CD19-CAR_Lenti T Cells in Pediatric Patients Affected by Relapsed/Refractory CD19+ ALL and DLBCL or PML

Phase I/II Study of Anti-CD19 Chimeric Antigen Receptor-Expressing T Cells in Pediatric Patients Affected by Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia and Diffuse Large B Cell Lymphoma (DLBCL) or Primary Mediastinal B Cell Lymphoma (PML)

This study aims at evaluating the feasibility and safety of the administration of autologous T cells that have been modified through the introduction of a chimeric antigen receptor targeting the B-cell surface antigen CD19, following administration of lymphodepleting chemotherapy regimen, in children and adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B- ALL) or aggressive B-cell Non-Hodgkin lymphoma (B-NHL). The phase II extension is aimed at testing the efficacy of the treatment at the optimal dose defined in the phase I. In addition, the investigators hypothesize that it is feasible to successfully manufacture CAR T cells to meet the established release criteria at a maximum target dose of 3.0 x 10^6 cells/kilogram recipient total body weight in this patient population using the Miltenyi CliniMACS Prodigy® closed transduction system.

Study Overview

Study Type

Interventional

Enrollment (Anticipated)

32

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

      • Roma, Italy, 00165
        • Recruiting
        • IRCCS Ospedale Pediatrico Bambino Gesu
        • Contact:
        • Contact:
        • Principal Investigator:
          • Franco Locatelli, MD, PhD
        • Principal Investigator:
          • Francesca del Bufalo, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 25 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Diagnosis of CD19 expressing B-ALL or DLBCL or PML and one of the following:

    1. Patients in 1st relapse, with High-Risk (HR) features including: MLL- rearrangements, E2A/TCF3-PBX1, TCF3-HLF [t(17;19)], hypodiploidy (i.e., <44 chromosomes), TP53 alterations, early (i.e., <30 months from diagnosis)/very early (i.e., <18 months from diagnosis) isolated or combined bone marrow relapse
    2. MRD > 0.1% after either reinduction therapy or any course of consolidation for relapsed ALL
    3. Patients with DLBCL or PML in 1st or subsequent relapse, after at least one standard frontline chemotherapy
  2. Age: 1 year - 25 years for Bcp-ALL and 1-35 years for B-NHL.
  3. Voluntary informed consent is given. For subjects < 18 year-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.
  4. Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients < 16 years of age: Lansky scale greater than or equal to 60%.
  5. 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.
  6. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.

Exclusion Criteria:

  1. Pregnant or lactating women
  2. Severe, uncontrolled active infections
  3. HIV, or active HCV and/or HBV infection (detection of viral RNA/DNA in blood)
  4. Life-expectancy < 6 weeks
  5. Hepatic function: Inadequate liver function defined as total bilirubin > 4x upper limit of normal (ULN) or transaminase (ALT and AST) > 6 x ULN
  6. Renal function: serum creatinine > 3x ULN for age.
  7. Blood oxygen saturation < 90%.
  8. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO.
  9. Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject.
  10. BM blasts > 50% pre-infusion.
  11. Hyperleukocytosis (greater than or equal to 20,000 blasts/microliter) or rapidly progressive disease that in the evaluation of the investigator would compromise ability to complete study therapy
  12. Presence of active, grade 2-4 acute or moderate-severe chronic GvHD
  13. Recurrent or refractory ALL with testicular involvement
  14. Concurrent or recent prior therapies, before infusion:

    1. Systemic steroids (at a dose > 2 mg/kg prednisone) in the 2 weeks before infusion. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary.
    2. Systemic chemotherapy in the week preceding infusion.
    3. Anti-thymocyte globulin (ATG) in the 4 weeks preceding infusion.
    4. Immunosuppressive agents in the 1 week preceding infusion.
    5. Radiation therapy must have been completed at least 3 weeks prior to enrollment.
    6. Other anti-neoplastic investigational agents currently administered or within 30 days prior to infusion (i.e. start of protocol therapy);
    7. Exceptions:

    i. There is no time restriction with respect to prior intrathecal chemotherapy, provided that there is complete recovery from any acute toxic effects of such; ii. Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study provided that they meet all other eligibility criteria; iii. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided that there has been no increase in dose for at least 2 weeks prior to starting apheresis;

  15. Patient-derived CD19-CAR_Lenti production failure: vitality of the fresh product <80%, CD3+ cells <80%, CD3+ CAR+ cells <10%, non-sterility in IPC at day 5, endotoxin contamination (> 5 EU/ml) in IPC at day 5, mycoplasma contamination in IPC at day 5, failure of the visual inspection.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: CD19-CAR_Lenti
Following lymphodepletion with chemotherapy (fludarabine + cyclophosphamide), patients will be treated with 1.0 to 3.0 x 10^6/kg CD19-Chimeric Antigen Receptor (CAR)_Lenti positive cells as a single dose. The product will be infused fresh, at the end of manufacturing.
Fresh peripheral blood mononuclear cells are manufactured to obtain CD19-CAR_Lenti T cell, second generation CAR T cells incorporating the 4-1BB costimulatory domain. The fresh product is infused following lymphodepletion chemotherapy at a dose of 1.0-3.0x10^6 CAR+ cells/kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase I - Identification of dose limiting toxicities (DLTs) and recommended dose (RD)
Time Frame: 4 weeks after CAR T cell infusion
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) scale, version 5.0
4 weeks after CAR T cell infusion
Phase I - Identification of recommended dose (RD)
Time Frame: 4 weeks after CAR T cell infusion of the last patient in the last dose level
The recommended dose of CD19-CAR_Lenti will be defined as the maximum tolerated dose (MTD) or the highest dose studied, if an MTD is not reached.
4 weeks after CAR T cell infusion of the last patient in the last dose level
Phase II - Efficacy
Time Frame: Up to 6 months after CAR T cell infusion
Bone marrow morphological and minimal residual disease complete remission rate at day 28 after infusion for BCP-ALL; Overall Response Rate (CR, CRi, PR and SD) at day 28, day 90 and day 180 after CAR T cells infusion
Up to 6 months after CAR T cell infusion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival (OS)
Time Frame: Up to 2 years
Up to 2 years
Relapse Rate (RR)
Time Frame: Up to 2 years
Up to 2 years
Disease-Free Survival (DFS)
Time Frame: Up to 2 years
Up to 2 years
In vivo persistence/expansion of infused CAR T cell
Time Frame: Up to 2 years
Detection of infused CAR T cell in the peripheral and bone marrow blood
Up to 2 years
Cytokine profiling
Time Frame: Up to 10 days after CAR T cell infusion
Define serum cytokine profile (Th1/Th2) after T cell infusion and correlation with cytokine release syndrome (CRS)
Up to 10 days after CAR T cell infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 4, 2021

Primary Completion (Anticipated)

March 3, 2025

Study Completion (Anticipated)

March 3, 2038

Study Registration Dates

First Submitted

March 2, 2021

First Submitted That Met QC Criteria

March 5, 2021

First Posted (Actual)

March 8, 2021

Study Record Updates

Last Update Posted (Actual)

March 26, 2021

Last Update Submitted That Met QC Criteria

March 24, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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