Trial of PI-88 With Dacarbazine in Patients With Metastatic Melanoma

A Phase II Study of PI-88 With Dacarbazine in Patients With Metastatic Melanoma

The aim of the study is to compare the safety and effectiveness of a new drug called PI-88, when used in combination with an approved chemotherapy drug called dacarbazine, in the treatment of metastatic melanoma.

PI-88 blocks new blood vessel growth in tumours (starves it of nutrients) and dacarbazine stops the cancer cells from growing. The results from this study will be analysed to see if it is worthwhile for the two drugs to be tested in future studies involving larger numbers of melanoma patients.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Drug: PI-88 and dacarbazine; Drug: dacarbazine or DTIC

Detailed Description

Metastatic melanoma is a difficult-to-treat cancer for which available treatment options are limited and minimally effective. Dacarbazine is currently one of the standard chemotherapy drugs used for the treatment of metastatic melanoma. However, it is associated with low response rates (10-20%) and median survival of less than 12 months (6-11 months in most studies). PI-88 is an antiangiogenic and antimetastatic drug that has already shown some evidence of efficacy when used alone in an intermittent dosage regimen (4 consecutive days per week) in the treatment of patients with advanced melanoma. The FDA has designated PI-88 as an Orphan Drug for this indication, as well as for Stage III and high-risk stage II disease. The aim of this randomised pilot phase II trial is to determine whether PI-88 in combination with a standard regimen of dacarbazine (1000 mg/m2 every 3 weeks) should be considered for further investigation in a larger-scale trial.

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Sydney Cancer Centre, Royal Prince Alfred Hospital
    • Sydney, New South Wales, Australia, 2145
      • Westmead Institute for Cancer Research
  • Queensland
    • Auchenflower, Queensland, Australia, 4066
      • Wesley Research Institute
    • Townsville, Queensland, Australia, 4814
      • Townsville Cancer Centre
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Woodville, South Australia, Australia, 5011
      • The Queen Elizabeth Hospital
  • Victoria
    • Wodonga, Victoria, Australia, 3690
      • Border Medical Oncology
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
    • Perth, Western Australia, Australia, 6001
      • Royal Perth Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Arizona Cancer Centre
  • Colorado
    • Denver, Colorado, United States, 80010-0510
      • University of Colorado Health Science Centre
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6307
      • Vanderbilt-Ingram Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically proven metastatic melanoma
• Surgery not feasible or inappropriate
• Measurable disease. Metastatic lesions must be measurable by magnetic resonance imaging (MRI) or computed tomography (CT) as defined in Response Evaluation Criteria in Solid Tumors (RECIST), and cutaneous lesions by physical examination.
• Have voluntarily given written informed consent to participate in this study
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1
• Life expectancy at least 3 months
• Neutrophil count > 1.5 x 10^9/L (1,500/mm3)
• Platelet count > 100 x 10^9/L (100,000/mm3)
• Acceptable liver function tests (see Exclusion Criteria for maximum allowable elevations of ALT, AST, ALP and LDH)
• PT < 1.5 x upper limit of normal (ULN)
• APTT < 1.5 x ULN
• Creatinine clearance > 40 mL/min, calculated using the Cockcroft-Gault formula (if just below 40 mL/min, then GFR > 40 mL/min as determined by 24-hour urine collection)

Exclusion Criteria:

• Current or history of central nervous system involvement, brain or meningeal metastases
• Ocular melanoma
• Clinically significant non-malignant disease
• Prior or co-existent malignancies (other than stage I internal malignancy where treated and disease-free for > 5 years, non-melanomatous skin cancer or in situ cancer of the cervix)
• Prior chemotherapy
• Prior treatment with vaccines and/or biological response modifiers within the previous 4 weeks
• Prior treatment with radiotherapy within the previous 4 weeks (local palliative radiotherapy is permitted)
• Radiotherapy to > 30% of marrow-bearing bone within the previous 3 months
• Major surgery within the past 4 weeks
• Concomitant use of aspirin (> 150 mg/day), non-steroidal anti-inflammatory drugs (except specific COX-2 inhibitors), heparin, low molecular weight heparin, 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.
• Heparin or low molecular weight heparin within the previous 2 weeks
• History of acute or chronic gastrointestinal bleeding within the last 2 years, inflammatory bowel disease or other abnormal bleeding tendency
• Patients at risk of bleeding due to open wounds or planned surgery
• Bilirubin > 1.5 x ULN
• AST or ALT > 3 x ULN unless patient has hepatic metastases
• LDH > 2 x ULN
• Alkaline phosphatase > 5 x ULN, unless patient has bone metastases
• Myocardial infarction, stroke or congestive heart failure within the past 3 months
• Women who are pregnant or breast feeding
• Women of childbearing potential in whom pregnancy cannot be excluded or who are not using an adequate method of contraception
• History of allergy and/or hypersensitivity to anti-coagulants/thrombolytic agents, especially heparin
• History of immune-mediated thrombocytopenia, thrombotic thrombocytopenic purpura or other platelet disease, or laboratory evidence of anti-heparin antibodies
• Uncontrolled or serious infection within the past 4 weeks
• Patients who are unable to be compliant or to follow instructions given to them by clinic staff

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1- PI-88 plus dacarbazine; PI-88 (muparfostat) 190 mg daily by subcutaneous injection and dacarbazine 1000 mg/m2 on day 1 of each 21 day cycle	Drug: PI-88 and dacarbazine; 190 mg daily by subcutaneous injection for PI-88 and 1000 mg/m2 on day 1 of each 21 day cycle by intravenous infusion
Active Comparator: Arm 2- dacarbazine alone; dacarbazine 1000 mg/m2 on day 1 of every 21 day cycle by intravenous infusion	Drug: dacarbazine or DTIC; intravenous infusion 1000 mg/m2 on day 1 of every 21 day cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-progression Rate After Six Cycles	The Proportion of Patients With Objective Response or Stable Disease (Non-progression Rate) after six treatment cycles	In week 3 of every second cycle (each cycle was 21 days) for all subjects enrolled, up to the end of cycle 6 (About 5 months after randomization)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-progression Rate	The Proportion of Patients With Objective Response or Stable Disease (Non-progression Rate) after 2 or 4 treatment cycles	In week 3 of every second cycle (each cycle was 21 days) for all subjects enrolled in cycle 2 and cycle 4.
Time to Progression	treatment was to continue until the subject experienced disease progression.	At screening and in week 3 of every second cycle up to the end of cycle 6 and every third cycle after cycle 6 . Each cycle was 21 days.Assessed from date of randomization until the date of first documented progression, up to 50 months.
Duration of Response	time from commencement to radiological evidence of progression	At screening and in week 3 of every second cycle up to the end of cycle 6 and every third cycle after cycle 6. Each cycle was 21 days. Assessed from date of randomization until the date of first documented progression, up to 50 months.
Survival	time to death and also at time-points 6 month and 12 months	It was to assess time to death. The time frame is at least 6th month, 12th month and data was continuously collected till the end of the study, up to 50 months..

Collaborators and Investigators

• Sponsor: Cellxpert Biotechnology Corp.
• Collaborators: Medigen Biotechnology Corporation
• Investigators: Study Chair: Michael Millward, MD, Sir Charles Gairdner Hospital; Principal Investigator: Anne Hamilton, PhD, Sydney cancer centre; Principal Investigator: Damien Thomson, MD, Princess Alexandra Hospital

Study record dates

Study Major Dates

• Study Start: June 1, 2005
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: August 12, 2005
• First Submitted That Met QC Criteria: August 12, 2005
• First Posted (Estimate): August 15, 2005

Study Record Updates

• Last Update Posted (Actual): June 23, 2022
• Last Update Submitted That Met QC Criteria: June 21, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: phase II; metastatic melanoma; dacarbazine; combination; PI-88
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Dacarbazine
• Other Study ID Numbers: PR88205