A Dose-Finding Study of E7389 in Combination With Carboplatin in Patients With Solid Tumors

A Phase Ib Open-Label, Two-Arm, Dose-Finding Study of E7389 in Combination With Carboplatin in Patients With Solid Tumors

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.

This is a Phase Ib open-label, two-arm, dose-finding study of E7389 in combination with carboplatin in patients with solid tumors.

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.