Clinical trial NCT01369888
Conditions: Metastatic Melanoma Skin Cancer
Keywords: Immunotherapy Cell Therapy IL-15 Cytokine Melanoma Metastatic Melanoma Skin Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2011-05-01; Completion date: 2014-05-01
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

\- Researchers have developed an experimental cancer treatment called cell therapy. White blood cells called lymphocytes are taken from a tumor, grown in large numbers in the lab, and then given back to the patient. Interleukin-15, given to the patient after the cells (now called Young tumor-infiltrating lymphocytes of Young TIL cells) are replaced, helps the cells to grow and boosts the immune system. This process changes your normal cells into cells that are able to recognize your tumor has been studied in the lab. These cells can destroy tumor cells in the test tube, but scientists want to see if they work inside the body.

Objectives:

-To test the effectiveness of lymphocytes drawn from tumor cells combined with interleukin-15 in treating metastatic melanoma.

Eligibility:

* Patients must be 18 - 66 years of age and have a diagnosis of metastatic melanoma.
* They will have heart and lung function tests, lab tests, and imaging procedures.
* Patients may not have conditions such as active systemic infections, blood clotting disorders, or other active major medical illnesses.
* Patients may not be pregnant or nursing.

Detailed description:
Background:

* Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered to the autologous patient along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen.
* In our analysis of factors that relate to the ability of this treatment to mediate objective responses, we have found a highly significant inverse correlation between reconstitution of cluster of differentiation 4 (CD4)+ forkhead box P3 (Foxp3) + T regulatory cells and the likelihood of achieving an objective response.
* Interleukin 2 (IL-2) administration has been shown to increase the number of T regulatory cells and in our trials we have found a direct relationship between the number of IL-2 doses and the reconstitution of patients at one week with CD4+ Foxp3 + T regulatory cells.
* Interleukin 15 (IL-15) is a strong T cell growth factor, but unlike IL-2, IL-15 is not involved in the generation and maintenance of CD4+ Foxp3 + T regulatory cells that can inhibit immune reactions.
* In pre-clinical adoptive cell transfer studies utilizing a murine melanoma model, the administration of IL-15 following adoptive cell transfer improved anti-tumor effects.

Objectives:

* The primary objective of this trial is to determine the safety, toxicity, and maximum tolerated dose of intravenous recombinant IL-15 administered as a daily intravenous bolus for 10 consecutive days in patients with metastatic melanoma who have received a lymphodepleting chemotherapy regimen and adoptive transfer of tumor infiltrating lymphocytes.
* An additional primary objective is to determine whether this combination is able to produce a modest number of clinical responses.
* The secondary objective involves the determination of the level of reconstitution of T regulatory cells in patients who receive cell transfer followed by IL-15 and to determine the pharmacokinetics of IL-15 levels in the serum following intravenous administration.

Eligibility:

* Patients greater than or equal to 18 years old with pathologically confirmed diagnosis of metastatic melanoma.
* Patients with measurable disease, absolute neutrophil count greater than 1000/mm\^3 and platelet count greater than 100,000/mm\^3.
* No serious comorbid conditions such as active systemic infections, coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory or immune systems.

Design:

* Patients with metastatic melanoma will undergo resection to obtain tumor for generation of autologous TIL cultures.
* Patients will receive a non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of autologous Young TIL. In the phase 1 portion of this study, patients will receive recombinant human IL-15 at doses of 0.25, 0.5, 1 or 2 micrograms per kilogram give intravenously daily for 10 days starting on the day of cell transfer. One patient will be treated at the first dose level, if this patient experiences a dose limiting toxicity (DLT), additional patients will be treated at the dose to confirm that no greater than 1/6 patients have DLT prior to proceeding to the next higher level. If 2 DLTs are encountered in this cohort, the study will be terminated. In all other cohorts, groups of three to six patients will receive recombinant human IL-15. Should a single patient experience a dose limiting toxicity due to the cell transfer at a particular dose level, additional patients will be treated at the dose to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the next higher level. If a level 2 or more DLTs in 3-6 patients has been identified, three additional patients will be accrued at the next-lowest dose, for a total of 6, in order to further characterize the safety of the maximum tolerated dose prior to starting the phase 2 portion. In the phase 2 portion of this study, patients will receive a non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of autologous Young TIL and IL-15 at the maximum tolerated dose (MTD) established in the phase 1 portion.
* Studies will be performed to determine the reconstitution of patients with T regulatory cells and to determine the pharmacokinetics of IL-15 concentration in serum.

Arms: arm 1: 0.25 mcg/kg/day x 10 arm 2: 0.50 mcg/kg/day x 10 arm 3: 1 mcg/kg/day x 10 arm 4: 2 mcg/kg/day x 10
Interventions: intervention 1: Cyclophosphamide intervention 2: Fludarabine intervention 3: Tumor Infiltrating Lymphocytes intervention 4: IL-15
Intervention descriptions: intervention 1: 60 mg/m\^2, intravenous (IV) (in the vein) x 2 days intervention 2: 25 mg/m\^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days (days -5 to -1) intervention 3: IV over 30 minutes on day 0 intervention 4: IV over 30 minutes, daily for 10 days, starting 3-4 hours after the TIL infusion. (day 0 to day 9). Doses will be increased every 3-6 patients.

Protocol documents: