Melanoma (Skin)
Conditions
Keywords
stage III melanoma, stage IV melanoma, recurrent melanoma
Brief summary
RATIONALE: Vaccines made from melanoma cells may make the body build an immune response to and kill tumor cells. Colony-stimulating factors such as GM-CSF may increase the number of immune cells found in the bone marrow or peripheral blood. Interleukin-2 may stimulate a person's white blood cells to kill melanoma cells. Combining vaccine therapy with GM-CSF and interleukin-2 may be kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of vaccines made from melanoma cells with or without GM-CSF followed by interleukin-2 in treating patients with stage III or stage IV melanoma.
Detailed description
OBJECTIVES: I. Compare the effectiveness of vaccination with synthetic melanoma peptides pulsed on autologous dendritic cells versus vaccination with synthetic melanoma peptides plus sargramostim (GM-CSF) in decreasing tumor burden in patients with high risk melanoma (pulsed autologous dendritic cell arm closed 1/8/2001). II. Determine whether these regimens result in increased tumor specific immune responses as measured in vitro and in vivo. III. Determine whether these regimens stimulate T-cell responses in these patients. OUTLINE: This is an open label study. Patients are included in treatment arm II only (arm I closed 1/8/2001): Arm I: Patients undergo leukapheresis to collect dendritic cells. Patients receive a mixture of synthetic melanoma peptides (gp100 antigen, tyrosinase, and tetanus peptides) pulsed on autologous dendritic cells IV and subcutaneously (SC). Arm II: Patients receive a mixture of synthetic melanoma peptides (gp100 antigen, tyrosinase, and tetanus peptides) and sargramostim (GM-CSF) emulsified in Montanide ISA-51 SC and intradermally. Patients receive vaccination during weeks 0, 1, 2, 4, 5, and 6 for a total of 6 doses and interleukin-2 SC daily on days 7-49. Patients receive 3 additional vaccinations at different sites not involved with the tumor concurrently with the first 3 vaccinations. Patients are evaluated at 8 weeks, 12 weeks, 6 months, 12 months, and 24 months. PROJECTED ACCRUAL: A total of 27-54 patients will be accrued for this study within 2 years.
Interventions
BIOLOGICALtyrosinase peptide
BIOLOGICALaldesleukin
Systemic subcutaneous delivery of low-dose IL-2.
BIOLOGICALgp100 antigen
BIOLOGICALincomplete Freund's adjuvant
BIOLOGICALsargramostim
BIOLOGICALtetanus peptide melanoma vaccine
Sponsors
National Cancer Institute (NCI)
University of Virginia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: Histologically or cytologically confirmed stage III or IV melanoma gp100 positive tumor cells and/or tyrosinase positive tumor cells HLA type A1, A2, or A3 Measurable disease May have up to 3 brain metastases if all are less than 2 cm in diameter and are asymptomatic, and there is no mass effect or they have been treated successfully by surgical excision or by gamma knife radiation therapy PATIENT CHARACTERISTICS: Age: 18 to 79 Performance status: ECOG 0-1 Life expectancy: Not specified Hematopoietic: Absolute neutrophil count greater than 1,000/mm3 Platelet count greater than 100,000/mm3 Hemoglobin greater than 9 g/dL Hepatic: Bilirubin no greater than 2.5 times upper limit of normal (ULN) AST and ALT no greater than 2.5 times ULN Alkaline phosphatase no greater than 2.5 times ULN Renal: Creatinine no greater than 1.5 times ULN Cardiovascular: No New York Heart Association class II, III, or IV heart disease Other: No known or suspected allergy to any component of the vaccine No medical condition that would preclude study Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: At least 3 months since prior growth factors At least 3 months since prior agents with putative immunomodulating activity (except nonsteroidal antiinflammatory agents) At least 1 year since other prior melanoma vaccinations Chemotherapy: At least 3 months since prior chemotherapy No concurrent chemotherapy Endocrine therapy: At least 3 months since prior corticosteroids No concurrent corticosteroids Radiotherapy: At least 3 months since prior radiotherapy No concurrent radiotherapy Surgery: See Disease Characteristics Other: At least 3 months since other prior investigational drugs or therapy At least 3 months since prior allergy desensitization injections At least 14 days since completion of acute treatment for a serious infection No concurrent allergy desensitization injections
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Objective Clinical Response (CR/PR/SD) | Weeks 0-6,12; Months 6,12 and 24 | The primary end point for this trial was clinical response. This was assessed by measurement of assessable metastatic deposits by CT, MRI, or direct measure of cutaneous deposits. Baseline tumor measurements used for assessment of clinical response were those obtained most immediately before the first vaccine administration and within 6 weeks of protocol entry. Measurements were made and reviewed by a multidisciplinary team. The original protocol defined tumor response on the basis of changes in cross-sectional area calculated as the product of two perpendicular measures. However, since the initiation of this study, the Response Evaluation Criteria in Solid Tumors Group (RECIST) system was employed as the current standard for clinical trials, in which response is based on changes in maximum cross-sectional dimensions. Computed tomography scans of clinical responders were reviewed again by a senior faculty radiologist not otherwise involved in the study. |
| Measure of Tumor-antigen-specific Immunity in Peripheral Blood Mononuclear Cells (PBMC) by Elispot Assay | Weeks 0-6,12; Months 6,12 and 24 | — |
| Measure of Tumor-antigen-specific Immunity in Sentinel Immunized Node (SIN) by Elispot Assay | Weeks 0-6,12; Months 6,12 and 24 | — |
Countries
United States
Participant flow
Pre-assignment details
13 participants were assigned to each arm in Stage I. 14 additional participants were assigned in Stage II to study arm 2. Data are reported for stage I. Reporting is planned for stage II when data are available.
