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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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Metastatic Melanoma, Metastatic Renal Cell Cancer, Metastatic Cancer

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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).

Inclusion Criteria


- INCLUSION CRITERIA:

- Metastatic cancer that expresses ESO as assessed by one of the following methods:
RT-PCR on tumor tissue, or by immunohistochemistry of resected tissue, or serum
antibody reactive with ESO. Metastatic cancer diagnosis will be confirmed by the
Laboratory of Pathology at the NCI.

- Patients with histologies other than metastatic melanoma, must have previously
received systemic standard care (or effective salvage chemotherapy regimens) for
metastatic disease, if known to be effective for that disease, and have been either
non-responders (progressive disease) or have recurred.

- Greater than or equal to 18 years of age.

- Willing to sign a durable power of attorney.

- Able to understand and sign the Informed Consent Document.

- Clinical performance status of ECOG 0 or 1.

- Life expectancy of greater than three months.

- Patients of both genders must be willing to practice birth control for four months
after receiving the preparative regimen.

- Patients must be HLA-A*0201 positive

- Serology:

- Seronegative for HIV antibody. (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who are HIV
seropositive can have decreased immune -competence and thus be less responsive
to the experimental treatment and more susceptible to its toxicities.)

- Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen
negative.

- Hematology:

- Absolute neutrophil count greater than 1000/mm(3) without the support of
filgrastim.

- WBC (greater than 3000/mm(3)).

- Platelet count greater than 100,000/mm(3).

- Hemoglobin greater than 8.0 g/dl.

- Chemistry:

- Serum ALT/AST less or equal to 2.5 times the upper limit of normal.

- Serum creatinine less than or equal to 1.6 mg/dl.

- Total bilirubin less than or equal to 1.5 mg/dl, except in patients with
Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

- More than four weeks must have elapsed since any prior systemic therapy at the time
the patient receives the preparative regimen, and patients' toxicities must have
recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).

- Six weeks must have elapsed since prior MDX-010 therapy to allow antibody levels to
decline.

- Patients who have previously received MDX-010 or ticilimumab must have a normal
colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

- Prior vaccination with an ALVAC containing vaccine for patients who will receive the
ALVAC ESO-1 vaccine (cohorts 3 or 4).

- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

- Active systemic infections, coagulation disorders or other major medical illnesses of
the cardiovascular, respiratory or immune system, myocardial infarction, cardiac
arrhythmias, obstructive or restrictive pulmonary disease.

- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).

- Concurrent opportunistic infections (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who have decreased immune
competence may be less responsive to the experimental treatment and more susceptible
to its toxicities).

- Concurrent Systemic steroid therapy.

- Known systemic hypersensitivity to any of the vaccine components, including egg
products or Neomycin for patients who will receive the ALVAC ESO-1 vaccine (cohorts 3
or 4).

- History of severe immediate hypersensitivity reaction to any of the agents used in
this study.

- History of coronary revascularization or ischemic symptoms.

- Any patient known to have an LVEF less than or equal to 45 percent.

- Documented LVEF of less than or equal to 45 percent tested in patients with:

- History of ischemic heart disease, chest pain, or clinically significant atrial
and/or ventricular arrhythmias including but not limited to: atrial
fibrillation, ventricular tachycardia, second or third degree heart block.

- Age greater than or equal to 60 years old.

- Documented FEV1 less than or equal to 60 percent predicted tested in patients with:

- A prolonged history of cigarette smoking (20 pk/year of smoking within the past
2 years).

- Symptoms of respiratory dysfunction

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Clinical tumor regression

Safety Issue:

No

Principal Investigator

Steven A Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

080121

NCT ID:

NCT00670748

Start Date:

April 2008

Completion Date:

March 2014

Related Keywords:

  • Metastatic Melanoma
  • Metastatic Renal Cell Cancer
  • Metastatic Cancer
  • Metastatic Cancer
  • Gene Therapy
  • Immunotherapy
  • Tumor Regression
  • Metastatic Melanoma
  • Metastatic Renal Cell Cancer
  • Carcinoma, Renal Cell
  • Melanoma
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892