Study of Denileukin Diftitox in Participants With Stage IIIC and Stage IV Melanoma
- Conditions
- Stage IIIC MelanomaStage IV Melanoma
- Interventions
- Registration Number
- NCT01127451
- Lead Sponsor
- Eisai Inc.
- Brief Summary
The purpose of this study is to determine whether participants with Stage IIIC and Stage IV Melanoma experience benefit when treated with Denileukin diftitox in two different dosing schedules.
- Detailed Description
This is a multicenter, open-label, dose/schedule and clinical efficacy study in participants with Stage IIIC and Stage IV melanoma.
Dose-Schedules: This is a schedule, dose, and pharmacodynamic study of Denileukin diftitox in participants with Stage IIIC and Stage IV melanoma. Two arms of 40 participants each were originally planned (see below) for a total of 80 participants. Participants were randomly assigned to 1 of 2 arms: 1. 12 mcg/kg/day on Days 1 through 4 of each 21-day treatment cycle, for a total of 4 cycles (12 weeks); 2. 12 mcg/kg/day on Days 1, 8, and 15 of each 21-day treatment cycle, for a total of 4 cycles (12 weeks). Participants will be evaluated for (clinical response, safety and tolerability, and pharmacodynamic measures of ONTAK activity. An optional substudy will be conducted that will involve collection of serial tumor biopsies at study entry and Day 84 in order to assess tissue pharmacodynamic markers of ONTAK activity (Treg depletion in tumor, appearance of melanoma antigen-specific CD8+lymphocytes, and other markers of mucosal immunity and inflammatory response).
Following an amendment, participants will be enrolled in Arm 1 only (expanded to a total of 55 participants) and Arm 2 was closed. According to the original design, if two responses or less were observed among 22 participants on either arm, that arm would be discontinued.
Participants experiencing clinical benefit (immune-related stable disease \[irSD\], immune-related partial response \[irPR\], or immune-related complete response \[irCR\] per irRC) after 4 cycles of treatment, may continue their denileukin diftitox treatment for up to 8 cycles.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 75
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Denileukin Diftitox on Days 1, 8, and 15 Denileukin diftitox Participants received Denileukin Diftitox 12 mcg/kg/day on Days 1, 8, and 15 of each 21-day treatment cycle, for a total of 4 cycles (12 weeks). ARM 2 was closed. Participants experiencing clinical benefit (irSD, irPR, or irCR per irRC) after 4 cycles of treatment, may continue their denileukin diftitox treatment for up to 8 cycles. Denileukin Diftitox on Days 1 to 4 Denileukin diftitox Participants received Denileukin Diftitox 12 mcg/kg/day (microgram per kilogram) on Days 1 through 4 of each 21-day treatment cycle, for a total of 4 cycles (12 weeks).
- Primary Outcome Measures
Name Time Method Percentage of Participants With Immune-related Overall Response Rate (irORR) From the start of treatment up to 1 year 6 months irORR was defined as the percentage of participants with best confirmed response (immune-related complete response \[irCR\] or immune-related partial response \[irPR\]). irORR was assessed by immune-related response criteria (irRC). Per irRC criteria, irCR was defined as complete disappearance of all tumor lesions, whether measurable or not, and no new lesions. irPR was defined as decrease in tumor burden by 50 percent (%) or greater (confirmed in 2 observations at least 4 weeks apart).
- Secondary Outcome Measures
Name Time Method Progression Free Survival (PFS) From the start of treatment to the date of first documentation of irPD, or date of death, whichever occurred first up to 1 year 6 months The PFS was defined as time from start of study treatment until immune-related progressive disease (irPD) or death. If the participant did not progress, the participant was censored at the date of last tumor assessment, known alive, or until starting a next line of therapy, whichever occurred first. PFS was assessed by irRC. irPD was defined as at least 25% increase in tumor burden relative to nadir (at any single time point) in 2 consecutive observations at least 4 weeks apart. The PFS was estimated using the Kaplan-Meier method. The median time (weeks) and the corresponding 90% confidence interval were estimated for each treatment group are reported.
Percentage of Participants With PFS at Month 6 Month 6 The PFS was defined as time from start of study treatment until irPD or death. If the participant did not progress, the participant was censored at the date of last tumor assessment, known alive, or until starting a next line of therapy, whichever occurred first. PFS was assessed by irRC. irPD was defined as at least 25% increase in tumor burden relative to nadir (at any single time point) in 2 consecutive observations at least 4 weeks apart. Percentage of participants with PFS at month 6 are reported and was estimated using the Kaplan-Meier method.
Duration of Response From date of the first demonstration of irCR or irPR until the date of first demonstration of PD, date of death, or withdrawal from study up to 1 year 6 months Duration of response was defined as the time from date of the first assessment demonstrating an irCR or irPR to date of the first assessment demonstrating progressive disease (PD), death, or withdrawal from study. In the absence of confirmation of death or PD, duration of response was censored at the last date of follow-up when the participant was known to be alive and have maintained a response. Duration of response was assessed by irRC. Per irRC criteria, irCR was defined as complete disappearance of all tumor lesions, whether measurable or not, and no new lesions. irPR was defined as decrease in tumor burden by 50% or greater (confirmed in 2 observations at least 4 weeks apart). The duration of response was estimated using the Kaplan-Meier method.
Overall Survival (OS) From the date of randomization until the date of death up to 1 year 6 months The OS was defined as the time from the date of randomization until the date of death. OS was estimated by Kaplan-Meier method. The median time (weeks) and the corresponding 90% confidence interval were estimated for each treatment group were reported.
Percentage of Participants With OS at 1 Year From the date of randomization up to 1 year The OS was defined as the time from the date of randomization until the date of death. OS at 1 year was estimated by Kaplan-Meier method. OS at 1 year was measured as the percentage of participants still alive at 1 year from the date of randomization.
Change From Baseline in CD4+CD127-/loCD25+CD152- Cells Expression Pattern at Weeks 12 Baseline, Week 12 Treg (regulatory T cells) from peripheral blood and tumor tissues were assessed for best immune-related response. Assessment of Treg cells was done by immunohistochemical (IHC) analysis. Change from baseline in CD4+CD127-/loCD25+CD152- (surface marker expressed in Treg cells) expression pattern, by treatment and immune-related response are reported.
Change From Baseline in CD4+CD127-/loCD25hiCD152- Cells Expression Pattern at Weeks 12 Baseline, Week 12 Treg (regulatory T cells) from peripheral blood and tumor tissues were assessed for best immune-related response. Assessment of Treg cells was done by IHC analysis. Change from baseline in CD4+CD127-/loCD25hiCD152- (surface marker expressed in Treg cells) expression pattern, by treatment and immune-related response are reported.