patients with recurrent high-grade meningioma and 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. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion 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 intraand
extracranial manifestations).
♦Measurable disease (10 x10 mm) on cranial MRI or CT
thorax/abdomen no more than 2 weeks prior to randomization
♦WHO performance status 0-2
♦Adequate liver, renal and hematological function within 2 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 ≤ ULN, SGPT/ALT and SGOT/AST ≤ 2.5 x ULN
♦Alkaline phosphatase ≤ 2.5 x ULN; if alkaline phosphatase > 2.5 ULN,
hepatic isoenzymes 5-nucleotidase 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
Women of child bearing potential (WOCBP) must have a negative serum
(or urine) pregnancy test within 72 hours prior randomization (and
again within 72 hours prior to to the first dose of study treatment).
Patients of childbearing / reproductive potential should use adequate
birth control measures, as defined below, 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. Methods that can achieve a
failure rate of less than 1% per year when used consistently and
correctly are considered as highly effective birth control methods. Such
methods include:
♦ combined (estrogen and progestogen containing) hormonal
contraception associated with inhibition of ovulation:
♦ oral
♦ intravaginal
♦ transdermal
♦ progestogen-only hormonal contraception associated with inhibition
of ovulation:
♦ oral
♦ injectable
♦ implantable
♦ intrauterine device (IUD)
♦ intrauterine hormone-releasing system ( IUS)
♦ bilateral tubal occlusion
♦ vasectomised partner
♦ sexual abstinence
♦ Acceptable birth control methods that result in a failure rate of more
than 1% per year include:
♦ progestogen-only oral hormonal contraception, where inhibition of
ovulation is not the primary mode of action
♦ male or female condom with or without spermicide
♦ cap, diaphragm or sponge with spermicide
♦Female subjects who are breast feeding should discontinue nursing
prior to the first dose of study treatment and until 3 months after the
last study treatment.
♦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
♦Before patient randomization, written informed consent must be given
according to ICH/GCP, and national/local regulations. |
|
E.4 | Principal exclusion criteria |
♦More option for local therapy (resection or radiotherapy) after maximal
feasible surgery and radiotherapy.
♦Prior systemic anti-neoplastic therapy for meningioma (patient may
have received prior radionuclide therapy).
♦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).
♦Serious illness or medical conditions, specifically: active infectious
process; chronic active liver disease, including chronic hepatitis B, C or
cirrhosis.
♦ Concomitant use of any other investigational agent, phenytoin, or
vaccination to yellow fever.
♦ Known hypersensitivity or contraindication to trabectedin or any of
the ingredients of the trabectedin solution for infusion
♦ Known MRI or CT, including contrast media, contraindications. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Progression Free Survival (PFS) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. PFS will be measured from the date of randomization until the date of first objective progression or the date of patient's death whichever occurs first. Patients without evidence of progression will be censored at the last follow-up visit date. If a patient received a second anti-tumoral therapy without prior documentation of disease progression, the patient will be censored at the date of starting new anti-tumoral therapy. |
|
E.5.2 | Secondary end point(s) |
1. Progression Free Survival at 6 months (PFS-6), median PFS (mPFS)
2. Best overall response (BOR). Objective response (CR/PR), rate and median duration. Complete response (CR), rate and median duration.
3. Overall survival (OS), OS probability at 6 (OS6) and 12 months (OS12), median OS (mOS)
4. Safety (CTCAE v.4.0)
5. Health-related Quality of life (HRQol) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.PFS-6 will be measured from the date of randomization until the date of first objective progression or the date of patient's death whichever occurs first.
2.BOR will be measured from date of randomization until disease progression.CR/PR will be measured similar to PFS but starting from the time measurement criteria for CR/PR are first met.
3.From date of randomiwation up t the date of death (any cause).For patients still alive or lost to f/up at the time of analysis, survival will be censored at lastf/upvisitdate.
4.From the randomization until 30 days after last protocol treatment administration; or until the start of a new antitumor therapy.
5.At every scheduled visit, 4 weeks prior to randomization. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Health-related Quality of life (HRQol) |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 49 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
France |
Germany |
Italy |
Netherlands |
Spain |
Switzerland |
United Kingdom |
|
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
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after last treatment administration to the last patient on protocol.
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol.
3. The database has been fully cleaned and frozen for this analysis.
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |