Clinical trial NCT01593696: Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma
Official title: Phase I Study of T Cells Expressing an Anti-CD19 Chimeric Receptor in Children and Young Adults With B Cell Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-05-08
Enrollment: 53
Sex: ALL
Minimum age (years): 1
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Detailed description: Background:

Chimeric antigen receptors (CAR) that recognize the cluster of differentiation 19(CD19) antigen have been constructed and are in clinical trials at several institutions. In this trial, the Pediatric Oncology Branch (POB) will utilize a chimeric receptor containing the signaling domains of cluster of differentiation 28 (CD28) and cluster of differentiation 3 (CD3)-zeta, currently under study in the Center for Cancer Research (CCR) in adults, for children and young adults with CD19 expressing malignancies.

In co-cultures with CD19-expressing acute lymphoblastic leukemia cells, anti-CD19-CAR-transduced T cells show robust killing, and in xenograft models, can rapidly clear CD19- expressing ALL cell lines.

Objectives:

1. Primary: To determine the safety and feasibility of administering escalating doses of anti-CD19-CAR engineered peripheral blood lymphocytes in two strata (prior allogeneic stem cell transplant \[SCT\] vs. no prior SCT) of children and young adults with B cell malignancies following a cyclophosphamide/fludarabine preparative regimen. COMPLETED March 2014.
2. Primary: To determine the safety of administering cells in two groups of children and young adults with B-cell malignancies expressing CD19:

   * Arm 1 - Patients without high-burden disease or patients for whom chemotherapy toxicity is a concern will receive standard preparative regimen.
   * Arm 2 - Patients with high-burden disease who receive standard chemotherapy to reduce burden, (defined as patients with ALL who have M3 bone marrow blasts and/or presence of peripheral blood blasts on routine complete blood count (CBC), or patients with lymphoma).
3. Primary: To determine the feasibility of administering anti-CD19 CAR transduced T cells within 21 days of the target date in children and young adults with B-cell malignancies expressing CD19 enrolled on arm 2: Patients with high-burden disease who receive standard chemotherapy to reduce burden.

1) Secondary: 1) To determine if the administration of anti-CD19-CAR engineered peripheral blood lymphocytes can mediate antitumor effects in children with B cell high-burden disease after standard chemotherapy, or in patients without high-burden disease who receive standard preparative regimen. 2) To evaluate the ability of CRS treatment algorithm to reduce the incidence of Grade 4 Cytokine Release Syndrome (CRS) to less than or equal to 10% of patients. 3) To measure persistence of adoptively-transferred anti-CD19-CAR-transduced T cells in the blood, bone marrow and cerebrospinal fluid (CSF) of patients. 4) To describe the toxicity of administration of anti-CD19-CAR engineered peripheral blood lymphocytes in children and young adults with central nervous system (CNS) disease.

Eligibility:

Patients 1-30 years of age, at least 15 kg, with a CD19-expressing B-cell malignancy that has recurred after or not responded to one or more standard chemotherapy-containing regimens for their malignancy and is deemed incurable by standard therapy. Patients with a history of allogeneic stem cell transplant who meet all eligibility criteria are eligible to participate.

Design:

* PBMC will be obtained by leukapheresis. Anti-CD19 CAR T cells will be manufactured from fresh or frozen peripheral blood mononuclear cells (PBMCs). On Day -7, PBMC will be enriched for cluster of differentiation 3 (CD3)+ cells and cultured in the presence of anti-CD3/-cluster of differentiation 28 (CD28) beads followed by retroviral vector supernatant containing the anti-cluster of differentiation 19 (CD19) CAR. Total culture time is approximately 7-14 days.
* Patients will be divided into the 2 groups listed above.

Arm 1: Patients will begin preparative regimen comprising fludarabine 25 mg/m(2) on Days -4, -3 and -2 and cyclophosphamide 900 mg/m(2) on day -2.

Arm 2: Patients with high-disease burden will be treated with intensive standard of care chemotherapy to decrease disease burden during cell manufacturing.

* All patients: The CD19-CAR cells will be infused on Day 0, with up to a 72h delay allowed for fresh cells or a 21 day delay if cells are cryopreserved, if needed for resolution of clinical toxicities or to generate adequate cell numbers.
* The previously determined maximum tolerated dose (MTD) of 1 X 10(6) will be administered intravenously.
* Patients will be monitored for toxicity, response and T cell persistence.

Eligibility criteria: * INCLUSION CRITERIA
* 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.
* Patients with history of allogeneic stem cell transplantation are eligible if at least 100 days post-transplant, if there is no evidence of active graft versus host disease (GVHD) and no longer taking immunosuppressive agents for at least 30 days prior to enrollment.

EXCLUSION CRITERIA

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)
    * 5 \< 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;

Exceptions:

* There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such;
* Subjects receiving hydroxyurea may be enrolled provided there has been no increase in dose for at least 2 weeks prior to starting apheresis;
* Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study provided they meet all other eligibility criteria;
* Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis;
* For radiation therapy: Radiation therapy must have been completed at least 3 weeks prior to enrollment, with the exception that there is no time restriction if the volume of bone marrow treated is less than 10% and also the subject has measurable/evaluable disease outside the radiation port.

  * Other anti-neoplastic investigational agents currently or within 30 days prior to apheresis (i.e. start of protocol therapy);
  * Subjects must have recovered from the acute side effects of their prior therapy, such that eligibility criteria are met. Cytopenias deemed to be disease-related and not therapy-related are exempt from this exclusion.

    * Human immunodeficiency virus/hepatitis B virus/Hepatitis C virus (HIV/HBV/HCV) Infection:
* Seropositive for HIV antibody. (Patients with HIV are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy in the future should study results indicate effectiveness.)
* Seropositive for hepatitis C or positive for Hepatitis B surface antigen (HbsAG).

  * Monoclonal antibody therapy administered within 30 days of the agent prior to apheresis;
  * Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the principal investigator (PI) would pose an unacceptable risk to the subject;
  * Second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and subject is in remission;
  * History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells (i.e. gentamicin);

Primary outcomes:
measure: 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
timeFrame: Beginning of preparative regimen through Day 28 after CD19 CAR infusion
measure: 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
timeFrame: Apheresis through completion of CAR manufacturing process, approximately 2 weeks
Secondary outcomes:
measure: Number of Participants Who Were Administered Intensive Chemotherapy Prior to Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR Infusion
timeFrame: 21 days of target date
measure: Mean Percentage Cluster of Differentiation 19 (CD19) - Chimeric Antigen-Receptor (CAR) T-Cells in Blood, Bone Marrow (BM) and Cerebrospinal Fluid (CSF)
timeFrame: 28 days (+/- 4 days) after infusion of CD19 CAR T-cells
measure: Number of Patients With a Complete Response (CR)
timeFrame: Day 28 (+/- 4 days) after CD19 CAR infusion
measure: Number of Participants With Grade 4 Cytokine Release Syndrome (CRS)
timeFrame: Day 28 (+/- 4 days) after CD19 CAR infusion.
measure: Number of Participants With Serious and Non-Serious Adverse Events
timeFrame: Date treatment consent signed to date off study, from 1.5 months up to 3.1 years.
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Nirali N Shah, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.