PI-88 may stop the growth of tumour cells by blocking blood flow to the tumour. Drugs used in chemotherapy, such as dacarbazine, work in different ways to stop the growth of tumour cells, either by killing the cells or by stopping them from dividing. Giving PI-88 together with dacarbazine may kill more tumour cells. This randomized phase II trial is studying how well PI-88 and/or dacarbazine works in treating patients with metastatic melanoma that cannot be removed by surgery.
Official Title
A Phase II Study of PI-88 With Dacarbazine in Patients With Metastatic Melanoma
Conditions
Melanoma (Skin)
Study Type
Interventional
Study Design
Treatment, Randomized, Open Label
Further Details
Primary Objectives
- Compare the safety and efficacy of PI-88 and dacarbazine vs dacarbazine alone as first-line therapy in patients with unresectable metastatic melanoma.
Secondary Objectives
- Determine the duration of clinical benefit in patients whose disease is controlled by treatment with PI-88 and dacarbazine.
- Determine the safety and efficacy of PI-88 monotherapy as second-line therapy in patients who progress during treatment with dacarbazine alone.
This is an open-label, multicenter study with a lead-in phase comprising dose-escalation of PI-88 followed by a pilot, randomized phase. Patients enrolled in the randomized phase are stratified according to participating center.
- Lead-in phase (part 1): Patients receive PI-88 subcutaneously (SC) once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may receive second-line therapy with PI-88 and dacarbazine.
- Lead-in phase (part 2): Patients receive PI-88 as in part 1. Patients also receive dacarbazine IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease who experience dacarbazine-related toxicity or who opt not to continue dacarbazine may receive PI-88 alone as maintenance therapy at the discretion of the principal investigator (PI).
Cohorts of 3-6 patients receive escalating doses of PI-88 alone or in combination with dacarbazine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
-
Randomized phase: Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive dacarbazine IV over 1 hour on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease after 6 courses of therapy may continue to receive dacarbazine in the absence of disease progression. Patients who experience unacceptable dacarbazine-related toxicity or disease progression may receive PI-88 alone as second-line therapy at the discretion of the PI.
- Arm II: Patients receive dacarbazine and PI-88 as in the lead-in phase, part 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease after 6 courses of therapy may continue to receive dacarbazine and PI-88 in the absence of disease progression. Patients who experience unacceptable dacarbazine-related toxicity after 6 courses of therapy but who continue to have responding or stable disease may receive PI-88 alone as maintenance therapy at the discretion of the PI.
Study Start
Eligibility & Criteria
Disease Characteristics:
-
Histologically confirmed melanoma
- Metastatic disease
- Unresectable disease
-
Measurable disease by MRI or CT scan
- Cutaneous lesions must be measurable by physical exam
- No ocular melanoma
- No history of CNS involvement, including brain or meningeal metastases
Patient Characteristics:
Performance status: ECOG 0-1
Life expectancy: At least 3 months
Hematopoietic
- Absolute neutrophil count > 1,500/mm^3
- Platelet count > 100,000/mm^3
- WBC > 3,000/mm^3
- No other abnormal bleeding tendency
Hepatic
- PT < 1.5 times upper limit of normal (ULN)
- APTT < 1.5 times ULN
- Bilirubin ≤ 1.5 times ULN
- AST or ALT ≤ 3 times ULN, unless patient has hepatic metastases
- Lactic dehydrogenase ≤ 2 times ULN
- Alkaline phosphatase ≤ 5 times ULN, unless patient has bone metastases
Renal
- Creatinine clearance or glomerular filtration rate > 40 mL/min
Cardiovascular
-
None of the following within the past 3 months:
- Myocardial infarction
- Stroke
- Congestive heart failure
Immunologic
- No history of allergy and/or hypersensitivity to anti-coagulants or thrombolytic agents, especially heparin
- No history of immune-mediated thrombocytopenia, thrombotic thrombocytopenic purpura, or other platelet disease
- No laboratory evidence of anti-warfarin antibodies
- No uncontrolled or serious infection within the past 4 weeks
Other
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment
- No acute or chronic gastrointestinal bleeding within the past 2 years
- No inflammatory bowel disease
- No risk of bleeding due to open wounds or planned surgery
- No clinically significant non-malignant disease
- No other malignancy except previously treated stage I malignancy for which the patient has been disease-free for ≥ 5 years, nonmelanoma skin cancer, or carcinoma in situ of the cervix
Prior Concurrent Therapy:
Biologic therapy
- More than 4 weeks since prior vaccines and/or biologic response modifiers
Chemotherapy
- No prior chemotherapy
Endocrine therapy
- Not specified
Radiotherapy
-
More than 4 weeks since prior radiotherapy, except for local palliative radiotherapy
- Concurrent local palliative radiotherapy for symptomatic control allowed
- More than 3 months since prior radiotherapy to > 30% of the bone marrow
Surgery
- More than 4 weeks since prior major surgery
Other
- More than 2 weeks since prior and no concurrent heparin or low molecular weight heparin
-
No concurrent administration of any of the following:
-
Aspirin (> 150 mg/day) or other non-steroidal anti-inflammatory drug (except specific cyclooxygenase-2 [COX-2] inhibitors)
- Concurrent low-dose aspirin (≤ 150 mg/day) allowed
-
Warfarin (> 1 mg/day)
- Concurrent low-dose warfarin (≤ 1 mg/day) allowed
-
Anti-platelet drugs, including, but not limited to, any of the following:
- Abciximab
- Clopidogrel
- Dipyridamole
- Ticlopidine
- Tirofiban
-
- No other concurrent investigational or antineoplastic drugs
Total Enrolment
118
Contact Details
Sydney Cancer Centre at Royal Prince Alfred Hospital, Sydney, New South Wales, 2050, Australia; Recruiting
Queensland
Princess Alexandra Hospital, Brisbane, Queensland, 4102, Australia; Recruiting
Western Australia
Sir Charles Gairdner Hospital – Perth, Perth, Western Australia, 6009, Australia; Recruiting
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