Clinical trial NCT01106248: QT Interval Prolongation Study of Eribulin Mesylate (E7389) in Patients With Advanced Solid Tumors
Official title: An Open-Label, Multicenter, Single Arm QT Interval Prolongation Study of Eribulin Mesylate (E7389) in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumor
Keywords: tumor
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2010-04-19
Enrollment: 26
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess whether eribulin mesylate (E7389) has an impact on the electrocardiogram (ECG) with focus on cardiac repolarization, as measured by QT/QTc interval as well as through a pharmacokinetic-pharmacodynamic (PK/PD) analysis.

Detailed description: This is an open-label, multicenter, single arm QT Interval prolongation study of eribulin mesylate (E7389) in patients with advanced solid tumors.

Eligibility criteria: Personal history of unexplained syncope within the last year prior to entry

Inclusion Criteria:

1. Patients with histologically or cytologically confirmed advanced solid tumor that has progressed following standard therapy or for which no standard therapy exists (including surgery or radiation therapy).
2. Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy \</= Grade 2 and alopecia.
3. Age \>/= 18 years.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
5. Patients must have a sinus rhythm and QRS \< 120msec.
6. Adequate renal function as evidenced by serum creatinine \</= 2.0 mg/dL or calculated creatinine clearance \>/= 40 mL/min per the Cockcroft and Gault formula.
7. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) \>/= 1.5 x 10\^9/L, hemoglobin \>/= 10.0 g/dL (a hemoglobin \<10.0 g/dL is acceptable if it is corrected by growth factor or transfusion), and platelet count \>/= 100 x 10\^9/L.
8. Adequate liver function as evidenced by bilirubin \>/= 1.5 times the upper limits of normal (ULN) and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) \</= 3 x ULN (in the case of liver metastases \</= 5 x ULN), unless there are bone metastases, in which case liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase.
9. Patients willing and able to comply with the study protocol for the duration of the study.
10. 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:

1. Patients who have received any of the following treatments within the specified period before start of treatment with eribulin mesylate:

   * Chemotherapy, radiation or biological therapy within three weeks
   * Hormonal therapy within one week
   * Any investigational drug within four weeks
2. Have had radiation therapy encompassing \> 30% of bone marrow.
3. Have received prior treatment with mitomycin C or nitrosourea.
4. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.
5. Patients 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 before starting treatment in this study. Any signs (e.g. radiologic) and/or symptoms of brain metastases must be stable for at least 4 weeks.
6. Patients with meningeal carcinomatosis.
7. 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).
8. Patients with marked baseline prolongation of QT/QTc interval (QTc interval \> 500 msec).
9. Patients with a history of additional risk factors for Torsades des pointes (e.g., heart failure, cardiac ischemia, recent Myocardial Infarction (MI), family history of Long QT Syndrome).
10. Patients with uncontrolled metabolic disorders (e.g hypokalemia, hypercalcemia and hypomagnesemia) at entry to the study.
11. Patients treated with antiarrythmic drugs or other medications that prolong the QT/QTc, that cannot be discontinued prior to entry into the study phase.
12. Patients with implantable pacemaker or automatic implantable cardioverter defibrillator (AICD).
13. .Bradycardia (defined as \</= 50 beats/minute).
14. Personal history of unexplained syncope within the last year prior to entry into the study.
15. Patients with other significant disease or disorders that, in the Investigator's opinion, should exclude the patient from the study.
16. 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) or international normalized ratio (INR) must be closely monitored.
17. Women who are pregnant or breast-feeding; women of childbearing potential with either 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 to be considered of non-childbearing potential.
18. Severe/uncontrolled intercurrent illness/infection.
19. Patients with organ allografts requiring immunosuppression.
20. Patients with known positive HIV status.
21. Patients who have had a prior malignancy, other than carcinoma in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated \>/= 5 years previously with no subsequent evidence of recurrence.
22. Patients with pre-existing neuropathy \> Grade 2.
23. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative.
24. Patients who participated in a prior eribulin mesylate clinical trial.
25. Patients with pericardial effusion or pericardial metastases.

Primary outcomes:
measure: Mean Time-matched, Baseline Corrected QTcF at Any Time Point Postdosing.
timeFrame: 48 hours postdose after Day 1 and after Day 8
Secondary outcomes:
measure: Pharmacokinetic Profile of Eribulin Mesylate: Observed Maximal Plasma Concentration (Cmax)
timeFrame: Days 1 and 8
measure: To Assess Best Overall Response Using RECIST Criteria in Patients With Measurable Disease.
timeFrame: 21 day cycle
measure: To Further Explore the Safety and Tolerability of Eribulin Mesylate When Administered on Days 1 and 8 of a 21-day Cycle in Patients With Solid Tumors.
timeFrame: 21 day cycle
measure: Pharmacokinetic Profile of Eribulin Mesylate: Time to Maximum Observed Plasma Concentration (Tmax).
timeFrame: Days 1 and 8
Other outcomes:
Locations:
city: Dunkerque
country: France
facility: Medicale
state: *CS
city: Dunkerque
country: France
facility: Service d'Oncologie
state: *CS
Study officials:
affiliation: Eisai Inc.
name: Jantien Wanders, MD
role: STUDY_DIRECTOR
References: