E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Histologically proven advanced and/or metastatic malignant soft tissue sarcoma intermediate/high grade, excluding the following tumor types : Well-differentiated liposarcoma Embryonal rhabdomyosarcoma Chondrosarcoma (excluding extraskeletal myxoid chondrosarcoma) Osteosarcoma (excluding extraskeletal osteosarcoma) Ewing tumors / primitive neuroectodermal tumor (PNET) Gastro-intestinal stromal tumors (GIST) Dermatofibrosarcoma protuberans |
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E.1.1.1 | Medical condition in easily understood language |
advanced and/or metastatic malignant soft tissue sarcoma. |
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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 | 15.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10041299 |
E.1.2 | Term | Soft tissue sarcomas |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The principal objective of the trial is to evaluate whether trabectedin given as 1st line chemotherapy for advanced / metastatic soft tissue sarcoma prolongs progression free survival, as compared to doxorubicin. |
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E.2.2 | Secondary objectives of the trial |
Overall survival, Response rate and response duration, Safety profile, Quality of life and Correlative translational research |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Histologically proven advanced and/or metastatic malignant soft tissue sarcoma intermediate/high grade.
Presence of measurable disease according to RECIST 1.1.
Prior to study enrolment, all patients need to have confirmed disease progression based on investigator's judgment.
At least 18 years old.
Within 21 days prior to treatment start:
WHO performance status 0 or 1 ( Adequate bone marrow function (neutrophils ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL or hemoglobin ≥ 5.6 mmol/L, platelets ≥ 100 x 109/L) Adequate hepatic function (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 GGT tests must be performed; hepatic isoenzymes 5 nucleotidase and/or GGT must be within the normal range Albumin > 30 g/L Adequate renal function: Serum creatinine ≤ 1.5 x ULN Creatinine clearance > 30 ml/min (will be calculated by Cockcroft and Gault formula) 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).
Women should agree to use an adequate contraceptive method (with a documented failure rate < 1%, e.g. vasectomized partner sterile prior to trial entry and sole sexual partner or double-barrier contraception).
Sexually active male participants must use barrier methods of contraception. Contraception period: from two weeks prior to randomization, throughout the study, and for 3 months after the end of treatment for women and 5 months after the end of treatment for men.
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/randomization in the trial.
Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
Patients will be eligible for the translational research program if they are eligible for the clinical trial and have given their written informed consent to participate in this program. If patient refuses to take part in the translational research project, patient remains eligible for the clinical trial.
Patients with any history of malignancies who are disease-free for more than 5 years |
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E.4 | Principal exclusion criteria |
Are excluded following tumor types: Well-differentiated liposarcoma Embryonal rhabdomyosarcoma Chondrosarcoma (excluding extraskeletal myxoid chondrosarcoma) Osteosarcoma (excluding extraskeletal osteosarcoma) Ewing tumors / primitive neuroectodermal tumor (PNET) Gastro-intestinal stromal tumors (GIST) Dermatofibrosarcoma protuberans
Known history of central nervous system metastases or leptomeningeal tumor spread.
Prior treatments: Prior anticancer therapy for advanced or metastatic malignant soft tissue sarcoma. Patients who had received prior anthracycline. (Non anthracycline therapy for non metastatic disease is acceptable) Anti-cancer therapy including: systemic therapy, radiotherapy, surgery within 28 days prior to treatment start and while on protocol treatment. Other investigational agents within 28 days prior to treatment start and while on protocol treatment.
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
Active or uncontrolled infections or serious illnesses or medical conditions, including a history of chronic alcohol abuse, hepatitis, HIV and/or cirrhosis.
History, within the past five years, of malignancies other than soft tissue sarcoma (except: basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, resected incidental prostate cancer staged pT2 with Gleason Score 6 and postoperative PSA < 0.5 ng/ml).
Women with childbearing potential (are considered as not being of childbearing potential those having had a hysterectomy, a bilateral oophorectomy or bilateral tubal ligation or post-menopausal with a total cessation of menses of >1 year),
Pregnant women (as prove of absence of of pregnancy is accepted negative serum pregnancy test within 21 days prior to randomization); or breastfeeding.
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase IIb: The primary end-points for this step are progression free survival and treatment safety of the two experimental arms. Progression will be defined according to the "RECIST V1.1"
Phase III: The primary end-point will be progression free survival. Progression will be defined according to the "RECIST V1.1" |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 6 weeks, after 3 months every 12 weeks. |
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E.5.2 | Secondary end point(s) |
Overall survival Response rate and response duration Safety profile. Adverse events will be graded according to the "Common Terminology Criteria for Adverse events" CTCAE, version 4.0. Quality of life |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every 6 weeks, after 3 months every 12 weeks. |
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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 |
Quality of life & Translational research |
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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) | Yes |
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 | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
A different treatment schedule. |
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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 | 3 |
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 | 34 |
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 |
Switzerland |
United States |
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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
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End of study occurs when all of the following criteria have been satisfied: 1. Thirty days after all patients have stopped protocol treatment 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 |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |