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Trial record 76 of 157 for:    eribulin

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
Sponsor:
Information provided by (Responsible Party):
Eisai Inc. ( Eisai Limited )

Brief Summary:
Study E7389-E044-112 is a Phase 1 study designed to assess the safety, tolerability and preliminary efficacy of E7389 liposomal formulation (E7389-LF) in patients with solid tumors. This dose-escalation study will determine the maximum tolerated dose, dosing schedules tested, the dose schedule regimen with a more favorable tolerability profile, and a preliminary indication of efficacy.

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: E7389-LF Phase 1

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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).

Drug: E7389-LF
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).
Drug: E7389-LF



Primary Outcome Measures :
  1. 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.

  2. 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) ]

Secondary Outcome Measures :
  1. 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.

  2. 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).

  3. 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.

  4. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 years or older.
  2. Histological or cytological evidence of an unresectable or refractory solid tumor.
  3. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1.
  4. Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the upper limits of normal (ULN) and alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (in the case of liver metastases less than or equal to 5 x ULN). In case ALP is greater than 3 x ULN (in absence of liver metastases) or greater than 5 x ULN (in presence of liver metastases) AND subject also is known to have bone metastases, the liver specific ALP must be separated from the total and used to assess the liver function instead of the total ALP.
  5. Adequate renal function as evidenced by serum creatinine less than or equal to 2.0 mg/dL (177 umol/L) or calculated creatinine clearance greater than or equal to 40 mL/min per the Cockcroft and Gault formula.
  6. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L, hemoglobin greater than or equal to 9 g/dL (5.5 mmol/L) and platelet count greater than or equal to 100 x 10^9/L.
  7. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [B-hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 h before the first dose of study drug.
  8. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least one month before dosing).
  9. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use two highly effective methods of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method [condom and occlusive cap - diaphragm or cervical/vault caps - with spermicidal foam/gel/film/cream/suppository], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double barrier method with spermicide as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.
  10. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation.
  11. Provide written informed consent.
  12. Willing and able to comply with all aspects of the protocol.

Exclusion Criteria:

  1. Females who are pregnant (positive B-hCG [or hCG] test) or breastfeeding.
  2. Subjects who have received any anticancer therapy within 21 days prior to study entry for cytotoxic agents (42 days for mitomycin C and nitrosoureas), radiotherapy, hormonal, biological (including humanized antibodies) and targeted agents, or within 30 days for an investigational agent.
  3. Subjects who have not recovered from acute toxicities as a result of prior anti-cancer therapy to less than Grade 2, according to CTCAE, except alopecia.
  4. Subjects who have previously been treated with eribulin.
  5. Radiation therapy encompassing greater than 30% of the bone marrow.
  6. Major surgery within 21 days prior to enrollment.
  7. Pre-existing peripheral neuropathy greater than CTCAE Grade 1.
  8. Significant cardiovascular impairment, defined as:

    1. Congestive heart failure greater than Class II according to the New York Heart Association.
    2. Unstable angina or myocardial infarction within 6 months of enrollment, or cardiac arrhythmia requiring treatment.
    3. A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolonged QT/QTc interval (e.g., a repeated demonstration of a QTc interval greater than 500 ms).
    4. A history of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT Syndrome) or the use of concomitant medications that prolonged the QT/QTc interval.
  9. Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject's safety or interfere with the study assessments.
  10. Diagnosed with meningeal carcinomatosis.
  11. Subjects with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks prior to enrollment. Any symptom(s) attributed to brain metastases must be stable for at least 4 weeks prior to enrollment, and radiographic stability should be confirmed by comparing a brain scan (CT with contrast or MRI with and without contrast) performed during the Screening Period to a brain scan performed at least 4 weeks earlier using the same modality.
  12. Any serious concomitant illness or infection requiring treatment: known active human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C infection (asymptomatic positive serology is not exclusionary).
  13. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.
  14. History of drug or alcohol dependency or abuse within approximately the last 2 years or current use of illegal recreational drugs.
  15. Known intolerance to Halaven (eribulin mesilate; E7389) or any of the excipients.
  16. Any medical or other condition that in the opinion of the investigator(s) would preclude the subject's participation in a clinical study.
  17. Scheduled for surgery during the study.
  18. Subjects with body mass index (BMI) less than 35.
  19. Subjects with proven abdominal malignancy with concurrent refractory ascites defined by one of the following criteria:

    1. Symptomatic ascites (more than 2 L) that did not respond clinically to at least 2 weeks of diuretics OR
    2. Removal of at least 10 L in the preceding 2 months for symptoms relief OR
    3. Symptomatic ascites that recurred on at least three occasions within a 2 month period despite diuretic treatment.
  20. Subjects with concurrent refractory pleural effusion defined by the following criteria:

    1. Symptomatic pleural effusion that did not respond clinically to the treatment and needed pleural drainage in the preceding 2 months for symptoms relief OR
    2. Recurrent symptomatic pleural effusion on at least three occasions within a 2 month period despite treatment.
  21. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days or 5X the half-life, whichever is longer preceding informed consent.

Information from the National Library of Medicine

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


Locations
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United Kingdom
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
Sponsors and Collaborators
Eisai Limited

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Responsible Party: Eisai Limited
ClinicalTrials.gov Identifier: NCT01945710     History of Changes
Other Study ID Numbers: E7389-E044-112
2012-001184-69 ( EudraCT Number )
First Posted: September 18, 2013    Key Record Dates
Last Update Posted: August 10, 2016
Last Verified: July 2016

Keywords provided by Eisai Inc. ( Eisai Limited ):
Tumors