Melanoma (Skin)
Conditions
Keywords
recurrent melanoma, stage IV melanoma
Brief summary
RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Interleukin-2 may stimulate a person's white blood cells to kill tumor cells and may help a person's immune system recover from the side effects of chemotherapy. PURPOSE: This phase II trial is studying how well giving cyclophosphamide and fludarabine together with high-dose interleukin-2 works in treating patients with metastatic melanoma.
Detailed description
OBJECTIVES: Primary * Determine the objective response rate in lymphodepleted patients with metastatic melanoma treated with cyclophosphamide, fludarabine, and high-dose interleukin-2. * Determine the feasibility of this regimen in these patients. Secondary * Determine the quality and quantity of lymphocyte recovery in these patients during and after treatment with this regimen. * Determine time to disease progression and survival in patients treated with this regimen. OUTLINE: This is an open-label, multicenter study. Patients receive lymphodepleting therapy comprising cyclophosphamide IV over 1 hour on days 1 and 2 and fludarabine IV over 30 minutes on days 3-7. Patients then receive high-dose interleukin-2 IV every 8 hours (14 doses) on days 8-12 and 22-26. Patients also receive sargramostim (GM-CSF) subcutaneously beginning on day 8 and continuing until blood counts recover. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months. PROJECTED ACCRUAL: A total of 18-33 patients will be accrued for this study.
Interventions
BIOLOGICALaldesleukin
‡Interleukin-2 (aldesleukin) IV (600,000 U/kg; Chiron, Emeryville, CA): two 5-day courses on days 8 and 22. Interleukin-2 was given over 15 minutes every 8 hours. Goal is 14 doses/5-day course
BIOLOGICALsargramostim
GM-CSF was given subcutaneously daily from day 8 until absolute granulocyte count exceeds 5,000 cells/mL for 2 consecutive days.
DRUGcyclophosphamide
Cyclophosphamide (60 mg/kg/d; Baxter, Deerfield, IL) intravenously (IV) for 2 days with sodium 2- mercaptoethanesulfonate (Mesna; Sicor, Irvine, CA) at 20% of cyclophosphamide dose IV 15 minutes before and 40% of the cyclophosphamide dose orally at 2 and 6 hours after the initiation of chemotherapy.
DRUGfludarabine phosphate
Fludarabine IV (25 mg/M2/day)-five daily doses from Day 3
Sponsors
National Cancer Institute (NCI)
Dartmouth-Hitchcock Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed melanoma * Metastatic disease * Measurable disease * No history of brain metastases * Over 18 * Karnofsky 60-100% * Life expectancy At least 12 weeks * Hematopoietic * Absolute neutrophil count ≥ 1,000/mm\^3 * Platelet count ≥ 75,000/mm\^3 * Hemoglobin ≥ 8.5 g/dL * aspartate aminotransferase ≤ 2 times upper limit of normal (ULN) (5 times ULN if liver metastases are present) * Bilirubin ≤ 2 times ULN (except for patients with Gilbert's syndrome) * Hepatitis B and C negative * Creatinine ≤ 2.0 times ULN * Creatinine clearance ≥ 50 mL/min * Cardiovascular * Ejection fraction ≥ 50% * No evidence of congestive heart failure * No symptoms of coronary artery disease * No serious cardiac arrhythmias * No myocardial infarction within the past 6 months * Cardiac stress test negative or of low probability for patients \> 40 years of age OR who have had prior myocardial infarction \> 6 months ago * Pulmonary Forced expiratory volume 1 ≥ 2.0 liters OR at least 75% of predicted for height and age * Diffusing capacity of lung for carbon monoxide ≥ 60% * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * HIV negative
Exclusion criteria
* No uncontrolled diabetes * No history of autoimmune disease * No active infection * No other concurrent significant illness that would preclude study participation * No other malignancy within the past 5 years except nonmelanoma skin cancer or non-invasive cancer (e.g., carcinoma in situ of the cervix, superficial bladder cancer without local recurrence, or carcinoma in situ of the breast) * At least 4 weeks since prior immunotherapy and recovered * No other concurrent anticancer biologic agents * At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) and recovered * No concurrent chemotherapy * At least 4 weeks since prior steroid therapy * No concurrent corticosteroids * At least 4 weeks since prior radiotherapy and recovered * No concurrent radiotherapy * At least 4 weeks since prior surgery and recovered * No concurrent immunosuppressive therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of partiCIPANTS WITH OBJECTIVE RESPONSE AS MEASURED BY RECIST | Response at 12 weeks | Objective response as measured by radiological and physical examination using RECIST criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Lymphocyte Recovery as Measured by Blood Count | on days 1-15, weekly for 2 weeks, and then every 2-3 months | Lymphocyte recovery to a greater than 1000 cells/mcL was determined by differential peripheral blood cell counts on sequential days as noted in time frame. |
| Time to Progression as Measured by RECIST | From date of randomization until the first date of documented progression or date of death from any cause, which ever came first, assessed up till 100 months | Clinical outcome used the National Cancer Institute's Response Evaluation Criteria in Solid Tumors (RECIST)1.0. |
Countries
United States
Participant flow
Recruitment details
recruitment was open from February 2004 to December 2008.
Participants by arm
| Arm | Count |
|---|---|
| Lymphodepleting Chemotherapy + High Dose IL-2 intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 microg/m(2)/d beginning day 8) was given until granulocyte recovery. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | screen failure | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Lymphodepleting Chemotherapy + High Dose IL-2 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants |
| Age Continuous | 52 years STANDARD_DEVIATION 11.3 |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 18 |
| serious Total, serious adverse events | 8 / 18 |
Outcome results
Primary
Number of partiCIPANTS WITH OBJECTIVE RESPONSE AS MEASURED BY RECIST
Objective response as measured by radiological and physical examination using RECIST criteria.
Time frame: Response at 12 weeks
Population: Response was determined by physical examination and radiologic testing. Percent of the total number of patients treated was calculated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Number of partiCIPANTS WITH OBJECTIVE RESPONSE AS MEASURED BY RECIST | 3 participants |
Secondary
Number of Participants With Lymphocyte Recovery as Measured by Blood Count
Lymphocyte recovery to a greater than 1000 cells/mcL was determined by differential peripheral blood cell counts on sequential days as noted in time frame.
Time frame: on days 1-15, weekly for 2 weeks, and then every 2-3 months
Population: each patient's differential blood counts were used to determine the time of recovery to the lower limit of normal lymphocytes in the peripheral blood.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Number of Participants With Lymphocyte Recovery as Measured by Blood Count | 18 participants |
Secondary
Time to Progression as Measured by RECIST
Clinical outcome used the National Cancer Institute's Response Evaluation Criteria in Solid Tumors (RECIST)1.0.
Time frame: From date of randomization until the first date of documented progression or date of death from any cause, which ever came first, assessed up till 100 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group 1 | Time to Progression as Measured by RECIST | .3 years |