Clinical trial NCT01468818
Conditions: Metastatic Melanoma Skin Cancer
Keywords: Metastatic Melanoma Adoptive Cell Therapy Skin Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2011-09-01; Completion date: 2013-08-01
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient with aldesleukin (IL-2) a drug that keeps the white blood cells active. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 200 patients with melanoma.
* This study will use chemotherapy to prepare the immune system before this white blood cell treatment. Our prior studies indicate that aldesleukin may not be required for cell transfer.

Objectives:

\- To see if chemotherapy and white blood cell therapy without aldesleukin is a safe and effective treatment for metastatic melanoma.

Eligibility:

\- Individuals at least 18 years of age and less than or equal to 70 years of age with metastatic melanoma.

Design:

* Work up stage: Patients will be seen as an outpatient at the National Institute of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed.
* Surgery: If the patients meet all of the requirements for the study they will undergo surgery to remove a tumor that can be used to grow the TIL product.
* Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.}
* Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.
* Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.

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.

* 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 cluster of differentiation 4 + forkhead box P3 (CD4+ Foxp3) + T regulatory cells.
* 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 CD4+ Foxp3+ T regulatory cells and the likelihood of achieving an objective response.
* In our prior clinical trials of cell transfer using TIL after lymphodepletion with or without

  2 (gray)Gy total body irradiation, patients who experienced an objective response received fewer doses of IL-2 compared to non-responders (p=0.007 and 0.03 respectively).
* High levels of the homeostatic T cell growth factor, IL-15, are present in patient serum after the lymphodepleting regimen at the time of cell transfer.
* These factors raise the possibility that IL-2 administration is not required after cell transfer.

OBJECTIVES:

* The primary objective of this trial is to determine whether objective responses can be mediated in patients with metastatic melanoma who have received a lymphodepleting chemotherapy regimen and adoptive transfer of young tumor infiltrating lymphocytes and no IL-2 administration.
* The secondary objective involves the determination of the level of transferred cells in the blood that persist at about 1 week and 1 month after transfer.

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).
* Patients not eligible to receive IL-2.

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 young

autologous TIL.

\- Patients will be evaluated for objective clinical response and for persistence of the transferred cells.

Arms: arm 1: Patients will receive non-myeloablative lymphodepleting preparative regimen cons
Interventions: intervention 1: Cyclophosphamide intervention 2: Fludarabine intervention 3: Young Tumor Infiltrating Lymphocytes (TIL)
Intervention descriptions: intervention 1: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr. intervention 2: Fludarabine 25 mg/m2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days. intervention 3: Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of young TIL. On day 0, cells (1x10e9 to 2x10e11) will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Protocol documents: