QT Interval Prolongation Study of Eribulin Mesylate (E7389) in Patients With Advanced Solid Tumors
Condition: Advanced Solid Tumor
MeSH terms: Neoplasms
Intervention: Eribulin Mesylate
Intervention description: 1.4 mg/m^2 intravenous (IV) bolus given over 2-5 minutes on Days 1 and 8 every 21 days.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Healthy volunteers: No
Keywords: tumor

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.
    

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.