A Dose-Finding Study of E7389 in Combination With Carboplatin in Patients With Solid Tumors
Condition: Cancer
Intervention: E7389 + carboplatin AUC 5; E7389 + carboplatin AUC 6; E7389+carboplatin AUC 6
Intervention description: Patients will receive E7389 before (Schedule A) or after (Schedule B) carboplatin AUC 5 infusion. E7389 will be administered as a 2-5 minute intravenous (IV) bolus infusion at a starting dose of 0.7 mg/m^2 on Days 1 and 8 every 21 days. Carboplatin 5 AUC will be administered as a 30-minute IV infusion on Day 1 every 21 days. Dose escalation will be performed in cohorts of three patients per dose level per schedule.; After MTD is reached with carboplatin AUC 5, dose escalation of E7389 in combination with carboplatin at AUC 6 will begin at one dose level below MTD, using the preferred schedule (A or B).
If carboplatin AUC 6 with E7389 is tolerated, the MTD reached will be used to enroll 20 additional patients with Stage IIIB or IV non-small cell lung cancer (NSCLC). If carboplatin AUC 6 is not tolerated, these patients will be enrolled at the MTD determined with the combination of E7389 and carboplatin AUC 5.; In a population of patients who had generally received multiple prior chemotherapies, the eribulin MTD has been determined to be 1.1 mg/m2 in combination with carboplatin at an AUC of 6. The first-line NSCLC patients in the extension arm may tolerate a higher dose of eribulin, because they have not been exposed to the toxicity of other chemotherapies. To investigate this possibility, the dose of eribulin will be increased to 1.4 mg/m2 for subsequent patients, if the first six of these patients do not experience a DLT during their first cycle of eribulin at 1.1 mg/m2 and carboplatin at AUC 6 combination therapy. If no more than one of the first six patients experience a DLT during the first cycle with the 1.4 mg/m2 dose of eribulin, then the 1.4 mg/m2 dose will be considered the recommended dose for front-line NSCLC therapy and the remaining patients will be treated using this dose.
Intervention MeSH terms: Carboplatin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 64.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to determine the maximum tolerated dose (MTD) and to explore the
      safety and anti-tumor activity of E7389 in combination with carboplatin in patients with
      advanced solid tumors.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients ≥ 18 years of age.

          2. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status score of
             0 or 1.

          3. Patients with a life expectancy of ≥ three months.

          4. Patients with 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.

          5. Patients with adequate bone marrow function as evidenced by absolute neutrophil count
             (ANC) ≥ 1.5 × 10^9/L, hemoglobin ≥ 10.0 g/dL (this may have been corrected by
             transfusion or growth factors) and platelet count ≥ 100 × 10^9/L.

          6. Patients with adequate liver function as evidenced by bilirubin ≤ 1.5 mg/dL and
             alkaline phosphatase (ALP), alanine transaminase (ALT) and aspartate aminotransferase
             (AST) ≤ 3 times the upper limits of normal (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. to assess the liver function instead of the
             total alkaline phosphatase.

          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.

        For patients in the dose finding phase, the following additional inclusion criteria must be
        fulfilled:

          1. Patients with pathologically diagnosed, 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. Patients with disease progression despite standard therapy or have disease for which
             no standard therapy exists.

          3. Patients with ≤ Grade 2 chemotherapy or radiation-related toxicities except alopecia.

        For NSCLC patients at the MTD, the following additional inclusion criteria must be
        fulfilled:

          1. Patients with pathologically diagnosed, histologically or cytologically confirmed
             advanced NSCLC (Stage IIIB or IV) with measurable disease, not amenable to surgical or
             radiation treatment.

          2. Patients with no prior chemotherapy for NSCLC including neoadjuvant or adjuvant
             treatment.

        Exclusion Criteria:

          1. Patients are excluded if they have received any of the following within three weeks
             prior to first study treatment: investigational drugs, immunotherapy, gene therapy,
             hormone therapy (except leuprolide, and megestrol acetate for appetite stimulation),
             other biological therapy, chemotherapy or radiation. Patients with major surgery
             without full recovery or major surgery within 3 weeks prior to first study treatment
             are also excluded. Patients must have recovered from any previous major
             therapy-related toxicity (Grade 3 or 4) to < Grade 2 at study entry (except for
             neuropathy).

          2. Patients who have received radiation ≤ 3 weeks prior to study enrollment, whose marrow
             exposure has exceeded 30% or who have not recovered from the toxic effects of the
             treatment prior to study enrollment (except for alopecia).

          3. Patients who have received prior high dose chemotherapy with hematopoietic stem cell
             rescue or stem cell or bone marrow transplant in the past two years.

          4. Patients with pulmonary lymphangitic involvement that results in pulmonary dysfunction
             requiring active treatment, including the use of oxygen

          5. Patients with active symptomatic brain metastases. Patients with central nervous
             system (CNS) metastases are considered eligible if they have had adequately treated
             brain metastases, ie, have completed treatment (tapered off steroids) at least four
             weeks before starting treatment with E7389. Patients who have no evidence that the
             metastases are symptomatic or actively growing (no evidence of midline shift on
             computed tomography scan or magnetic resonance imaging) may be enrolled without
             initiation of local therapy for the CNS metastases. In this case, a repeat scan must
             be performed within four weeks of the original scan to ensure that disease progression
             is not occurring. It is not the intention of this study to treat patients with active
             brain metastases.

          6. Patients with meningeal carcinomatosis.

          7. Patients who require therapeutic anti-coagulant therapy with warfarin or related
             compounds.

          8. 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 (e.g., using 2 forms of contraception
             including a barrier method). Perimenopausal women must be amenorrheic for at least 12
             months to be considered of non-childbearing potential.

          9. Fertile men who are not willing to use contraception or fertile men with a female
             partner who is not willing to use contraception.

         10. Patients with severe/uncontrolled intercurrent illness or infection.

         11. Patients with significant cardiovascular impairment (history of congestive heart
             failure > New York Heart Association Grade II, unstable angina or myocardial
             infarction within the past six months, or serious cardiac arrhythmia).

         12. Patients with organ allografts.

         13. Patients who have a history of positive testing for HIV and/or have active hepatitis B
             or active hepatitis C at study entry.

         14. Patients with pre-existing neuropathy > Grade 2.

         15. Patients with a hypersensitivity to halichondrin B and/or to a halichondrin B chemical
             derivative.

         16. Patients who participated in a prior E7389 clinical trial.

         17. Patients with other significant disease or disorders that, in the investigator's
             opinion, would exclude the patient from the study.

        For NSCLC patients at the MTD, the following additional exclusion criterion must be
        fulfilled:

        1. 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 ≥ five years previously with no subsequent evidence of recurrence.