Phase II Study Of E7389, Halichondrin B Analogue, In Patients With Advanced Non-Small Cell Lung Cancer, NSCLC, Who Progressed During Or After Platinum-Based Doublet Chemotherapy

Study Overview
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Brief Summary
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This is a study of E7389 in patients with recurrent and/or metastatic Non-Small-Cell Lung Cancer (NSCLC) who progressed during or after treatment with a platinum agent and another chemotherapy.

Official Title
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Phase II Study of E7389, a Halichondrin B Analog, in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC), Who Progressed During or After Platinum-Based Doublet Chemotherapy Stratified for Prior Taxane Therapy

Conditions
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Non-Small-Cell Lung Carcinoma

Intervention / Treatment
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* Drug: E7389 28 Day Cycle
* Drug: E7389 21 Day Cycle


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have a histologically or cytologically confirmed diagnosis of non-small cell lung cancer with at least one site of measurable disease by the RECIST criteria. Patients must have failed prior platinum-containing doublet chemotherapy. Patients who have received single agent chemotherapy with or without a subsequent taxane containing regimen may be enrolled after discussion with Sponsor. Patients must be ≥ 18 years of age. Patients must have a performance score of 0 or 1 using the ECOG performance scale. Patients must have a life expectancy of ≥ 3 months. Patients must have adequate renal function as evidenced by a serum creatinine ≤ 2.0 mg/dL or a calculated creatinine clearance ≥ 40 mL/min per the Cockcroft and Gault formula. Patients must have adequate hepatic function as evidenced by bilirubin ≤1.5 mg/dL and alkaline phosphatase, AST and ALT ≤ 3 times upper limit of normal, unless there is evidence of liver metastases, in which case the alkaline phosphatase, AST and ALT must be ≤ 5 times upper limit of normal. Patients must have adequate bone marrow function as evidenced by absolute neutrophil counts (ANC) ≥ 1.5 X 10^9/L, hemoglobin ≥ 10.0 g/dL (a hemoglobin < 10.0 g/dL would be acceptable if it can be corrected by growth factor or transfusion), and platelet count ≥ 100 X 10^9/L. Patients must be willing and able to comply with the protocol guidelines for the duration of the study. Patients must be willing and able to complete the Lung Cancer Symptom Scale (LCSS) instrument. The biopsy specimen (paraffin block or at least 10 unstained slides) must be available from either the initial diagnosis or any subsequent diagnostic or surgical procedure of patients participating in the pharmacogenomics sub-study only. However, no additional biopsies are obligatory for participation in this study except those required for confirmation of the diagnosis. Patients must give written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice. EXCLUSION CRITERIA: Patients with pre-existing peripheral neuropathy > Grade 2 Patients who require therapeutic doses of warfarin Patients who have not recovered from any chemotherapy, radiation or other therapy related toxicity deemed to be clinically significant at study entry Patients with active symptomatic brain metastases. Patients with central nervous system (CNS) metastases are considered eligible if they have had adequately treated brain metastases, i.e. have completed treatment (tapered off steroids) at least four weeks before starting treatment with E7389. Patients who have no evidence that the metastases are symptomatic or actively growing (no evidence of midline shift on CT scan or MRI) may be enrolled without initiation of local therapy for the CNS metastases. In this case, a repeat scan must be performed within four weeks of the original scan to ensure that disease progression is not occurring. It is not the intention of this study to treat patients with active brain metastases. Patients who have a positive history for HIV, active hepatitis B or active hepatitis C. Patients with other significant medical, or psychiatric disorders that, in the opinion of the investigator, will exclude the patient from the study for compliance or safety reasons Patients who have received investigational drugs, including immunotherapy, gene therapy, hormone therapy (except megestrol acetate for appetite stimulation), or other biological therapy; conventional chemotherapy or radiation therapy (except for palliation, defined as less than 10% of the bone marrow reserve and less than 20 Gy), within three weeks of E7839 enrollment Patients who have received non-cytotoxics (eg, gefitinib, erlotinib) within one week of E7389 enrollment Patients who have not recovered from major surgery within three weeks of E7389 enrollment Patients with severe/uncontrolled intercurrent illness/infection Patients with 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) Patients with organ allografts Patients with hypersensitivity to halichondrin B and/or halichondrin B-related compounds Patients who participated in a prior E7389 clinical trial Patients with second malignancy within the past 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma of the skin Women who are pregnant or breast-feeding; woman of childbearing potential with a positive pregnancy test at screening or no pregnancy test. Women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception in the opinion of the Investigator. Perimenopausal women must be amenorrheic for at least 12 months or using adequate contraception to be considered of non-childbearing potential. Fertile men who are not willing to use contraception or fertile men with a female partner who is not willing to use contraception

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>E7389 28 day cycle | Drug: E7389 28 Day Cycle<br>* E7389 1.4 mg/m^2 IV bolus on Days 1, 8, and 15 of a 28 day cycle.<br>|
| Experimental: 2<br>E7389 21 day cycle | Drug: E7389 21 Day Cycle<br>* E7389 1.4 mg/m^2 IV bolus on Days 1 and 8 of a 21 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Objective Response Rate (ORR) | Based on Response Evaluation Criteria in Solid Tumors (RECIST), consisting of complete response (CR) plus partial response (PR). Defined as the best response from the start of treatment until disease progression or recurrence. Lesions measured by computed tomography (CT) scan and magnetic resonance imaging (MRI). Objective response rate: complete response (CR-disappearance of all lesions)+ partial response (PR-30% decrease in lesion diameter), Progressive Disease (PD-20% increase in lesion diameter), stable disease (SD-neither shrinkage nor increase of lesions). | From start of treatment until disease progression or recurrence | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Measured from the time that measurement criteria were met for complete response (CR) and partial response (PR) until the first date that recurrence or progressive disease was objectively documented. | From time of CR or PR until recurrence or progressive disease | 
| Progression Free Survival | Defined as the time from the start of study medication until progressive disease or death from any cause during the study period. | From start of study medication until progressive disease or death | 
| Overall Survival | Defined as the time from the start of study medication until death from any cause. | From time of start of study medication until death |