Study of AS1404 With Docetaxel in Patients With Hormone Refractory Metastatic Prostate Cancer

An Open Label, Randomized, Phase II Study of AS1404 in Combination With Docetaxel in Patients With Hormone Refractory Metastatic Prostate Cancer

The purpose of this trial is to confirm a safe dose of AS1404, to be given with docetaxel, and to see whether adding AS1404 and docetaxel together improves the outcome of the treatment, when compared to docetaxel alone.

The overall aim of this study is to determine the safety, tolerability and efficacy of AS1404 in combination with docetaxel in patients with hormone refractory metastatic prostate cancer.

Inclusion Criteria:

• Age equal to, or greater than 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Life expectancy greater than or equal to 3 months

• Histopathologically confirmed adenocarcinoma of the prostate

• Metastatic progressive androgen-independent prostate cancer with no previous chemotherapy treatment

• At least 4 weeks off of flutamide and 6 weeks off of bicalutamide and nilutamide

• Patients who have not undergone surgical castration must continue treatment with an luteinizing hormone-releasing hormone (LHRH) agonist. In those patients where, for some reason, the LHRH agonist has been discontinued prior to entry on the study, it should be reinstituted and disease progression must be documented.

• Hematological and biochemical indices at screening within the following ranges:

  • An absolute neutrophil count of greater than or equal to 1.5 x 10^9/L;
  • A platelet count of greater than or equal to 100 x 10^9/L;
  • A hemoglobin level of greater than or equal to 10 g/dL.

• Adequate hepatic and renal function, as defined by:

  • Serum bilirubin less than or equal to upper limit of normal (ULN);
  • SGOT and/or SGPT less than or equal to 1.5 x ULN concomitant with alkaline phosphatase less than or equal to 2.5 x ULN;
  • Serum creatinine less than or equal to 120 micromol/L or creatinine clearance greater than or equal to 60 mL/min.

• Be willing and able to provide written informed consent and, in the opinion of the Investigator, be able to comply with the study assessments and follow-up

• Serum testosterone no greater than 50 ng/mL (chemically castrated patients only)

Exclusion Criteria:

• Decreasing PSA levels after antiandrogen withdrawal

• Previous chemotherapy treatment for prostate cancer

• Patients who have received blood transfusions or growth factors to aid hematological recovery within two weeks of scheduled baseline visit

• Concurrent severe and/or uncontrolled co-morbid medical condition within 2 weeks of screening

• Previous exposure to AS1404 or other vascular targeting agents

• Clinically significant cardiac arrhythmias and known QTc prolongation (interval >450 msec)

• Evidence of severe or uncontrolled systemic disease that, in the opinion of the Investigator, might interfere with the patient's participation in the study

• A history of alcoholism; drug addiction; or any psychiatric condition, which, in the opinion of the Investigator, would impair the patient's ability to comply with study procedures

• A history of hypersensitivity to taxanes or other drugs formulated with polysorbate 80

• Treatment with the following medications within two weeks of AS1404 administration or the expected need for such treatments during the study period:

  • Medications known to modulate serotonin;
  • Medications known to affect the QT interval;
  • Current treatment with, or the expected need during the treatment period for ketoconazole, erythromycin, troleandomycin, and/or cyclosporine. The use of other agents known to induce, inhibit, or that are metabolized by cytochrome P450-3A4 should be undertaken with caution.

• Concurrent or previous malignancy of a different tumor type within five years of starting the study, except for adequately treated non-melanoma skin cancer

• Clinical or radiological evidence of central nervous system (CNS) metastases

• Symptomatic peripheral neuropathy greater than or equal to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade II

• Evidence of any other significant clinical disorder or laboratory finding that, in the opinion of the Investigator, compromises the patient safety during study participation

• Participation in any prostate cancer investigational drug study in which the study drug has not subsequently obtained a product license

• Any other concurrent treatment for prostate cancer (with the exception of palliative radiotherapy) other than that specified in the protocol, including the use of herbal remedies, (e.g. saw palmetto)