Clinical trial NCT01495572
Conditions: Metastatic Melanoma Skin Cancer
Keywords: Malignant Melanoma Immunotherapy Cell Therapy HLA-A2 Positive Skin Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2011-12-01; Completion date: 2014-02-01
Enrollment: 5 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Some cancer treatments collect a patient s own blood cells to use as specialized cancer-fighting cells. Collected white blood cells known as PBL (peripheral blood lymphocytes) can use to isolate special cells that can fight tumors. Before treatment with PBL, chemotherapy is given to destroy existing white blood cells so that the new cells can survive and attack the tumors. After PBL treatment, aldesleukin is given to help the new cells grow. Researchers want to see if special white blood cells that recognize a specific protein that is present in melanoma cells (melanoma antigen recognized by T cells (MART)) can cause tumors to shrink. These white blood cells will be tested with and without aldesleukin.

Objectives:

* To test the safety and effectiveness of white blood cells that target MART in the treatment of melanoma.
* To test white blood cells that target MART with and without aldesleukin.

Eligibility:

\- Individuals at least 18 years of age who have melanoma that has not responded to standard treatments.

Design:

* Participants will be screened with a medical history and physical exam. Blood and urine samples will be taken. Imaging studies such as x-rays or magnetic resonance imaging scans will be performed.
* Participants will provide white blood cells through leukapheresis. Researchers will attempt to isolate white blood cells that recognize MART
* Seven days before the start of treatment, participants will have chemotherapy.
* After the last dose of chemotherapy, participants will receive the MART reactive PBL cells. Filgrastim doses will also be given to help white blood cell counts return to normal. Participants will have frequent blood tests.
* Participants who are able to have aldesleukin treatment will start within 24 hours after receiving the MART reactive PBL cells. Treatment will continue for up to 5 days.
* Participants may have an optional tumor or lymph node biopsy to study the effects of treatment.
* If the tumor continues to grow after MART PBL treatment, participants may have one more round of cell collection and treatment.
* Participants will have followup visits for up to 6 months after receiving the MART reactive PBL treatment.

Detailed description:
Background:

* TIL transfer studies in patients with metastatic melanoma following lymphodepletion have resulted in 50 percent objective response rates with a 10-15 percent rate of complete responses. Despite these important clinical findings, adoptive cell transfer has not become widely available for patient treatment. Significant obstacles to this therapy are the need for invasive surgery and the inability of some patients to tolerate high dose aldesleukin. Further, the specific characteristics of the T cells that are responsible for the therapeutic effect of tumor infiltrating lymphocyte (TIL) are unknown, thus, resulting in significant treatment variability.
* Pre-clinical and correlative clinical studies of adoptive immunotherapy have suggested putative favorable characteristics for transferred lymphocytes, such as, high avidity for the target antigen, limited in vitro stimulation, and high expression of CD27+. However, these characteristics have not been prospectively evaluated in human clinical trials.
* We have developed a novel non invasive T cell isolation strategy using the heteroclitic MART-1:26-35(27L) peptide for in vitro sensitization of human PBL and high throughput quantitative polymerase chain reaction (qPCR) screening to rapidly isolate antigen specific cluster of differentiation 8 (CD8) + T cells from the cluster of differentiation 4 (CD4) + T cell depleted peripheral blood repertoire. These isolated T cells possess the above mentioned favorable characteristics and recognize the native MART-1:27-35 epitope, an abundantly expressed melanoma antigen presented by human leukocyte antigen serotype within HLA-A A serotype group (HLA-A2) on the tumor surface.
* The current proposed transfer of these select MART-1:27-35 reactive lymphocytes in conjunction with a lymphodepleting preparative regimen with or without high dose aldesleukin would represent a novel therapeutic option for patients with advanced melanoma and provide a desperately needed option for patients who are not medically eligible for aldesleukin treatment.

Objectives:

* To determine whether MART-1:27-35 reactive lymphocytes infused with or without the administration of high-dose aldesleukin may result in clinical tumor regression in patients with metastatic melanoma receiving a non-myeloablative lymphoid depleting preparative regimen.
* To evaluate the safety of the treatment in patients receiving the non-myeloablative conditioning regimen and cell transfer with or without the administration of high-dose aldesleukin
* To determine the survival in patients, of infused cells following the administration of the non-myeloablative regimen, using analysis of the sequence of the variable region of the T cell receptor or flow cytometry (fluorescence activated cell sorting (FACS)).

Eligibility:

-Patients with refractory metastatic melanoma who are greater than or equal to 18 years of age, are HLA-A2+, who have MART-1:27-35 reactive peripheral blood lymphocytes available and are physically able to tolerate non-myeloablative chemotherapy. Patients must be refractory to prior high dose aldesleukin treatment if they are medically eligible to receive it. Patients who can tolerate high-dose aldesleukin will receive it with cell infusion; those who cannot tolerate high-dose aldesleukin due to medical comorbidities or refuse high-dose aldesleukin will receive cell infusion without aldesleukin.

Design:

* Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide (60 mg/kg/day X 2 days intravenous (IV)), fludarabine (25 mg/m\^2/day IV X 5 days).
* Patients will receive intravenous adoptive transfer of MART-1:27-35 reactive peripheral blood lymphocytes (minimum 1 X 10\^8 and up to a maximum of 3 X 10\^11 lymphocytes) followed by high-dose intravenous (IV) aldesleukin (720,000 IU/kg/dose every 8 hours for up to 15 doses) or no aldesleukin if they are not medically eligible to receive it.
* A complete evaluation of evaluable lesions will be conducted 4-6 weeks after the last dose of aldesleukin in the aldesleukin arm and 4-6 weeks after the cell administration in the no aldesleukin arm. Patients will be enrolled into two cohorts. The cohort receiving high-dose aldesleukin will be conducted using a small optimal two-stage Phase II design, initially 19 patients will be enrolled, and if 4 or more of the first 19 patients have a clinical response ((partial response ) PR or (complete response) CR), accrual will continue to 33 patients, targeting a 35 percent goal for objective response. For the cohort who will not receive aldesleukin, the study will be conducted as a Minimax two stage phase II trial. Initially 12 evaluable patients will be enrolled to this cohort, and if 1 or more the first 12 have a response, then accrual would continue until a total of 21 patients, targeting a 20 percent goal for objective response.

Arms: arm 1: Pts receiving high dose aldesleukin: Cyclophosphamide 60 mg/kg intravenous (IV) for days -7 and -6, Fludarabine 25 mg/m\^2 IV for days -5 to -1, plus melanoma antigen recognized by T cells (MART)-127-35 reactive CD8+ peripheral blood lymphocytes (PBL) up to 3x10\^11 IV over 20-30 minutes on day 0, plus aldesleukin 720,000 IU/kg IV over 15 minutes, every 8 hrs for up to 5 days. arm 2: Cyclophosphamide 60 mg/kg intravenous (IV ) for days -7 and -6, Fludarabine 25 mg/m\^2 IV for days -5 to -1, plus MART-127-35 reactive CD8+ PBL up to 3x10\^11 IV over 20-30 minutes on day 0
Interventions: intervention 1: Fludarabine intervention 2: Cyclophosphamide intervention 3: Aldesleukin intervention 4: MART-1 Reactive CD8+ PBL
Intervention descriptions: intervention 1: 25 mg/m\^2 IV (in the vein) for 5 days (day -5 to -1) intervention 2: 60 mg/kg IV (in the vein) for days -7 and -6 intervention 3: Only given to patients assigned to high dose (HD) Arm - 720,000 IU/kg intravenous (IV) over 15 minutes, every 8 hrs (+/- 1 hr) for up to 5 days (max 15 doses).-6 intervention 4: Intravenous (IV) over 30 minutes on day 0

Protocol documents: