Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma

NCT01593696 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 12011212-C-0112
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- Although progress has been made in treating children with B-cell cancers such as leukemia or lymphoma, many children do not respond to the standard treatments. One possible treatment involves collecting white blood cells called T cells from the person with cancer and modifying the cells to attack the B-cell cancer. The cells can then be given back to the participant. This study will use T cells that have been modified to attack the cluster of differentiation 19 (CD19) protein, which is found on the surface of some B-cell cancers. Objectives: \- To see if anti-CD19 modified white blood cells are a safe and effective treatment for children and young adults with advanced B-cell cancer. Eligibility:

• Children and young adults between 1 and 30 years of age who have B-cell cancer (leukemia or lymphoma) that has not responded to standard treatments.
• The leukemia or the lymphoma must have the CD19 protein.
• There must be adequate organ function. Design:
• Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies or bone marrow biopsies may be performed depending on the type of cancer.
• Participants will undergo a process where white blood cells are collected, called apheresis. These cells will be modified to contain the anti-CD19 gene.
• Participants will have 3 days of chemotherapy to prepare their immune system to accept the modified cells.
• Participants will receive an infusion of their own modified white blood cells. They will remain in the hospital until they have recovered from the treatment.
• Participants will have frequent follow-up visits to monitor the outcome of the treatment.
• If the participant benefits from the treatment, then he/she may have the option for another round of treatment.

Conditions

ALL; B Cell Lymphoma; Leukemia; Large Cell Lymphoma; Non-Hodgkin Lymphoma

Keywords

CD 19 Expressing B Cells; B Cell Lymphoma; ALL; Anti-CD19 Chimeric Antigen Receptor; Adoptive Immunotherapy

Outcome Measures

Primary Outcomes (2)

• Number of Participants Who Received Preparative Chemotherapy Followed by Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR T-cells With < Grade 4 Cytokine Release Syndrome

  Participants with B cell malignancies who received preparative chemotherapy followed by CD19 CAR T-cells with \< Grade 4 cytokine release syndrome.

  Beginning of preparative regimen through Day 28 after CD19 CAR infusion

• Number of Participants in Which the Prescribed Dose of Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR T-cells Were Successfully Manufactured

  Participants who had T-cells collected by apheresis and subsequently had the amount of CAR T-cells manufactured as prescribed by the dose level they were enrolled in.

  Apheresis through completion of CAR manufacturing process, approximately 2 weeks

Secondary Outcomes (5)

• Number of Participants Who Were Administered Intensive Chemotherapy Prior to Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR Infusion

  21 days of target date

• Mean Percentage Cluster of Differentiation 19 (CD19) - Chimeric Antigen-Receptor (CAR) T-Cells in Blood, Bone Marrow (BM) and Cerebrospinal Fluid (CSF)

  28 days (+/- 4 days) after infusion of CD19 CAR T-cells

• Number of Patients With a Complete Response (CR)

  Day 28 (+/- 4 days) after CD19 CAR infusion

• Number of Participants With Grade 4 Cytokine Release Syndrome (CRS)

  Day 28 (+/- 4 days) after CD19 CAR infusion.

• Number of Participants With Serious and Non-Serious Adverse Events

  Date treatment consent signed to date off study, from 1.5 months up to 3.1 years.

Study Arms (2)

Lymphodepleting regimen of Fludarabine and Cyclophosphamide

EXPERIMENTAL

Lymphodepleting regimen of Fludarabine and Cyclophosphamide.

Biological: Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR)

Intensive standard of care chemotherapy

EXPERIMENTAL

Intensive standard of care chemotherapy, in lieu of the lymphodepleting chemotherapy regimen, to decrease tumor burden in preparation for the administration of the Chimeric antigen receptor (CAR) T cells.

Biological: Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR)

Interventions

Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR) BIOLOGICAL

Cells extracted, followed by induction chemotherapy before Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR) infusion (dose escalation.)

Intensive standard of care chemotherapy; Lymphodepleting regimen of Fludarabine and Cyclophosphamide

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patient must have a cluster of differentiation 19 (CD19)-expressing B cell ALL or lymphoma and must have relapsed or refractory disease after at least one standard chemotherapy and one salvage regimen. In view of the principal investigator (PI) and the primary oncologist, there must be no available alternative curative therapies and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have disease activity that prohibits SCT at this time.
• CD19 expression must be detected on greater than 15% of the malignant cells by immunohistochemistry or greater than 30% by flow cytometry in a 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), or from the referring institution or reference laboratory. 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. In general immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples.
• Patients must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis.
• Greater than or equal to 1 year of age (and at least 15 kg) and less than or equal to 30 years of age.
• Adequate absolute CD3 count estimated to be required to obtain target cell dose based on discussion with Department of Transfusion Medicine (DTM) apheresis and Cell Processing Section, DTM.
• Subjects with the following central nervous system (CNS) status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:
• CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs;
• CNS 2, defined as presence of \< 5/uL white blood cells (WBCs) in CSF and cytospin positive for blasts, or \> 5/uL WBCs but negative by Steinherz/Bleyer algorithm
• CNS3 with marrow disease who has failed salvage systemic and intensive IT chemotherapy (and therefore not eligible for radiation)
• Patients with isolated CNS relapse will be eligible if they have previously been treated with cranial radiation (at least centigray (cGy)).
• Ability to give informed consent. For subjects \<18 years old their legal guardian must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate.
• Clinical performance status: Patients \> 10 years of age: Karnofsky greater than or equal to 50%; Patients less than or equal to 10 years of age: Lansky scale greater than or equal to 50%. Subjects who are unable to walk because of paralysis, but who are upright in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.
• Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
• Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.
• Cardiac function: Left ventricular ejection fraction greater than or equal to 40% by multi-gated acquisition scan (MUGA) or cardiac magnetic resonance imaging (MRI), or fractional shortening greater than or equal to 28% by echocardiogram (ECHO) or left ventricular ejection fraction greater than or equal to 50% by ECHO.

You may not qualify if:

• Subjects meeting any of the following criteria are not eligible for participation in the study:
• Recurrent or refractory ALL limited to isolated testicular disease.
• Hepatic function: Inadequate liver function defined as total bilirubin \> 2x upper limit of normal (ULN) (except in the case of subjects with documented Gilbert's disease \> 3x ULN) or transaminase (alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \> 20x ULN based on age and laboratory specific normal ranges;
• Renal function: Greater than age-adjusted normal serum creatinine (see below) and a creatinine clearance \< 60 mL/min/1.73 m\^2.
• Age:
• \<= 5 yrs (Maximum Serum Creatinine = 0.8 mg/dL)
• \< age \<=10 yrs (Maximum Serum Creatinine =1.0 mg/dL)
• \> 10 yrs (Maximum Serum Creatinine = 1.2 mg/dL)
• Hematologic function:
• Absolute neutrophil count (ANC) \< 750/microliter, or platelet count \< 50,000/microliter, if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy);
• A subject will not be excluded because of pancytopenia greater than or equal to Grade 3 if it is due to disease, based on the results of bone marrow studies.
• Hyperleukocytosis (greater than or equal to 50,000 blasts/microliter) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy;
• Pregnant or breast-feeding females;
• Recent prior therapy:
• Systemic chemotherapy less than or equal to 2 weeks (6 weeks for nitrosoureas) or radiation therapy less than or equal to 3 weeks prior to apheresis;

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 (9)

• Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N, Smith DD, Forman SJ, Jensen MC, Cooper LJ. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 2006 Nov 15;66(22):10995-1004. doi: 10.1158/0008-5472.CAN-06-0160.

  PMID: 17108138 BACKGROUND

• 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 BACKGROUND

• Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010 Apr;18(4):843-51. doi: 10.1038/mt.2010.24. Epub 2010 Feb 23.

  PMID: 20179677 BACKGROUND

• Silbert SK, Madan S, Holland EM, Steinberg SM, Little L, Foley T, Epstein M, Sarkisian A, Lee DW, Nikitina E, Kakumanu S, Ruppin E, Shalabi H, Yates B, Shah NN. A comprehensive analysis of adverse events in the first 30 days of phase 1 pediatric CAR T-cell trials. Blood Adv. 2023 Sep 26;7(18):5566-5578. doi: 10.1182/bloodadvances.2023009789.

  PMID: 37486616 DERIVED

• Shalabi H, Martin S, Yates B, Wolters PL, Kaplan C, Smith H, Sesi CR, Jess J, Toledo-Tamula MA, Struemph K, Delbrook CP, Khan OI, Mackall CL, Lee DW, Shah NN. Neurotoxicity following CD19/CD28zeta CAR T-cells in children and young adults with B-cell malignancies. Neuro Oncol. 2022 Sep 1;24(9):1584-1597. doi: 10.1093/neuonc/noac034.

  PMID: 35148417 DERIVED

• Molina JC, Steinberg SM, Yates B, Lee DW, Little L, Mackall CL, Shalabi H, Shah NN. Factors Impacting Overall and Event-Free Survival following Post-Chimeric Antigen Receptor T Cell Consolidative Hematopoietic Stem Cell Transplantation. Transplant Cell Ther. 2022 Jan;28(1):31.e1-31.e9. doi: 10.1016/j.jtct.2021.10.011. Epub 2021 Oct 20.

  PMID: 34687939 DERIVED

• Shah NN, Lee DW, Yates B, Yuan CM, Shalabi H, Martin S, Wolters PL, Steinberg SM, Baker EH, Delbrook CP, Stetler-Stevenson M, Fry TJ, Stroncek DF, Mackall CL. Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL. J Clin Oncol. 2021 May 20;39(15):1650-1659. doi: 10.1200/JCO.20.02262. Epub 2021 Mar 25.

  PMID: 33764809 DERIVED

• Shalabi H, Sachdev V, Kulshreshtha A, Cohen JW, Yates B, Rosing DR, Sidenko S, Delbrook C, Mackall C, Wiley B, Lee DW, Shah NN. Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies. J Immunother Cancer. 2020 Sep;8(2):e001159. doi: 10.1136/jitc-2020-001159.

  PMID: 32883871 DERIVED

• Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015 Feb 7;385(9967):517-528. doi: 10.1016/S0140-6736(14)61403-3. Epub 2014 Oct 13.

  PMID: 25319501 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma, B-Cell; Leukemia; Dendritic Cell Sarcoma, Interdigitating; Lymphoma, Non-Hodgkin

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Hematologic Diseases; Histiocytic Disorders, Malignant; Histiocytosis

Results Point of Contact

• Title: Dr. Nirali N. Shah
• Organization: National Cancer Institute

shahnn@nih.gov

240-760-6199

Study Officials

• Nirali N Shah, M.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: May 5, 2012
• First Posted: May 8, 2012
• Study Start: June 29, 2012
• Primary Completion: November 11, 2016
• Study Completion: October 2, 2017
• Last Updated: August 31, 2020
• Results First Posted: August 31, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)