Advanced Solid Tumor
Conditions
Keywords
tumor
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.
Interventions
DRUGEribulin Mesylate
1.4 mg/m\^2 intravenous (IV) bolus given over 2-5 minutes on Days 1 and 8 every 21 days.
Sponsors
Eisai Limited
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Time-matched, Baseline Corrected QTcF at Any Time Point Postdosing. | 48 hours postdose after Day 1 and after Day 8 | The primary endpoint is mean time-matched, baseline corrected QTcF at any time point postdosing. This was to determine the effect of eribulin on cardiac repolarization as measured by QT/QTc interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Profile of Eribulin Mesylate: Observed Maximal Plasma Concentration (Cmax) | Days 1 and 8 | Pharmacokinetic profile of eribulin mesylate (Cmax). |
| To Assess Best Overall Response Using RECIST Criteria in Patients With Measurable Disease. | 21 day cycle | — |
| 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. | 21 day cycle | — |
| Pharmacokinetic Profile of Eribulin Mesylate: Time to Maximum Observed Plasma Concentration (Tmax). | Days 1 and 8 | Pharmacokinetic profile of eribulin mesylate (tmax). |
Countries
France
Participant flow
Recruitment details
This study was recruited at 5 centers in France from Feb 2009 to Jul 2009.
Participants by arm
| Arm | Count |
|---|---|
| Eribulin Mesylate 1.4 mg/m\^2 intravenous (IV) bolus given over 2-5 minutes on Days 1 and 8 every 21 days. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative | 2 |
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Eribulin Mesylate |
|---|---|
| Age Continuous | 55.9 years STANDARD_DEVIATION 12.28 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment France | 26 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 26 / 26 |
| serious Total, serious adverse events | 11 / 26 |
Outcome results
Primary
Mean Time-matched, Baseline Corrected QTcF at Any Time Point Postdosing.
The primary endpoint is mean time-matched, baseline corrected QTcF at any time point postdosing. This was to determine the effect of eribulin on cardiac repolarization as measured by QT/QTc interval.
Time frame: 48 hours postdose after Day 1 and after Day 8
Population: Per Protocol Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eribulin Mesylate | Mean Time-matched, Baseline Corrected QTcF at Any Time Point Postdosing. | Postdosing Day 1 | 2 msec | Standard Deviation 12.3 |
| Eribulin Mesylate | Mean Time-matched, Baseline Corrected QTcF at Any Time Point Postdosing. | Postdosing Day 8 | 11 msec | Standard Deviation 18.7 |
Secondary
Pharmacokinetic Profile of Eribulin Mesylate: Observed Maximal Plasma Concentration (Cmax)
Pharmacokinetic profile of eribulin mesylate (Cmax).
Time frame: Days 1 and 8
Population: Pharmacokinetic Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eribulin Mesylate | Pharmacokinetic Profile of Eribulin Mesylate: Observed Maximal Plasma Concentration (Cmax) | Day 1 | 516.5 ng/mL | Standard Deviation 137.91 |
| Eribulin Mesylate | Pharmacokinetic Profile of Eribulin Mesylate: Observed Maximal Plasma Concentration (Cmax) | Day 8 | 502.4 ng/mL | Standard Deviation 138.31 |
Secondary
Pharmacokinetic Profile of Eribulin Mesylate: Time to Maximum Observed Plasma Concentration (Tmax).
Pharmacokinetic profile of eribulin mesylate (tmax).
Time frame: Days 1 and 8
Population: Pharmacokinetic Population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eribulin Mesylate | Pharmacokinetic Profile of Eribulin Mesylate: Time to Maximum Observed Plasma Concentration (Tmax). | Day 1 | 0.08 hours |
| Eribulin Mesylate | Pharmacokinetic Profile of Eribulin Mesylate: Time to Maximum Observed Plasma Concentration (Tmax). | Day 8 | 0.08 hours |
Secondary
To Assess Best Overall Response Using RECIST Criteria in Patients With Measurable Disease.
Time frame: 21 day cycle
Secondary
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.
Time frame: 21 day cycle