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

Sponsor

Progen Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT00268593

Collaborator

Northern Sydney and Central Coast Area Health Service (Other), Aventis Pharmaceuticals (Industry)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: PI-88 Drug: docetaxel Drug: prednisone	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

48 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Aug 1, 2005

Actual Primary Completion Date :

Feb 1, 2008

Actual Study Completion Date :

Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 130 mg PI-88 + docetaxel 130 mg PI-88 7 days/week + docetaxel 75 mg/m2	Drug: PI-88 Subcutaneous injection administered 7 days/week for 130 mg PI-88 and 4 days/week for 250 mg PI-88; patients to be treated until progression or withdrawal from study. Drug: docetaxel Subcutaneous injection administered 7 days/week for 130 mg PI-88 and 4 days/week for 250 mg PI-88; patients to be treated until progression or withdrawal from study. Drug: prednisone 5 mg twice a day orally
Experimental: 250 mg PI-88 + docetaxel 250 mg PI-88 4 days/week + docetaxel 75 mg/m2	Drug: PI-88 Subcutaneous injection administered 7 days/week for 130 mg PI-88 and 4 days/week for 250 mg PI-88; patients to be treated until progression or withdrawal from study. Drug: docetaxel Subcutaneous injection administered 7 days/week for 130 mg PI-88 and 4 days/week for 250 mg PI-88; patients to be treated until progression or withdrawal from study. Drug: prednisone 5 mg twice a day orally

Arm

Intervention/Treatment

Experimental: 130 mg PI-88 + docetaxel

130 mg PI-88 7 days/week + docetaxel 75 mg/m2

Drug: PI-88

Subcutaneous injection administered 7 days/week for 130 mg PI-88 and 4 days/week for 250 mg PI-88; patients to be treated until progression or withdrawal from study.

Drug: docetaxel

Subcutaneous injection administered 7 days/week for 130 mg PI-88 and 4 days/week for 250 mg PI-88; patients to be treated until progression or withdrawal from study.

Drug: prednisone

5 mg twice a day orally

Experimental: 250 mg PI-88 + docetaxel

250 mg PI-88 4 days/week + docetaxel 75 mg/m2

Drug: PI-88

Subcutaneous injection administered 7 days/week for 130 mg PI-88 and 4 days/week for 250 mg PI-88; patients to be treated until progression or withdrawal from study.

Drug: docetaxel

Subcutaneous injection administered 7 days/week for 130 mg PI-88 and 4 days/week for 250 mg PI-88; patients to be treated until progression or withdrawal from study.

Drug: prednisone

5 mg twice a day orally

Outcome Measures

Primary Outcome Measures

Prostate Specific Antigen (PSA) response (incidence and duration) [Baseline and 6-8 weeks post enrolment]
70% of patients (n = 36) had a >50% reduction in PSA from baseline.

Secondary Outcome Measures

Radiologic response rate in patients with measurable disease [Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.]
Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.
PSA progression-free survival [Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.]
Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.
Disease progression-free survival [Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.]
Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.
Overall survival [Survival data collected to 100 weeks]
Median survival was 61 weeks and 1-year survival was 71%.
Safety and tolerability [Recruitment was stopped early due to elevated rates of febrile neutropenia. Safety data collected throughout duration.]
Recruitment was stopped due to higher than expected febrile neutropenia rate (27%). Fifty-one SAEs were reported in 33 patients, of which 7 were related to PI-88 treatment: non-neutropenic sepsis, neutropenic sepsis, pulmonary embolism, febrile dyspnoea, haematuria (x2), left middle cerebral artery infarction. Grade 3 or 4 AEs reported in >5% of patients comprise dehydration, fatigue, diarrhoea, nausea and thrombocytopenia. Two patients died during the study, one due to a ruptured abdominal aortic aneurysm, and one due to metastatic prostate cancer.
Quality of life Functional Assessment of Cancer Therapy - Prostate questionnaire (FACT-P) [Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.]
Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.
Exploratory predictive value of biologic parameters C-reactive protein (CRP), vascular endothelial growth factor (VEGF), interleukin-6 (IL6), D-dimer [Baseline and 6-8 weeks post enrolment]
Change in VEGF trended towards prediction of survival (p = 0.056); pre-treatment and post-treatment levels of CRP were predictive of survival (p = 0.026, and p = 0.005 respectively) but the change in CRP was not (p = 0.999). IL-6 pretreatment levels were not predictive (p = 0.5111) but post-treatment (p = 0.0008) and change (p = 0.0020) were. These data need to interpreted with caution due to the small patient numbers involved.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sydney Haematology and Oncology Clinics	Hornsby	New South Wales	Australia	2077
2	St George Hospital	Kogarah	New South Wales	Australia	2217
3	Lismore Base Hospital	Lismore	New South Wales	Australia	2477
4	Port Macquarie Base Hospital	Port Macquarie	New South Wales	Australia	2444
5	Liverpool Cancer Therapy Centre	Randwick	New South Wales	Australia	2031
6	Royal North Shore Hospital	St Leonards	New South Wales	Australia	2065
7	Ashford Cancer Centre	Ashford	South Australia	Australia	5035
8	Border Medical Oncology	Wodonga	Victoria	Australia	3690