Stage IV Melanoma
Conditions
Keywords
recurrent melanoma
Brief summary
RATIONALE: Aldesleukin may stimulate the white blood cells to kill tumor cells. Vaccines may help the body build an effective immune response to kill tumor cells. Giving aldesleukin together with vaccine therapy may kill more tumor cells. It is not yet known whether aldesleukin is more effective with or without vaccine therapy in treating melanoma. PURPOSE: This randomized phase II trial is studying how well aldesleukin works when given with or without vaccine therapy in treating patients with stage IV melanoma.
Detailed description
OBJECTIVES: Primary * To compare the progression-free survival of patients with stage IV melanoma treated with aldesleukin with vs without allogeneic large multivalent immunogen melanoma vaccine LP2307. Secondary * To compare the clinical response in patients treated with these regimens. * To compare the 1- and 2-year survival rates in patients treated with these regimens. * To determine whether an immune response is generated after vaccination in these patients. OUTLINE: Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive allogeneic large multivalent immunogen melanoma vaccine LP2307 intradermally on day 1 and aldesleukin subcutaneously (SC) on days 7 and 8. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. * Arm II (control): Patients receive aldesleukin SC on days 1 and 2. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross over and receive treatment on arm I. Patients undergo blood sample collection periodically for correlative laboratory studies. Samples are analyzed for immune responses to keyhole limpet hemocyanin and tetanus toxoid (control antigens) by ELISA assay; IFN-γ production by CD8 T cells in response to melanoma-derived peptides by ELISpot assay; delayed-type hypersensitivity response to vaccination; and frequency of peripheral blood lymphocytes, including T cells, B cells, NK cells, and monocytes, by flow cytometry. * Arm III Crossover: Patients who have progressive disease on Arm II will be offered crossover to Arm I provided they continue to meet all study criteria. After completion of study treatment, patients are followed every 2 months for 1 year, every 3 months until disease progression, and then periodically thereafter.
Interventions
BIOLOGICALaldesleukin
IL-2 Alone - administer 10 x 10\^6 International Units subcutaneously (SQ) will be given on day 1 and day 2 every 4 weeks until disease progression or for a maximum of 12 treatment cycles.
BIOLOGICALallogeneic large multivalent immunogen vaccine
Allogeneic tumor cell membrane-coated large multivalent immunogen (LMI \[1 x 10\^7, 5-μm silica spheres\]) will be given as an intradermal injection every 4 weeks for up to 12 injections. Each vaccine dose will be 0.2 ml.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Stage IV melanoma. * Prior systemic chemotherapy, immunotherapy, or biological therapy is allowed if at least 4 weeks since last treatment. Patient must recover from the acute toxic effects of the treatment prior to study enrollment. * Disease status must be that of measurable or nonmeasurable disease as defined by Solid Tumor Response Criteria (RECIST) * Karnofsky performance status \>70% (Eastern Cooperative Oncology Group 0-1) * Age 18 years or older * Adequate organ function within 14 days of study enrollment including the following: * Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥ 1.5 x 10\^9/L, platelets ≥100 x 10\^9/L, and hemoglobin ≥ 10 g/dL * Hepatic: bilirubin \< 3 times the upper limit of normal (× ULN), aspartate transaminase (AST) \< 3 × ULN * Renal: creatinine ≤ 2.0 * Must share at least one class I HLA allele with the HLA-type SK23-CD80+ cell (class I alleles (A1, A2, B7, B8, C7)) * Meets eligibility criteria for and agrees to enroll in MT1999- 06: Vaccination with Tetanus Toxoid and Keyhole Limpet Hemocyanin (KLH) to Assess Antigen-Specific Immune Responses (IRB # 9904M01581, CPRC #2002LS032) * Women of childbearing potential and men whose partners are of childbearing potential are required to use an effective method of contraception (ie, a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) during the study and for 3 months after the last dose of study drug. * Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
Exclusion criteria
