Clinical trial NCT00314106
Conditions: Metastatic Melanoma
Keywords: Clinical Response Stage IV Melanoma Adoptive Cell Therapy Tumor Infiltrating Lymphocytes Immunologic Response Metastatic Melanoma
Sponsor: National Cancer Institute (NCI)
Start date: 2006-04-01; Completion date: 2009-03-01
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

* In a study in humans with melanoma, patients given total body irradiation to suppress the immune system in conjunction with chemotherapy showed a significant clinical response.
* In previous studies, about one-half of patients given tumor-fighting cells (cells created from the patient's tumor cells and grown in the laboratory) showed some anti-tumor response.

Objective: To determine whether tumor-fighting cells taken from a melanoma tumor and grown in the lab can more effectively at fight melanoma when the patient's immune system is suppressed and cannot attack them.

Eligibility: Patients 18 years of age or older with metastatic melanoma who have tumor reactive cells available.

Design:

-Patients are assigned to one of two groups - those having received prior therapy with Interleukin-2 (IL-2) and those who have not.

After five days of injections of filgrastim, a medicine to stimulated the growth of white blood cells, patients undergo apheresis or bone marrow harvesting, or both, to collect stem cells for later re-infusion. For apheresis, whole blood is collected through a needle in an arm vein and circulated through a cell-separating machine where the stem cells are extracted. The rest of the blood is returned through the same needle or a needle in the other arm. Bone marrow harvesting is done under general anesthesia. Stem cells are collected through a large needle inserted into the hipbone.-Patients' immune system cells and bone marrow function are eliminated with chemotherapy (7 days) and total body irradiation (3 days) so the patient's immune system cells will not fight the tumor-fighting cells they are given in treatment.

* 1 to 3 days after total body irradiation, patients receive the tumor-fighting cells by intravenous (IV) infusion. After the cells are infused, they receive interleukin-2 (IL-2) infusions every 8 hours for 5 days.
* 2 days after infusion of the tumor-fighting cells, patients receive the stem cells collected earlier by apheresis.
* Patients are evaluated 4 to 6 weeks after cell infusion to look for tumor response to treatment. Patients whose tumor has not grown return to the National Institutes of Health (NIH) every 1 to 3 months for blood tests, scans and x-rays.

Detailed description:
Background:

The use of immunosuppression prior to adoptive transfer of lymphocytes from tumor bearing mice was based on a variety of murine models demonstrating improved therapeutic effectiveness of the adoptive transfer of lymphocytes following immunosuppression of the host.

Because the degree of immunosuppression has been highly correlated with the ability to eliminate large tumors in murine models, we have been conducting a clinical trial, 04-C-0288, in which 200cGy of total body irradiation is used in conjunction with the same cyclophosphamide and fludarabine regimen used in our prior adoptive cell therapy trials which have demonstrated significant clinical responses.

We have measured T-regulatory cells in patients participating in 04-C-0288 and have demonstrated that despite the addition of 200cGy total body irradiation (TBI), T-regulatory cells promptly reconstituted in the host. Complete clinical responses have not been significantly improved over other adoptive cell therapy regimens.

Thus, in this trial we would like to more adequately test our hypothesis that more intensive lymphodepletion will increase complete responses and persistence of the transferred cells.

Objective:

To determine whether tumor reactive lymphocytes infused in conjunction with the administration of high-dose IL-2 in patients who have received prior therapy with IL-2 and those who have not may result in complete clinical tumor regression in patients with metastatic melanoma receiving a myeloablative lymphoid depleting preparative regimen.

To evaluate the safety of the treatment in patients receiving the myeloablative conditioning regimen, cell transfer and IL-2.

To determine the survival in patients, of infused cells following the administration of the myeloablative regimen, using analysis of the sequence of the variable region of the T cell receptor or flow cytometry (FACS).

Eligibility:

Patients who are greater than or equal to 18 years of age who have tumor reactive cells available, with metastatic melanoma, and are physically able to tolerate high-dose IL-2.

Design:

Patients will be assigned to one of two cohorts, those having received prior therapy with IL-2 and those who have not.

Patients will receive a myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide (60 mg/kg/day x 2 days IV), fludarabine (25mg/m\^2/day IV X 5 days) and 1200 cGy total body irradiation (TBI).

Patients will receive intravenous adoptive transfer of tumor reactive lymphocytes (minimum 3 X 10 (9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous (IV) IL-2 (720,000 IU/kg/dose every 8 hours for up to 15 doses).

On day 1 of patients will receive intravenous administration of cryopreserved autologous CD34+ cells.

A complete evaluation of evaluable lesions will be conducted 4-6 weeks after cell infusion. Patients will be enrolled into two strata, using a phase II optimal design to rule out a modest CR rate of 24%, with 33-54 patients enrolled in each strata.

Arms: arm 1: Patients that received prior interleukin 2 (IL-2) therapy will receive a myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide (60 mg/kg/day x 2 days intravenous (IV)), fludarabine (25mg/m\^2/day IV X 5 days) and 1200 cGy total body irradiation (TBI). Following the lymphodepleting regimen, patient will receive intravenous adoptive transfer of tumor reactive lymphocytes (minimum 3 X 10 (9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous (IV) IL-2 (720,000 IU/kg/dose every 8 hours for up to 15 doses). arm 2: Patients that have not received prior interleukin 2 (IL-2) therapy will receive a myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide (60 mg/kg/day x 2 days intravenous (IV)), fludarabine (25mg/m\^2/day IV X 5 days) and 1200 cGy total body irradiation (TBI). Following the lymphodepleting regimen, patient will receive intravenous adoptive transfer of tumor reactive lymphocytes (minimum 3 X 10 (9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous (IV) IL-2 (720,000 IU/kg/dose every 8 hours for up to 15 doses)
Interventions: intervention 1: Melanoma Reactive TIL intervention 2: Cyclophosphamide intervention 3: IL-2 intervention 4: Fludarabine intervention 5: 1200 total body irradiation (TBI)
Intervention descriptions: intervention 1: None intervention 2: 60 mg/kg/ day x 2 days intravenous intervention 3: 720,000 IU/kg/dose every 8 hours for up to 15 doses intervention 4: 25 mg/m\^2/day intravenous x 5 days intervention 5: 1200 cGY total body radiation

Protocol documents: