Phase I/II Study of Metastatic Cancer That Expresses MAGE-A3/12 Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3/12 TCR-Gene Engineered Lymphocytes
We have constructed a single retroviral vector that contains both alpha and beta chains of a
T cell receptor (TCR) that recognizes the MAGE-A3/12 tumor antigen, which can be used to
mediate genetic transfer of this TCR with high efficiency (> 30%) without the need to
perform any selection.
In co-cultures with human leukocyte antigen serotype within HLA-A serotype group (HLA-A2)
and MAGE-A3/12 double positive tumors, anti-MAGE-A3/12 TCR transduced T cells secreted
significant amounts of Interferon (IFN)-gamma with high specificity.
- Determine if the administration of anti-MAGE-A3/12 engineered peripheral blood
lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid
depleting preparative regimen will result in clinical tumor regression in patients with
metastatic cancer that expresses the MAGE-A3/12 antigen.
- Determine the toxicity profile of this treatment regimen
-Determine the in vivo survival of TCR gene-engineered cells.
Patients who are human leukocyte antigen (HLA)-A*0201 positive and 18 years of age or older
- metastatic cancer whose tumors express the MAGE-A3/12 antigen;
- previously received and have been a non-responder to or recurred following standard
care for metastatic disease;
Patients may not have:
-contraindications for high dose aldesleukin administration.
PBMC obtained by leukapheresis (approximately 10^10) cells) will be cultured in the presence
of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth.
Transduction is initiated by exposure of approximately 10^7 to 5 X 10^8 cells to retroviral
vector supernatant containing the anti-MAGE-A3/12 TCR genes.
The study will begin by evaluating the safety of two ranges of cells, 5 x 10^9 - 3 x 10^10,
and greater than 3 x 10^10- 1 x 10^11 in a standard phase I dose escalation fashion using a
3+3 design. Once this safety has been confirmed, patients will be enrolled into the phase 2
portion of the trial using up to 1 x 10^11 cells. In the phase 2 portion, patients will be
entered into two cohorts based on histology: cohort 1 will include patients with metastatic
melanoma or renal cell cancer; cohort 2 will include patients with other types of metastatic
Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo
tumor reactive, TCR gene-transduced peripheral blood mononuclear cells (PBMC) plus
intravenous (IV) aldesleukin (720,000 IU/kg every (q)8h for a maximum of 15 doses).
Patients will undergo complete evaluation of tumor with physical examination, computed
tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four to
six weeks after treatment. If the patient has stable disease (SD) or tumor shrinkage, repeat
complete evaluations will be performed every 1-3 months. After the first year, patients
continuing to respond will continue to be followed with this evaluation every 3-4 months
until off study criteria are met.
For each of the 2 strata evaluated in the phase 2 portion, the study will be conducted using
a phase II optimal design where initially 21 evaluable patients will be enrolled. For each
of these two arms of the trial, if 0 or 1 of the 21 patients experiences a clinical
response, then no further patients will be enrolled but if 2 or more of the first 21
evaluable patients enrolled have a clinical response, then accrual will continue until a
total of 41 evaluable patients have been enrolled in that stratum.
For both strata, the objective will be to determine if the combination of high dose
aldesleukin, lymphocyte depleting chemotherapy, and anti-MAGE-A3/12 TCR-gene engineered
lymphocytes is able to be associated with a clinical response rate that can rule out 5%
(p0=0.05) in favor of a modest 20% partial response (PR) + complete response (CR) rate
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Steven A Rosenberg, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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