Trial Information

Phase II Study of Metastatic Cancer That Expresses NY-ESO-1 Using Lymphodepleting Conditioning Followed by Infusion of Anti-NY ESO-1 TCR-Gene Engineered Lymphocytes

Background:

- We have constructed a single retroviral vector that contains both alpha and beta chains
of a T cell receptor (TCR) that recognizes the NY-ESO-1 (ESO) 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 HLA-A2 and ESO double positive tumors, anti-ESO TCR transduced T
cells secreted significant amount of IFN-gamma and additional secretion of cytokines
with high specificity.

- Poxviruses encoding tumor antigens, similar to the ALVAC ESO-1 vaccine have been shown
to successfully immunize patients against these antigens.

Objectives:

Primary objectives:

- Determine if the administration of anti-ESO -TCR engineered peripheral blood
lymphocytes (PBL) 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 ESO antigen.

- Determine if the administration of anti-ESO -TCR engineered PBL, aldesleukin, and ALVAC
ESO-1 vaccine to patients following a nonmyeloablative but lymphoid depleting
preparative regimen will result in clinical tumor regression in patients with
metastatic cancer that expresses the ESO antigen.

Secondary objectives:

- Determine the in vivo survival of TCR gene-engineered cells.

- Determine the toxicity profile of this treatment regimen.

Eligibility:

- Patients who are HLA-A*0201 positive and 18 years of age or older must have:

- metastatic cancer whose tumors express the ESO antigen;

- previously received and have been a non-responder to or recurred to standard care
for metastatic disease, except for melanoma patients;

- Patients may not have:

- contraindications for high dose aldesleukin administration.

Design:

- PBMC obtained by leukapheresis (approximately 5 X 10(9) 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(8) to 5 X 10(8) cells to
retroviral vector supernatant containing the anti-ESO TCR genes.

- 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 genetransduced PBMC plus IV aldesleukin (720,000 IU/kg q8h for
a maximum of 15 doses) with or without ALVAC ESO-1 vaccine. Subcutaneous injection of
ALVAC ESO-1 vaccine will be administered on day 0 approximately 2 hours prior to
intravenous infusion of cells and a second dose of ALVAC ESO-1 vaccine is given on day
14 (+/- 2 days).

- Patients will undergo complete evaluation of tumor with physical examination, CT of the
chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after
treatment. If the patient has 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.

Cohorts 1 and 2:

- 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 cancer.

- For each of the 2 strata evaluated, 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-ESO 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% PR + CR rate (p1=0.20).

Cohorts 3 and 4:

- For patients receiving ALVAC ESO-1 vaccine, patients will also be entered into two
cohorts based on histology: cohort 3 for patients with metastatic melanoma or renal
cell cancer and cohort 4 for patients with other histologies and all patients will
receive the treatment regimen including the ALVAC ESO-1 vaccine.

- For each of these 2 new strata, the study will be conducted using a phase II optimal
design where initially 21 evaluable patients will be enrolled. For each of these two
new cohorts 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, anti-ESO TCR-gene engineered
lymphocytes, and ALVAC ESO-1 vaccine is able to be associated with a clinical response
rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).