Cancer
Conditions
Keywords
Cancer, advanced solid tumors
Brief summary
This is an open-label, three-parallel group pharmacokinetic study. Patients with advanced solid tumors will be assigned to one of three groups to receive I.V. doses of eribulin (E7389). The three groups are: normal hepatic function, mild hepatic impairment (Child-Pugh A) and moderate hepatic impairment (Child-Pugh B) according to the Child-Pugh System for classifying hepatic impairment.
Interventions
DRUGE7389
E7389 Intravenous injection starting dose on Day 1 is 1.4 mg/m\^2 for normal hepatic function.
Sponsors
Eisai Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must have a 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. Age ≥ 18 years 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2. 4. Life expectancy of ≥ 3 months 5. Adequate renal function as evidenced by serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥ 40 mL/minute (min) per the Cockcroft and Gault formula. 6. 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 7. Patients willing and able to comply with the study protocol for the duration of the study 8. Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice. Additional Inclusion Criteria for the Group of Patients with No Hepatic Impairment: * All the general inclusion criteria listed above plus: Normal hepatic function as evidenced by bilirubin ≤ 34 μmol/l (≤2.0 mg/dL) and alkaline phosphatase, alanine transaminase (ALT), and aspartate transaminase (AST) ≤3 times the upper limits of normal (ULN) (in the case of liver metastases ≤5 x ULN), or in the case of bone metastases, the liver specific alkaline phosphatase ≤3 times the upper limits of normal (ULN), and in the case of concomitant liver metastases, ≤5 x ULN. Additional Inclusion Criteria for the Group of Patients with Hepatic Impairment: * All the general inclusion criteria listed above plus: * Mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic dysfunction according to the Child-Pugh scoring system criteria, where patients with laboratory values within normal ranges will not be included in the Child-Pugh A category * Or, Moderate hepatic dysfunction (Child-Pugh B) according to the Child-Pugh scoring system criteria
Exclusion criteria
1. Patients who have received any of the following treatments within the specified period before E7389 treatment start: 1. Chemotherapy, radiation, biological therapy within 3 weeks. 2. Hormonal therapy within 1 week. 3. Any investigational drug within 4 weeks. 2. Patients with any clinically significant laboratory abnormality except for those parameters influenced by hepatic impairment. 3. Patients with severe (Child-Pugh C) hepatic dysfunction according to the Child-Pugh scoring system. 4. Patients with encephalopathy ≥ Grade 1. 5. Patients receiving any drug known to induce or inhibit CYP3A4 activity. Clinically significant drugs are listed in a comprehensive list that can be found at http://medicine/iupui.edu/flockhart/table.htm. 6. Patients, who require therapeutic anti-coagulant therapy other than for line patency with warfarin or related compounds and cannot be changed to heparin-based therapy, are not eligible. 7. 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. 8. Fertile men who are not willing to use contraception or fertile men with a female partner who are not willing to use contraception 9. Severe/uncontrolled intercurrent illness/infection. 10. Significant cardiovascular impairment (history of congestive heart failure \> New York Heart Association \[NYHA\] Grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia). 11. Patients with organ allografts requiring immunosuppression (not including blood and blood components transfusions). 12. Patients with known positive HIV status. 13. Patients with brain or subdural metastases are not eligible, unless they are stable and have completed local therapy and have discontinued the use of corticosteroids for this indication for at least four weeks before starting treatment with E7389. 14. Patients with meningeal carcinomatosis. 15. Patients with a hypersensitivity to halichondrin B and/or halichondrin B-like compounds. 16. Patients who participated in a prior E7389 clinical trial. 17. Patients with preexisting neuropathy \> Grade 2. 18. Patients with other significant disease or disorders that, in the Investigator's opinion, would exclude the patient from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean (SD) Pharmacokinetic (PK) Parameter Area Under Concentration Time Curve From Zero to Infinity (AUC0-oo) | Pre-dose (-0.5h); post-dose at 15 min, 30 min, 60 min, 2 hrs, 4 hrs, 6 hrs, 10 hrs, 24 hrs, 48 hrs, 72hrs, 96 hrs, 120 hrs and 144 hours. | — |
| Mean (SD) Pharmacokinetic (PK) Parameter Maximum Observed Plasma Concentration (Cmax) | Pre-dose (-0.5h); post-dose at 15 min, 30 min, 60 min, 2 hrs, 4 hrs, 6 hrs, 10 hrs, 24 hrs, 48 hrs, 72hrs, 96 hrs, 120 hrs and 144 hours. | — |
| Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | throughout the study and up to 30 days after the last dose of study drug | Defined as the best response from the start of treatment until disease progression or recurrence. Lesions measured by computed tomography (CT) scan and magnetic resonance imaging (MRI). Objective response rate: complete response (CR-disappearance of all lesions)+ partial response (PR-30% decrease in lesion diameter), Progressive Disease (PD-20% increase in lesion diameter), stable disease (SD-neither shrinkage nor increase of lesions). |
Countries
Netherlands
Participant flow
Recruitment details
This study was recruited at 2 centers in The Netherlands during the period of Feb 2008 to Jan 2010.
Participants by arm
| Arm | Count |
|---|---|
| E7389 1.4 mg/m^2 E7389 Intravenous injection starting dose on Day 1 is 1.4 mg/m\^2 for normal hepatic function. | 6 |
| E7389 1.1 mg/m^2 E7389 Intravenous injection starting dose on Day 1 is 1.1 mg/m\^2 for mild hepatic impairment (Child-Pugh A) | 7 |
| E7389 0.7 mg/m^2 E7389 Intravenous injection starting dose on Day 1 is 0.7 mg/m\^2 for moderate hepatic impairment (Child-Pugh B) | 5 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Clinical Progression | 1 | 2 | 2 |
| Overall Study | Progressive Disease | 4 | 5 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | E7389 1.4 mg/m^2 | E7389 1.1 mg/m^2 | E7389 0.7 mg/m^2 | Total |
|---|---|---|---|---|
| Age Continuous | 60.2 years STANDARD_DEVIATION 5.98 | 59.9 years STANDARD_DEVIATION 4.88 | 65.2 years STANDARD_DEVIATION 2.68 | 61.4 years STANDARD_DEVIATION 5.14 |
| Race/Ethnicity, Customized White | 6 participants | 7 participants | 5 participants | 18 participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 4 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 7 / 7 | 5 / 5 |
| serious Total, serious adverse events | 1 / 6 | 4 / 7 | 3 / 5 |
Outcome results
Primary
Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST)
Defined as the best response from the start of treatment until disease progression or recurrence. Lesions measured by computed tomography (CT) scan and magnetic resonance imaging (MRI). Objective response rate: complete response (CR-disappearance of all lesions)+ partial response (PR-30% decrease in lesion diameter), Progressive Disease (PD-20% increase in lesion diameter), stable disease (SD-neither shrinkage nor increase of lesions).
Time frame: throughout the study and up to 30 days after the last dose of study drug
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E7389 1.4 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Progressive Disease | 2 Number of Participants |
| E7389 1.4 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Stable Disease | 4 Number of Participants |
| E7389 1.4 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Complete Response | 0 Number of Participants |
| E7389 1.4 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Partial Response | 0 Number of Participants |
| E7389 1.4 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Missing | 0 Number of Participants |
| E7389 1.1 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Stable Disease | 1 Number of Participants |
| E7389 1.1 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Complete Response | 0 Number of Participants |
| E7389 1.1 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Partial Response | 0 Number of Participants |
| E7389 1.1 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Progressive Disease | 5 Number of Participants |
| E7389 1.1 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Missing | 1 Number of Participants |
| E7389 0.7 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Missing | 0 Number of Participants |
| E7389 0.7 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Progressive Disease | 1 Number of Participants |
| E7389 0.7 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Complete Response | 0 Number of Participants |
| E7389 0.7 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Stable Disease | 4 Number of Participants |
| E7389 0.7 mg/m^2 | Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST) | Best Overall Response - Partial Response | 0 Number of Participants |
Primary
Mean (SD) Pharmacokinetic (PK) Parameter Area Under Concentration Time Curve From Zero to Infinity (AUC0-oo)
Time frame: Pre-dose (-0.5h); post-dose at 15 min, 30 min, 60 min, 2 hrs, 4 hrs, 6 hrs, 10 hrs, 24 hrs, 48 hrs, 72hrs, 96 hrs, 120 hrs and 144 hours.
Population: Pharmacokinetic Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| E7389 1.4 mg/m^2 | Mean (SD) Pharmacokinetic (PK) Parameter Area Under Concentration Time Curve From Zero to Infinity (AUC0-oo) | 600 ng*hr/mL | Standard Deviation 267.1 |
| E7389 1.1 mg/m^2 | Mean (SD) Pharmacokinetic (PK) Parameter Area Under Concentration Time Curve From Zero to Infinity (AUC0-oo) | 731 ng*hr/mL | Standard Deviation 288.3 |
| E7389 0.7 mg/m^2 | Mean (SD) Pharmacokinetic (PK) Parameter Area Under Concentration Time Curve From Zero to Infinity (AUC0-oo) | 720 ng*hr/mL | Standard Deviation 407.4 |
Primary
Mean (SD) Pharmacokinetic (PK) Parameter Maximum Observed Plasma Concentration (Cmax)
Time frame: Pre-dose (-0.5h); post-dose at 15 min, 30 min, 60 min, 2 hrs, 4 hrs, 6 hrs, 10 hrs, 24 hrs, 48 hrs, 72hrs, 96 hrs, 120 hrs and 144 hours.
Population: Pharmacokinetic Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| E7389 1.4 mg/m^2 | Mean (SD) Pharmacokinetic (PK) Parameter Maximum Observed Plasma Concentration (Cmax) | 186 ng/mL | Standard Deviation 67.4 |
| E7389 1.1 mg/m^2 | Mean (SD) Pharmacokinetic (PK) Parameter Maximum Observed Plasma Concentration (Cmax) | 147 ng/mL | Standard Deviation 47.6 |
| E7389 0.7 mg/m^2 | Mean (SD) Pharmacokinetic (PK) Parameter Maximum Observed Plasma Concentration (Cmax) | 113 ng/mL | Standard Deviation 47.2 |