Clinical trial NCT02111863
Conditions: Melanoma Skin Cancer
Keywords: Skin Cancer Metastatic Melanoma Adoptive Cell Therapy Immunotherapy Clinical Response
Sponsor: National Cancer Institute (NCI)
Start date: 2014-02-21; Completion date: 2016-07-21
Enrollment: 6 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. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 100 patients. In this study, we are selecting a specific subset of white blood cells from the tumor that we think are the most effective in fighting tumors and will use only these cells in making the tumor fighting cells.

Objective:

The purpose of this study is to see if these specifically selected tumor fighting cells can cause melanoma tumors to shrink and to see if this treatment is safe.

Eligibility:

\- Adults age 18-70 with metastatic melanoma who have a tumor that can be safely removed.

Design:

* Work up stage: Patients will be seen as an outpatient at the National Institutes 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 tumor infiltrating lymphocytes (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 take up to 2 days.

...

Detailed description:
Background:

* Autologous tumor infiltrating lymphocytes (TIL) followed by high dose aldesleukin can mediate the regression of bulky metastatic melanoma when administered to a patient following a non-myeloablative but lymphodepleting chemotherapy preparative regimen.
* In animal models, mixing irrelevant (non-reactive) cells with tumor-reactive cells negatively impacts on tumor treatment possibly by competing for cytokines, suggesting that enrichment for tumor-reactive cells could enhance clinical efficacy. Additionally, preclinical animal models and clinical investigation have demonstrated that prolonged in vitro culture negatively impacts on tumor treatment.
* The current method for enrichment of tumor-reactive TIL requires screening of multiple independent TIL cultures for anti-tumor specificity using gamma-interferon production by TIL. However, in vitro screening depends on autologous tumor reagents that are often unavailable, and interferon (IFN) gamma release in vitro may not be the best effector function to evaluate tumor recognition. The screen increases the length of in vitro culture times (30 days), which results in shorter telomere lengths and more differentiated cells. Additionally, selection of a few highly reactive cultures for further expansion may reduce the diversity of cluster of differentiation 8 (CD8+) repertoire recognizing the tumor.
* 4-1BB is a co-stimulatory molecule up-regulated on the cell surface of T cells upon T-cell receptor (TCR) engagement. Pre-clinical studies in the Surgery Branch have evaluated a fast and simplified method to select and expand a diverse tumor-reactive repertoire, regardless of knowledge of the specific antigen recognized, based on selection of 4-1BB expressing TIL from the fresh tumor digest.

Objectives:

* To determine the safety and objective response rate of patients with metastatic melanoma receiving ACT using 4-1BB selected TIL plus aldesleukin treatment following a chemotherapy preparative regimen.
* To determine the survival of patients receiving this treatment regimen.

Eligibility:

Patients who are 18 years or older must have:

* Evaluable metastatic melanoma;
* Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL;
* No contraindications to high-dose aldesleukin administration;
* No concurrent major medical illnesses or any form of immunodeficiency

Design:

* Patients with metastatic melanoma will have a lesion resected and 4-1BB expressing tumor infiltrating lymphocytes will be isolated using a fluorescence-activated cell sorting (FACS) sorter approved for clinical use. The 4-1BB selected cells will be rapidly expanded in vitro and administered plus aldesleukin following a non-myeloablative chemotherapy preparative regimen.
* The study will be conducted using a stage 2 optimal design to determine if this treatment is able to be associated with a clinical response rate that can rule out 10% (p0=0.10) in favor of a modest 30% partial response (PR) + complete response (CR) rate (p1=0.30).
* Up to 35 patients may be enrolled over 2 years.

Arms: arm 1: Patients will receive a lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of 4-1BB selected tumor infiltrating lymphocytes (TIL) plus IV aldesleukin.
Interventions: intervention 1: Aldesleukin intervention 2: Fludarabine intervention 3: Cyclophosphamide intervention 4: 4-1BB Selected Tumor Infiltrating Lymphocytes (TIL)
Intervention descriptions: intervention 1: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses). intervention 2: Fludarabine 25 mg/m\^2/day (intravenous piggyback) IVPB daily X 5 days.(The fludarabine will be started approximately 1-2 hours after the cyclophosphamide on Days -5 and -4) intervention 3: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml 5% dextrose in water (D5W) over 1 hr. intervention 4: On day 0, cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (one to four days after the last dose of fludarabine).

Protocol documents: