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

Primary Purpose

Acute Lymphoblastic Leukemia, Diffuse Large B Cell Lymphoma, Primary Mediastinal Lymphoma

Status
Recruiting
Phase
Phase 1
Locations
Italy
Study Type
Interventional
Intervention
CD19-CAR_Lenti T cell
Sponsored by
Bambino Gesù Hospital and Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia

Eligibility Criteria

1 Year - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • IRCCS Ospedale Pediatrico Bambino GesùRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CD19-CAR_Lenti

Arm Description

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.

Outcomes

Primary Outcome Measures

Phase I - Identification of dose limiting toxicities (DLTs) and recommended dose (RD)
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) scale, version 5.0
Phase I - Identification of recommended dose (RD)
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.
Phase II - Efficacy
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

Secondary Outcome Measures

Relapse Rate (RR)
Overall survival (OS)
Disease-Free Survival (DFS)
In vivo persistence/expansion of infused CAR T cell
Detection of infused CAR T cell in the peripheral and bone marrow blood
Cytokine profiling
Define serum cytokine profile (Th1/Th2) after T cell infusion and correlation with cytokine release syndrome (CRS)

Full Information

First Posted
March 2, 2021
Last Updated
March 24, 2021
Sponsor
Bambino Gesù Hospital and Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT04787263
Brief Title
CD19-CAR_Lenti T Cells in Pediatric Patients Affected by Relapsed/Refractory CD19+ ALL and DLBCL or PML
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2021
Overall Recruitment Status
Recruiting
Study Start Date
March 4, 2021 (Actual)
Primary Completion Date
March 3, 2025 (Anticipated)
Study Completion Date
March 3, 2038 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bambino Gesù Hospital and Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia, Diffuse Large B Cell Lymphoma, Primary Mediastinal Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
32 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
CD19-CAR_Lenti
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
CD19-CAR_Lenti T cell
Intervention Description
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.
Primary Outcome Measure Information:
Title
Phase I - Identification of dose limiting toxicities (DLTs) and recommended dose (RD)
Description
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) scale, version 5.0
Time Frame
4 weeks after CAR T cell infusion
Title
Phase I - Identification of recommended dose (RD)
Description
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.
Time Frame
4 weeks after CAR T cell infusion of the last patient in the last dose level
Title
Phase II - Efficacy
Description
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
Time Frame
Up to 6 months after CAR T cell infusion
Secondary Outcome Measure Information:
Title
Relapse Rate (RR)
Time Frame
Up to 2 years
Title
Overall survival (OS)
Time Frame
Up to 2 years
Title
Disease-Free Survival (DFS)
Time Frame
Up to 2 years
Title
In vivo persistence/expansion of infused CAR T cell
Description
Detection of infused CAR T cell in the peripheral and bone marrow blood
Time Frame
Up to 2 years
Title
Cytokine profiling
Description
Define serum cytokine profile (Th1/Th2) after T cell infusion and correlation with cytokine release syndrome (CRS)
Time Frame
Up to 10 days after CAR T cell infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of CD19 expressing B-ALL or DLBCL or PML and one of the following: 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 MRD > 0.1% after either reinduction therapy or any course of consolidation for relapsed ALL Patients with DLBCL or PML in 1st or subsequent relapse, after at least one standard frontline chemotherapy Age: 1 year - 25 years for Bcp-ALL and 1-35 years for B-NHL. 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. 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%. 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. Exclusion Criteria: Pregnant or lactating women Severe, uncontrolled active infections HIV, or active HCV and/or HBV infection (detection of viral RNA/DNA in blood) Life-expectancy < 6 weeks Hepatic function: Inadequate liver function defined as total bilirubin > 4x upper limit of normal (ULN) or transaminase (ALT and AST) > 6 x ULN Renal function: serum creatinine > 3x ULN for age. Blood oxygen saturation < 90%. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO. 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. BM blasts > 50% pre-infusion. 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 Presence of active, grade 2-4 acute or moderate-severe chronic GvHD Recurrent or refractory ALL with testicular involvement Concurrent or recent prior therapies, before infusion: 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. Systemic chemotherapy in the week preceding infusion. Anti-thymocyte globulin (ATG) in the 4 weeks preceding infusion. Immunosuppressive agents in the 1 week preceding infusion. Radiation therapy must have been completed at least 3 weeks prior to enrollment. Other anti-neoplastic investigational agents currently administered or within 30 days prior to infusion (i.e. start of protocol therapy); 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; 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Franco Locatelli, MD, PhD
Phone
0039 066859
Ext
2678
Email
franco.locatelli@opbg.net
First Name & Middle Initial & Last Name or Official Title & Degree
Francesca Del Bufalo, MD
Phone
0039 066859
Ext
2739
Email
francesca.delbufalo@opbg.net
Facility Information:
Facility Name
IRCCS Ospedale Pediatrico Bambino Gesù
City
Roma
ZIP/Postal Code
00165
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Franco Locatelli, MD, PhD
Phone
0039 066859
Ext
2678
Email
franco.locatelli@opbg.net
First Name & Middle Initial & Last Name & Degree
Francesca del Bufalo, MD
Phone
0039 066859
Ext
2739
Email
francesca.delbufalo@opbg.net
First Name & Middle Initial & Last Name & Degree
Franco Locatelli, MD, PhD
First Name & Middle Initial & Last Name & Degree
Francesca del Bufalo, MD

12. IPD Sharing Statement

Learn more about this trial

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

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