Melanoma
Conditions
Keywords
phase II, metastatic melanoma, dacarbazine, combination, PI-88
Brief summary
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
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.
Interventions
DRUGPI-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
DRUGdacarbazine or DTIC
intravenous infusion 1000 mg/m2 on day 1 of every 21 day cycle
Sponsors
Medigen Biotechnology Corporation
Cellxpert Biotechnology Corp.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Non-progression Rate After Six 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) | The Proportion of Patients With Objective Response or Stable Disease (Non-progression Rate) after six treatment cycles |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-progression Rate | In week 3 of every second cycle (each cycle was 21 days) for all subjects enrolled in cycle 2 and cycle 4. | The Proportion of Patients With Objective Response or Stable Disease (Non-progression Rate) after 2 or 4 treatment cycles |
| Time to 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. | treatment was to continue until the subject experienced disease progression. |
| Duration of Response | 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. | time from commencement to radiological evidence of progression |
| Survival | 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.. | time to death and also at time-points 6 month and 12 months |
Countries
Australia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
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 | 65 |
| Arm 2- Dacarbazine Alone dacarbazine 1000 mg/m2 on day 1 of every 21 day cycle by intravenous infusion
dacarbazine or DTIC: intravenous infusion 1000 mg/m2 on day 1 of every 21 day cycle | 66 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | did not meet criteria | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1- PI-88 Plus Dacarbazine | Arm 2- Dacarbazine Alone | Total |
|---|---|---|---|
| Age, Continuous | 60.4 years STANDARD_DEVIATION 13.26 | 57.9 years STANDARD_DEVIATION 13.07 | 59.1 years STANDARD_DEVIATION 13.17 |
| BMI | 28.15 kg/m^2 STANDARD_DEVIATION 5.277 | 27.64 kg/m^2 STANDARD_DEVIATION 5.1 | 27.89 kg/m^2 STANDARD_DEVIATION 5.175 |
| ECOG status 0 | 44 participants | 45 participants | 89 participants |
| ECOG status 1 | 21 participants | 21 participants | 42 participants |
| Height | 174.0 cm STANDARD_DEVIATION 8.11 | 171.2 cm STANDARD_DEVIATION 9.57 | 172.6 cm STANDARD_DEVIATION 8.95 |
| Race/Ethnicity, Customized Caucasian | 63 Participants | 65 Participants | 128 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 15 Participants | 27 Participants | 42 Participants |
| Sex: Female, Male Male | 50 Participants | 39 Participants | 89 Participants |
| Weight | 85.11 kg STANDARD_DEVIATION 15.46 | 81.54 kg STANDARD_DEVIATION 17.25 | 83.31 kg STANDARD_DEVIATION 16.42 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 65 / 65 | 61 / 66 |
| serious Total, serious adverse events | 20 / 65 | 13 / 66 |
Outcome results
Primary
Non-progression Rate After Six Cycles
The Proportion of Patients With Objective Response or Stable Disease (Non-progression Rate) after six treatment cycles
Time frame: 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)
Population: ITT population consisted of all subjects randomised to treatment who received at least one dose of study medication, had a valid baseline measurement and who had returned for at least one visit post-baseline
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1- PI-88 Plus Dacarbazine | Non-progression Rate After Six Cycles | Non-progressed | 13 Participants |
| Arm 1- PI-88 Plus Dacarbazine | Non-progression Rate After Six Cycles | Progressed | 52 Participants |
| Arm 2- Dacarbazine Alone | Non-progression Rate After Six Cycles | Non-progressed | 18 Participants |
| Arm 2- Dacarbazine Alone | Non-progression Rate After Six Cycles | Progressed | 47 Participants |
Secondary
Duration of Response
time from commencement to radiological evidence of progression
Time frame: 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.
Population: ITT population consisted of all subjects randomised to treatment who received at least one dose of study medication, had a valid baseline measurement and who had returned for at least one visit post-baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1- PI-88 Plus Dacarbazine | Duration of Response | 117.0 days | Standard Deviation 65.73 |
| Arm 2- Dacarbazine Alone | Duration of Response | 140.6 days | Standard Deviation 89.38 |
Secondary
Non-progression Rate
The Proportion of Patients With Objective Response or Stable Disease (Non-progression Rate) after 2 or 4 treatment cycles
Time frame: In week 3 of every second cycle (each cycle was 21 days) for all subjects enrolled in cycle 2 and cycle 4.
Population: ITT population, consisted of all subjects randomised to treatment who received at least one dose of study medication, had a valid baseline measurement and who had returned for at least one visit post-baseline.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1- PI-88 Plus Dacarbazine | Non-progression Rate | End of cycle 2_Non-progressed | 33 Participants |
| Arm 1- PI-88 Plus Dacarbazine | Non-progression Rate | End of cycle 2_progressed | 32 Participants |
| Arm 1- PI-88 Plus Dacarbazine | Non-progression Rate | End of cycle 4_Non-progressed | 24 Participants |
| Arm 1- PI-88 Plus Dacarbazine | Non-progression Rate | End of cycle 4_progressed | 41 Participants |
| Arm 2- Dacarbazine Alone | Non-progression Rate | End of cycle 4_progressed | 33 Participants |
| Arm 2- Dacarbazine Alone | Non-progression Rate | End of cycle 2_Non-progressed | 35 Participants |
| Arm 2- Dacarbazine Alone | Non-progression Rate | End of cycle 4_Non-progressed | 31 Participants |
| Arm 2- Dacarbazine Alone | Non-progression Rate | End of cycle 2_progressed | 30 Participants |
Secondary
Survival
time to death and also at time-points 6 month and 12 months
Time frame: 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..
Population: ITT population consisted of all subjects randomised to treatment who received at least one dose of study medication, had a valid baseline measurement and who had returned for at least one visit post-baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1- PI-88 Plus Dacarbazine | Survival | 304.00 days |
| Arm 2- Dacarbazine Alone | Survival | 416.00 days |
Secondary
Time to Progression
treatment was to continue until the subject experienced disease progression.
Time frame: 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.
Population: ITT population consisted of all subjects randomised to treatment who received at least one dose of study medication, had a valid baseline measurement and who had returned for at least one visit post-baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1- PI-88 Plus Dacarbazine | Time to Progression | 66 days |
| Arm 2- Dacarbazine Alone | Time to Progression | 82 days |