Pilot Efficacy Study of PI-88 With Docetaxel to Treat Prostate Cancer

A Randomised Phase II Study of Two Dose Schedules of PI-88 in Combination With Docetaxel in Patients With Androgen-independent Prostate Cancer

Docetaxel (Taxotere) is an approved chemotherapeutic drug for the treatment of androgen-independent prostate cancer. The aim of the study is to investigate whether addition of the investigational drug PI-88 will increase the efficacy of docetaxel in this disease. PI-88 inhibits cancer growth by inhibiting the development of new blood vessels and starving the tumour of oxygen and nutrients (anti-angiogenic). Because PI-88 and docetaxel have different mechanisms of action, they are expected to have increased (synergistic) activity when combined.

The trial is a multi-centre, open-label randomised phase II study in patients with androgen-independent prostate cancer (AIPC), with a lead-in combination tolerance study. The aim of the lead-in phase is to establish the maximum tolerated dose (MTD) of PI-88 administered either 4 days/week or 7 days/week) in combination with fixed doses of docetaxel (75 mg/m^2 every 21 days) and prednisone (5 mg twice daily). In the randomized phase II component, patients will receive PI-88 at the MTD, either 4 days/week or 7 days/week, in combination with docetaxel and prednisone. The patients will receive up to 10 treatment cycles of the combination therapy. Response to treatment will be assessed by measuring serum levels of prostate specific antigen (PSA). Other efficacy measures will include radiological assessment, progression-free survival, overall survival and quality of life.

Inclusion Criteria:

• Histologically/cytologically proven prostate adenocarcinoma that is unresponsive or refractory to hormone therapy
• Patients must have received prior hormonal therapy, defined as castration by orchiectomy and/or luteinizing hormone releasing hormone (LHRH) agonists
• Patients must have documented progression detected by PSA increase, physical examination and/or imaging
• Patients must have achieved stable pain control for a minimum of seven consecutive days prior to study entry.
• Prior radiation therapy (to < 25% of the bone marrow only) is permitted. At least 4 weeks must have elapsed since the completion of radiation therapy and the patient must have recovered from side effects prior to study entry.
• Prior surgery is allowed. At least 4 weeks must have elapsed since the completion of surgery
• Life expectancy > 3 months
• ECOG Performance score of < 2.
• Neutrophil count > 1.5 x 109/L (1,500/mm3)
• Haemoglobin > 10 g/dL
• Platelet count > 100 x 109/L (100,000/mm3)
• Total bilirubin < the upper limit of normal (ULN) of the institution
• ALT (SGPT) and AST (SGOT) < 1.5 x the ULN of the institution
• Calculated creatinine clearance, using Cockroft and Gault formula, >60 mL/min
• APTT and PT < 1.5 X ULN
• Patients (or legally acceptable representative) must have voluntarily given written informed consent to participate in this study.
• Patients must be willing to comply with the scheduled visit, treatment plans, laboratory tests, and other study procedures

Exclusion Criteria:

• Prior cytotoxic chemotherapy
• Prior isotope therapy (e.g., strontium, samarium)
• Prior radiotherapy to >25% of bone marrow (whole pelvic irradiation is not allowed)
• Prior treatment with biological response modifiers within the previous 4 weeks
• Prior malignancy except the following: adequately treated basal cell or squamous cell skin cancer, or any other cancer from which the patient has been disease-free for > 5 years
• Known brain or leptomeningeal involvement
• Symptomatic peripheral neuropathy > grade 2 according to the NCI Common Terminology Criteria for Adverse Events v3 (NCI CTCAE v3)
• Serious intercurrent medical illness that does not permit adequate follow-up and compliance with the study protocol
• History of immune-mediated thrombocytopenia, thrombotic thrombocytopenic purpura or other platelet disease, or laboratory evidence of anti-heparin antibodies
• Use of drugs that may inhibit the metabolism of docetaxel (cyclosporin, terfenadine, ketoconazole, erythromycin, troleandomycin) within the previous week or during the study
• Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study screening
• Treatment with any other anti-cancer therapy (except LHRH agonists) including any prescribed compounds and/or over-the-counter (OTC) products for the treatment of prostate cancer must be stopped prior to day of enrolment
• Treatment with systemic corticosteroids used for reasons other than specified by the protocol must be stopped prior to day of enrolment
• Concomitant bisphosphonate therapy is not allowed. Patients already receiving bisphosphonates must be stopped prior to day of enrolment
• Concomitant use of aspirin (> 150 mg/day), non-steroidal anti-inflammatory drugs (except specific COX-2 inhibitors), heparin, low molecular weight heparin (LMWH), warfarin (> 1 mg/day) or anti-platelet drugs (abciximab, clopidogrel, dipyridamole, ticlopidine and tirofiban). Low-dose aspirin (≤ 150 mg/day) and low-dose warfarin (≤ 1 mg/day) are permitted as concomitant medications
• Treatment with heparin or low molecular weight heparin within the previous two weeks is not permitted
• History of allergy and/or hypersensitivity to heparin or other anti-coagulants/thrombolytic agents
• History of acute or chronic gastrointestinal bleeding within the last two years, inflammatory bowel disease or other abnormal bleeding tendency
• Patients at risk of bleeding due to open wounds or planned surgery
• Myocardial infarction, stroke or congestive heart failure within the past three months
• Uncontrolled or serious infection within the past four weeks