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

NCT00924326 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 09008209-C-0082
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

Background: The National Cancer Institute (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-cluster of differentiation 19 (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 18-70 with B cell lymphomas or leukemias expressing the CD19 molecule. Design: Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (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.

Conditions

Primary Mediastinal B-cell Lymphoma; Diffuse, Large B-cell Lymphoma; Diffuse Large B-Cell Lymphoma Transformed From Follicular Lymphoma; Mantle Cell

Keywords

B Cell Malignancies; T Cell Persistence; Immunotherapy; Cell Transfer; Leukemia; Chronic Lymphocytic Leukemia; CLL; Lymphoma

Outcome Measures

Primary Outcomes (1)

• Number of Participants With a Response Assessed by the Response Criteria for Malignant Lymphoma

  Participants were assessed by the Response Criteria for Malignant Lymphoma. Complete Remission (CR) is complete disappearance of all detectable evidence of disease and disease-related symptoms if present before therapy. Partial Remission (PR) requires ≥50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease. Progressive disease (PD) is defined by ≥50% increase from nadir in the sum of the products of at least two lymph nodes, or if a single node is involved at least a 50% increase in the product of the diameters of this one node; and appearance of a new lesion greater than 1.5 cm in any axis even if other lesions are decreasing in size. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

  Scans performed at 6 weeks, 12 weeks and every 3-6 months for approximately 2 years

Secondary Outcomes (1)

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0).

  Date treatment consent signed to date off study, approximately 101 months and 17 days.

Study Arms (10)

1x10^9-1x10^10+ high dose Interleukin-2

EXPERIMENTAL

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + cryopreserved anti-CD19-CAR PBL

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL; Drug: Aldesleukin

1x10^9-1x10^10 + high dose Retreat

EXPERIMENTAL

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL; Drug: Aldesleukin

0.5x10^7 cells/kg

EXPERIMENTAL

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL

2.5x10^6 cells/kg

EXPERIMENTAL

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL

1.0x10^6 cells/kg

EXPERIMENTAL

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL

1.0x10^6 cells/kg (Reduced chemo)

EXPERIMENTAL

Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL; Drug: Fludarabine; Drug: Cyclophosphamide

2.0x10^6 cells/kg (Reduced chemo)

EXPERIMENTAL

Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL; Drug: Fludarabine; Drug: Cyclophosphamide

6.0x10^6 cells/kg (Reduced chemo)

EXPERIMENTAL

Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL; Drug: Fludarabine; Drug: Cyclophosphamide

2.0x10^6 cells/kg (Moderate chemo)

EXPERIMENTAL

Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL; Drug: Fludarabine; Drug: Cyclophosphamide

2.0x10^6 cells/kg (9-12 days culture)

EXPERIMENTAL

Biological: Anti-cluster of differentiation 19 (CD19)-CAR PBL; Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

Fludarabine DRUG

Days -5 to -1 (after administration of cyclophosphamide): 25 mg/m\^2 intravenous (IV) over 30 minutes

Also known as: Fludara

0.5x10^7 cells/kg; 1.0x10^6 cells/kg; 1x10^9-1x10^10 + high dose Retreat; 1x10^9-1x10^10+ high dose Interleukin-2; 2.5x10^6 cells/kg

Cyclophosphamide DRUG

Days -5 to -4: 60mg/kg intravenous (IV) over 60 minutes

Also known as: Cytoxan

0.5x10^7 cells/kg; 1.0x10^6 cells/kg; 1x10^9-1x10^10 + high dose Retreat; 1x10^9-1x10^10+ high dose Interleukin-2; 2.5x10^6 cells/kg

Anti-cluster of differentiation 19 (CD19)-CAR PBL BIOLOGICAL

Anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) peripheral blood lymphocytes ( PBL). Day 0 (two to four days after the last dose of fludarabine); Cells will be infused via intravenous (IV) on the Patient Care Unit over 20-30 minutes.

0.5x10^7 cells/kg; 1.0x10^6 cells/kg; 1.0x10^6 cells/kg (Reduced chemo); 1x10^9-1x10^10 + high dose Retreat; 1x10^9-1x10^10+ high dose Interleukin-2; 2.0x10^6 cells/kg (9-12 days culture); 2.0x10^6 cells/kg (Moderate chemo); 2.0x10^6 cells/kg (Reduced chemo); 2.5x10^6 cells/kg; 6.0x10^6 cells/kg (Reduced chemo)

Aldesleukin DRUG

Day 0: 720,000 IU/kg intravenously (IV) every 8 hours for a maximum of 15 doses.

Also known as: Interleukin-2, IL-2

1x10^9-1x10^10 + high dose Retreat; 1x10^9-1x10^10+ high dose Interleukin-2

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must have a cluster of differentiation 19 (CD19)-expressing B-cell lymphoma. 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 National Cancer Institute (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 Eastern Cooperative Oncology Group (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:
• 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.).
• 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 reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative.
• Hematology:
• Absolute neutrophil count greater than or equal to 1000/mm\^3 without the support of filgrastim.

You may not qualify if:

• 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 central nervous system (CNS) metastases or cerebrospinal fluid malignant cells.
• Note: patients who are asymptomatic but are found to have malignant cells in the cerebrospinal fluid (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.)

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (13)

• Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013 May;10(5):267-76. doi: 10.1038/nrclinonc.2013.46. Epub 2013 Apr 2.

  PMID: 23546520 RESULT

• Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, Hakim FT, Halverson DC, Fowler DH, Hardy NM, Mato AR, Hickstein DD, Gea-Banacloche JC, Pavletic SZ, Sportes C, Maric I, Feldman SA, Hansen BG, Wilder JS, Blacklock-Schuver B, Jena B, Bishop MR, Gress RE, Rosenberg SA. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013 Dec 12;122(25):4129-39. doi: 10.1182/blood-2013-08-519413. Epub 2013 Sep 20.

  PMID: 24055823 RESULT

• James N. Kochenderfer, M.D., Mark E. Dudley, Ph.D., Sadik H. Kassim, Ph.D., Robert O. Carpenter, James C. Yang, MD, Giao Q. Phan, MD, Marybeth S. Hughes, MD, Richard M. Sherry, MD, Steven Feldman, Ph.D., David Spaner, MD, PhD, Debbie-Ann N. Nathan, RN, Kathleen E. Morton, RN, Mary Ann Toomey, RN, and Steven A. Rosenberg, M.D., Ph.D. Effective Treatment of Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma with Autologous T Cells Genetically-Engineered to Express an Anti-CD19 Chimeric Antigen Receptor. Oral Abstract Presentation 12-8-13 in New Orleans, LA at the American Society of Hematology annual meeting. Blood Annual Meeting abstract 2013. 122:168.

  RESULT

• 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.

  PMID: 25154820 RESULT

• Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, Xue A, Goff SL, Yang JC, Sherry RM, Klebanoff CA, Kammula US, Sherman M, Perez A, Yuan CM, Feldman T, Friedberg JW, Roschewski MJ, Feldman SA, McIntyre L, Toomey MA, Rosenberg SA. Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. J Clin Oncol. 2017 Jun 1;35(16):1803-1813. doi: 10.1200/JCO.2016.71.3024. Epub 2017 Mar 14.

  PMID: 28291388 RESULT

• James N. Kochenderfer, Mark E. Dudley, Robert O. Carpenter, Sadik H. Kassim, Jeremy J. Rose, William G. Telford, Frances T. Hakim, David C. Halverson, Daniel H. Fowler, Nancy M. Hardy, Anthony R. Mato, Dennis D. Hickstein, Juan C. Gea-Banacloche, Steven Z. Pavletic, Claude Sportes, Irina Maric, Steven A. Feldman, Brenna G. Hansen, Jennifer S. Wilder, Bazetta Blacklock-Schuver, Bipulendu Jena, Michael R. Bishop, Steven A. Rosenberg*, Ronald E. Gress* (co-senior authors). Donor-derived anti-CD19 chimeric-antigen-receptor-expressing T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Oral Abstract Presentation 12-8-13 in New Orleans, LA at the American Society of Hematology annual meeting. Blood Annual Meeting abstracts 2013. 122:151.

  RESULT

• Kochenderfer, J.N., Somerville, R., Lu, T., Shi, V., Yang, J.C., Sherry, R., Klebanoff, C., Kammula, U.S., Goff, S.L., Bot, A., Rossi, J., Sherman, M., Perez, A., Xue, A., Feldman, T.A., Friedberg, J.W., Roschewski, M.J., Feldman, S., McIntyre, L., Rosenberg, S.A. Anti-CD19 Chimeric Antigen Receptor T cells Preceded by Low-Dose Chemotherapy to Induce Remissions of Advanced Lymphoma. 2016 ASCO Annual Meeting. J Clin Oncol 34, 2016 (suppl; abstr LBA3010).

  RESULT

• Kochenderfer JN, Somerville RPT, Lu T, Yang JC, Sherry RM, Feldman SA, McIntyre L, Bot A, Rossi J, Lam N, Rosenberg SA. Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy. Mol Ther. 2017 Oct 4;25(10):2245-2253. doi: 10.1016/j.ymthe.2017.07.004. Epub 2017 Jul 13.

  PMID: 28803861 RESULT

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

  PMID: 34515338 DERIVED

• Cappell KM, Sherry RM, Yang JC, Goff SL, Vanasse DA, McIntyre L, Rosenberg SA, Kochenderfer JN. Long-Term Follow-Up of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy. J Clin Oncol. 2020 Nov 10;38(32):3805-3815. doi: 10.1200/JCO.20.01467. Epub 2020 Oct 6.

  PMID: 33021872 DERIVED

• Rossi J, Paczkowski P, Shen YW, Morse K, Flynn B, Kaiser A, Ng C, Gallatin K, Cain T, Fan R, Mackay S, Heath JR, Rosenberg SA, Kochenderfer JN, Zhou J, Bot A. Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. Blood. 2018 Aug 23;132(8):804-814. doi: 10.1182/blood-2018-01-828343. Epub 2018 Jun 12.

  PMID: 29895668 DERIVED

• 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.

  PMID: 22160384 DERIVED

• 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.

  PMID: 20668228 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Dendritic Cell Sarcoma, Interdigitating; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma

Interventions

fludarabine; fludarabine phosphate; Cyclophosphamide; aldesleukin; Interleukin-2

Condition Hierarchy (Ancestors)

Histiocytic Disorders, Malignant; Neoplasms by Histologic Type; Neoplasms; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Hematologic Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Results Point of Contact

• Title: Steven Rosenberg, M.D., Ph.D.
• Organization: National Cancer Institute

sar@nih.gov

240-858.3080

Study Officials

• Steven A Rosenberg, M.D., Ph.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 18, 2009
• Study Start: February 17, 2009
• Primary Completion: September 30, 2015
• Study Completion: November 17, 2021
• Last Updated: January 12, 2022
• Results First Posted: March 21, 2019

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)