Clinical trial NCT01000376: Evaluating the Pharmacokinetics and Tolerance of Co-administration of Oral Multiple Dose of Ketoconazole and an IV (Bolus) Infusion of Eribulin in Patients With Advanced Solid Tumors
Official title: An Open-Label, Phase I Study to Evaluate the Pharmacokinetics and Tolerance of Co-administration of Oral Multiple Dose of Ketoconazole and an IV (Bolus) Infusion of Eribulin in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cancer
Keywords: Cancer
solid tumors
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2009-10-23
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to investigate whether ketoconazole, taken orally, influences the level of eribulin in the blood when the two drugs are given at the same time. The study will enroll patients with solid tumors whose cancer became worse even after standard treatment, or for whom there is no standard treatment available. The study will also investigate whether eribulin given together with ketoconazole is safe (has few side-effects) and is effective against cancer.


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. Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy ≤ Grade 2 and alopecia.
3. Patients must be aged ≥ 18 years.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
5. Life expectancy of ≥ 3 months.
6. Patients must have adequate renal function as evidenced by serum creatinine ≤ 2.0 mg/dL (≤ 176 mol/L) or calculated creatinine clearance ≥ 40 mL/minute (min) per the Cockcroft and Gault formula.
7. Patients must have adequate hepatic function as evidenced by bilirubin ≤ 1.5 times the upper limit of normal (ULN) and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 times the ULN, (in the case of liver metastases ≤ 5 times ULN or in the case of bone metastases, the liver specific alkaline phosphatase ≤ 3 times ULN).
8. Patients must have adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L, hemoglobin ≥ 10.0 g/dL or ≥ 6.2 mmol/L (a hemoglobin \< 10.0 g/dL or \< 6.2 mmol/L is acceptable if it is corrected by growth factor or transfusion), and platelets ≥ 100 x 10\^9/L.
9. Patients must be willing and able to comply with the study protocol for the duration of the study.
10. Patients must give 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 eribulin treatment starts:

   1. Chemotherapy, radiation or biological therapy within 2 weeks.
   2. Hormonal therapy within 1 week.
   3. Any investigational drug within 4 weeks.
2. 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.
3. Patients receiving, at the time the study starts, any medication, dietary supplements or other compounds or substances known to induce or inhibit CYP3A4 activity, with the exception of ketoconazole. A comprehensive list can be found at http://medicine/iupui.edu/flockhart/table.htm.
4. Patients for whom the use of ketoconazole is contraindicated.
5. Patients who are receiving drugs that might influence ketoconazole metabolism.
6. 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.
7. Fertile men who are not willing to use contraception or fertile men with a female partner who is not willing to use contraception.
8. Patients whose intestinal absorption is impaired.
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 6 months, or serious cardiac arrhythmia.
11. Patients with organ allografts requiring immunosuppression (not including blood and blood components transfusions).
12. Patients with known positive human immunodeficiency virus (HIV) status.
13. 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 with eribulin.
14. Patients with meningeal carcinomatosis.
15. Patients with a hypersensitivity to halichondrin B and/or halichondrin B-like compounds.
16. Patients with pre-existing neuropathy \> Grade 2.
17. 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) Maximum Observed Concentration (Cmax) of Eribulin
timeFrame: 7 days after dosing on Days 1 and 15
measure: Mean (SD) Area Under Concentration Time Curve From Zero to Infinity (AUC 0-oo) of Eribulin
timeFrame: 7 days after dosing on Days 1 and 15
Secondary outcomes:
measure: Safety of Eribulin Administered Alone or Coadministered With Oral Ketoconazole, as Measured by Number of Subjects With Adverse Events.
timeFrame: monitored throughout
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute
state: Noord-Holland
Study officials:
affiliation: Eisai Limited
name: Jantien Wanders, M.D.
role: STUDY_DIRECTOR
References: