| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Translocation-Related Sarcomas |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10041299 |
| E.1.2 | Term | Soft tissue sarcomas |
|
| 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 |
| To evaluate the efficacy of trabectedin vs. standard DXCT as first-line treatment of patients with advanced TRS, by comparing PFS in each treatment arm. |
|
| E.2.2 | Secondary objectives of the trial |
•To compare 6-month PFS rates.
• To compare response rates and duration of response, by the Response Evaluation Criteria In Solid Tumors (RECIST).
• To compare the exploratory computed tomography (CT) evaluations conducted using the Choi response criteria.
• To compare PFS and response rates in the subgroups of patients stratified by histological type (MRCL vs. other TRS subtypes).
• To compare OS.
• To compare the safety profile in each treatment arm.
• To perform exploratory, pharmacogenomic (PGx) studies so as to correlate fusion protein type and variants, and DNA repair markers with clinical outcomes. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Patient’s written informed consent before any study-specific procedures.
2) Adult patients (age ≥ 18 years).
3) Patients with pathological diagnosis of TRS (institutional assessment) of any, but restricted to the following subtypes: alveolar soft part sarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma (prior hormone therapy allowed), low grade fibromyxoid sarcoma, myxoid chondrosarcoma, MRCL and synovial sarcoma. Availability of adequate tumor material for external review is mandatory.
4) Patients must have unresectable locally advanced or metastatic progressive disease prior to enrolment.
5) Measurable disease as defined by the radiological (CT-scan and MRI) Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines.
6) ECOG PS score of 0-2.
7) Adequate cardiac function, defined as LVEF within normal limits according to institutional standards, as shown by echocardiography or scintigraphy (MUGA).
8) Hematological variables:
a) Hemoglobin ≥ 9 g/dl.
b) ANC ≥ 1,500/μl.
c) Platelet count ≥ 100,000/μl.
9) Biochemical variables:
a) Serum creatinine ≤ 1.5 mg/dl
b) CPK ≤ 2.5 x ULN.
10) Hepatic function variables:
a) Total bilirubin ≤ ULN, unless in case of Gilbert's syndrome
b) Total AP ≤ 2.5 x ULN, or if > 2.5 x ULN consider AP liver fraction, and/or GGT, and/or 5’ nucleotidase must be ≤ ULN
c) AST/SGOT and ALT/SGPT must be ≤ 2.5 x ULN
d) Albumin ≥ 25 g/l.
|
|
| E.4 | Principal exclusion criteria |
1) Known hypersensitivity to any of the components of the i.v. formulation of trabectedin or the comparators.
2) Prior chemotherapy treatment.
3) Prior irradiation of the lesion if only one target lesion (i.e., measurable) is available.
4) Pregnant or lactating women or men and women of reproductive potential who are not using effective contraceptive methods (one or more of the following):
a) Complete abstinence from intercourse from two weeks prior to administration of the study treatment, throughout the study, and for at least six months after completion or premature discontinuation from the study to account for elimination of the investigational drug(s); or,
b) Physical sterilization of the patient or the patient’s partner; or, c) One of the following, for female patients or female partners of male patients: - Implants of levonorgestrel; or, - Injectable progestogen; or, - Oral contraceptive (combined or progestogen only; patients taking oral contraceptives should have been on a stable regimen for at least two months prior to screening), or, - Any IUD with published data showing that the lowest expected failure rate is less than 1% per year (not all IUDs meet this criterion); or, - Double barrier method (two physical barriers or one physical barrier plus spermicide); or, - Any other methods with published data showing that the lowest expected failure rate for that method is less than 1% per year.
5) History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for five years or more.
6) Brain metastases and/or leptomeningeal metastases, even if treated.
7) Other serious illnesses, such as:
a) Congestive heart failure or angina pectoris; myocardial infarction within one year before enrolment; uncontrolled arterial hypertension (according to WHO criteria), arrhythmias or abnormal LVEF.
8) Psychiatric disorder or any other personal circumstances that prevent compliance with the study protocol.
9) Active viral hepatitis or chronic liver disease.
10) Active infection.
11) Any other unstable medical condition.
12) Inability or unwillingness to comply with the study protocol.
13) Prior treatment with any investigational drugs/treatments within 30 days before inclusion into the current study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary end point:
PFS: will be calculated as the time from the date of randomization to the date of documented PD or death (regardless of the cause of death). If the patient receives further antitumor therapy before PD and within the timeframe expected for first follow-up, PFS will be censored on the date of administration of this antitumor therapy. If the patient is lost to follow-up for the assessment of progression, or has more than one missing follow-up between the date of last tumor assessment and the date of death or further antitumor therapy, the PFS will be censored at the date of last tumor assessment.
Secondary end points:
• Best objective response: will be the best response obtained in any evaluation according to RECIST, done at least six weeks after randomization.
• PFS at six months: will be the Kaplan-Meier estimate of the probability of being free from progression and death at six months.
• OS: will be calculated from the date of randomization to the date of death (death event) or last contact (in this case, survival will be censored on that date).
• Duration of response: will be calculated from the date of first documentation of response (CR or PR, whichever comes first) to the date of documented PD or death. The censoring rules defined above for PFS will be used for duration of response.
• Exploratory CT evaluations: performed by Choi response criteria (52) and correlation with RECIST response.
• Saftey profile: The AEs, SAEs, laboratory evaluations, deaths and study discontinuations due to AEs will be analyzed as described in Section 9.3.
• Exploratory, pharmacogenomic studies: fusion protein type and variants, and DNA-repair markers will be correlated with clinical outcomes. |
|
| 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 | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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