Adoptive Transfer of MART-1 F5 TCR Engineered Peripheral Blood Mononuclear Cells (PBMC) After a Nonmyeloablative Conditioning Regimen, With Administration of MART-126•35-Pulsed Dendritic Cells and Interleukin-2, in Patients With Advanced Melanoma
This is a two-stage phase II clinical trial with the combined primary endpoints to determine
the safety, feasibility and anti-tumor activity of adoptive transfer of peripheral blood
mononuclear cells (PBMC) genetically engineered to express the alpha and beta chains of a
high affinity T cell receptor (TCR) specific for the HLA-A*0201-restricted MART-1 melanoma
tumor antigen to patients with locally advanced or metastatic melanoma. This gene transfer
will be facilitated by a retroviral vector pseudotyped with a gibbon ape leukemia virus
(GaLV) envelope. The two transgenes are linked by a picornavirus 2A sequence. Their
expression is driven by the retroviral long terminal repeat (LTR).
Patients with MART-1-positive locally advanced or metastatic melanoma who are
HLA-A*0201-positive, and HIV, hepatitis B and C seronegative, will receive a
non-myeloablative but lymphocyte depleting chemotherapy conditioning regimen consisting of
cyclophosphamide and fludarabine, and then receive the adoptive transfer of autologous PBMC
transduced with the MSGV1-F5AfT2AB retroviral vector, which expresses a high affinity TCR
for the MART-1 melanoma antigen (MART-1 F5 TCR). The cell dose will be up to 10^9 autologous
PBMC transduced with the MSGV1-F5AfT2AB retroviral vector. The transgenic T cells will be
infused fresh on the day of harvest as done in the last three patients within this protocol,
prior to which, thawed cryopreserved cells were infused. Following adoptive cell transfer,
patients will receive MART-1.26-35 peptide-pulsed dendritic cell (DC) vaccines and low dose
The MART-1 F5 TCR was provided by Dr. Stephen A. Rosenberg from the Surgery Branch, National
Cancer Institute (NCI). The MART-1 F5 TCR is derived from the DMF5 tumor infiltrating
lymphocyte (TIL) clone, and was selected from several MART-1-specific TCRs because of its
high affinity and biological activity. This TCR delivered by the same retroviral vector is
currently in clinical testing at the Surgery Branch/NCI. Both the NCI clinical trial and the
trial at UCLA are based on the same retrovirus expressing the MART-1 F5 TCR used to
transduce whole PBMC and re-infused to patients after a non-myeloablative but
lymphodepleting chemotherapy conditioning regimen. Major differences between both clinical
trials include the shorter ex vivo expansion of TCR transduced PBMC, the use of MART-126-35
peptide pulsed DC and the use of positron imaging tomography (PET) for non-invasive imaging
of adoptively transferred TCR transgenic cells in the UCLA clinical trial.
The primary endpoints will be safety, feasibility and objective tumor response. The phase II
clinical trial design will have two treatment stages following a Simon optimal two-stage
clinical phase II clinical trial design 1. The clinical trial will have an initial stage
with 8 patients followed by a second stage with up to 22 patients.
Safety will be determined in stage one, and if 3 out of 8 patients have MART-1 F5
TCR-induced dose limiting toxicities (DLT), then further accrual will not be warranted.
Feasibility will be also determined in the first stage, and if 3 out of 8 patients cannot
receive the intended cellular therapies, or if they result in suboptimal TCR transgenic cell
in vivo persistence, further accrual will not be warranted to the protocol as currently
designed. Objective tumor responses will be determined by RECIST objective response criteria
with a design to rule out a 10% response rate as the null hypothesis, and a 35% response
rate as the alternative hypothesis. With this statistical design, if 2 or more of 8 patients
in stage one have an objective response, the study will proceed to stage two and accrue a
total of 22 patients. If 5 or more patients in the overall study have a complete response
(CR) or partial response (PR), which combined result in the objective response rate, the
study will be declared positive.
Secondary study endpoints are transgenic T cell persistence in humans and their ability to
home to MART-1 positive melanoma metastasis. Analysis will be performed by sampling of
peripheral blood and tumor deposits for T cell persistence and by non-invasive metabolic
imaging using PET scans.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Response rate: The two-stage phase II study design includes response rate by RECIST criteria as the primary endpoint.
Antoni Ribas, MD
University of California, Los Angeles
United States: Food and Drug Administration
|University of California Los Angeles, David Geffen School of Medicine||Los Angeles, California 90095|