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

November 4, 2014 updated by: Keiya Ozawa, Jichi Medical University

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

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

18

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 Locations

  • Japan
    • Tochigi
      • Shimotsuke, Tochigi, Japan, 329-0498
        • Recruiting
        • Jichi Medical University
        • Contact:
        • Principal Investigator:
          • Keiya Ozawa, MD, PhD

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

20 years to 70 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

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: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Dose Level -1
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.
Drug: Cyclophosphamide or Bendamustine
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.
Genetic: Dose Level -1
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.
EXPERIMENTAL: Dose Level 1
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.
Drug: Cyclophosphamide or Bendamustine
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.
Genetic: Dose Level 1
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.
EXPERIMENTAL: Dose Level 2
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.
Drug: Cyclophosphamide or Bendamustine
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.
Genetic: Dose Level 2
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.
EXPERIMENTAL: Dose Level 3
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.
Drug: Cyclophosphamide or Bendamustine
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.
Genetic: Dose Level 3
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Toxicity Profile
Time Frame: 12 weeks
Confirm the toxicity profile with CTCAE ver4.0.
12 weeks
Toxicity Profile
Time Frame: 12 weeks
Confirm existence or non-existence of normal B-lymphocytes decrease by flow cytometry.
12 weeks
Toxicity Profile
Time Frame: 12 weeks
Measure immunoglobulin by PCR.
12 weeks
Toxicity Profile
Time Frame: 12 weeks
Confirm replication competent retrovirus (RCR) by PCR.
12 weeks
Toxicity Profile
Time Frame: 12 weeks
Confirm clonality by linear amplification mediated (LAM)-PCR.
12 weeks
Quality test of CD19-CAR-T
Time Frame: Before administration
Transduction efficiency, viability, sterility and potency.
Before administration

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Tumor shrinkage effect
Time Frame: 12 weeks
Confirm the efficacy with "Revised response criteria for malignant lymphoma" J Clin Oncol. 25: 579-586 (2007).
12 weeks
Lymphocyte subset analysis of CD19-CAR-T
Time Frame: 12 weeks
Confirm the state of immune mechanism by flow cytometry.
12 weeks
Human anti-mouse antibody (HAMA) test
Time Frame: 12 weeks
Examine HAMA with ELISA.
12 weeks

Collaborators and Investigators

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

Sponsor

Jichi Medical University

Collaborators

Takara Bio Inc.

Investigators

  • Study Chair: Keiya Ozawa, MD, PhD, 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

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

May 1, 2014

Primary Completion (ANTICIPATED)

March 1, 2017

Study Completion (ANTICIPATED)

March 1, 2017

Study Registration Dates

First Submitted

April 16, 2014

First Submitted That Met QC Criteria

May 7, 2014

First Posted (ESTIMATE)

May 9, 2014

Study Record Updates

Last Update Posted (ESTIMATE)

November 6, 2014

Last Update Submitted That Met QC Criteria

November 4, 2014

Last Verified

November 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • JMU-CD19CAR

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.

Clinical Trials on Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Clinical Trials on Cyclophosphamide or Bendamustine

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Burkina Faso

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe