Clinical trial NCT00706095: Study Of Eribulin (E7389) In Patients With Advanced Solid Tumors And Normal Or Reduced Hepatic Function As Per Child-Pugh System
Official title: An Open-label, Parallel Group Study to Explore the Pharmacokinetics of Eribulin Mesylate (E7389) in Patients With Advanced Solid Tumors and Normal or Reduced Hepatic Function According to the Child-Pugh System
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cancer
Keywords: Cancer
advanced solid tumors
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2008-06-27
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Mean (SD) Pharmacokinetic (PK) Parameter Area Under Concentration Time Curve From Zero to Infinity (AUC0-oo)
timeFrame: 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.
measure: Mean (SD) Pharmacokinetic (PK) Parameter Maximum Observed Plasma Concentration (Cmax)
timeFrame: 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.
measure: Best Overall Response Per Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: throughout the study and up to 30 days after the last dose of study drug
Secondary outcomes:
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
city: Utrecht
country: Netherlands
facility: Utrecht Medical Centre
Study officials:
affiliation: National Cancer Institute-Antoni van Leuwenhoek Hospital
name: Prof. JHM Schellens
role: PRINCIPAL_INVESTIGATOR
References: