Melanoma (Skin)
Conditions
Keywords
stage IV melanoma, recurrent melanoma
Brief summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving paclitaxel together with carboplatin is more effective than giving temozolomide alone in treating patients with melanoma. PURPOSE: This phase II trial is studying the side effects and how well giving paclitaxel together with carboplatin or giving temozolomide alone works in treating patients with stage IV melanoma.
Detailed description
OBJECTIVES: * To assess the anti-tumor activity and toxicity profile of timed delivery of conventional paclitaxel and carboplatin (PC) in patients with stage IV melanoma who have received prior chemotherapy for their metastatic disease. * To assess the anti-tumor activity and toxicity profile of timed delivery of conventional temozolomide (TMZ) chemotherapy in patients with stage IV melanoma who have received prior chemotherapy for their metastatic disease. * To assess the anti-tumor activity and toxicity profile of timed delivery of conventional PC in patients with stage IV melanoma who have not received prior chemotherapy for their metastatic disease. * To assess the anti-tumor activity and toxicity profile of timed delivery of conventional TMZ chemotherapy in patients with stage IV melanoma who have not received prior chemotherapy for their metastatic disease. * To evaluate the changes of T-regulator cells, melanoma-specific functional parameters as a function of time in all four patient cohorts. OUTLINE: Patients are stratified according to prior chemotherapy for metastatic disease (yes vs no) and scheduled chemotherapy regimen (paclitaxel and carboplatin vs temozolomide). Beginning at the predicted day of C-reactive peptide (CRP) peak levels, patients receive paclitaxel IV and carboplatin IV on days 1, 8, and 15 OR oral temozolomide alone on days 1-5. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection periodically for pharmacological studies. Samples are analyzed for CRP quantification via ELISA; presence and number of circulating blood T-regulator cells via immunophenotyping for CD4/CD25+ and CD4/fox-p3+ T cells; level of functional immunity against melanoma specific antigens (MART-1, tyrosinase, and gp100) and survivin in patients that are HLA-A2+ via intracellular staining; total number of cytotoxic T lymphocytes (CTLs) capable of reacting against melanoma targets via tetramer staining (Becton-Coulter); and quantification of interferon γ-producing, peptide-specific CTLs via multicolor conventional flow cytometry. After completion of study treatment, patients are followed every 3 months for up to 2 years.
Interventions
DRUGcarboplatin
AUC=2 intravenously on days 1, 8 and 15. Re-treat every 4 weeks until progression, unacceptable toxicity, or refusal
DRUGpaclitaxel
100mg/m\^2 intravenously on days 1, 8 and 15. Re-treat every 4 weeks until progression, unacceptable toxicity, or refusal
DRUGtemozolomide
150mg/m\^2 at cycle 1, 200mg/m\^2 at cycle 2 and beyond, orally on days 1-5. Re-treat every 4 weeks until progression, unacceptable toxicity, or refusal. One treatment cycle=four weeks
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed metastatic melanoma * Stage IV disease * Progressive disease * No known standard therapy that is potentially curative or proven capable of extending life expectancy exists * Planning to undergo chemotherapy with paclitaxel and carboplatin OR temozolomide alone for progressive disease * Measurable disease as defined by RECIST criteria PATIENT CHARACTERISTICS: * ECOG performance status 0-2 * Life expectancy ≥ 3 months * ANC ≥ 1,500/mL * Platelet count ≥ 100,000/mL * Hemoglobin ≥ 9 g/dL * Creatinine ≤ 2.5 x upper limit of normal (ULN) * AST ≤ 3 x ULN * Alkaline phosphatase ≤ 3.0 x ULN * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 1 month after completion of study therapy * No uncontrolled intercurrent illness including, but not limited to, any of the following: * Active infection * NYHA class III or IV congestive heart failure * No history of other malignancy within the past 5 years except for basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix * Willing to provide research blood samples PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Recovered from prior therapy * At least 4 weeks since prior radiotherapy * At least 4 weeks since prior chemotherapy (patients who received chemotherapy in the metastatic setting) * No prior chemotherapy treatment with agents similar to study drugs * No prior chemotherapy in the metastatic setting (for chemo-naive patients) * No concurrent enrollment in a different clinical study in which investigational procedures or agents are being used * No other concurrent investigational agents * No other concurrent chemotherapy or radiotherapy, including palliative radiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Objective Tumor Status of Either a Complete Response(CR) or Partial Response (PR), According to RECIST (Response Evaluation Criteria in Solid Tumors) Criteria | Every other cycle of therapy (cycle=4 weeks) for the first 6 cycles of treatment | Response that was noted on 2 consecutive evaluations for at least 4 weeks apart. CR: Disappearance of all target lesions; PR: At least a 30 percent of decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Target lesions: All measurable lesions up to a maximum of 10 lesions representative of all involved organs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival Time | up to 2 years | Survival time was defined as the time from registration to death due to any cause. |
| Duration of Response for All Evaluable Patients Who Have Achieved an Objective Response | up to 2 years | Duration of response was defined as the date at which the participant's objective status was first noted to be either a Complete Response or Partial Response to the date the progression was documented. |
| Time to Disease Progression | up to 2 years | Time to disease progression was defined as the time from registration to documentation of disease progression. Disease progression was measured according to the RECIST criteria. Progression: At least a 20 percent increase in the sum of of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. |
| Number of Participants Who Experienced Changes in Immunologic Profile (MART-1, Tyrosinase, and gp100) Within a Treatment | up to 2 years | For those patients who are HLA-A2+, the maximum post-treatment levels of MART-1, tyrosinase, and gp100 will be determined. For each of these specific melanoma specific antigens, the number of participants (within a given treatment) who gained or maintained immunity based on the maximum post-treatment level of that specific melanoma specific antigen will be determined. |
| Number of Participants Who Experienced Changes in Immunologic Profile (IFNγ Producing Peptide Specific CTLs) Within a Treatment | up to 2 years | For each patient, a time series plot of the number of IFNγ producing peptide specific CTLs will be constructed. The resulting plots will be visually inspected for trends within and between treatments. A point and an interval estimate of the number of participants (receiving a given treatment) who had at least a 2-fold increase in the number of the number of IFNγ producing peptide specific CTLs will be constructed using the properties of the binomial distribution. |
| Number of Participants Who Experienced Changes in Immunologic Profile (CD4/CD25+ Cells, CD4/Fox-p3+ T Cells) Within a Treatment | up to 2 years | Time series plot of the number of circulating cells will be constructed. The resulting plots will be visually inspected for trends within and between treatments. For each cell type, a point and an interval estimate of the number of participants (receiving a given treatment) who had at least a 2-fold increase in the number of circulating cells of that type will be constructed using the properties of the binomial distribution. |
Countries
United States
Participant flow
Recruitment details
Twelve (12) participants with un-resectable stage IV malignant melanoma were enrolled in the study between June 2006 and November 2008 at Mayo Clinic Rochester.
Pre-assignment details
One patient canceled participation in the trial prior to starting Temozolomide therapy. This patient was excluded from all analysis.
Participants by arm
| Arm | Count |
|---|---|
| PC (Previously Treated) Previously chemotherapy treated cohorts: Paclitaxel and Carboplatin (PC) | 0 |
| PC (Chemo Naive) Chemotherapy-naive cohorts: Paclitaxel and Carboplatin (PC) | 0 |
| TMZ (Previously Treated) Previously chemotherapy treated cohorts: Temozolomide (TMZ) | 2 |
| TMZ (Chemo Naive) Chemotherapy-naive cohorts: Temozolomide (TMZ) | 9 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Disease Progression | 0 | 0 | 2 | 7 |
Baseline characteristics
| Characteristic | TMZ (Previously Treated) | TMZ (Chemo Naive) | Total |
|---|---|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 14.85 | 63.3 years STANDARD_DEVIATION 14.05 | 62.4 years STANDARD_DEVIATION 12.97 |
| Gender Female | 0 participants | 3 participants | 3 participants |
| Gender Male | 2 participants | 6 participants | 8 participants |
| M Stage M1a (skin/subcutaneous tissue/lymph node only) | 0 participants | 1 participants | 1 participants |
| M Stage M1b (lung) | 1 participants | 3 participants | 4 participants |
| M Stage M1c (other visceral sites) | 1 participants | 5 participants | 6 participants |
| Number of Metastatic Sites | 2 Sites | 2 Sites | 2 Sites |
| Region of Enrollment United States | 2 participants | 9 participants | 11 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 2 | 8 / 9 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 2 | 1 / 9 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Participants With an Objective Tumor Status of Either a Complete Response(CR) or Partial Response (PR), According to RECIST (Response Evaluation Criteria in Solid Tumors) Criteria
Response that was noted on 2 consecutive evaluations for at least 4 weeks apart. CR: Disappearance of all target lesions; PR: At least a 30 percent of decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Target lesions: All measurable lesions up to a maximum of 10 lesions representative of all involved organs.
Time frame: Every other cycle of therapy (cycle=4 weeks) for the first 6 cycles of treatment
Population: All subjects enrolled, met the eligibility criteria who have signed a consent form and have begun their study treatment were evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TMZ (Previously Treated) | Number of Participants With an Objective Tumor Status of Either a Complete Response(CR) or Partial Response (PR), According to RECIST (Response Evaluation Criteria in Solid Tumors) Criteria | 0 participants |
| TMZ (Chemo Naive) | Number of Participants With an Objective Tumor Status of Either a Complete Response(CR) or Partial Response (PR), According to RECIST (Response Evaluation Criteria in Solid Tumors) Criteria | 2 participants |
Secondary
Duration of Response for All Evaluable Patients Who Have Achieved an Objective Response
Duration of response was defined as the date at which the participant's objective status was first noted to be either a Complete Response or Partial Response to the date the progression was documented.
Time frame: up to 2 years
Population: Two complete tumor responses were documented. Both participants have since discontinued the study drug after 35 and 24 cycles respectively, and remain disease-free at 39 and 31.5 months since study entry. There is not enough participants to perform this analysis.
Secondary
Number of Participants Who Experienced Changes in Immunologic Profile (CD4/CD25+ Cells, CD4/Fox-p3+ T Cells) Within a Treatment
Time series plot of the number of circulating cells will be constructed. The resulting plots will be visually inspected for trends within and between treatments. For each cell type, a point and an interval estimate of the number of participants (receiving a given treatment) who had at least a 2-fold increase in the number of circulating cells of that type will be constructed using the properties of the binomial distribution.
Time frame: up to 2 years
Population: There is not enough participants to perform this analysis.
Secondary
Number of Participants Who Experienced Changes in Immunologic Profile (IFNγ Producing Peptide Specific CTLs) Within a Treatment
For each patient, a time series plot of the number of IFNγ producing peptide specific CTLs will be constructed. The resulting plots will be visually inspected for trends within and between treatments. A point and an interval estimate of the number of participants (receiving a given treatment) who had at least a 2-fold increase in the number of the number of IFNγ producing peptide specific CTLs will be constructed using the properties of the binomial distribution.
Time frame: up to 2 years
Population: There is not enough participants to perform this analysis.
Secondary
Number of Participants Who Experienced Changes in Immunologic Profile (MART-1, Tyrosinase, and gp100) Within a Treatment
For those patients who are HLA-A2+, the maximum post-treatment levels of MART-1, tyrosinase, and gp100 will be determined. For each of these specific melanoma specific antigens, the number of participants (within a given treatment) who gained or maintained immunity based on the maximum post-treatment level of that specific melanoma specific antigen will be determined.
Time frame: up to 2 years
Population: There is not enough participants to perform this analysis.
Secondary
Survival Time
Survival time was defined as the time from registration to death due to any cause.
Time frame: up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PC (Previously Treated) | Survival Time | 12.5 Months |
Kaplan-Meier
Secondary
Time to Disease Progression
Time to disease progression was defined as the time from registration to documentation of disease progression. Disease progression was measured according to the RECIST criteria. Progression: At least a 20 percent increase in the sum of of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Time frame: up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PC (Previously Treated) | Time to Disease Progression | 74 Days |