Phase II Study of E7389 Administered as an IV Bolus Infusion Day 1 and Day 8 Every 3 Weeks in Pre-Treated Patients With Advanced and/or Metastatic Soft Tissue Sarcoma
1. Histologically proven advanced and/or metastatic malignant soft tissue sarcoma of
high or intermediate grade, and of one of the following histologies (World Health
Organization (WHO) classification 2002):
- Adipocytic (liposarcoma dedifferentiated, myxoid/round cell, pleomorphic,
mixed-type not otherwise specified)
- Synovial sarcoma
- Other types of sarcoma, including:
- Fibroblastic (adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid
- So-called fibrohistiocytic (pleomorphic Malignant Fibrous Histiocytoma (MFH),
giant cell "MFH", inflammatory "MFH")
- Malignant glomus tumors.
- Skeletal muscles (rhabdomyosarcoma, alveolar or pleomorphic) excluding embryonal
- 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).
- The following tumor types are not eligible:
- Embryonal rhabdomyosarcoma
- Ewing tumors / PNET
- Gastro-intestinal stromal tumors (GIST)
- Dermatofibrosarcoma protuberans
- Inflammatory myofibroblastic sarcoma
- 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 109/L, platelets >100
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) while on treatment and
during a period of 3 months after the end of treatment. Sexually active male
participants must use barrier methods of contraception.
16. Before patient registration/randomization, written informed consent must be given
according to International Conference on Harmonization/Good Clinical Practice
(ICH/GCP), and national/local regulations.
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 > New York
Heart Association (NYHA) grade II, unstable angina or myocardial infarction within
the past six months, or serious cardiac arrhythmia).
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
6. Patients who participated in a prior E7389 clinical trial.
7. Patients without freedom (by the law or administrative decision), hospitalized
without their consent (mental disability, upon legal request), admitted in medical or
social establishment for other reasons than clinical research, with any
psychological, familial, sociological, 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.