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

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.

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