Melanoma (Skin)
Conditions
Keywords
stage IV melanoma, recurrent 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. Radiation therapy uses high-energy x-rays to damage tumor cells. Biological therapies, such as cellular adoptive immunotherapy, work in different ways to stimulate the immune system and stop tumor cells from growing. Autologous stem cell transplant may be able to replace immune cells that were destroyed by chemotherapy and radiation therapy. Interleukin-2 may stimulate a person's lymphocytes to kill tumor cells. Combining chemotherapy, radiation therapy, and biological therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cyclophosphamide and fludarabine together with radiation therapy followed by cellular adoptive immunotherapy, autologous stem cell transplant, and interleukin-2 works in treating patients with metastatic melanoma.
Detailed description
OBJECTIVES: Primary * Determine complete clinical tumor regression in patients with metastatic melanoma treated with a myeloablative lymphoid-depleting preparative regimen comprising cyclophosphamide, fludarabine, and total body irradiation followed by autologous tumor-reactive tumor-infiltrating lymphocyte infusion, autologous CD34+ stem cell transplantation, and low-dose or high-dose interleukin-2. * Evaluate the safety of this regimen in these patients. Secondary * Determine the survival of the infused lymphocytes by analyzing the sequence of the variable region of the T-cell receptor or flow cytometry in patients treated with this regimen. OUTLINE: * Autologous stem cell collection: Patients receive filgrastim (G-CSF) subcutaneously (SC) twice daily for 8 days. Beginning on day 5 of G-CSF, patients undergo apheresis daily for up to 3 days. Patients may receive 1 additional course of G-CSF and apheresis or use stem cells stored from a prior stem cell harvest in order to obtain an adequate number of cells. * Lymphocyte-depleting myeloablative preparative regimen: Patients receive cyclophosphamide intravenous (IV) over 1 hour on days -5 and -6 and fludarabine IV over 15-30 minutes on days -6 to -2. Patients also undergo total body irradiation on day -1. * Autologous lymphocyte infusion: Patients receive autologous tumor-reactive tumor-infiltrating lymphocytes IV over 20-30 minutes on day 0\* followed by G-CSF SC once daily until blood counts recover. * Autologous stem cell transplantation: Patients receive autologous CD34+ stem cells IV on day 2. * Interleukin therapy: Patients are assigned to 1 of 2 cohorts, depending on whether they have received prior high-dose interleukin-2 (IL-2). * Cohort 1 (patients who received prior high-dose IL-2): Beginning on day 0\*, patients receive high-dose IL-2 IV over 15 minutes 3 times daily for up to 5 days (maximum of 15 doses). * Cohort 3 (patients who have not received prior high-dose IL-2): Patients receive treatment as in cohort 1. NOTE: \*Day 0 is 1-4 days after the last dose of fludarabine. Patients are evaluated at 4-6 weeks. PROJECTED ACCRUAL: A total of 116 patients will be accrued for this study.
Interventions
BIOLOGICALaldesleukin
high dose: 720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days (maximum 5 doses) or low dose: 250,000 IU/kg subcutaneously daily for 5 days, after a two day rest, 125,000 IU/kg subcutaneously daily for 5 days for five weeks (2 days rest per week)
BIOLOGICALfilgrastim
10 mcg/kg/day daily subcutaneously until neutrophil count \>1x10\^9/1.
Lymphocytes that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.
DRUGcyclophosphamide
60 mg/kg/day x 2 days intravenously over 1 hour
DRUGfludarabine phosphate
25 mg/m\^2/day intravenous piggyback daily over 15-20 minutes for 5 days
RADIATIONradiation therapy
Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator.
Sponsors
National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of metastatic melanoma * Measurable disease * Resected or stable brain metastases are allowed PATIENT CHARACTERISTICS: Age * 18 and over Performance status * Eastern Cooperative Oncology Group (ECOG) 0-1 Life expectancy * At least 3 months Hematopoietic * See Immunologic * Absolute neutrophil count \> 1,000/mm\^3 (without support of filgrastim \[G-CSF\]) * Platelet count \> 100,000/mm\^3 * Hemoglobin ≥ 8 g/dL (transfusion allowed) * No coagulation disorders Hepatic * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3 times upper limit of normal * Bilirubin ≤ 2 mg/dL (\< 3 mg/dL in patients with Gilbert's syndrome) * No hepatitis B or C Renal * Creatinine ≤ 1.6 mg/dL Cardiovascular * Left ventricular ejection fraction (LVEF) ≥ 45% by cardiac stress test\* * No active major cardiovascular illness as evidenced by stress thallium or other comparable test * No myocardial infarction * No cardiac arrhythmias NOTE: \*For patients ≥ 50 years of age receiving high-dose interleukin-2 (IL-2) OR patients with a history of electrocardiogram (EKG) abnormalities, symptoms of cardiac ischemia, or arrhythmias Pulmonary * Forced expiratory volume 1 (FEV\_1) ≥ 60% of predicted by pulmonary function test in patients with prolonged history of cigarette smoking or symptoms of respiratory dysfunction\* * No active major respiratory illness * No obstructive or restrictive pulmonary disease NOTE: \*For patients receiving high-dose IL-2 only Immunologic * No active major immunologic illness * No active systemic infections * No primary or secondary immunodeficiency * Fully recovered immune competence after prior chemotherapy or radiotherapy as evidenced by both of the following: * Absolute neutrophil count \> 1,000/mm\^3 * No opportunistic infections * Human Immunodeficiency virus (HIV) negative * Epstein-Barr virus positive Other * Not pregnant or nursing * Fertile patients must use effective contraception during and for 4 months after study treatment PRIOR CONCURRENT THERAPY: Biologic therapy * See Disease Characteristics Chemotherapy * At least 6 weeks since prior nitrosourea therapy * No prior cyclophosphamide and fludarabine as part of a preparative regimen on National Cancer Institute (NCI) Surgery Branch adoptive cell therapy studies unless sufficient numbers of CD34+ stem cells (more than 2 x10\^6/kg patient weight) have been obtained prior to the administration of chemotherapy Endocrine therapy * No concurrent systemic steroid therapy Radiotherapy * Not specified Surgery * See Disease Characteristics * Prior minor surgery within the past 3 weeks allowed if recovered Other * Recovered from all prior therapy * At least 30 days since prior systemic therapy * No other concurrent experimental agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Tumor Regression | Every 4-6 weeks for up to 1 year, and then every 6 months for up to 5 years. | Tumor regression is defined as a complete response (CR) or partial response (PR) and was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. |
| Safety | 4 years | Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module. |
Countries
United States
Participant flow
Pre-assignment details
Of the 34 participants who were enrolled, 8 patients were not assigned to treatment since their TIL did not grow. Of the 26 assigned to treatment, 1 patient was not actually treated therefore only 25 patients were evaluable.
Participants by arm
| Arm | Count |
|---|---|
| TBI 200cGy + TIL +HD IL-2, Prior IL-2 Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator.
Lymphocytes that that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient. | 23 |
| TBI 200cGy + TIL +HD IL-2, No Prior IL-2 Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator.
Lymphocytes that that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient. | 3 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death during treatment | 1 | 0 |
| Overall Study | Not treated | 1 | 0 |
Baseline characteristics
| Characteristic | TBI 200cGy + TIL +HD IL-2, Prior IL-2 | TBI 200cGy + TIL +HD IL-2, No Prior IL-2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 3 Participants | 26 Participants |
| Age, Continuous | 43.9 years STANDARD_DEVIATION 9.6 | 48.3 years STANDARD_DEVIATION 12 | 44.4 years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 3 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 3 Participants | 26 Participants |
| Region of Enrollment United States | 23 participants | 3 participants | 26 participants |
| Sex: Female, Male Female | 8 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Male | 15 Participants | 3 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 22 | 3 / 3 |
| serious Total, serious adverse events | 3 / 22 | 1 / 3 |
Outcome results
Primary
Clinical Tumor Regression
Tumor regression is defined as a complete response (CR) or partial response (PR) and was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
Time frame: Every 4-6 weeks for up to 1 year, and then every 6 months for up to 5 years.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TBI 200cGy + TIL +HD IL-2, Prior IL-2 | Clinical Tumor Regression | Complete Response | 1 Participants |
| TBI 200cGy + TIL +HD IL-2, Prior IL-2 | Clinical Tumor Regression | Partial Response | 9 Participants |
| TBI 200cGy + TIL +HD IL-2, No Prior IL-2 | Clinical Tumor Regression | Complete Response | 1 Participants |
| TBI 200cGy + TIL +HD IL-2, No Prior IL-2 | Clinical Tumor Regression | Partial Response | 2 Participants |
Primary
Safety
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
Time frame: 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TBI 200cGy + TIL +HD IL-2, Prior IL-2 | Safety | 23 Participants |
| TBI 200cGy + TIL +HD IL-2, No Prior IL-2 | Safety | 3 Participants |