Clinical trial of trabecetedin versus doxorrubicin in patients with Translocation-Related Sarcomas.

• Register: EUCTR
• Last refreshed on: 24 August 2015
• Main ID: EUCTR2008-002326-11-DE
• Date of registration: 03/09/2008
• Prospective Registration: Yes
• Primary sponsor: Pharma Mar, S.A., Sociedad Unipersonal
• Public title: Clinical trial of trabecetedin versus doxorrubicin in patients with Translocation-Related Sarcomas.
• Scientific title: A Randomized, Multicenter, Phase III Trial of Trabectedin (Yondelis®) versus Doxorubicin-based Chemotherapy as First-Line Therapy in Patients with Translocation-Related Sarcomas (TRS)
• Date of first enrolment: 17/10/2008
• Target sample size: 80
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-002326-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: yes Other specify the comparator: Doxorrubicin Number of treatment arms in the trial: 2

Countries of recruitment

France, Germany, Italy, Spain, United Kingdom, United States

Contacts

• Name: Clinical Trials
• Affiliation: PharmaMar S.A. Sociedad Unipersonal

• Name: Clinical Trials
• Affiliation: PharmaMar S.A. Sociedad Unipersonal

Key inclusion & exclusion criteria

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.

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 86
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 17

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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Translocation-Related Sarcomas
MedDRA version: 14.1 Level: HLGT Classification code 10041299 Term: Soft tissue sarcomas System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intervention(s)

Trade Name: Yondelis® 0.25 mg
Product Name: Yondelis
Product Code: ET-743
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: Trabectedin
CAS Number: 114899-77-3
Current Sponsor code: ET-743
Other descriptive name: Ecteinascidin 743
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.25-

Product Name: Doxorubicin hydrochloride
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: DOXORUBICIN HYDROCHLORIDE
CAS Number: 25316409
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: equal
Concentration number: 75 or 60-

Product Name: Ifosfamide
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: IFOSFAMIDE
CAS Number: 3778732
Concentration unit: gm/m2 gram(s)/square meter
Concentration type: range
Concentration number: 6-9-

Trade Name: Yondelis® 1 mg
Product Name: Yondelis
Product Code: ET-743
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: Trabectedin
CAS Number: 114899-77-3
Current Sponsor code: ET-743
Other descriptive name: Ecteinascidin 743
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-

Primary Outcome(s)

Main Objective: 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.

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.

Secondary Objective: •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.

Timepoint(s) of evaluation of this end point: Interim analysis of the primary endpoint (PFS) to reject H0 (HR=1) will occur in the first stage of the trial when ˜45 independently assessed PFS events from the first 80 evaluable patients occur. Recruitment should last 20 months and 45 events should occur 30 months after enrolment starts. At the latest, this milestone should occur ca. 10 months after the last evaluable patient is recruited. After interim analysis, the sample size will be increased if the desired power cannot be achieved with the observed hazard ratio but is still clinically significant. In this case, the second stage will be redesigned to maintain conditional type I error. The significance level will be determined by the observed number of events and a-spending function defined by the Pocock boundary.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Secondary endpoints (if applicable) would be assessed at the same time than primary endpoint analysis.

Secondary end point(s): 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 (myxoid – round cell liposarcoma vs.
other TRS subtypes).
To compare overall survival (OS).
To compare the safety profile in each treatment arm.
To conduct exploratory, pharmacogenomic (PGx) studies to correlate
fusion-protein type and variants, and deoxyribonucleic acid (DNA)
repair markers with clinical outcomes.

Secondary ID(s)

ET-C-002-07

2008-002326-11-FR

Source(s) of Monetary Support

Pharma Mar, S.A. Sociedad Unipersonal