Protocol Number: 09-C-0082

Title:

Phase I/II Study of B Cell Malignancies using T Cells Expressing an Anti-CD19 Chimeric Receptor: Assessment of the Impact of Lymphocyte Depletion Prior to T Cell Transfer

Number:

09-C-0082

Summary:

Background:

We have constructed a retroviral vector that encodes an anti-CD19 chimeric antigen receptor (CAR) that recognizes the CD19 antigen. This chimeric receptor also contains the signaling domains of CD28 and CD3-zeta. The retroviral vector can be used to mediate genetic transfer of this CAR to T cells with high efficiency (greater than 50%) without the need to perform any selection.

In co-cultures with CD19-expressing target cells, anti-CD19-CAR-transduced T cells secreted significant amounts of IFN-Gamma sign and IL-2. Anti-CD19-CAR-transduced T cells could specifically recognize and kill primary chronic lymphocytic leukemia cells.

Objectives:

Primary objectives:

-Phase 1 and 2 portion:

--Determine the safety of the administration of anti-CD19-CAR engineered peripheral blood lymphocytes and aldesleukin either with or without a nonmyeloablative conditioning regimen in patients with B cell malignancies.

-Phase 2 portion only:

--Determine if lymphocyte-depletion with fludarabine plus cyclophosphamide given prior to infusion of anti-CD19-CAR-transduced T cells and aldesleukin can enhance persistence of the anti-CD19-CAR-transduced T cells.

Secondary objectives:

-Phase 1 and 2 portion:

--Determine if the administration of anti-CD19-CAR engineered peripheral blood lymphocytes and aldesleukin either with or without the non-myeloablative conditioning regimen cause regression of B cell malignancies.

Eligibility:

Patients of 18 years of age or older must:

-have a CD19-expressing lymphoma or chronic lymphocytic leukemia

-be a non-responder to, or recurred after one or more standard chemotherapy-containing regimens for their malignancy

-currently require treatment due to progressive malignancy

-deemed to be incurable by standard therapy

Patients may not have:

-contraindications for high dose aldesleukin administration

-a history of allogeneic stem cell transplantation

Design:

PBMC obtained by leukapheresis (approximately 5 X 109 cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell proliferation.

Transduction is initiated by exposure of approximately 10(8) to 5 X 10(8) cells to retroviral vector supernatant containing the anti-CD19-CAR.

This trial will have two phases. Phase I will be a dose escalation design to determine the maximal tolerated dose of anti-CD19-CAR-transduced T cells. All patients in this phase of the trial will receive fludarabine and cyclophosphamide chemotherapy for lymphocyte-depletion, and anti-CD19-CAR-transduced T cells followed by high dose aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses). Initially three patients will be treated at each dose level. Should a single patient experience a dose limiting toxicity (DLT) 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 of the trial. 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.

In phase II of this trial, patients will be randomized to receive or to not receive a nonmyeloablative but lymphocyte-depleting preparative regimen consisting of cyclophosphamide and fludarabine prior to cell therapy. All patients will receive anti-CD19-CAR-transduced T cells followed by high dose aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses). Patients will be stratified so that an equal number of patients on each arm of phase II of the trial have peripheral blood total CD3 counts less than 500 cells/microliter and an equal number of patients on each arm have a total peripheral blood CD3 count greater than or equal to 500 cells/microliter. Randomization will also be stratified so that an equal number of patients with circulating malignant cells (leukemia) will be entered on each arm of the phase II part of the trial.

Patients will undergo complete evaluation of tumor wi...

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. Patient must have a CD19-expressing B cell malignancy of the following types: chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, or large cell lymphoma. The patients with CLL, mantle cell lymphoma, and follicular lymphoma must have progressive disease after at least one standard chemotherapy regimen. The large cell lymphoma patients must have progressive disease after at least two prior chemotherapy regimens one of which must have contained doxorubicin and rituximab. All patients enrolled on this trial must be deemed incurable by standard therapies. CD19 expression must be detected on greater than 50% of the malignant cells of each patient by immunohistochemistry or flow cytometry.

b. CD19 expression must be detected on greater than 50% of the malignant cells by immunohistochemistry or by flow cytometry in a CLIA approved test in the Laboratory of Pathology, CCR, NCI, NIH. The choice of whether to use flow cytometry or immuohistochemistry will be determined by what is the most easily available tissue sample in each patient. Immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples.

c. Patients must have indications for treatment for their B cell malignancy at the time of enrollment on this trial.

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 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 hepatitis C antibody unless antigen 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/mm3 without the support of filgrastim.

--2. WBC (greater than 3000/mm3).

--3. Platelet count greater than 75,000/mm3, unless thrombocytopenia is attributable to lymphoma/leukemia involvement of the bone marrow based on assessment of the bone marrow biopsy

--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. 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:

a. Patients that require urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.

b. Patients that have active hemolytic anemia.

c. 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.

d. 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

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

f. 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)

g. Concurrent Systemic steroid therapy.

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

i. History of coronary revascularization or ischemic symptoms

j. Any patient known to have an LVEF less than or equal to 45%

k. 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

l. 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

m. History of allogeneic stem cell transplantation

n. Patients with CNS metastases

Special Instructions:

Currently Not Provided

Keywords:

B Cell Malignancies

T Cell Persistence

Safety

Immunotherapy

Recruitment Keyword(s):

Leukemia

Chronic Lymphocytic Leukemia

CLL

Lymphoma

Condition(s):

Chronic Lymphocytic Leukemia

Small Lymphocytic Lymphoma

Mantle Cell Lymphoma

Follicular Lymphoma

Large Cell Lymphoma

Investigational Drug(s):

PG13-CD19-H3 (anti-CD19-CAR) transduced PBL)

Investigational Device(s):

None

Intervention(s):

Gene Transfer: Anti-CD19-CAR Transduced PBL

Drug: Aldesleukin

Drug: Fludarabine

Drug: Cyclophosphamide

Drug: PG13-CD19-H3 (anti-CD19-CAR) transduced PBL)

Supporting Site:

National Cancer Institute

Contact(s):

Recruitment Center - SB
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Building 10, Room 2-1730, Bethesda, Maryland 20892, United States
Phone: (866) 820-4505
Fax: (301) 451-1927
Electronic Address: ncisbirc@mail.nih.gov

Citation(s):

Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002 Oct 25;298(5594):850-4. Epub 2002 Sep 19.

Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol. 2006 May;6(5):383-93.

Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005 Apr 1;23(10):2346-57.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Clinical Research Informatics, CC.

Search The Studies | Help | Questions |
Clinical Center Home | NIH Home

National Institutes of Health Clinical Center Bethesda, Maryland 20892. Last update: 05/05/2009