Clinical trial NCT02134262: 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
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: Jichi Medical University
Sponsor class: OTHER
Collaborators: name: Takara Bio Inc.
First posted: 2014-05-09
Enrollment: 18
Sex: ALL
Minimum age (years): 20
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Toxicity Profile
timeFrame: 12 weeks
measure: Toxicity Profile
timeFrame: 12 weeks
measure: Toxicity Profile
timeFrame: 12 weeks
measure: Toxicity Profile
timeFrame: 12 weeks
measure: Toxicity Profile
timeFrame: 12 weeks
measure: Quality test of CD19-CAR-T
timeFrame: Before administration
Secondary outcomes:
measure: Tumor shrinkage effect
timeFrame: 12 weeks
measure: Lymphocyte subset analysis of CD19-CAR-T
timeFrame: 12 weeks
measure: Human anti-mouse antibody (HAMA) test
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Shimotsuke
country: Japan
facility: Jichi Medical University
state: Tochigi
Study officials:
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
name: Keiya Ozawa, MD, PhD
role: STUDY_CHAIR
References: