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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Melanoma

Intervention / Treatment
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* Drug: PI-88 and dacarbazine
* Drug: dacarbazine or DTIC


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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.. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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phase II, metastatic melanoma, dacarbazine, combination, PI-88