T-cells Expressing Anti-CD19 CAR in Pediatric and Young Adults With B-cell Malignancies

A Phase 1 / 2 Single Arm Study of T-cells Expressing Anti-CD19 Chimeric Antigen Receptor in Pediatric and Young Adult Patients With B-cell Malignancies

This phase 1 / 2 study will evaluate the response of B-cell malignancies expressing CD19 to autologous T cells transduced with a second generation anti-CD19 chimeric antigen receptor in children and young adults.

Study Overview

• Status: Unknown
• Conditions: Acute Lymphoblastic Leukemia, B-precursor; Non-Hodgkin Lymphoma, B-cell
• Intervention / Treatment: Biological: CD19 CAR T cells

Detailed Description

Autologous T cells transduced with chimeric antigen receptors (CAR) that recognize the CD19 antigen (CD19-CAR T cells) have been used in multiple clinical trials at several institutions worldwide. We established an in-house manufacturing process for CD19-CAR T cells with a CD28 (cluster of differentiation 28) costimulatory domain.

Primary Objectives:

1. To study the safety of administration of CAR T cell at the Sheba Medical Center
2. To determine the feasibility and efficacy of administering anti-CD19-CAR T cells in children and young adults with B cell malignancies.

Secondary Objectives

1. To study in vivo and in vitro behavior of CAR T cell in patients, including persistence, expansion, cytotoxic potential and exhaustion.
2. To study the cytokine milieu in CAR treated patients.

Eligibility Patients 1-50 years of age, with a CD19-expressing B-cell malignancy that has recurred after, or not responded to, one or more standard chemotherapy-containing regimens.

Design Peripheral blood mononuclear cells (PBMCs)will be obtained by leukapheresis. Anti-CD19 CAR T cells will be manufactured from fresh autologous PBMCs. PBMC will be cultured in the presence of anti-CD3 (cluster of differentiation 3) antibody and interleukin-2 followed by retroviral vector supernatant containing the anti-CD19 CAR. Total culture time is between 7-10 days. Patients will receive lymphodepleting chemotherapy composed of cyclophosphamide and fludarabine prior to cell infusion, and on day 0 will receive one million CAR T cells per kilogram. Patients will be monitored for toxicity including cytokine release syndrome, hematologic toxicities and B-cell aplasia; for response of their underlying malignancy; and for CAR-T cell persistence in the blood, marrow and cerebral spinal fluid (CSF).

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Israel
  • Ramat Gan, Israel
    • Recruiting
    • Chaim Sheba Medical Center
    • Contact: Diana Bar; Phone Number: +972-3-5303699; Email: Diana.Chigalayev@sheba.health.gov.il
    • Contact: Elad Jacoby, MD; Phone Number: +972-3-5302934; Email: elad.jacoby@sheba.health.gov.il

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient with relapsed or refractory B-cell malignancy
• Age 1-50 years
• CD19 expression shown by flow cytometry or immunohistochemistry on at least 70% of leukemic blasts / lymphoma cells
• Adequate CD3 count (above 250 CD3+ cells per microliter blood)
• Clinical performance status: Patients > 10 years of age: Karnofsky ≥ 50%; Patients ≤ 10 years of age: Lansky scale ≥ 50%. Exception for neurologic symptoms (e.g. paralysis) that are explained by the malignancy.
• Females of child-bearing potential must have a negative pregnancy test
• Cardiac function: Left ventricular ejection fraction >45% or shortening fraction >28%
• For patients following allogeneic bone marrow transplantation - at least 100 days post BMT with no signs or symptoms of active graft-versus-host disease.

Key Exclusion Criteria:

• Hyperleukocytosis (WBC>50,000) or rapidly progressive disease
• Pregnant or breast-feeding females
• Hepatic dysfunction, defined as bilirubin > x2 upper normal limit (except when explained by hemolysis or Gilbert) or serum glutamate oxaloacetate transaminase > x25 upper normal limit.
• Hepatitis B, Hepatitis C or HIV infection.
• Anti-neoplastic treatment given in the 2 weeks prior to apheresis, with the exception of intrathecal chemotherapy.
• Active immunosuppressive therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single Arm; All patients will be treated on this single arm	Biological: CD19 CAR T cells; Autologous T cells activated and transduced with a chimeric antigen receptor targeting CD19

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with treatment related adverse events as assessed by CTCAE v4.		2 years
Overall Response Rate	Overall response rate = complete response (CR) + partial response (PR) + complete response with incomplete count recovery (CRi) in leukemia patients; Assessment using bone marrow evaluation for patients with leukemia, and imaging (CT / PET CT) for patients with lymphoma	28 days
Feasibility of CD19 CAR T cell production as defined by number of products successfully meeting release criteria	For each participant, the feasibility of generating sufficient autologous CAR T cells within 12 days will be evaluated.	12 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CAR T cell persistence as measured by enumeration of CAR T cells in the blood and bone marrow of participants	Enumeration of CAR T cells in the blood and bone marrow of participants	1 year
T cell activity and exhaustion profile as measured by flow cytometry	Assessment of T cells from peripheral blood by flow cytometry for expression of activation and exhaustion markers.	3 months
Cytokine levels in the peripheral blood of the patients	Measurement of cytokines in the blood of participants following CAR T cell administration	30 days

Collaborators and Investigators

• Sponsor: Sheba Medical Center

Publications and helpful links

General Publications

• 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.
• Itzhaki O, Jacoby E, Nissani A, Levi M, Nagler A, Kubi A, Brezinger K, Brayer H, Zeltzer LA, Rozenbaum M, Vernitsky H, Markel G, Toren A, Avigdor A, Schachter J, Besser MJ. Head-to-head comparison of in-house produced CD19 CAR-T cell in ALL and NHL patients. J Immunother Cancer. 2020 Mar;8(1):e000148. doi: 10.1136/jitc-2019-000148.
• Fried S, Avigdor A, Bielorai B, Meir A, Besser MJ, Schachter J, Shimoni A, Nagler A, Toren A, Jacoby E. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant. 2019 Oct;54(10):1643-1650. doi: 10.1038/s41409-019-0487-3. Epub 2019 Feb 26.
• Jacoby E, Bielorai B, Avigdor A, Itzhaki O, Hutt D, Nussboim V, Meir A, Kubi A, Levy M, Zikich D, Zeltzer LA, Brezinger K, Schachter J, Nagler A, Besser MJ, Toren A. Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. Am J Hematol. 2018 Dec;93(12):1485-1492. doi: 10.1002/ajh.25274. Epub 2018 Sep 26.
• Nissani A, Lev-Ari S, Meirson T, Jacoby E, Asher N, Ben-Betzalel G, Itzhaki O, Shapira-Frommer R, Schachter J, Markel G, Besser MJ. Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy. J Immunother Cancer. 2021 May;9(5):e001743. doi: 10.1136/jitc-2020-001743.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Anticipated): July 1, 2022
• Study Completion (Anticipated): November 1, 2022

Study Registration Dates

• First Submitted: May 9, 2016
• First Submitted That Met QC Criteria: May 12, 2016
• First Posted (Estimate): May 13, 2016

Study Record Updates

• Last Update Posted (Actual): November 3, 2020
• Last Update Submitted That Met QC Criteria: November 1, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Leukemia, Lymphoid; Leukemia; Lymphoma; Lymphoma, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Other Study ID Numbers: SHEBA-15-2076-AT-CTIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided