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

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ClinicalTrials.gov Identifier: NCT02134262
Recruitment Status : Unknown
Verified November 2014 by Keiya Ozawa, Jichi Medical University.
Recruitment status was:  Recruiting
First Posted : May 9, 2014
Last Update Posted : November 6, 2014
Sponsor:
Collaborator:
Takara Bio Inc.
Information provided by (Responsible Party):
Keiya Ozawa, Jichi Medical University

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.

Condition or disease Intervention/treatment Phase
Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma Drug: Cyclophosphamide or Bendamustine Genetic: Dose Level -1 Genetic: Dose Level 1 Genetic: Dose Level 2 Genetic: Dose Level 3 Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : May 2014
Estimated Primary Completion Date : March 2017
Estimated Study Completion Date : March 2017


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.




Primary Outcome Measures :
  1. Toxicity Profile [ Time Frame: 12 weeks ]
    Confirm the toxicity profile with CTCAE ver4.0.

  2. Toxicity Profile [ Time Frame: 12 weeks ]
    Confirm existence or non-existence of normal B-lymphocytes decrease by flow cytometry.

  3. Toxicity Profile [ Time Frame: 12 weeks ]
    Measure immunoglobulin by PCR.

  4. Toxicity Profile [ Time Frame: 12 weeks ]
    Confirm replication competent retrovirus (RCR) by PCR.

  5. Toxicity Profile [ Time Frame: 12 weeks ]
    Confirm clonality by linear amplification mediated (LAM)-PCR.

  6. Quality test of CD19-CAR-T [ Time Frame: Before administration ]
    Transduction efficiency, viability, sterility and potency.


Secondary Outcome Measures :
  1. Tumor shrinkage effect [ Time Frame: 12 weeks ]
    Confirm the efficacy with "Revised response criteria for malignant lymphoma" J Clin Oncol. 25: 579-586 (2007).

  2. Lymphocyte subset analysis of CD19-CAR-T [ Time Frame: 12 weeks ]
    Confirm the state of immune mechanism by flow cytometry.

  3. Human anti-mouse antibody (HAMA) test [ Time Frame: 12 weeks ]
    Examine HAMA with ELISA.



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Ages Eligible for Study:   20 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02134262


Contacts
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Contact: Ken Ohmine, MD, PhD +81-285-58-7353 omineken@jichi.ac.jp
Contact: Keiya Ozawa, MD, PhD +81-285-58-7353 kozawa@ms2.jichi.ac.jp

Locations
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Japan
Jichi Medical University Recruiting
Shimotsuke, Tochigi, Japan, 329-0498
Contact: Ken Ohmine, MD, PhD    +81-285-58-7353    omineken@jichi.ac.jp   
Principal Investigator: Keiya Ozawa, MD, PhD         
Sponsors and Collaborators
Jichi Medical University
Takara Bio Inc.
Investigators
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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

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Responsible Party: Keiya Ozawa, Professor, Jichi Medical University
ClinicalTrials.gov Identifier: NCT02134262     History of Changes
Other Study ID Numbers: JMU-CD19CAR
First Posted: May 9, 2014    Key Record Dates
Last Update Posted: November 6, 2014
Last Verified: November 2014

Keywords provided by Keiya Ozawa, Jichi Medical University:
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

Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Bendamustine Hydrochloride
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists