Clinical trial NCT00328861
Conditions: Metastatic Melanoma Metastatic Kidney Cancer
Keywords: Adoptive Cell Therapy Cutaneous Melanoma Clinical Response Rate of Repopulation Toxicity Profile Metastatic Melanoma Metastatic Kidney Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2006-05-01; Completion date: 2009-04-01
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

* Natural killer (NK) cells are large lymphocytes (a type of white blood cell) that are important in the immune response to cancer.
* IL-2 (Aldesleukin) is a substance the body makes that controls the growth and function of many types of cells. The Food and Drug Administration has approved IL-3 for treating metastatic melanoma and kidney cancer. (Metastatic disease is cancer that has spread beyond the primary site.)

Objectives: To determine the safety and effectiveness of treating metastatic melanoma and kidney cancer with laboratory-treated NK cells and IL-2.

Eligibility: Patients 18 years of age or older with metastatic melanoma or kidney cancer who have previously been treated with high-dose IL-2.

Design:

* Leukapheresis. Patients under leukapheresis to obtain NK cells for the treatment regimen. Blood is collected through a needle in an arm vein and directed through a cell separator machine where white blood cells are extracted. The rest of the blood is returned to the patient through a needle in the other arm. NK cells are removed from the white blood cells and treated for re-infusion into the patient.
* Chemotherapy. Starting 8 days before infusion of the treated NK cells, patients receive intravenous (IV, through a vein) infusions of cyclophosphamide and fludarabine to suppress the immune system.
* NK cell infusion. Patients receive a 30-minute IV infusion of NK cells 2 days after the last dose of chemotherapy.
* IL-2 therapy. Within 24 hours of the NK cell infusion, patients receive high-dose IL-2 as a 15-minute IV infusion every 8 hours for up to 5 days. A second cycle of IL-2 is given about 14 days after the first.
* Blood tests and biopsy. Patients have frequent blood tests during the treatment period and may be asked to undergo a biopsy (surgical removal of a small piece of tumor or lymph node) at the end of treatment to look at the effects of the treatment on the tumor immune cells.
* Follow-up evaluation. Patients are evaluated 4-6 weeks after completing treatment. They have a physical examination, scans of tumor sites, blood tests and blood sampling (or leukapheresis) to examine the response to treatment. Patients who improve with treatment return for evaluations every month. Those whose tumor grows again after originally shrinking may receive one additional treatment course.

Detailed description:
Background:

* Natural killer (NK) cells are large granular lymphocytes that are critical effector cells in the early innate immune response to pathogens and cancer.
* Previous and current clinical investigations have clearly demonstrated that T lymphocytes can mediate the regression of metastatic melanoma. However, not all patients with cancer are eligible for this type of immunotherapy either because resectable tumor is not available, the TIL do not expand sufficiently, or the tumor infiltrating lymphocytes (TIL) that do proliferate do not exhibit sufficient tumor specific reactivity.
* We have recently developed techniques for the in vitro isolation and expansion of anti-tumor NK cells to levels suitable for the treatment of cancer patients and are proposing in this protocol to evaluate therapy using these NK cells.
* In Surgery Branch pre-clinical experiments, we evaluated lysis of fresh melanoma cell digests, melanoma cell lines, renal cell carcinoma (RCC) lines, and normal peripheral blood mononuclear cells (PBMCs) by NK cells from several patients and demonstrated that NK cells could lyse some fresh melanoma digests, as well as melanoma cell lines and renal cell cancer (RCC) lines, while sparing normal allogeneic and autologous PBMCs.

Objectives:

* Determine the ability of the administration of autologous natural killer (NK) cells plus aldesleukin (IL-2) following a non-myeloablative lymphodepleting preparative regimen to mediate tumor regression in patients with metastatic melanoma or kidney cancer.
* Determine the rate of repopulation of the natural killer cells in treated patients.
* Determine the toxicity of this treatment regimen.

Eligibility:

* Patients, 18 years of age or older with metastatic melanoma or metastatic kidney cancer who have previously received high dose IL-2, with an Eastern Cooperative Oncology Group (ECOG) of 0 or 1.
* Patients may not have any active systemic infections, coagulations disorders, major medical illnesses of the cardiovascular, respiratory or immune systems or any form of autoimmune disease or immunodeficiency.

Patients must be eligible to receive high-dose IL-2.

Design:

* Patients will undergo apheresis on 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols) to obtain cells for generation of autologous natural killer cells.
* All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -8 and -7 and fludarabine (25 mg/m\^2/day IV) on days -6 through -2.
* On day 0 patients will receive the infusion of autologous natural killer lymphocytes and then begin the first cycle of high-dose IL-2 (720,000 IU/kg IV every 8 hours for up to 15 doses). A second cycle of IL-2 will be administered approximately 14 days later.
* Clinical and Immunologic response will be evaluated about 4 to 6 weeks

after the second cycle of IL-2.

-Using a small optimal Phase II design, two cohorts of patients, initially 16 in each cohort, will be enrolled, and if at least one of the first 16 patients has a clinical response (partial response (PR) or complete response (CR)), accrual will continue to 29 patients, targeting a 15% goal for objective response.

Arms: arm 1: Melanoma (skin cancer). Cyclophosphamide 60 mg/kg/day intravenous on days -8 and -7. Fludarabine 25 mg/m\^2 day intravenous on days -6 through -2. IL-2 720,000 IU/kg/intravenous every 8 hours for up to 5 days. Thirty minutes infusion of natural killer (NK) cells 2 days after last dose of chemotherapy. arm 2: Renal cell (kidney cancer). Cyclophosphamide 60 mg/kg/day intravenous on days -8 and -7. Fludarabine 25 mg/m\^2 day intravenous on days -6 through -2. IL-2 720,000 IU/kg/intravenous every 8 hours for up to 5 days. Thirty minutes infusion of natural killer (NK) cells 2 days after last dose of chemotherapy.
Interventions: intervention 1: Natural Killer (NK) Lymphocytes intervention 2: IL-2 intervention 3: Cyclophosphamide intervention 4: Fludarabine
Intervention descriptions: intervention 1: Thirty minutes infusion of natural killer (NK) cells 2 days after last dose of chemotherapy. intervention 2: IL-2 720,000 IU/kg/intravenous every 8 hours for up to 5 days. intervention 3: Cyclophosphamide 60 mg/kg/day intravenous on days -8 and -7. intervention 4: Fludarabine 25 mg/m\^2 day intravenous on days -6 through -2.

Protocol documents: