Protocol Number: 09-C-0041

Title:

Phase I/II Study of Metastatic Cancer that Expresses Her-2 Using Lymphodepleting Conditioning Followed by Infusion of Anti-Her-2 Gene Engineered Lymphocytes

Number:

09-C-0041

Summary:

Background:

- We have constructed a single retroviral vector that contains a chimeric T cell receptor (CAR) that recognizes the Her-2 tumor antigen, which can be used to mediate genetic transfer of this CAR with high efficiency (greater than 30%) without the need to perform any selection.

- In co-cultures with Her-2 positive tumors, anti-Her-2 CAR transduced T cells secreted significant amount of IFN-gamma( Her-2 high specificity).

Objectives:

Primary objectives:

- To evaluate the safety of the administration of anti-Her-2 -CAR engineered peripheral blood lymphocytes in patients receiving the non- myeloablative conditioning regimen, and aldesleukin.

- Determine if the administration of anti-Her-2 -CAR 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 Her-2 antigen.

Secondary objective:

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

Eligibility:

Patients who are 18 years of age or older must have

- metastatic cancer whose tumors express the Her-2 antigen;

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

Patients may not have:

- contraindications for high dose aldesleukin administration.

Design:

- 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-Her-2 CAR 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, CAR genetransduced PBMC plus IV aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses).

- 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.

- The study will be conducted using a Phase I/II optimal design. The protocol will proceed in a phase 1 dose escalation design, with three cohorts. Should a single patient experience a dose limiting toxicity at a particular dose level, three more patients would be treated at that 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 prior to starting the phase II portion. If a dose limiting toxicity occurs in the first cohort, that cohort will be expanded to 6 patients. If 2 DLTs are encountered in this cohort, the study will be terminated.

- 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 breast cancer, and 3 cohort 2 will include patients with other types of metastatic cancer that express Her-2.

- 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-Her-2 CAR-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).

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

a. Metastatic cancer that expresses Her-2 at greater than or equal to 2+ and assessed by IHC in the CLIA approved test in the Laboratory of Pathology, CCR, NCI, NIH.

b. 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. Subjects with estrogen receptor-positive or progesterone receptor-positive breast cancer must have progressed on or not be candidate for anti-estrogens or aromatase inhibitors and all breast cancer patients must have progressed on or not be a candidate for an anthracycline-containing regimen and a taxane-containing regimen.

c. Patients with breast cancer must have previously received trastuzumab. Patients will not continue to receive trastuzumab during the trial period.

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

e. Willing to sign a durable power of attorney

f. Able to understand and sign the Informed Consent Document

g. Clinical performance status of ECOG 0 or 1.

h. Life expectancy of greater than three months.

i. 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.

j. Serology:

1. 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.)

2. Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.

3. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.

k. Hematology:

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

2. WBC (> 3000/mm(3)).

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

4. Hemoglobin greater than 8.0 g/dl.

l. Chemistry:

1. Serum ALT/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.

m. LVEF greater than or equal to 50%.

n. 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).

o. Patients who have previously received anti-CTLA4 antibody therapy must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA

a. 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.

b. 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.

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

d. 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).

e. Concurrent Systemic steroid therapy

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

g. History of coronary revascularization or ischemic symptoms

h. Documented 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

Special Instructions:

Currently Not Provided

Keywords:

Metastatic Cancer

Tumor Regression

Immunotherapy

Safety

Recruitment Keyword(s):

None

Condition(s):

Metastatic Cancer

Investigational Drug(s):

(PG13-4D5-D12(anti-Her-2 CAR) retroviral vector-transduced autologous PBL)

Investigational Device(s):

None

Intervention(s):

Drug: (PG13-4D5-D12(anti-Her-2 CAR) retroviral vector-transduced autologous PBL)

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR,Appella E, Rosenberg SA. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med. 1994 Jul 1;180(1):347-52.

Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL, Schwartzentruber DJ, Hwu P, Marincola FM, Sherry R, Leitman SF, Rosenberg SA. Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother. 2001 Jul-Aug;24(4):363-73.

Dudley ME, Wunderlich JR, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL,Sherry RM, Marincola FM, Leitman SF, Seipp CA, Rogers-Freezer L, Morton KE, Nahvi A, Mavroukakis SA, White DE, Rosenberg SA. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother. 2002 May-Jun;25(3):243-51.

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