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
Condition: Soft Tissue Sarcoma
MeSH terms: Sarcoma
Intervention: E7389
Intervention description: 1.4 mg/m^2 administered as an intravenous (I.V.) bolus infusion on Days 1 and 8 of every 21 days.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 128.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the therapeutic activity and safety of E7389 in
      patients with advanced/metastatic soft tissue sarcoma who have failed standard chemotherapy.
    

Eligibility criteria:

        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 (World Health
             Organization (WHO) classification 2002):

               -  Leiomyosarcoma

               -  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
                  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).

               -  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 109/L, platelets >100
             x 109/L)

         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.

        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 > 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
             chemical derivative.

          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.