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Phase I/II Study of Metastatic Cancer That Expresses Carcinoembryonic Antigen (CEA) Using Lymphodepleting Conditioning Followed by Infusion of Anti-CEA TCR-Gene Engineered Lymphocytes


Phase 1
18 Years
N/A
Not Enrolling
Both
Metastatic Cancer

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Trial Information

Phase I/II Study of Metastatic Cancer That Expresses Carcinoembryonic Antigen (CEA) Using Lymphodepleting Conditioning Followed by Infusion of Anti-CEA TCR-Gene Engineered Lymphocytes


Background:

- We have constructed a single retroviral vector that contains both the alpha and beta
chains of a T cell receptor (TCR) that recognizes the carcinoembryonic antigen (CEA),
which can be used to mediate genetic transfer of this TCR with high efficiency (greater
than 30%) without the need to perform any selection.

- In co-cultures with HLA-A2 and CEA positive tumors, anti-CEA TCR transduced T cells
secreted significant amounts of interferon-gamma (IFN-gamma) with high specificity.

Objectives:

Primary objectives:

- To evaluate the safety of the administration of anti-CEA TCR engineered peripheral
blood lymphocytes in patients receiving the non-myeloablative conditioning regimen and
aldesleukin.

- To determine if the administration of anti-CEA TCR 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 CEA.

- To determine the in vivo survival of TCR gene-engineered cells.

Secondary objective:

- To determine the in vivo survival of TCR gene-engineered cells.

Eligibility:

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

- metastatic cancer whose tumors express the CEA antigen where the life limiting
component of the disease is hepatic metastases;

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

Patients should not have:

- contraindications for high dose aldesleukin administration.

Design:

- Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis (approximately 5
times 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 times 10(8) cells to
retroviral vector supernatant containing the anti-CEA TCR genes.

- Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of
ex vivo tumor reactive, TCR gene-transduced PBMC plus IV aldesleukin (720,000 IU/kg q8h
for a maximum of 15 doses). Patients will receive CD8-enhanced anti-CEA TCR transduced
cells.

- 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.

- The study will be conducted using a Phase I/II optimal design. The protocol will
proceed in a phase 1 dose escalation design, with six cohorts. Should a single patient
experience a dose limiting toxicity (DLT) at a particular dose level, three more
patients would be treated at that 3 dose to confirm that no greater than 1/6 patients
have a DLT prior to proceeding to the next higher level. If a level with 2 or more DLTs
in 3-6 patients has been identified, three additional patients will be accrued at the
next-lowest dose, for a total of 6, in order to further characterize the safety of the
maximum tolerated dose (MTD) prior to starting the phase II portion. If a DLT occurs in
the first cohort, that cohort will be expanded to 6 patients. If 2 DLTs are encountered
in this cohort, patients will be accrued to the de-escalation cohort.

- Once the MTD has been determined, the study then would proceed to the phase II portion.
Patients will be entered into two cohorts based on histology: cohort 1 will include
patients with metastatic colorectal cancer, and cohort 2 will include patients with
other types of metastatic cancer that express CEA.

- 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.

- The objective will be to determine if the combination of high dose aldesleukin,
lymphocyte depleting chemotherapy, and anti-CEA 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 (p1=0.20).

Inclusion Criteria


-INCLUSION CRITERIA:

1. Metastatic cancer that expresses carcinoembryonic antigen (CEA) as assessed by one of
the following methods:

- Immunohistochemistry of resected tissue, assessed by immunohistochemistry (IHC)
in the Clinical Laboratory Improvement Amendments (CLIA) approved test in the
Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer
Institute (NCI), National Institutes of Health (NIH). Since the affinity of the
antibody is weak, a result of greater than or equal to 1+ is considered
positive.

- Detection of elevated levels of circulating CEA using a standard clinical
enzyme-linked immunosorbent (ELISA) assay. Results will be considered positive
if CEA level is greater than 10 mcg/L.

- Metastatic cancer diagnosis will be confirmed by the Laboratory of Pathology at
the NCI.

2. Hepatic metastases must represent the life limiting components of the disease defined
as liver disease with a very high likelihood of causing the death of a patient
according to the best clinical judgment of the attending physician.

3. Patients 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.

4. Greater than or equal to 18 years of age.

5. Willing to sign a durable power of attorney

6. Able to understand and sign the Informed Consent Document

7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

8. Life expectancy of greater than three months.

9. Patients of both genders must be willing to practice birth control from the time of
enrollment on this study and for up to four months after receiving the preparative
regimen.

10. Patients must be human leukocyte antigen (HLA-A*0201) positive

11. Serology:

1. Seronegative for human immunodeficiency virus (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.)

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

12. Hematology:

1. Absolute neutrophil count greater than 1000/mm^3 without the support of
filgrastim.

2. White blood cell (WBC) (greater than 3000/mm^3.

3. Platelet count greater than 100,000/mm^3.

4. Hemoglobin greater than 8.0 g/dl.

13. Chemistry:

1. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or
equal to 2.5 times the upper limit of normal.

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

3. 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.

14. 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).

EXCLUSION CRITERIA:

1. 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.

2. 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.

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

4. 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).

5. Concurrent systemic steroid therapy

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

7. History of coronary revascularization or ischemic symptoms

8. Any patient known to have an left ventricular ejection fraction (LVEF) less than or
equal to 45%.

9. Documented LVEF of less than or equal to 45% tested in patients with:

1. 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

2. Age greater than or equal to 60 years old

10. Documented forced expiratory volume (FEV1) less than or equal to 60% predicted tested
in patients with:

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

2. Symptoms of respiratory dysfunction

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

clinical response of the administration of anti-CEA TCR engineered peripheral blood lymphocytes in patients receiving the non-myeloablative conditioning regimen and aldesleukin in patients with metastatic cancer.

Safety Issue:

No

Principal Investigator

Steven Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health

Authority:

United States: Federal Government

Study ID:

090047

NCT ID:

NCT00923806

Start Date:

December 2008

Completion Date:

November 2011

Related Keywords:

  • Metastatic Cancer
  • Metastatic Cancer
  • Tumor Regression
  • Safety
  • Immunotherapy
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary

Name

Location

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