Participants by arm
| Arm | Count |
|---|---|
| Peptides Pulsed on Dendritic Cells | 13 |
| Peptides in GMCSF-in-adjuvant | 28 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Peptides in GMCSF-in-adjuvant | Peptides Pulsed on Dendritic Cells | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 4 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 9 Participants | 32 Participants |
| Age, Continuous | 55 years STANDARD_DEVIATION 11 | 57 years STANDARD_DEVIATION 13 | 55 years STANDARD_DEVIATION 12 |
| Region of Enrollment United States | 28 participants | 13 participants | 41 participants |
| Sex: Female, Male Female | 9 Participants | 7 Participants | 16 Participants |
| Sex: Female, Male Male | 19 Participants | 6 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 10 | 27 / 27 |
| serious Total, serious adverse events | 0 / 10 | 5 / 27 |
Outcome results
Primary
Evaluation of Objective Clinical Response (CR/PR/SD)
The primary end point for this trial was clinical response. This was assessed by measurement of assessable metastatic deposits by CT, MRI, or direct measure of cutaneous deposits. Baseline tumor measurements used for assessment of clinical response were those obtained most immediately before the first vaccine administration and within 6 weeks of protocol entry. Measurements were made and reviewed by a multidisciplinary team. The original protocol defined tumor response on the basis of changes in cross-sectional area calculated as the product of two perpendicular measures. However, since the initiation of this study, the Response Evaluation Criteria in Solid Tumors Group (RECIST) system was employed as the current standard for clinical trials, in which response is based on changes in maximum cross-sectional dimensions. Computed tomography scans of clinical responders were reviewed again by a senior faculty radiologist not otherwise involved in the study.
Time frame: Weeks 0-6,12; Months 6,12 and 24
Population: The analysis of this outcome measure was performed on subjects enrolled in Stage I of the trial, which included 13 subjects in each arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peptides Pulsed on Dendritic Cells | Evaluation of Objective Clinical Response (CR/PR/SD) | Partial Response | 1 participants |
| Peptides Pulsed on Dendritic Cells | Evaluation of Objective Clinical Response (CR/PR/SD) | Progressive Disease | 11 participants |
| Peptides Pulsed on Dendritic Cells | Evaluation of Objective Clinical Response (CR/PR/SD) | Stable Disease | 1 participants |
| Peptides Pulsed on Dendritic Cells | Evaluation of Objective Clinical Response (CR/PR/SD) | Complete Response | 0 participants |
| Peptides in GMCSF-in-adjuvant | Evaluation of Objective Clinical Response (CR/PR/SD) | Stable Disease | 2 participants |
| Peptides in GMCSF-in-adjuvant | Evaluation of Objective Clinical Response (CR/PR/SD) | Partial Response | 2 participants |
| Peptides in GMCSF-in-adjuvant | Evaluation of Objective Clinical Response (CR/PR/SD) | Complete Response | 0 participants |
| Peptides in GMCSF-in-adjuvant | Evaluation of Objective Clinical Response (CR/PR/SD) | Progressive Disease | 9 participants |
Primary
Measure of Tumor-antigen-specific Immunity in Peripheral Blood Mononuclear Cells (PBMC) by Elispot Assay
Time frame: Weeks 0-6,12; Months 6,12 and 24
Population: The analysis of this outcome measure was performed on subjects enrolled in Stage I of the trial, which included 13 subjects in each arm. Some patients were not evaluable because of inadequate sample availability.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peptides Pulsed on Dendritic Cells | Measure of Tumor-antigen-specific Immunity in Peripheral Blood Mononuclear Cells (PBMC) by Elispot Assay | 1 responders |
| Peptides in GMCSF-in-adjuvant | Measure of Tumor-antigen-specific Immunity in Peripheral Blood Mononuclear Cells (PBMC) by Elispot Assay | 5 responders |
Comparison: This is a test for differences between the response rates of the two arms. The null hypothesis is that the arms have equal response rates and the alternative hypothesis is that they are different.p-value: 0.13Chi-squared
Primary
Measure of Tumor-antigen-specific Immunity in Sentinel Immunized Node (SIN) by Elispot Assay
Time frame: Weeks 0-6,12; Months 6,12 and 24
Population: Analysis of this outcome measure was performed on subjects in Stage I of the trial. Sentinel immunized nodes (SIN) were not evaluable for early tumor progression (5 arm 1, 2 arm 2) and patient refusal (1 arm 2). Thus, SINs were evaluable from 8 in arm 1 and 10 on arm 2, exceeding the protocol requirement for at least 6 subjects on each arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peptides Pulsed on Dendritic Cells | Measure of Tumor-antigen-specific Immunity in Sentinel Immunized Node (SIN) by Elispot Assay | 1 responders |
| Peptides in GMCSF-in-adjuvant | Measure of Tumor-antigen-specific Immunity in Sentinel Immunized Node (SIN) by Elispot Assay | 8 responders |
Comparison: This is a test for differences between the response rates of the two arms. The null hypothesis is that the arms have equal response rates and the alternative hypothesis is that they are different.p-value: 0.004Chi-squared