Evaluating E7389 in Patients With Hormone Refractory Prostate Cancer With Advanced and/or Metastatic Disease Stratified by Prior Chemotherapy

A Phase II, Multicenter, Open Label, Two Stage Design Study Evaluating E7389 in Patients With Hormone Refractory Prostate Cancer With Advanced and/or Metastatic Disease Stratified by Prior Chemotherapy

This is a multi-centre, phase II, open-label, two-stage design, single-arm study in patients with hormone-refractory prostate cancer (HRPC) with advanced (rising PSA) and/or metastatic disease and who have had prior anti-androgen therapy. The study will further explore the efficacy of E7389 by enrollment of patients into two strata: those who have had no prior systemic chemotherapy for their disease (except for mitoxantrone and estramustine), and those who failed no more than one previous chemotherapeutic regimen with tubulin-binding agents such as docetaxel.

Inclusion criteria:

1. Males with histologically proven adenocarcinoma of the prostate that has progressed (ie. a minimum of 3 consecutive rises in Prostate Specific Antigen (PSA) (with the last value ≥ 4 ng/mL) taken at least 1 week apart prior to study entry) despite castration or maintenance of castrate-level testosterone (defined as serum testosterone ≤ .50 ng/dL or 1.7 nmol/L), or progressed during non-hormonal chemotherapy.

   Note: Patients previously treated with an antiandrogen must have disease progression documented after antiandrogen withdrawal. Those who have not undergone orchiectomy must continue medical castration with a gonadotropin-releasing hormone analog. At least 4 weeks must have elapsed between the withdrawal of antiandrogens (6 weeks in the case of nilutamide or bicalutamide and four weeks in the case of flutamide or other secondary hormonal therapy) and enrollment, so as to avoid the possibility of confounding results of the response due to antiandrogen withdrawal.

2. Patients must fulfill one of the following two criteria to be stratified:

   • No prior chemotherapy (except mitoxantrone or estramustine) for advanced and/or metastatic disease as defined in inclusion criteria #1.
   • Failure of no more than one previous chemotherapeutic regimen with tubulin binding agents such as docetaxel.

3. Resolution of all chemotherapy or radiation-related toxicities to less than grade 2 severity, except neuropathy and alopecia

4. Age ≥ 18 years.

5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.

6. Life expectancy of ≥ 3 months.

7. Adequate renal function as evidenced by serum creatinine ≤ 1.5 times upper limits of normal (ULN) or calculated creatinine clearance ≥ 40 mL/minute (min) per the Cockcroft and Gault formula.

8. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L, hemoglobin ≥ 9.0 g/dL (or 5.5 mmol/L), and platelet count ≥ 100 x 10^9/L. Adequate liver function as evidenced by bilirubin ≤ 1.5 x ULN, alanine transaminase (ALT), and aspartate transaminase (AST) ≤ 3 x ULN (in the case of liver metastases ≤ 5 x ULN).

9. Patients willing and able to complete the VAS (Visual Analog Scale).

10. Patients willing and able to comply with the study protocol for the duration of the study.

11. 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 chemotherapy, radiation, or experimental therapy within 4 weeks of start of E7389 treatment
2. Radiation therapy encompassing ≥30% of marrow or treatment with radioactive strontium
3. Patients who require therapeutic anti-coagulant therapy with warfarin or related compounds; (mini dose warfarin or related compounds are permitted).
4. Severe / uncontrolled intercurrent illness/infection.
5. Significant cardiovascular impairment (history of congestive heart failure > NYHA grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia)
6. Patients with organ allografts.
7. Patients with known immunosuppression such as positive HIV status.
8. Patients who have had a prior malignancy, other than nonmelanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated ≥ 5 years previously with no subsequent evidence of recurrence.
9. Patients with pre-existing neuropathy > Grade 2
10. Patients with brain or subdural metastases are not eligible, except if they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least two weeks before starting treatment with E7389.
11. Patients with meningeal carcinomatosis.
12. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative.
13. Patients who participated in a prior E7389 clinical trial.
14. Patients with other significant disease or disorders that, in the Investigator's opinion, would exclude the patient from the study.