Clinical trial NCT00096382
Conditions: Melanoma (Skin)
Keywords: stage IV melanoma recurrent melanoma
Sponsor: National Institutes of Health Clinical Center (CC)
Start date: 2004-09-01; Completion date: 2009-01-01
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 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.
Interventions: intervention 1: aldesleukin intervention 2: filgrastim intervention 3: therapeutic tumor infiltrating lymphocytes intervention 4: cyclophosphamide intervention 5: fludarabine phosphate intervention 6: radiation therapy
Intervention descriptions: intervention 1: 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) intervention 2: 10 mcg/kg/day daily subcutaneously until neutrophil count \>1x10\^9/1. intervention 3: Lymphocytes that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient. intervention 4: 60 mg/kg/day x 2 days intravenously over 1 hour intervention 5: 25 mg/m\^2/day intravenous piggyback daily over 15-20 minutes for 5 days intervention 6: Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator.

Protocol documents: