Stage IIIC Melanoma, Stage IV Melanoma
Conditions
Keywords
Neoplasms
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.
Interventions
Denileukin diftitox intravenous infusion over 30-60 minutes.
Sponsors
PharmaBio Development Inc.
Eisai Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants may be entered in the study only if they meet all of the following criteria. 1. Male or female participants greater than or equal to18 years of age; 2. Participants with histologically confirmed melanoma (Stage IIIC or Stage IV, American Joint Commission on Cancer); 3. Naive to prior systemic chemotherapy, targeted therapy (eg, BRAF), or immunotherapy (eg, interleukin-2 \[IL-2\] or interferon) for the treatment of melanoma, including any cytotoxic agents or IL-2 used for adjuvant therapy (adjuvant interferon is allowed). Prior granulocyte macrophage colony-stimulating factor (GM-CSF) is allowed; 4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2; 5. Life expectancy greater than or equal to 3 months; 6. At least 1 site of radiographically measurable disease by immune-related response criteria (irRC); 7. Serum albumin greater than or equal to 3 g/dL; 8. Adequate hematologic, renal, and liver function as defined by laboratory values performed within 21 days prior to initiation of dosing: * Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L; * Platelet count greater than or equal to 100 x 10\^9/L; * Hemoglobin greater than or equal to 9 g/dL; * Serum creatinine less than or equal 1.5 x upper limit of normal (ULN) or creatinine clearance greater than or equal to 50 mL/min; * Total serum bilirubin less than or equal to 1.5 x ULN; * Serum aspartate transaminase (AST/SGOT) or serum alanine transaminase (ALT/SGPT) less than or equal to 2.5 x ULN, and less than or equal to 5 x ULN if liver metastases are present. 9. Fertile males should use an effective method of contraception during treatment and for at least 3 months after completion of treatment, as directed by their physician; 10. Pre-menopausal females and females less than 2 years after the onset of menopause should have a negative pregnancy test at Screening. Pre-menopausal females must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 90 days after the last dose of study drug. Females of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for greater than or equal to 1 year; Before study entry, written informed consent must be obtained from the participants prior to performing any study-related procedures.
Exclusion criteria
Participants will not be entered in the study for any of the following: 1. Known central nervous system (CNS) lesions, except for asymptomatic non-progressing, treated brain metastases. Treated brain metastases are defined as having no evidence of progression or hemorrhage for 2 months, as ascertained by clinical examination and brain imaging (magnetic resonance imaging \[MRI\] or computerized tomography \[CT\]) during the Screening period (using the pretreatment brain image as Baseline). Treatment for brain metastases must have been completed at least 2 months prior to Day 1 of the first treatment cycle and may include whole brain radiotherapy, radiosurgery (Gamma Knife, LINAC, or equivalent), or a combination as deemed appropriate by the treating physician. Dexamethasone must be discontinued at least 4 weeks prior to Day 1. Participants with CNS metastases treated by neurosurgical resection or brain biopsy performed within 2 months prior to Day 1 will be excluded; 2. Carcinomatous meningitis; 3. Prior treatment with denileukin diftitox; 4. Known hypersensitivity to denileukin diftitox or any of its components: diphtheria toxin, IL-2, or excipients; 5. Prior surgery for melanoma less than 4 weeks before enrollment; 6. Other malignancy within 3 years of randomization, with the exception of adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer, with no subsequent evidence of recurrence and/or malignancies diagnosed at a stage where definitive therapy results in near certain cures. The Medical Monitor must be consulted in such cases; 7. Currently receiving any other anticancer treatment for melanoma (including palliative radiotherapy); 8. Received treatment in another clinical study within the 4 weeks prior to commencing study treatment or participants who have not recovered from side effects of an investigational drug to Common Terminology Criteria for Adverse Events (CTCAE) Grade less than or equal to 1, except for alopecia; 9. Received radiotherapy for non-CNS disease within the 2 weeks prior to commencing study treatment or have not recovered from side effects of all radiation-related toxicities to Grade less than or equal to 1, except for alopecia; 10. Significant cardiovascular impairment (history of congestive heart failure New York Heart Association \[NYHA\] Grade greater than 2 \[see Appendix 5\], unstable angina, or myocardial infarction within the past 6 months, or serious cardiac arrhythmia); 11. Use of chronic systemic steroids (\>5 days) within 2 weeks of Day 1 of the first treatment cycle (replacement therapy for adrenal insufficiency is allowed); 12. Participants with an allograft requiring immunosuppression; 13. Known positive human immunodeficiency virus (HIV), known hepatitis B surface antigen, or hepatitis C positive; 14. Pregnant, breast-feeding, or refusing double barrier contraception, oral contraceptives, or avoidance of pregnancy measures; Have any other uncontrolled infection or medical condition that could interfere with the conduct of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 12 investigative sites in the United States from 22 June 2010 to 07 April 2015.
Pre-assignment details
A total of 75 participants were randomized and treated.
Participants by arm
| Arm | Count |
|---|---|
| Denileukin Diftitox on Days 1 to 4 Participants received Denileukin Diftitox 12 mcg/kg/day on Days 1 to 4 of 21-day treatment cycle for a total of 4 cycles (12 weeks) or until unacceptable toxicity or rapid and life-threatening progressive disease. | 43 |
| Denileukin Diftitox on Days 1, 8, and 15 Participants received Denileukin Diftitox 12 mcg/kg/day on Days 1, 8 and 15 of 21-day treatment cycle for a total of 4 cycles (12 weeks) or until unacceptable toxicity or rapid and life-threatening progressive disease. | 32 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Reason by Sponsor | 2 | 2 |
| Overall Study | Completed 1 Year Follow-up after last dose of study drug | 14 | 12 |
| Overall Study | Death | 22 | 17 |
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Other | 2 | 1 |
Baseline characteristics
| Characteristic | Denileukin Diftitox on Days 1, 8, and 15 | Total | Denileukin Diftitox on Days 1 to 4 |
|---|---|---|---|
| Age, Continuous | 68 years | 66 years | 66 years |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 31 Participants | 71 Participants | 40 Participants |
| Sex: Female, Male Female | 12 Participants | 23 Participants | 11 Participants |
| Sex: Female, Male Male | 20 Participants | 52 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 22 / 43 | 17 / 32 |
| other Total, other adverse events | 43 / 43 | 9 / 32 |
| serious Total, serious adverse events | 15 / 43 | 8 / 32 |
Outcome results
Primary
Percentage of Participants With Immune-related Overall Response Rate (irORR)
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).
Time frame: From the start of treatment up to 1 year 6 months
Population: MITT included all participants enrolled and randomized to treatment and had an efficacy evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Denileukin Diftitox on Days 1 to 4 | Percentage of Participants With Immune-related Overall Response Rate (irORR) | 9.5 percentage of participants |
| Denileukin Diftitox on Days 1, 8, and 15 | Percentage of Participants With Immune-related Overall Response Rate (irORR) | 3.1 percentage of participants |
Secondary
Change From Baseline in CD4+CD127-/loCD25+CD152- Cells Expression Pattern at Weeks 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.
Time frame: Baseline, Week 12
Population: MITT included all participants enrolled and randomized to treatment and had an efficacy evaluation. Here 'N' (overall number of participants analyzed) included all participants who were evaluable for this outcome measure and 'n' (number analyzed) included all participants who were evaluable at specified timepoints for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Denileukin Diftitox on Days 1 to 4 | Change From Baseline in CD4+CD127-/loCD25+CD152- Cells Expression Pattern at Weeks 12 | At Baseline | 135.9 cells per microliter | Standard Deviation 86.17 |
| Denileukin Diftitox on Days 1 to 4 | Change From Baseline in CD4+CD127-/loCD25+CD152- Cells Expression Pattern at Weeks 12 | Change at Week 12 | 6.4 cells per microliter | Standard Deviation 69.63 |
| Denileukin Diftitox on Days 1, 8, and 15 | Change From Baseline in CD4+CD127-/loCD25+CD152- Cells Expression Pattern at Weeks 12 | At Baseline | 184.9 cells per microliter | Standard Deviation 114.9 |
| Denileukin Diftitox on Days 1, 8, and 15 | Change From Baseline in CD4+CD127-/loCD25+CD152- Cells Expression Pattern at Weeks 12 | Change at Week 12 | -46.1 cells per microliter | Standard Deviation 74.72 |
Secondary
Change From Baseline in CD4+CD127-/loCD25hiCD152- Cells Expression Pattern at Weeks 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.
Time frame: Baseline, Week 12
Population: MITT included all participants enrolled and randomized to treatment and had an efficacy evaluation. Here 'N' (overall number of participants analyzed) included all participants who were evaluable for this outcome measure and 'n' (number analyzed) included all participants who were evaluable at specified timepoints for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Denileukin Diftitox on Days 1 to 4 | Change From Baseline in CD4+CD127-/loCD25hiCD152- Cells Expression Pattern at Weeks 12 | At Baseline | 34.8 cells per microliter | Standard Deviation 16.58 |
| Denileukin Diftitox on Days 1 to 4 | Change From Baseline in CD4+CD127-/loCD25hiCD152- Cells Expression Pattern at Weeks 12 | Change at Week 12 | -8.0 cells per microliter | Standard Deviation 19.22 |
| Denileukin Diftitox on Days 1, 8, and 15 | Change From Baseline in CD4+CD127-/loCD25hiCD152- Cells Expression Pattern at Weeks 12 | At Baseline | 40.0 cells per microliter | Standard Deviation 21.01 |
| Denileukin Diftitox on Days 1, 8, and 15 | Change From Baseline in CD4+CD127-/loCD25hiCD152- Cells Expression Pattern at Weeks 12 | Change at Week 12 | -13.3 cells per microliter | Standard Deviation 13.37 |
Secondary
Duration of Response
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.
Time frame: 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
Population: MITT included all participants enrolled and randomized to treatment and had an efficacy evaluation. Here overall number of participants analyzed signifies participants who had confirmed irCR or irPR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Denileukin Diftitox on Days 1 to 4 | Duration of Response | 32.9 weeks |
| Denileukin Diftitox on Days 1, 8, and 15 | Duration of Response | 54.3 weeks |
Secondary
Overall Survival (OS)
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.
Time frame: From the date of randomization until the date of death up to 1 year 6 months
Population: MITT included all participants enrolled and randomized to treatment and had an efficacy evaluation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Denileukin Diftitox on Days 1 to 4 | Overall Survival (OS) | 51.1 weeks |
| Denileukin Diftitox on Days 1, 8, and 15 | Overall Survival (OS) | 54.3 weeks |
Secondary
Percentage of Participants With OS at 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.
Time frame: From the date of randomization up to 1 year
Population: MITT included all participants enrolled and randomized to treatment and had an efficacy evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Denileukin Diftitox on Days 1 to 4 | Percentage of Participants With OS at 1 Year | 42.8 percentage of participants |
| Denileukin Diftitox on Days 1, 8, and 15 | Percentage of Participants With OS at 1 Year | 50.0 percentage of participants |
Secondary
Percentage of Participants With PFS at 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.
Time frame: Month 6
Population: MITT included all participants enrolled and randomized to treatment and had an efficacy evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Denileukin Diftitox on Days 1 to 4 | Percentage of Participants With PFS at Month 6 | 28.5 percentage of participants |
| Denileukin Diftitox on Days 1, 8, and 15 | Percentage of Participants With PFS at Month 6 | 23.0 percentage of participants |
Secondary
Progression Free Survival (PFS)
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.
Time frame: 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
Population: MITT included all participants enrolled and randomized to treatment and had an efficacy evaluation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Denileukin Diftitox on Days 1 to 4 | Progression Free Survival (PFS) | 12.1 weeks |
| Denileukin Diftitox on Days 1, 8, and 15 | Progression Free Survival (PFS) | 12.1 weeks |