Clinical trial NCT00513604
Conditions: Melanoma Malignant Melanoma Melanoma, Experimental Experimental Melanomas
Keywords: Clinical Response Immunotherapy Cancer Cytokines Adoptive Cell Therapy Melanoma Skin Cancer Malignant Melanoma
Sponsor: National Cancer Institute (NCI)
Start date: 2007-06-01; Completion date: 2012-11-01
Enrollment: 158 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Most therapeutic therapies for metastatic melanoma have focused on the ability of T-cell lymphocytes to kill cells of tumors.
* An adaptive cell transfer therapy has been pioneered, in which cells are grown for a short time in the laboratory. The way they are grown may have a better effect in a patient's body than do other cells that are cultured for a longer time.

Objectives:

* To determine whether tumor-infiltrating lymphocytes (TIL) can be put in cells removed from patients' tumors or blood and then reinfused, with the purpose of shrinking tumors.
* To evaluate safety and effectiveness of the treatment.

Eligibility:

* Patients 18 years of age or older with metastatic cancer melanoma (cancer that has spread beyond the original site).
* Patient's leukocyte antigen type is human leukocyte antigens (HLA-A) 0201.

Design:

-Patients undergo the following procedures:

* Leukapheresis (on two occasions). This is a method of collecting large numbers of white blood cells. The cells obtained in the first leukapheresis procedure are grown in the laboratory, and the TIL cells (called young TIL cells) are inserted into the cells using an inactivated (harmless) virus in a process called retroviral transduction. Cells collected in the second leukapheresis procedure are used to evaluate the effectiveness of the study treatment.
* Chemotherapy. Patients are given chemotherapy through a vein (intravenously, IV) over 1 hour for 2 days to suppress the immune system so that the patient's immune cells do not interfere with the treatment.
* Treatment with young TIL cells. Patients receive an IV infusion of the treated cells, followed by infusions the drug aldesleukin-2 (IL-2), which helps boost the effectiveness of the treated white cells.
* Patients are given support medications to prevent complications such as infections.
* Patients may undergo a tumor biopsy (removal of a small piece of tumor tissue).
* Patients are evaluated with laboratory tests and imaging tests, such as computed tomography (CT) scans, 4 to 6 weeks after treatment and then once a month for 3 to 4 months to determine the response to treatment.
* Patients have blood tests at 3, 6, and 12 months and then annually for 5 years.

Detailed description:
Background:

* Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered to an autologous patient with high dose (HD) IL-2 following a non-myeloablative (NMA) but lymphodepleting chemotherapy preparative regimen.
* Clinical investigations and preclinical animal models have demonstrated that less time in culture, longer telomeres, and a less differentiated lymphocyte phenotype are associated with TIL that are capable of mediating objective clinical responses and persisting long term in the host.
* Previous methods for generating TIL require screening for anti-tumor specificity using gamma-interferon (IFN) production by the TIL. However, in vitro screening depends on autologous tumor reagents that are often unavailable; and gamma-IFN release in vitro may not be the best correlate to in vivo efficacy. Additionally, this method necessitates long in vitro culture times (44 days), and therefore reduces the clonal heterogeneity of TIL cultures, and results in TIL cultures with shorter telomere lengths and phenotypes that are skewed toward a more differentiated phenotype.
* In Surgery Branch pre-clinical experiments, we evaluated a method for rapidly generating young TIL from melanoma tumors with optimal phenotypic characteristics.

Objectives:

* In cohort 1, to determine the ability of autologous TIL cells infused after minimal in vitro culture in conjunction with high dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting preparative regimen to mediate tumor regression in patients with metastatic melanoma.
* In cohort 2, to determine the ability of autologous cluster of differentiation 4 (CD4+) cell depleted TIL cells infused after minimal in vitro culture in conjunction with high dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting preparative regimen to mediate tumor regression in patients with metastatic melanoma.
* In cohort 3, to determine the ability of autologous CD4+ cell depleted TIL cells infused after minimal in vitro culture in conjunction with high dose aldesleukin following chemoradiation lymphoid depleting regimen to mediate complete tumor regression in patients with metastatic melanoma.
* In a prospective randomized fashion, to compare the ability of autologous TIL cells (cohort 4) and autologous CD4plus cell depleted TIL cells (cohort regimen, to mediate tumor regression, progression free survival, and overall survival in patients with metastatic melanoma.
* Evaluate the toxicity of these treatment regimens.
* Determine the rate of repopulation of the young TIL cells in treated patients and establish in vitro correlates of TIL cultures that mediate objective response and in vivo persistence.

Eligibility:

Patients who 18 years of age or older must have:

* Metastatic melanoma;
* Normal values for basic laboratory values.

Patients may not have:

* Received prior cell transfer therapy that included non-myeloablative or ablative chemotherapy;
* Concurrent major medical illnesses;
* Any form of immunodeficiency;
* Severe hypersensitivity to any of the agents used in this study;
* Contraindications for high dose IL-2 administration.

Design:

* Patients will undergo resection to obtain tumor for generation of autologous TIL cultures.
* Cohort 1:

  * All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m\^2/day IV) on days -5 through -1.
  * On day 0 patients will receive the infusion of autologous TIL and then begin high-dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).
  * Clinical and Immunologic response will be evaluated about 4-6 weeks after TIL infusion.
  * Using a small optimal two-stage Phase II design, initially 21 patients will be enrolled, and if two or more of the first 21 patients has a clinical response (partial response (PR) or complete response (CR)), accrual will continue to 41 patients, targeting a 20% goal for objective response. Cohort 1 will be closed with amendment D.
* Cohort 2 will be initiated with amendment D whereby CD4+ cells will be eliminated from the cultures, using the Miltenyi Clinimacs apparatus, prior to performing the rapid expansion of the young TIL cells. Patients in cohort 2 will receive CD4+ cell depleted young unselected TIL. Patients will also receive high dose IL-2 after non-myeloablative but lymphodepleting chemotherapy preparative regimen as described above for cohort 1. Clinical and immunologic response will be evaluated about 4-6 weeks after TIL infusion. Using a small optimal two-stage Phase II design, initially 18 patients will be enrolled, and if three or more of the first 18 patients have a clinical response (PR or CR), accrual will continue to 35 patients, targeting a 30% goal for objective response. With the initiation of Cohort 3 with amendment H, patients will only be accrued to Cohort 2 if they are not eligible to receive 600 cGy due to prior radiation, or to inability to mobilize cluster of differentiation 34 (CD34+) cells. Also at this time, accrual will be expanded to a total of 50 patients in cohort 2. Cohort 2 will be closed with amendment K.
* Cohort 3 will be initiated with amendment H, whereby patients will receive a chemoradiation lymphocyte depleting preparative regimen consisting of cyclophosphamide, fludarabine, and 600 cGy total body irradiation followed by intravenous infusion of autologous CD4+ cell depleted young TIL plus IV high dose IL-2. Clinical and immunologic response will be evaluated about 4-6 weeks after TIL infusion. Using a small optimal two-stage Phase II design, initially 26 patients will be enrolled, and if one or more of the first 26 patients have a complete response (CR), accrual will continue to 51 patients, targeting a 10% goal for complete response. Cohort 3 will be closed with amendment K.

Prospective randomization between cohorts 4 and 5:

* Cohort 4:

  * All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m\^2/day IV) on days -5 through -1.
  * On day 0 patients will receive the infusion of autologous TIL and then begin high-dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).
  * Clinical and immunologic response will be evaluated about 4-6 weeks after TIL infusion.
* Cohort 5

  * All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m\^2/day IV) on days -5 through -1.
  * On day 0 patients will receive the infusion of autologous CD4+ depleted TIL and then begin high-dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).
  * Clinical and immunologic response will be evaluated about 4-6 weeks after TIL infusion.

Arms: arm 1: Cohort 1 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), \& high dose (HD) aldesleukin:

Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose aldesleukin.

Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m\^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.

Cohort 1 = unselected TIL arm 2: Cohort 2 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes (TIL), aldesleukin:

Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.

Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m\^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.

Cohort 2 = CD4+ depleted (selected) TIL arm 3: Cohort 3 - Nonmyeloablative (NMA), total body irradiation (TBI):

Nonmyeloablative chemotherapeutic conditioning regimen and 2 gray units (Gy) of total body irradiation followed by cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin.

Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m\^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL 2Gy (gray units) of total body irradiation (TBI) twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute using a linear accelerator in Radiation Oncology Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.

Cohort 3 = CD4 + depleted (selected) TIL + 600Gy radiation arm 4: Cohort 4 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), aldesleukin:

Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose (HD) aldesleukin.

Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m\^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.

Cohort 4 = unselected TIL - it is the SAME as cohort 1 arm 5: Cohort 5 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) tumor infiltrating lymphocytes (TIL), high dose (HD) aldesleukin:

Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose aldesleukin.

Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m\^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days.

Cohort 5 = CD4 + depleted TIL - it is the SAME as cohort 2
Interventions: intervention 1: aldesleukin intervention 2: therapeutic autologous lymphocytes intervention 3: Cyclophosphamide intervention 4: Fludarabine phosphate intervention 5: Total body irradiation
Intervention descriptions: intervention 1: Given subcutaneously every 8 hours for up to 15 doses, day 0, 720,000 IU/kg intervention 2: Given as infusion, up to 3 x 10\^11 lymphocytes (minimum of 1 x 10\^9), day 0 intervention 3: Given intravenously 60 mg/kg/day, day -7 to -6 intervention 4: Given intravenously 25 mg/m\^2/day over 15-30 minutes, day -5 to -1 intervention 5: 600 cGy

Protocol documents: