Recurrent Melanoma, Stage IIIA Skin Melanoma, Stage IIIB Skin Melanoma, Stage IIIC Skin Melanoma, Stage IV Skin Melanoma
Conditions
Brief summary
This randomized phase III trial studies aldesleukin with vaccine therapy to see how well it works compared to aldesleukin alone in treating patients with melanoma that has spread from where it started to nearby tissue or lymph nodes or to other places in the body. Aldesleukin may stimulate a person's white blood cells to kill melanoma cells. Vaccines may make the body build an immune response to kill tumor cells. It is not yet known whether combining aldesleukin with vaccine therapy is more effective than aldesleukin alone in treating melanoma.
Detailed description
PRIMARY OBJECTIVES: I. To identify whether the addition of the peptide vaccine to high dose interleukin (IL)-2 (aldesleukin) can result in a clinical response rate which may be superior to that found in similar patients treated with high dose IL-2 alone. SECONDARY OBJECTIVES: I. To evaluate the toxicity profile of patients treated on this trial, according to the regimen received. II. To compare the disease free/progression free survival of patients treated on both arms of the study. III. To determine the immunologic response experienced by patients who have received the peptide vaccination, as measured by changes in T-cell precursors from before to after treatment. IV. To evaluate the quality of life of patients before and after high-dose IL-2. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive aldesleukin intravenously (IV) over 15 minutes every 8 hours for 12 doses. ARM II: Patients receive gp100 antigen emulsified in Montanide ISA-51 subcutaneously (SC) on day 1. Patients also receive aldesleukin as in Arm I beginning on day 2. In both arms, treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease 3 weeks after completing 2 courses may receive a maximum of 12 additional courses. Patients with complete response may receive a maximum of 2 additional courses. After completion of treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.
Interventions
BIOLOGICALAldesleukin
Given IV
BIOLOGICALgp100 Antigen
Given SC
Given SC
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
OTHERLaboratory Biomarker Analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Any patient with measurable metastatic (stage IV or locally advanced stage III) cutaneous melanoma and an expected survival of greater than three months will be considered * Serum creatinine of 1.6 mg/dl or less * Total bilirubin 1.6 mg/dl or less * White blood cell (WBC) 3000/mm\^3 or greater * Platelet count 90,000 mm\^3 or greater * Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less then three times normal * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Patients of both genders must be willing to practice effective birth control during this trial * Pathologic confirmation of cutaneous melanoma; patients may enter the study with a pathologic diagnosis of cutaneous melanoma from any institution; all slides will be reviewed at National Institutes of Health (NIH) (department of Anatomic Pathology) and if the diagnosis is not confirmed, the patient will be excluded from the study * Tissue type human leukocyte antigen (HLA) A0201
Exclusion criteria
* Patients who have types of melanoma other than cutaneous, i.e. ocular or mucosal * Patients who are undergoing or have undergone in the past 4 weeks any other form of therapy except surgery for their cancer, including radiation therapy to any site * Patients who have active systemic infections, coagulation disorders, autoimmune disease or history of other major medical illnesses such as insulin dependent diabetes mellitus, cardiac ischemia, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary diseases and inflammatory bowel disorders * Patients who have significant psychiatric disease which in the opinion of the principal investigator would prevent adequate informed consent or render immunotherapy unsafe or contraindicated * Patients who require steroid therapy or steroid-containing compounds, or have used systemic steroids in the past 4 weeks, or have used topical or inhalational steroids in the past 2 weeks * Patients who are pregnant * Patients who are known to be positive for viral hepatitis B or C (hepatitis B surface antigen \[HBsAg\] or anti hepatitis C virus \[HCV\]) or human immunodeficiency virus (HIV) (HIV antibody) * Patients who have any form of primary or secondary immunodeficiency * Patients who have received previous high dose IL-2 (\> 600,000 IU/kg) * Patients who have received previous gp100 vaccines * Patients who have an abnormal stress cardiac test (stress thallium, stress multi gated acquisition scan \[MUGA\], dobutamine echocardiogram or other stress test that will rule out cardiac ischemia) * Patients who have abnormal pulmonary function tests (forced expiratory volume in one second \[FEV1\] \< 65% or forced vital capacity \[FVC\] \< 65% of predicted) * Patients who have brain metastasis or history of brain metastasis * No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease free for 5 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Response Rate (Partial Response [PR] + Complete Response [CR]) | Up to 12 years | A complete response (CR) was defined as the disappearance of all clinical evidence of disease for at least 4 weeks. A partial response (PR) was defined as a 50% or greater decrease in the sum of the products of perpendicular diameters of all measurable lesions for at least one month. No new lesions could appear, and none could increase 25% or more. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From the date of randomization until documentation of progression or last follow up, assessed up to 12 years | Progression free survival was compared between groups by means of Kaplan-Meier curves using the log-rank test to evaluate the significance of the difference between the arms. |
| Change in T-cell Precursors | Baseline to up to 12 years | To measure change in T-cell precursors, PBMC were tested for reactivity by measuring gamma-interferon release after overnight coculture with peptide pulsed T2 cells. PBMC obtained after 4 cycles of study treatment were compared to pre treatment PBMC. A positive assay was defined as greater than 100pg/ml gamma-interferon release and at least twice the release (including all control peptides) by post treatment PBMC compared to pre treatment PBMC. |
| Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Baseline to up to 8 weeks | QOL was measured before and after 2 cycles of treatment using 4 measures: FACT-G is a 27 item measure of QOL. A total score is calculated by summing across responses on a 5 point scale and ranges from 0-135, with higher scores indicating better QOL. FACT-F is 13 item measure of fatigue. A total score is calculated by summing across responses on a 5 point scale. Total score ranges from 0-52, with higher scores indicating less fatigue. SF-36 is a 36 item measure of self-reported health status. SF-36 is comprised of 8 subscales: physical function, role physical, bodily pain vitality, role emotional function, mental health, social function and general health. Summated scores range from 0-100, with higher scores indicating a better health state. SDS is a 13 item measure of symptom distress. A total score is calculated by summing across responses on a 5 point scale. Total score ranges from 13 to 65, with higher scores indicating more symptom distress. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Aldesleukin) Patients receive aldesleukin IV over 15 minutes every 8 hours for 12 doses. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease 3 weeks after completing 2 courses may receive a maximum of 12 additional courses. Patients with complete response may receive a maximum of 2 additional courses.
Aldesleukin: Given IV
Quality-of-Life Assessment: Ancillary studies
Questionnaire Administration: Ancillary studies
Laboratory Biomarker Analysis: Correlative studies | 94 |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) Patients receive gp100 antigen emulsified in Montanide ISA-51 SC on day 1. Patients also receive aldesleukin as in Arm I beginning on day 2. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease 3 weeks after completing 2 courses may receive a maximum of 12 additional courses. Patients with complete response may receive a maximum of 2 additional courses.
Aldesleukin: Given IV
gp100 Antigen: Given SC
Montanide ISA 51 VG: Given SC
Quality-of-Life Assessment: Ancillary studies
Questionnaire Administration: Ancillary studies
Laboratory Biomarker Analysis: Correlative studies | 91 |
| Total | 185 |
Baseline characteristics
| Characteristic | Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Total | Arm I (Aldesleukin) |
|---|---|---|---|
| Age, Continuous | 46.9 years | 48.6 years | 50.3 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 91 Participants | 184 Participants | 93 Participants |
| Sex: Female, Male Female | 34 Participants | 65 Participants | 31 Participants |
| Sex: Female, Male Male | 57 Participants | 120 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 93 / 93 | 85 / 85 |
| serious Total, serious adverse events | 1 / 93 | 2 / 85 |
Outcome results
Primary
Best Response Rate (Partial Response [PR] + Complete Response [CR])
A complete response (CR) was defined as the disappearance of all clinical evidence of disease for at least 4 weeks. A partial response (PR) was defined as a 50% or greater decrease in the sum of the products of perpendicular diameters of all measurable lesions for at least one month. No new lesions could appear, and none could increase 25% or more.
Time frame: Up to 12 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Aldesleukin) | Best Response Rate (Partial Response [PR] + Complete Response [CR]) | 6 Participants |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Best Response Rate (Partial Response [PR] + Complete Response [CR]) | 14 Participants |
p-value: 0.035Chi-squared
Secondary
Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale)
QOL was measured before and after 2 cycles of treatment using 4 measures: FACT-G is a 27 item measure of QOL. A total score is calculated by summing across responses on a 5 point scale and ranges from 0-135, with higher scores indicating better QOL. FACT-F is 13 item measure of fatigue. A total score is calculated by summing across responses on a 5 point scale. Total score ranges from 0-52, with higher scores indicating less fatigue. SF-36 is a 36 item measure of self-reported health status. SF-36 is comprised of 8 subscales: physical function, role physical, bodily pain vitality, role emotional function, mental health, social function and general health. Summated scores range from 0-100, with higher scores indicating a better health state. SDS is a 13 item measure of symptom distress. A total score is calculated by summing across responses on a 5 point scale. Total score ranges from 13 to 65, with higher scores indicating more symptom distress.
Time frame: Baseline to up to 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Pre treatment FACT-G | 84.2 units on a scale | Standard Error 2.77 |
| Arm I (Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Pre treatment SF-36 | 49.1 units on a scale | Standard Error 1.93 |
| Arm I (Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Post treatment SF-36 | 42.6 units on a scale | Standard Error 1.94 |
| Arm I (Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Pre treatment FACT-F | 43.1 units on a scale | Standard Error 1.47 |
| Arm I (Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Pre treatment SDS | 21.3 units on a scale | Standard Error 1.05 |
| Arm I (Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Post treatment FACT-G | 76.4 units on a scale | Standard Error 2.75 |
| Arm I (Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Post treatment SDS | 24.6 units on a scale | Standard Error 1.17 |
| Arm I (Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Post treatment FACT-F | 36.1 units on a scale | Standard Error 1.78 |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Post treatment SDS | 22.8 units on a scale | Standard Error 1.17 |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Pre treatment FACT-G | 83.8 units on a scale | Standard Error 2.74 |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Post treatment FACT-G | 81.2 units on a scale | Standard Error 2.71 |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Pre treatment FACT-F | 41.5 units on a scale | Standard Error 1.42 |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Post treatment FACT-F | 36.3 units on a scale | Standard Error 1.73 |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Post treatment SF-36 | 42.9 units on a scale | Standard Error 1.89 |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Pre treatment SDS | 21.2 units on a scale | Standard Error 1.05 |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Change in Quality of Life (QOL) Score Assessed by the FACT-G (Functional Assessment of Cancer Therapy- General), FACT-F (Functional Assessment of Cancer Therapy- Fatigue), SF-36 (Short Form 36) and SDS (Symptom Distress Scale) | Pre treatment SF-36 | 46.6 units on a scale | Standard Error 1.85 |
Comparison: FACT-G scalep-value: >0.05Mixed Models Analysis
Comparison: FACT-F scalep-value: >0.05Mixed Models Analysis
Comparison: SF-36 scalep-value: >0.05Mixed Models Analysis
Comparison: SDS scalep-value: >0.05Mixed Models Analysis
Secondary
Change in T-cell Precursors
To measure change in T-cell precursors, PBMC were tested for reactivity by measuring gamma-interferon release after overnight coculture with peptide pulsed T2 cells. PBMC obtained after 4 cycles of study treatment were compared to pre treatment PBMC. A positive assay was defined as greater than 100pg/ml gamma-interferon release and at least twice the release (including all control peptides) by post treatment PBMC compared to pre treatment PBMC.
Time frame: Baseline to up to 12 years
Population: All patients with paired cryopreserved peripheral blood lymphocytes obtained before any treatment and after completing 4 cycles of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Aldesleukin) | Change in T-cell Precursors | 0 Participants with a positive assay |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Change in T-cell Precursors | 7 Participants with a positive assay |
p-value: >0.05Fisher Exact
Secondary
Progression Free Survival
Progression free survival was compared between groups by means of Kaplan-Meier curves using the log-rank test to evaluate the significance of the difference between the arms.
Time frame: From the date of randomization until documentation of progression or last follow up, assessed up to 12 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Aldesleukin) | Progression Free Survival | 1.6 months |
| Arm II (gp100 Antigen in Montanide IDA-51 and Aldesleukin) | Progression Free Survival | 2.2 months |
p-value: 0.008Log Rank