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Gene Therapy for B-Cell Non-Hodgkin Lymphoma Using CD19 CAR Gene Transduced T Lymphocytes

Primary Purpose

Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Status
Unknown status
Phase
Phase 1
Locations
Japan
Study Type
Interventional
Intervention
Cyclophosphamide or Bendamustine
Dose Level -1
Dose Level 1
Dose Level 2
Dose Level 3
Sponsored by
Jichi Medical University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma focused on measuring Anti-CD19 CAR Expressing T cells Therapy, CD19 CAR Gene-Transduced Lymphocyte, Adoptive Immunotherapy, Genetically Engineered Lymphocyte Therapy, Retroviral Vector, Burkitt Lymphoma, Lymphoma, Lymphoma, Follicular, Lymphoma, Non-Hodgkin, Lymphomatoid Granulomatosis, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Large-Cell, Immunoblastic, Lymphoma, B-Cell, Marginal Zone, Lymphoma, Extranodal NK-T-Cell, Lymphoma, Mantle-Cell, Neoplasms by Histologic Type, Neoplasms, Neoplasms, Experimental, Immune System Diseases

Eligibility Criteria

20 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Relapsed or refractory B-NHL.
  2. Evaluable region can be identified by CT scan and is positive by FDG-PET.
  3. 20 ≤ age ≤ 70 years at the time of informed consent.
  4. ECOG performance status of 0-2.
  5. Well preserved main organ functions.
  6. Life expectancy ≥3 months after informed consent.
  7. Written informed consent.

Exclusion Criteria:

  1. Other active malignancy.
  2. CNS infiltration of lymphoma.
  3. History of allogeneic stem cell transplantation.
  4. Already participated in a clinical trial in which CD19-CAR-T are administered within 24 weeks.
  5. Concurrent use of systemic steroids or immunosuppressive agents.
  6. Concurrent severe heart disease.
  7. History of severe cerebrovascular disease or sequela including paralysis.
  8. Known active or severe infection.
  9. HIV seropositive status.
  10. HBsAg-positive or both HBcAb and HBV-DNA positive.
  11. Active hepatitis C.
  12. Psychiatric disorder or drug addiction that affects the ability of informed consent.
  13. Pregnant or breastfeeding women, women who may be pregnant and women desiring to become pregnant. Men who desire impregnating a woman are also excluded (excluded: in case when sperm is cryopreserved prior to gene therapy and a child is born by using the sperm).
  14. Any other patients judged by the investigators to be inappropriate for the subject of this study.

Sites / Locations

  • Jichi Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Dose Level -1

Dose Level 1

Dose Level 2

Dose Level 3

Arm Description

Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.

Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.

Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.

Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.

Outcomes

Primary Outcome Measures

Toxicity Profile
Confirm the toxicity profile with CTCAE ver4.0.
Toxicity Profile
Confirm existence or non-existence of normal B-lymphocytes decrease by flow cytometry.
Toxicity Profile
Measure immunoglobulin by PCR.
Toxicity Profile
Confirm replication competent retrovirus (RCR) by PCR.
Toxicity Profile
Confirm clonality by linear amplification mediated (LAM)-PCR.
Quality test of CD19-CAR-T
Transduction efficiency, viability, sterility and potency.

Secondary Outcome Measures

Tumor shrinkage effect
Confirm the efficacy with "Revised response criteria for malignant lymphoma" J Clin Oncol. 25: 579-586 (2007).
Lymphocyte subset analysis of CD19-CAR-T
Confirm the state of immune mechanism by flow cytometry.
Human anti-mouse antibody (HAMA) test
Examine HAMA with ELISA.

Full Information

First Posted
April 16, 2014
Last Updated
November 4, 2014
Sponsor
Jichi Medical University
Collaborators
Takara Bio Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02134262
Brief Title
Gene Therapy for B-Cell Non-Hodgkin Lymphoma Using CD19 CAR Gene Transduced T Lymphocytes
Official Title
Clinical Research of Gene Therapy for Refractory B-Cell Non-Hodgkin Lymphoma Using Autologous T Cells Expressing a Chimeric Antigen Receptor Specific to the CD19 Antigen
Study Type
Interventional

2. Study Status

Record Verification Date
November 2014
Overall Recruitment Status
Unknown status
Study Start Date
May 2014 (undefined)
Primary Completion Date
March 2017 (Anticipated)
Study Completion Date
March 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Jichi Medical University
Collaborators
Takara Bio Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety, efficacy and blood kinetics of autologous T cells genetically modified to express anti-CD19 Chimeric Antigen Receptor in patients with relapsed or refractory B-Cell Non-Hodgkin Lymphoma.
Detailed Description
Peripheral blood (up to 600 mL) will be collected from a subject after obtaining a written informed consent and completing the 1st registration. Peripheral blood mononuclear cells (PBMCs) and plasma are obtained from the blood, and T cells contained in the PBMCs are transduced with anti-CD19 CAR gene by using SFG-1928z retroviral vector. Anti-CD19 CAR expressing T cells (CD19-CAR-T) will be expanded using a medium containing autologous plasma. After the T cells pass in quality control tests, the subject will go into 2nd registration. Subjects will be hospitalized and administered Cyclophosphamide on Day -2 or Bendamustine on Day -3 to Day -2 intravenously as Pre-treatment, and then subjects will receive 1st infusion of CD19-CAR-T on Day 0 and Day 1 (Day 1:1/3 dose, Day 2:2/3 dose) as a split dose. In case the sufficient cell number of CD19-CAR-T is manufactured, DLT is not observed after CD19-CAR-T infusion, certain clinical effect is observed and additional treatment is preferable, the necessity of 2nd infusion will be assessed. In the case that 2nd infusion is necessary, it is allowed to infuse at appropriate timing. This study is conducted based on the 3+3 dose escalation scheme. Three subjects are enrolled in each group of Dose Level. If one of the 3 subjects show DLT during DLT assessment period, another 3 subjects will be added; therefore, decision as to whether the next Dose Level can follow or not is made based on the results obtained from the total of 6 subjects. The investigator assesses the tumor shrinkage effect of CD19-CAR-T in accordance with "Revised response criteria malignant lymphoma", at 12 week after the 1st infusion of CD19-CAR-T (or at the time of termination). The investigator also assesses the safety during the follow-up period. Long-term follow-up study is conducted at frequency of once a year for 15 years after the 1st infusion of CD19-CAR-T in reference to guidelines of FDA.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
Keywords
Anti-CD19 CAR Expressing T cells Therapy, CD19 CAR Gene-Transduced Lymphocyte, Adoptive Immunotherapy, Genetically Engineered Lymphocyte Therapy, Retroviral Vector, Burkitt Lymphoma, Lymphoma, Lymphoma, Follicular, Lymphoma, Non-Hodgkin, Lymphomatoid Granulomatosis, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Large-Cell, Immunoblastic, Lymphoma, B-Cell, Marginal Zone, Lymphoma, Extranodal NK-T-Cell, Lymphoma, Mantle-Cell, Neoplasms by Histologic Type, Neoplasms, Neoplasms, Experimental, Immune System Diseases

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dose Level -1
Arm Type
Experimental
Arm Description
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
Arm Title
Dose Level 1
Arm Type
Experimental
Arm Description
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
Arm Title
Dose Level 2
Arm Type
Experimental
Arm Description
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
Arm Title
Dose Level 3
Arm Type
Experimental
Arm Description
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide or Bendamustine
Intervention Description
Cyclophosphamide [1.5 g/m^2 x 1 day Intravenous (IV)] or Bendamustine [120 mg/m^2 x 2 days Intravenous (IV)] is administered as Pre-treatment medication of CD19-CAR-T.
Intervention Type
Genetic
Intervention Name(s)
Dose Level -1
Intervention Description
CD19-CAR-T [1 x 10^5 cells/kg x 1 day and 2 x 10^5 cells/kg x 1 day Intravenous (IV)] are administered.
Intervention Type
Genetic
Intervention Name(s)
Dose Level 1
Intervention Description
CD19-CAR-T [1/3 x 10^6 cells/kg x 1 day and 2/3 x 10^6 cells/kg x 1 day Intravenous (IV)] are administered.
Intervention Type
Genetic
Intervention Name(s)
Dose Level 2
Intervention Description
CD19-CAR-T [1 x 10^6 cells/kg x 1 day and 2 x 10^6 cells/kg x 1 day Intravenous (IV)] are administered.
Intervention Type
Genetic
Intervention Name(s)
Dose Level 3
Intervention Description
CD19-CAR-T [1/3 x 10^7 cells/kg x 1 day and 2/3 x 10^7 cells/kg x 1 day Intravenous (IV)] are administered.
Primary Outcome Measure Information:
Title
Toxicity Profile
Description
Confirm the toxicity profile with CTCAE ver4.0.
Time Frame
12 weeks
Title
Toxicity Profile
Description
Confirm existence or non-existence of normal B-lymphocytes decrease by flow cytometry.
Time Frame
12 weeks
Title
Toxicity Profile
Description
Measure immunoglobulin by PCR.
Time Frame
12 weeks
Title
Toxicity Profile
Description
Confirm replication competent retrovirus (RCR) by PCR.
Time Frame
12 weeks
Title
Toxicity Profile
Description
Confirm clonality by linear amplification mediated (LAM)-PCR.
Time Frame
12 weeks
Title
Quality test of CD19-CAR-T
Description
Transduction efficiency, viability, sterility and potency.
Time Frame
Before administration
Secondary Outcome Measure Information:
Title
Tumor shrinkage effect
Description
Confirm the efficacy with "Revised response criteria for malignant lymphoma" J Clin Oncol. 25: 579-586 (2007).
Time Frame
12 weeks
Title
Lymphocyte subset analysis of CD19-CAR-T
Description
Confirm the state of immune mechanism by flow cytometry.
Time Frame
12 weeks
Title
Human anti-mouse antibody (HAMA) test
Description
Examine HAMA with ELISA.
Time Frame
12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Relapsed or refractory B-NHL. Evaluable region can be identified by CT scan and is positive by FDG-PET. 20 ≤ age ≤ 70 years at the time of informed consent. ECOG performance status of 0-2. Well preserved main organ functions. Life expectancy ≥3 months after informed consent. Written informed consent. Exclusion Criteria: Other active malignancy. CNS infiltration of lymphoma. History of allogeneic stem cell transplantation. Already participated in a clinical trial in which CD19-CAR-T are administered within 24 weeks. Concurrent use of systemic steroids or immunosuppressive agents. Concurrent severe heart disease. History of severe cerebrovascular disease or sequela including paralysis. Known active or severe infection. HIV seropositive status. HBsAg-positive or both HBcAb and HBV-DNA positive. Active hepatitis C. Psychiatric disorder or drug addiction that affects the ability of informed consent. Pregnant or breastfeeding women, women who may be pregnant and women desiring to become pregnant. Men who desire impregnating a woman are also excluded (excluded: in case when sperm is cryopreserved prior to gene therapy and a child is born by using the sperm). Any other patients judged by the investigators to be inappropriate for the subject of this study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ken Ohmine, MD, PhD
Phone
+81-285-58-7353
Email
omineken@jichi.ac.jp
First Name & Middle Initial & Last Name or Official Title & Degree
Keiya Ozawa, MD, PhD
Phone
+81-285-58-7353
Email
kozawa@ms2.jichi.ac.jp
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Keiya Ozawa, MD, PhD
Organizational Affiliation
Division of Hematology, Department of Medicine, Center for Molecular Medicine, Division of Genetic Therapeutics, Center for Molecular Medicine, Division of Immuno-Gene & Cell Therapy (Takara Bio), Jichi Medical University
Official's Role
Study Chair
Facility Information:
Facility Name
Jichi Medical University
City
Shimotsuke
State/Province
Tochigi
ZIP/Postal Code
329-0498
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ken Ohmine, MD, PhD
Phone
+81-285-58-7353
Email
omineken@jichi.ac.jp
First Name & Middle Initial & Last Name & Degree
Keiya Ozawa, MD, PhD

12. IPD Sharing Statement

Learn more about this trial

Gene Therapy for B-Cell Non-Hodgkin Lymphoma Using CD19 CAR Gene Transduced T Lymphocytes

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