Phase II Study in Patients With Metastatic Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of gp100 Reactive Peripheral Blood Lymphocytes (PBL) and High or Low Dose Aldesleukin
- Tumor infiltrating lymphocytes (TIL) transfer studies in patients with metastatic
melanoma following lymphodepletion have resulted in 50% objective response rates with a
10-15% rate of complete responses.
- Pre-clinical and clinical studies of adoptive immunotherapy have suggested that
effective lymphocytes for transfer have high avidity for the target antigen, undergo
limited in vitro antigen and IL-2 stimulation, and have high expression of cluster of
differentiation 27+ (CD27+).
- We have developed a novel in vitro strategy using high throughput polymerase chain
reaction (PCR) screening to rapidly isolate low frequency antigen specific cluster of
differentiation 8+ (CD8+) T cells from the peripheral blood repertoire that have these
characteristics, and that recognize the gp100:154-162 epitope, an abundantly expressed
melanoma antigen, presented by human leukocyte antigens (HLAA2) on the tumor surface.
- The current proposed transfer of gp100:154-162 reactive lymphocytes administered in
conjunction with a lymphodepleting preparative regimen and aldesleukin would represent
a significantly novel approach to adoptive immunotherapy.
- To determine whether gp100:154-162 reactive cluster of differentiation 4+ (CD4+) T cell
depleted lymphocytes infused in conjunction with the administration of high-dose
aldesleukin or low-dose aldesleukin may result in clinical tumor regression in patients
with metastatic melanoma receiving a non-myeloablative lymphoid depleting preparative
- To evaluate the safety of the treatment in patients receiving the non-myeloablative
conditioning regimen, cell transfer, and high-dose or low-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).
-Patients with refractory metastatic melanoma who are greater than or equal to 18 years of
age, are HLA-A2+, who have gp100:154-162 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 will receive low-dose aldesleukin.
- 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 gp100:154-162 reactive
peripheral blood lymphocytes (minimum 1 X 10^9) 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 low-dose subcutaneous (SQ) aldesleukin (125,000 IU
IL-2/kg/dose for 5 days for 6 weeks with 2 days rest per week).
- A complete evaluation of evaluable lesions will be conducted 4-6 weeks after the last
dose of aldesleukin in the high dose arm and 2-4 weeks after the last dose of
aldesleukin in the low dose 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 21 patients will be enrolled, and if two or more of the first 21
patients has a clinical response (partial response (PR) or complete response (CR)),
accrual will continue to 41 patients, targeting a 20% goal for objective response. For
the cohort who will receive low dose 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% goal for objective response.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.
Joohee Sul, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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