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

This study has been completed.
Sponsor:
Collaborators:
Northern Sydney and Central Coast Area Health Service
Aventis Pharmaceuticals
Information provided by:
Progen Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00268593
First received: December 20, 2005
Last updated: June 13, 2011
Last verified: June 2011
  Purpose

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 Intervention Phase
Prostate Cancer
Drug: PI-88
Drug: docetaxel
Drug: prednisone
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Progen Pharmaceuticals:

Primary Outcome Measures:
  • Prostate Specific Antigen (PSA) response (incidence and duration) [ Time Frame: Baseline and 6-8 weeks post enrolment ] [ Designated as safety issue: No ]
    70% of patients (n = 36) had a >50% reduction in PSA from baseline.


Secondary Outcome Measures:
  • Radiologic response rate in patients with measurable disease [ Time Frame: Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported. ] [ Designated as safety issue: No ]
    Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.

  • PSA progression-free survival [ Time Frame: Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported. ] [ Designated as safety issue: No ]
    Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.

  • Disease progression-free survival [ Time Frame: Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported. ] [ Designated as safety issue: No ]
    Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported.

  • Overall survival [ Time Frame: Survival data collected to 100 weeks ] [ Designated as safety issue: No ]
    Median survival was 61 weeks and 1-year survival was 71%.

  • Safety and tolerability [ Time Frame: Recruitment was stopped early due to elevated rates of febrile neutropenia. Safety data collected throughout duration. ] [ Designated as safety issue: Yes ]

    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) [ Time Frame: Recruitment was stopped early due to elevated rates of febrile neutropenia. This end point was not reported. ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and 6-8 weeks post enrolment ] [ Designated as safety issue: No ]

    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.



Enrollment: 48
Study Start Date: August 2005
Study Completion Date: February 2008
Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00268593

Locations
Australia, New South Wales
Sydney Haematology and Oncology Clinics
Hornsby, New South Wales, Australia, 2077
St George Hospital
Kogarah, New South Wales, Australia, 2217
Lismore Base Hospital
Lismore, New South Wales, Australia, 2477
Port Macquarie Base Hospital
Port Macquarie, New South Wales, Australia, 2444
Liverpool Cancer Therapy Centre
Randwick, New South Wales, Australia, 2031
Royal North Shore Hospital
St Leonards, New South Wales, Australia, 2065
Australia, South Australia
Ashford Cancer Centre
Ashford, South Australia, Australia, 5035
Australia, Victoria
Border Medical Oncology
Wodonga, Victoria, Australia, 3690
Sponsors and Collaborators
Progen Pharmaceuticals
Northern Sydney and Central Coast Area Health Service
Aventis Pharmaceuticals
Investigators
Study Chair: Gavin Marx, MD Sydney Haematology and Oncology Clinics
Study Chair: Nick Pavlakis, MD Royal North Shore Hospital
  More Information

Publications:
Responsible Party: Darryn Bampton, Progen Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00268593     History of Changes
Other Study ID Numbers: PR88206, PROPIT, XRP6976J/6216
Study First Received: December 20, 2005
Last Updated: June 13, 2011
Health Authority: United States: Food and Drug Administration
Australia: Therapeutic Goods Administration

Keywords provided by Progen Pharmaceuticals:
heparanase
angiogenesis

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Prednisone
Docetaxel
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 28, 2014