CAR T Cell Receptor Immunotherapy for Patients With B-cell Lymphoma

Tracking Information
First Submitted Date ICMJE	June 17, 2009
First Posted Date ICMJE	June 18, 2009
Last Update Posted Date	May 24, 2018
Study Start Date ICMJE	February 17, 2009
Actual Primary Completion Date	September 30, 2015 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: November 25, 2014)	Determine the safety and feasibility of the administration of anti-CD19-CAR engineered peripheral blood lymphocytes with a nonmyeloablative conditioning regimen in patients with B-cell malignancies. [ Time Frame: approximately 3 years ]
Original Primary Outcome Measures ICMJE; (submitted: June 17, 2009)	Determine the safety of the anti-CD19-CAR PBL and aldesleukin either with or without a nonmyeloablative regimen in patients with B cell malignancies, and determine if lymphocyte-depletion can enhance persistence of the cells.
Change History	Complete list of historical versions of study NCT00924326 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: July 29, 2016)	Determine the in vivo survival of the cryopreserved anti-CD19- CAR-transduced T cells. [ Time Frame: approximately 3 years ]; Determine if the treatment regimen can cause regression of B-cell malignancies. [ Time Frame: approximately 3 years ]
Original Secondary Outcome Measures ICMJE; (submitted: June 17, 2009)	Determine if the administration of anti-CD19-CAR engineered peripheral blood lymphocytes and aldesleukin either with or without the non-myeloblative conditioning regiment cause regression of B cell malignancies.
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	CAR T Cell Receptor Immunotherapy for Patients With B-cell Lymphoma
Official Title ICMJE	Assessment of the Safety and Feasibility of Administering T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor to Patients With B-cell Lymphoma
Brief Summary	Background: The NCI Surgery Branch has developed an experimental therapy for treating patients with B cell lymphomas or leukemias that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patient s white blood cells with a retrovirus that has the gene for anti-CD19 incorporated in the retrovirus. Objective: The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-CD19 cells) cause tumors to shrink. Eligibility: - Adults age 18-68 with B cell lymphomas or leukemias expressing the CD19 molecule. Design: Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti-CD19 cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.} Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy and the anti-CD19 cells. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.
Detailed Description	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 (> 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-y and IL-2.; We have developed a process for cryopreserving the cell product which may lead to the ability for this product to be manufactured at a central location and shipped to other institutions for treatment of a broader patient population OBJECTIVES: Primary objectives; With the approval of amendment S, determine the safety and feasibility of the administration of cryopreserved anti-CD19-CAR engineered peripheral blood lymphocytes with a nonmyeloablative conditioning regimen in patients with Bcell lymphomas. ELIGIBILITY: Patients of 18 years of age or older must: have a CD19-expressing B-cell malignancy of any type; 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: a history of allogeneic stem cell transplantation; CNS disease 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 108 to 5 X 108 cells to retroviral vector supernatant containing the anti-CD19 CAR.; With the approval of amendment S, patients will receive fludarabine and cyclophosphamide chemotherapy (NMA) for lymphocyte-depletion, followed by cryopreserved anti-CD19-CAR-transduced T cells.; Patients will be followed until disease progression; Patients who have responded to treatment and then progress may receive one retreatment
Study Type ICMJE	Interventional
Study Phase	Phase 1
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Primary Mediastinal B-cell Lymphoma; Diffuse, Large B-cell Lymphoma; Diffuse Large B-Cell Lymphoma Transformed From Follicular Lymphoma; Mantle Cell
Intervention ICMJE	Drug: Fludarabine On days -5 through -3, Fludarabine 30mg/m2 IV will be infused over 30 minutes.; Drug: Cyclophosphamide On days -5 through -3, Cyclophosphamide 500mg/m2 IV will be infused over 60 minutes followed by fludarabine.; Biological: Anti-CD19-CAR PBL On day 0, cells will infused intravenously (IV) on the patient care unit over 20 - 30 minutes (2-4 days after the last dose of fludarabine).
Study Arms	Experimental: Single Arm; Patients will receive fludarabine and cyclophosphamide chemotherapy (NMA) for lymphocyte-depletion followed by anti-CD19- CAR-transduced T cells; Interventions: Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Anti-CD19-CAR PBL
Publications *	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.; Sadelain M, Rivière I, Brentjens R. Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer. 2003 Jan;3(1):35-45. Review.; Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006 Oct 6;314(5796):126-9. Epub 2006 Aug 31.; Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM, Raffeld M, Feldman S, Lu L, Li YF, Ngo LT, Goy A, Feldman T, Spaner DE, Wang ML, Chen CC, Kranick SM, Nath A, Nathan DA, Morton KE, Toomey MA, Rosenberg SA. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015 Feb 20;33(6):540-9. doi: 10.1200/JCO.2014.56.2025. Epub 2014 Aug 25.; Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012 Mar 22;119(12):2709-20. doi: 10.1182/blood-2011-10-384388. Epub 2011 Dec 8.; Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, Morgan RA, Rosenberg SA. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010 Nov 18;116(20):4099-102. doi: 10.1182/blood-2010-04-281931. Epub 2010 Jul 28.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Actual Enrollment ICMJE; (submitted: February 26, 2016)	43
Original Enrollment ICMJE; (submitted: June 17, 2009)	52
Estimated Study Completion Date	December 31, 2020
Actual Primary Completion Date	September 30, 2015 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	INCLUSION CRITERIA: Patient must have a CD19-expressing B cell malignancy. Patients with Diffuse large B-cell lymphoma, Primary Mediastinal B-cell lymphoma, and Diffuse large B-cell lymphoma transformed from follicular lymphoma must have measurable disease after at least two prior chemotherapy regimens one of which must have contained doxorubicin and rituximab. Confirmation of diagnosis of B cell malignancy and positivity for CD19 confirmed by the Laboratory of Pathology of the NCI. The choice of whether to use flow Cytometry or immunohistochemistry 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, fine needle aspirates and bone marrow samples. Patients must have indications for treatment for their B cell malignancy at the time of enrollment on this trial. Greater than or equal to 18 years of age and less than or equal to age 70. 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 from the time of enrollment on this study and for four months after treatment. Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. 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. If hepatitis C antibody test is positive, then patients must be tested for the presence of antigen by RT-PCR and be HCV RNA negative. Hematology: 1. Absolute neutrophil count greater than or equal to 1000/mm(3) without the support of filgrastim. 2. Platelet count greater than or equal to 50,000/mm(3). 3. Hemoglobin greater than 8.0 g/dl. 4. Lymphocyte count less than or equal to 4,000/ mm(3) Chemistry: 1. Serum ALT/AST less or equal to 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 More than three 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). Normal cardiac ejection fraction and no evidence of pericardial effusion as determined by an echocardiogram. EXCLUSION CRITERIA: Patients that require urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.; Patients that have active hemolytic anemia.; Patients with active brain metastases, or with a history of any CNS metastases or cerebrospinal fluid malignant cells. Note: patients who are asymptomatic but are found to have malignant cells in the CSF on lumbar puncture prior to treatment will be considered eligible.; Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment 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.; History of severe immediate hypersensitivity reaction to any of the agents used in this study.; History of allogeneic stem cell transplantation; Patients with cardiac atrial or cardiac ventricular lymphoma involvement. Screening Evaluation: Within 4 weeks prior to starting the chemotherapy regimen: Complete history and physical examination, including, weight and vital signs, noting in detail the exact size and location of any lesions that exist. (Note: patient history may be obtained within 8 weeks.); Chest x-ray; EKG; Baseline CT of the chest, abdomen and pelvis, PET scan, and brain MRI to evaluate the status of disease. Additional scans and x-rays may be performed if clinically indicated based on patients signs and symptoms.; HIV antibody titer and HbsAG determination, and anti HCV, (Note: may be performed within 3 months of the chemotherapy start date).; Anti CMV antibody titer, HSV serology, and EBV panel (Note: patients who are known to be positive for any of the above do not need to be retested; may be performed within 3 months of chemotherapy start date); Patients with a LVEF of less than or equal to 55% will not proceed to treatment, (Note: may be performed within 8 weeks of treatment).; CD19 staining of malignant cells by immunohistochemistry or flow cytometry (testing is permitted to be conducted at any time prior to this point).; All patients must have a TBNK for Peripheral blood CD3 count and CD19#.; Patients with a history of leptomeningeal disease, or signs/symptoms suggestive of leptomeningeal involvement, or with symptoms of central nervous system malignancy such as new onset severe headaches, neck stiffness, or any focal neurologic findings on physical exam will have lumbar puncture for examination of cerebral spinal fluid.; Patients may undergo lumbar puncture (LP) for flow cytometry of the CSF in order to assess the presence of CD19 positive lymphocytes for potential correlation with neurologic toxicity. Patients who have no neurologic symptoms at the time of LP will be eligible for enrollment regardless of the results of the flow cytometry. Within 14 days prior to starting the chemotherapy regimen:; Chem 20: (Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid); Thyroid panel; CBC with differential and platelet count; PT/PTT; Urinalysis and culture, if indicated Within 7 days prior to starting the chemotherapy regimen:; <=-HCG pregnancy test (serum or urine) on all women of child-bearing potential; ECOG performance status of 0 or 1
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years to 70 Years (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00924326
Other Study ID Numbers ICMJE	090082; 09-C-0082
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor ICMJE	National Cancer Institute (NCI)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
PRS Account	National Institutes of Health Clinical Center (CC)
Verification Date	April 3, 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP