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

• ClinicalTrials.gov Identifier: NCT02772198
• Recruitment Status: Unknown
• First Posted: May 13, 2016
• Last Update Posted: November 3, 2020
• Sponsor: Sheba Medical Center
• Information provided by (Responsible Party): Sheba Medical Center

Tracking Information

• First Submitted Date: May 9, 2016
• First Posted Date: May 13, 2016
• Last Update Posted Date: November 3, 2020
• Actual Study Start Date: November 2016
• Estimated Primary Completion Date: July 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 2, 2016)

• Number of patients with treatment related adverse events as assessed by CTCAE v4. [ Time Frame: 2 years ]
• Overall Response Rate [ Time Frame: 28 days ]
  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
• Feasibility of CD19 CAR T cell production as defined by number of products successfully meeting release criteria [ Time Frame: 12 days ]
  For each participant, the feasibility of generating sufficient autologous CAR T cells within 12 days will be evaluated.

Original Primary Outcome Measures (submitted: May 12, 2016)

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

Current Secondary Outcome Measures (submitted: November 2, 2016)

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

Original Secondary Outcome Measures (submitted: May 12, 2016)

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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: T-cells Expressing Anti-CD19 CAR in Pediatric and Young Adults With B-cell Malignancies
• Official Title: 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
• Brief Summary: 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.

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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Lymphoblastic Leukemia, B-precursor
• Non-Hodgkin Lymphoma, B-cell

Intervention

Biological: CD19 CAR T cells

Autologous T cells activated and transduced with a chimeric antigen receptor targeting CD19

Study Arms

Experimental: Single Arm

All patients will be treated on this single arm

Intervention: Biological: CD19 CAR T cells

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: November 1, 2020): 300
• Original Estimated Enrollment (submitted: May 12, 2016): 40
• Estimated Study Completion Date: November 2022
• Estimated Primary Completion Date: July 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year to 50 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Israel

Administrative Information

• NCT Number: NCT02772198
• Other Study ID Numbers: SHEBA-15-2076-AT-CTIL
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Sheba Medical Center
• Original Responsible Party: Same as current
• Current Study Sponsor: Sheba Medical Center
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Sheba Medical Center
• Verification Date: October 2020