An Open-label, Multicenter, Multiple Dose, Phase 1 Study to Establish the Maximum Tolerated Dose of E7389 Liposomal Formulation in Patients With Solid Tumors
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|ClinicalTrials.gov Identifier: NCT01945710|
Recruitment Status : Completed
First Posted : September 18, 2013
Last Update Posted : August 10, 2016
|Condition or disease||Intervention/treatment||Phase|
|Solid Tumors||Drug: E7389-LF||Phase 1|
This is a Phase 1 first-in-human, non-randomized (individuals will not be assigned by chance to study treatments), open-label (individuals will know the identity of study treatments), multicenter, 2-part, dose-escalation study to evaluate the safety, pharmacokinetics (study of what the body does to a drug) of E7389 LF administered orally to patients with solid tumors. Each treatment cycle will be 21 days (Schedule 1) or 28 days (Schedule 1a or 2). Part 1 is the dose-escalation phase, which will be guided by pharmacokinetics and safety. Three to 6 new patients will be enrolled in sequential cohorts (first cohort will receive the starting dose and subsequent cohorts will receive increased doses of E7389 LF). Enrollment in each cohort will be staggered; the second and third participant in every cohort will not be dosed until the first patient in that cohort completes 2 weeks of Cycle 1. If no dose-limiting toxicities (DLTs) have been observed during the first 2 week of Cycle 1 in the first patient, the second and third patients in the cohort will initiate treatment. Enrollment will be first initiated into cohort 1 of Schedule 1 (dosing on Day 1 of 21 day cycle). Interim analysis will be conducted upon completion of this cohort. The following decisions will be made based upon the results of the interim analysis 1) proceed with escalating to next dose level (cohort 2) of Schedule 1 (dosing on Day 1 of 21 day cycle) and initiate cohort 1 of Schedule 2 (dosing on Day 1 and Day 15 of 28 day cycle), or 2) discontinue plans to evaluate Schedule 2 and initiate Schedule 1a (dosing on Day 1 of 28 day cycle).
After the last patient in each cohort completes Cycle 1, the safety for DLT determination will be evaluated and a decision will be made on whether to escalate the dose in a new cohort of 3 to 6 new patients. Dose escalation will halt when the maximum tolerated dose (MTD) is reached. The total number of patients to be enrolled in Part 1 will depend on the dose level at which the DLT will be achieved. After MTD for each schedule is determined, patients will be enrolled into Expansion Part of the study to confirm safety and tolerability of each dosing schedule. Nine to 12 patients will be treated with MTD for each schedule for 6 cycles. The total study duration for each participant will be approximately 18 months.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||71 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||An Open-label, Multicenter, Multiple Dose, Phase 1 Study to Establish the Maximum Tolerated Dose of E7389 Liposomal Formulation in Patients With Solid Tumors|
|Study Start Date :||December 2012|
|Actual Primary Completion Date :||October 2015|
|Actual Study Completion Date :||May 2016|
Experimental: E7389-LF Schedule 1
Schedule 1: E7389-LF administered as IV infusion on Day 1 of a 21-day cycle starting at 1 mg/m2 escalating up to 3.5 mg/m2.
Schedule 1a: E7389-LF administered as IV infusion on Day 1 of a 28-day cycle starting at 1 mg/m2 escalating up to 3.5 mg/m2 (only to be investigated in the event that a 21-day cycle is considered inappropriate).
Experimental: E7389-LF Schedule 2
Schedule 2: E7389-LF administered as IV infusion on Day 1 and Day 15 of a 28-day cycle starting at 1 mg/m2 escalating up to 3.5 mg/m2 (only to be investigated in the event that a 21-day cycle is considered appropriate).
- Maximum tolerated dose (MTD) of E7389 liposomal formulation (E7389-LF) [ Time Frame: Baseline to end of Cycle 3 (63 days for schedule 1; 84 days for schedules 1a and 2) ]The MTD will be the highest dose level at which no more than 1/6 subjects experiences a DLT, with the next higher dose having at least 2 of 3 or 2 of 6 subjects experiencing DLT. However, if fewer than 6 subjects have been tested at this dose level, additional subjects will be enrolled and tested to reach the minimum number of 6 subjects required for MTD to be declared. Subjects who fail to complete the first cycle for reasons other than a DLT will be replaced within their dose cohort.
- Dosing frequency of E7389 liposomal formulation (E7389-LF) [ Time Frame: Baseline to end of Cycle 3 (63 days for schedule 1; 84 days for schedules 1a and 2) ]
- Safety and Tolerability of E7389-LF [ Time Frame: Baseline to end of Cycle 6 (126 days for schedule 1; 168 days for schedules 1a and 2) ]Safety will be assessed by the monitoring and recording of all AEs and SAEs, regular monitoring of hematology, blood chemistry and urine values, regular measurement of vital signs, and the performance of physical examinations. In addition, resting 12-lead ECGs will be recorded at times noted in the Schedules of Assessments.
- Pharmacokinetics of E7389-LF [ Time Frame: Baseline to end of Cycle 6 (126 days for schedule 1; 168 days for schedules 1a and 2) ]Plasma and urine concentrations of eribulin will be tabulated and summarized by dosing schedule, dose level, day and time. Minimally, the following PK parameters will be calculated: Cmax, tmax, and AUC (t1/2, CL, Vdss and accumulation ratios will be calculated only if the data permit), CLR (renal clearance), and fe (fraction excreted).
- Evidence of efficacy by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [ Time Frame: Baseline to end of Cycle 6 (126 days for schedule 1; 168 days for schedules 1a and 2) ]All responses must be confirmed at least 28 days following the first response. The best overall response to treatment will be assessed according to RECIST 1.1.
- Effect of E7389-LF on cardiac repolarization [ Time Frame: Baseline to end of Cycle 6 (126 days for schedule 1; 168 days for schedules 1a and 2) ]The effects of E7389-LF on cardiovascular repolarization will be evaluated via 24-hour, 12-lead continuous Holter ECG monitoring in Cycle 1 Day 1 for Schedule 1 and Day 1 and Day 15 of Schedule 2.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01945710
|Royal Marsden Hospital|
|Sutton, Surrey, United Kingdom|
|Beatson West of Scotland Cancer Centre|
|Glasgow, United Kingdom|
|UCL Cancer Institute|
|London, United Kingdom|
|The Christie NHS Foundation Trust|
|Manchester, United Kingdom|