E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced and/or metastatic soft tissue sarcoma |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the activity and safety of E7389 at a dose of 1.4 mg/m(2) on days 1 and 8 every 3 weeks in patients with advanced soft tissue sarcoma who have relapsed following standard therapies. |
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically proven advanced and/or metastatic malignant soft tissue sarcoma of high or intermediate grade, and of one of the following histologies (WHO classification 2002):
a) Leiomyosarcoma b) Adipocytic (liposarcoma dedifferentiated, myxoid/round cell, pleomorphic, mixed- type not otherwise specified) c) Synovial sarcoma d) Other types of sarcoma, including: -Fibroblastic (adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid fibrosarcoma) -So-called fibrohistiocytic (pleomorphic Malignant Fibrous Histiocytoma (MFH), giant cell “MFH”, inflammatory “MFH”) -Malignant glomus tumors -Skeletal muscles (rhabdomyosarcoma, alveolar or pleomorphic) excluding embryonal rhabdomyosarcoma -Vascular (epithelioid haemangioendothelioma, angiosarcoma) -Uncertain differentiation (synovial, epithelioid, alveolar soft part, clear cell, desmoplastic small round cell, extra-renal rhabdoid, malignant mesenchymoma, perivascular epithelioid cell tumor (PEComa), intimal sarcoma) excluding chondrosarcoma, Ewing tumors / Primitive neuroectodermal tumor (PNET) -Malignant peripheral nerve sheath tumors -Malignant solitary fibrous tumors -Undifferentiated soft tissue sarcomas not otherwise specified -Other types of sarcoma (not listed as not eligible), if approved by the Study Coordinator (written or e-mail approval needed prior to registration)
e) The following tumor types are not eligible: -Embryonal rhabdomyosarcoma -Chondrosarcoma -Osteosarcoma -Ewing tumors / PNET -Gastro-intestinal stromal tumors (GIST) -Dermatofibrosarcoma protuberans -Inflammatory myofibroblastic sarcoma -Neuroblastoma -Malignant mesothelioma -Mixed mesodermal tumors of the uterus
2. Formalin fixed paraffin embedded tumor blocks and representative H/E (hematoxylin/eosin) slides must be available for histological central review. Histological central review is not required before treatment start but is mandatory within 10 days of registration. Local histopathological diagnosis will be accepted for entry into the study.
3. Relapsed, refractory and/or metastatic disease incurable by surgery or radiotherapy.
4. Evidence of objective progression within the last 6 months (RECIST) documented by measurements of disease, i.e. appearance of new lesions, increase of 20% in the sum of the diameters of measurable lesions, or progression of non measurable lesions to be confirmed by an external review, without other specific treatment since objective documentation of progression.
5. Presence of measurable disease, as defined by RECIST.
6. Patients must have received no more than one combination or two single agent chemotherapy regimens for advanced disease; (neo)adjuvant therapy is not counted towards this requirement.
7. No major surgery, hormonal therapy (other than replacement), chemotherapy or radiotherapy, immunotherapy or other investigational agent within the last 28 days and/or not recovered from prior therapy within the last 28 days. Use of erythropoietin is considered supportive care and is permitted.
8. Absence of brain or subdural metastases, unless patient has completed local therapy and has discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment with E7389. Any signs (e.g. radiologic) and/or symptoms of brain metastases must be stable for at least 4 weeks.
9. Absence of pre-existing neuropathy > Grade 2
10. At least 18 years of age
11. WHO performance status 0 or 1
12. Adequate bone marrow function (absolute neutrophil count >1.5 x 10*/L, platelets >100 x 10*/L) *=9
13. Adequate hepatic function (bilirubin < 1.5 mg/mL or 25 μmol/L, SGOT/AST and SGPT/ALT <= 3 x UNL or < 5 x UNL in patients with liver metastases)
14) Adequate renal function: serum creatinine < 2.0 mg/dl or 177 μmol/l or calculated (Cockcroft and Gault formula) creatinine clearance > 40 ml/min.
15) Women should either not be of childbearing potential (having had a hysterectomy, a bilateral oophorectomy or bilateral tubal ligation, or be post-menopausal with a total cessation of menses of >1 year), or not be pregnant (negative serum pregnancy test at entry), should not be lactating, should agree to use contraceptive methods (with a documented failure rate < 1%, 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.
16) Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. |
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E.4 | Principal exclusion criteria |
1) Prior history of malignancies other than sarcoma (except for basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or the patient has been free of any other malignancies for > 3 years).
2) Significant cardiovascular impairment (history of congestive heart failure > NYHA grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia) please refer appendix C.
3) Patients who are receiving anti-coagulant therapy with warfarin or related compounds, other than for line patency, and cannot be changed to heparin-based therapy, are not eligible. If a patient is to continue on mini-dose warfarin, then the prothrombin time (PT) / international normalized ratio (INR) must be closely monitored
4) Severe/uncontrolled intercurrent illness/infection
5) Patients with a known hypersensitivity to halichondrin B and/or halichondrin B chemical derivative
6) Patients who participated in a prior E7389 clinical trial
7) Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end-point is the progression free survival, assessed 12 weeks after start of treatment. Progression will be defined according to RECIST criteria. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
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) | Information not present in EudraCT |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
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 | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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 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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |