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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: E7389


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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. Relapsed, refractory and/or metastatic disease incurable by surgery or radiotherapy. 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. Presence of measurable disease, as defined by RECIST. 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. 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. 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. Absence of pre-existing neuropathy > Grade 2 At least 18 years of age. WHO performance status 0 or 1. Adequate bone marrow function (absolute neutrophil count >1.5 x 109/L, platelets >100 x 109/L) 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). Adequate renal function: serum creatinine < 2.0 mg/dl or 177 µmol/l or calculated (Cockcroft and Gault formula) creatinine clearance > 40 ml/min. 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. 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: 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). 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). 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. Severe/uncontrolled intercurrent illness/infection. Patients with a known hypersensitivity to halichondrin B and/or halichondrin B chemical derivative. Patients who participated in a prior E7389 clinical trial. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: E7389<br>* 1.4 mg/m^2 administered as an intravenous (I.V.) bolus infusion on Days 1 and 8 of every 21 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) at 12 Weeks | PFS was determined from the Week 12 visit tumor scan and the participant's date of death. Progression was defined as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), early death from any cause, or not assessable according to Response Evaluation Criteria In Solid Tumors (RECIST). CR defined as the loss of all target lesions. PR defined as ≥ 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD. PD defined as ≥ 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since treatment started or the appearance of new lesions. SD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD since treatment started. The number and percentage of successes were summarized by stratum and overall, together with 95% 2-sided confidence intervals (CIs) for the percentage of successes. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Progression Free Survival | Overall PFS was determined from any evidence that the participant had progressed, along with whether or not the participant was still alive at the end of the study. Tumors were evaluated every 6 weeks during treatment, and at least 4 weeks after the first observation of a complete or partial response. After discontinuation of study drug, participants without PD were re-evaluated every 12 weeks, unless a new anticancer therapy was started. Participants were considered as having progressed if they were classed as PD at Week 12, or had a best overall response (BOR) of PD, or had a date of progression, if they discontinued due to PD, died due to PD, or if the PI had recorded a date of progression. A participant was determined progression free if they were alive without PD at the time of study cut-off. The number and percentage of successes were summarized by stratum and overall, together with 95% 2-sided CIs for the percentage of successes. | First dose of study drug to the date of disease progression or date of death, whichever occurs first, or date of study cut-off 28 Jun 2012, up to 5.5 years | 
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants in the analysis set who had a BOR of CR or PR based on RECIST v. 1.0 for target lesions. Tumors were assessed using x-rays, magnetic resonance imaging (MRI), or computed tomography (CT) scans, or both, as appropriate. ORR was documented and confirmed by two measurements taken at least 4 weeks apart. CR was defined as the disappearance of all target lesions. PR defined as ≥ 30% decrease in the sum of LD of target lesions taking as reference the baseline sum LD. Best overall response was derived using the same hierarchy as used when determining the PFS status at Week 12. No adjustments were made for participants who started further anticancer therapy prior to disease progression. 95% CIs were calculated using the exact method of binomial distribution. ORR = CR + PR | Date of first dose of study drug until documentation of CR or PR, or up to data cutoff 28 Jun 2012, up to approximately 5.5 years | 
| Clinical Response Benefit (CRB) | CRB was defined as the percentage of participants with a BOR of CR or PR or SD as defined by RECIST, described previously. BOR was derived using the same hierarchy as used when determining the status at Week 12. No adjustments were made for participants who started further anticancer therapy prior to disease progression. 95% CIs were calculated using the exact method of binomial distribution. CRB = CR + PR + SD | Date of first dose of study drug to documentation of CR, PR, or SD, or until data cutoff date 28 Jun 2012, up to approximately 5.5 years | 
| Time to Onset of Response | Time to onset of response could be calculated only if a participant achieved an objective response (BOR of CR or PR as defined previously). Participants who never achieved CR or PR were not included in the Kaplan-Meier survival estimates for the time to onset of response by strata. Given the small number of participants with these responses and the large variation in time to onset of response between participants, no comparison could be made among the strata. | Date of first dose of study drug to date of first documented CR or PR, or until data cutoff date 28 Jun 2012, up to approximately 5.5 years | 
| Duration of Response | Duration of response could be calculated only if a participant achieved a BOR of CR or PR, as defined previously. For consistency with the formula used by the European Organization for Research and Treatment of Cancer (EORTC), the duration was derived as day of event minus day of first documented CR or PR (one was not added to the calculation). Participants who were alive without documented progression had their duration of response censored at the day of last follow-up for progression. Participants who never achieved CR or PR were not included in the Kaplan-Meier survival estimates for the duration of response by strata. No adjustment was made for participants who started further anticancer therapy prior to disease progression. | Date of first documented CR or PR until the date of first document disease progression (or death), or up to data cutoff 28 Jun 2012, up to approximately 5.5 years | 
| Overall Survival (OS) | Participants still alive at the end of the study had their time to event censored at the day last known to be alive. Participants lost to follow-up were also censored at the date last known to be alive. 95% CIs for the percentage of participants still alive at the end of the study were presented as described for the primary endpoint, PFS at Week 12. | Date of first dose of study drug to date of death from any cause, or up to cut-off date of 28 Jun 2012, up to approximately 5.5 years | 
| Summary of Adverse Events (AEs) | Treatment-emergent adverse events (TEAEs) and serious adverse events were reported. TEAEs are defined as an adverse event (AE) that emerged during treatment, having been absent at baseline or: reemerged during treatment, having been present at pretreatment (baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. All AEs and SAEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. A participant was counted only once within a System Organ Class (SOC) and preferred term (PT), even if the participant experienced more than one TEAE with a specific SOC and PT. Participants were summarized by treatment group according to the worst CTCAE grade assigned for each PT. Treatment-related TEAEs included TEAEs that were considered by the investigator to be possibly or probably related to study drug or TEAEs with a missing relationship. | Day 1 of study treatment until progressive disease, or up to cut-off date of 28 Jun 2012, up to approximately 5.5 years |