* History of brain metastases or positive brain scan at on-study * Immunosuppressive therapy i.e., prednisone or organ transplant patients, however topical or inhalational steroids are allowed. * Autoimmune diseases requiring immunosuppressive therapy. * History of symptomatic pulmonary disease will have pulmonary function tests (PFTs) performed. Patients with symptoms of dyspnea or rales, wheezes or rhonchi on physical exam will undergo PFTs. Those with FEV1 \<50% of predicted or corrected DLCO \<50% are not eligible. * Patients with cardiac disease such as recent myocardial infarction (\< 3 months prior), unstable angina, or heart failure requiring medical intervention will undergo cardiac evaluation. Cardiac testing may include ECG, MUGA or echocardiogram, and/or thallium stress test as indicated to evaluate cardiac risks. Those patients with exercise-induced ischemia or an ejection fraction by MUGA or echocardiogram \< 40% are not eligible. * Due to the origin of the KLH protein, patients with a history of seafood allergy are excluded from receiving KLH. * Hypersensitivity to any component of the vaccine, including Thimerosal, a mercury derivative, is a contraindication (taken from tetanus toxoid package insert). * The occurrence of any type of neurologic symptoms to tetanus vaccine in the past is a contraindication to further use (taken from tetanus toxoid package insert). * Subjects who have had tetanus toxoid within the last 7 years will not receive the tetanus vaccine component of this * Pregnant (positive pregnancy test) or lactating women. Use of LMI vaccine during pregnancy is not approved for use by the FDA during pregnancy. IL-2 is pregnancy category C - risk in pregnancy cannot be ruled out.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Time of Progression-free Survival | From Date of Randomization to Date of Disease Progression or Last Contact - up to 2 years. | Progression free survival (PFS) was measured in months from date of randomization to date of disease progression, or date of death. For patients who died without tumor progression, PFS assumes their deaths are randomly related to tumor progression. Therefore, PFS includes deaths if they came first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response of Lesion(s) | Month 2 through Month 12 | Beginning at 2 months Through End of Treatment: To determine clinical response of each treatment group - Best Clinical response will be determined using Solid Tumor Response Criteria (RECIST). Complete Response (CR) = complete disappearance of all target lesions. Partial Response (PR) = At least a 30% decrease in sum of longest diameters of target lesions. Progressive Disease (PD) = At least a 20% increase in sum of longest diameters of target lesions. Stable Disease (SD) = Neither sufficient shrinkage to qualify for PR or PD. |
| Overall Survival at 2 Years | 2 Years | Two year survival (alive at 2 years from randomization) rate of each treatment group. |
| Overall Survival at 1 Year | 1 Year | One year survival (alive at 1 year from randomization) rate of each treatment group. |
| Immune Response | 48 hours After Study Medication | Immune responses is be assessed by Delayed Type Hypersensitive (DTH) responses to LMI, IFN-γ production by CD8 T cells using the ELISPOT assay, and CD8 T cell binding to HLA-A2 multimers complexed with melanoma-derived peptides (pentamer analysis). DTH reactions are determined at 48 hours by measuring the largest diameter and right angle diameter of the area of induration and calculating the mean. DTH responses are recorded as present or absent but cannot be used as a quantitative measure of immune activation. |
Countries
United States
Participant flow
Recruitment details
All patients were evaluated for eligibility by one of the investigators prior to enrollment.
Pre-assignment details
This study requires concurrent registration to the University of Minnesota study MT1999-06: Vaccination with Tetanus Toxoid and Keyhole Limpet Hemocyanin (KLH) to Assess Antigen-Specific Immune Responses (IRB # 9904M01581, CPRC #2002LS032).
Participants by arm
| Arm | Count |
|---|---|
| Arm I and III Crossover Group - LMI + Aldesleukin Includes 6 patients who progressed and crossed over from Arm II. | 11 |
| Arm II (Control) - Aldesleukin Patients receive aldesleukin SC on days 1 and 2. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross over and receive treatment on Arm I. | 10 |
| Total | 21 |
Baseline characteristics
| Characteristic | Arm II (Control) - Aldesleukin | Arm I and III Crossover Group - LMI + Aldesleukin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 5 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Continuous | 64.0 years STANDARD_DEVIATION 14.9 | 63.8 years STANDARD_DEVIATION 11.4 | 63.9 years STANDARD_DEVIATION 12.8 |
| Region of Enrollment United States | 10 participants | 11 participants | 21 participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 10 / 10 |
| serious Total, serious adverse events | 1 / 10 | 3 / 10 |
Outcome results
Primary
Median Time of Progression-free Survival
Progression free survival (PFS) was measured in months from date of randomization to date of disease progression, or date of death. For patients who died without tumor progression, PFS assumes their deaths are randomly related to tumor progression. Therefore, PFS includes deaths if they came first.
Time frame: From Date of Randomization to Date of Disease Progression or Last Contact - up to 2 years.
Population: All patients who received at least one dose of study treatment are included. One patient who was originally screened and randomized did not receive treatment due to brain metastasis. This patient was included in PFS analysis based on the intent-to-treat principle, but was excluded from the evaluation of adverse events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I and III Crossover Group - LMI + Aldesleukin | Median Time of Progression-free Survival | 2.20 Months |
| Arm II (Control) - Aldesleukin | Median Time of Progression-free Survival | 1.95 Months |
Secondary
Clinical Response of Lesion(s)
Beginning at 2 months Through End of Treatment: To determine clinical response of each treatment group - Best Clinical response will be determined using Solid Tumor Response Criteria (RECIST). Complete Response (CR) = complete disappearance of all target lesions. Partial Response (PR) = At least a 30% decrease in sum of longest diameters of target lesions. Progressive Disease (PD) = At least a 20% increase in sum of longest diameters of target lesions. Stable Disease (SD) = Neither sufficient shrinkage to qualify for PR or PD.
Time frame: Month 2 through Month 12
Population: All patients who received at least one dose of study treatment are included. One patient who was originally screened did not receive treatment due to brain metastasis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I and III Crossover Group - LMI + Aldesleukin | Clinical Response of Lesion(s) | Missing information | 1 participants |
| Arm I and III Crossover Group - LMI + Aldesleukin | Clinical Response of Lesion(s) | Complete Response (CR) | 0 participants |
| Arm I and III Crossover Group - LMI + Aldesleukin | Clinical Response of Lesion(s) | Partial Response (PR) | 0 participants |
| Arm I and III Crossover Group - LMI + Aldesleukin | Clinical Response of Lesion(s) | Stable Disease (SD) | 2 participants |
| Arm I and III Crossover Group - LMI + Aldesleukin | Clinical Response of Lesion(s) | Progressive Disease (PD) | 8 participants |
| Arm II (Control) - Aldesleukin | Clinical Response of Lesion(s) | Progressive Disease (PD) | 8 participants |
| Arm II (Control) - Aldesleukin | Clinical Response of Lesion(s) | Stable Disease (SD) | 1 participants |
| Arm II (Control) - Aldesleukin | Clinical Response of Lesion(s) | Complete Response (CR) | 1 participants |
| Arm II (Control) - Aldesleukin | Clinical Response of Lesion(s) | Missing information | 0 participants |
| Arm II (Control) - Aldesleukin | Clinical Response of Lesion(s) | Partial Response (PR) | 0 participants |
Secondary
Immune Response
Immune responses is be assessed by Delayed Type Hypersensitive (DTH) responses to LMI, IFN-γ production by CD8 T cells using the ELISPOT assay, and CD8 T cell binding to HLA-A2 multimers complexed with melanoma-derived peptides (pentamer analysis). DTH reactions are determined at 48 hours by measuring the largest diameter and right angle diameter of the area of induration and calculating the mean. DTH responses are recorded as present or absent but cannot be used as a quantitative measure of immune activation.
Time frame: 48 hours After Study Medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I and III Crossover Group - LMI + Aldesleukin | Immune Response | Missing information | 1 participants |
| Arm I and III Crossover Group - LMI + Aldesleukin | Immune Response | KLH twofold responder | 5 participants |
| Arm I and III Crossover Group - LMI + Aldesleukin | Immune Response | KLH tenfold responder | 2 participants |
| Arm II (Control) - Aldesleukin | Immune Response | KLH tenfold responder | 7 participants |
| Arm II (Control) - Aldesleukin | Immune Response | Missing information | 0 participants |
| Arm II (Control) - Aldesleukin | Immune Response | KLH twofold responder | 8 participants |
Secondary
Overall Survival at 1 Year
One year survival (alive at 1 year from randomization) rate of each treatment group.
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I and III Crossover Group - LMI + Aldesleukin | Overall Survival at 1 Year | 45 Percentage of patients |
| Arm II (Control) - Aldesleukin | Overall Survival at 1 Year | 40 Percentage of patients |
Secondary
Overall Survival at 2 Years
Two year survival (alive at 2 years from randomization) rate of each treatment group.
Time frame: 2 Years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I and III Crossover Group - LMI + Aldesleukin | Overall Survival at 2 Years | 24 percentage of patients |
| Arm II (Control) - Aldesleukin | Overall Survival at 2 Years | 27 percentage of patients |