Phase II Study of E7389 Administered as an IV Infusion Day 1 and 8 every 3 Weeks in Pretreated Patients with Advanced and/or Metastatic Soft Tissue SarcomaProtocol Version 5.0 (2010-01-27) - E7389-E044-207

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 160

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 o

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.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 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<br>tissue sarcoma who have relapsed following standard therapies.;Secondary Objective: ;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.

Secondary Outcome Measures

Name	Time	Method

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