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
Condition: Cancer
Intervention: Eribulin alone; Eribulin plus Ketoconazole
Intervention description: Group 1 Cycle 1 (28 days): Eribulin IV 1.4 mg/m^2 alone on Day 1, then eribulin IV 0.7 mg/m^2 plus oral ketoconazole 200 mg on Day 15 and oral ketoconazole 200 mg alone on Day 16. Subsequently, subjects were able to receive eribulin 1.4 mg/m^2 on Days 1 and 8 every 21 days.; Group 2 Cycle 1 (28 days): Eribulin IV 0.7 mg/m^2 plus oral ketoconazole 200 mg on Day 1, then oral ketoconazole 200 mg alone on Day 2 and eribulin IV 1.4 mg/m^2 alone on Day 15. Subsequently, subjects were able to receive eribulin 1.4 mg/m^2 on Days 1 and 8 every 21 days.
Intervention MeSH terms: Ketoconazole
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cancer; solid tumors

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.