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

Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02134262
• Other study ID #: JMU-CD19CAR
• Status: Recruiting
• Phase: Phase 1/Phase 2
• First received: April 16, 2014
• Last updated: November 4, 2014
• Start date: May 2014
• Est. completion date: March 2017

Study information

• Verified date: November 2014
• Source: Jichi Medical University
• Contact: Ken Ohmine, MD, PhD
• Phone: +81-285-58-7353
• Email: omineken[@]jichi.ac.jp
• Is FDA regulated: No
• Health authority: Japan: Ministry of Health, Labor and Welfare
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: March 2017
• Est. primary completion date: March 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years to 70 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Intervention

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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Japan	Jichi Medical University	Shimotsuke	Tochigi

Sponsors (2)

Lead Sponsor	Collaborator
Jichi Medical University	Takara Bio Inc.

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Toxicity Profile	Confirm the toxicity profile with CTCAE ver4.0.	12 weeks	Yes
Primary	Toxicity Profile	Confirm existence or non-existence of normal B-lymphocytes decrease by flow cytometry.	12 weeks	Yes
Primary	Toxicity Profile	Measure immunoglobulin by PCR.	12 weeks	Yes
Primary	Toxicity Profile	Confirm replication competent retrovirus (RCR) by PCR.	12 weeks	Yes
Primary	Toxicity Profile	Confirm clonality by linear amplification mediated (LAM)-PCR.	12 weeks	Yes
Primary	Quality test of CD19-CAR-T	Transduction efficiency, viability, sterility and potency.	Before administration	Yes
Secondary	Tumor shrinkage effect	Confirm the efficacy with "Revised response criteria for malignant lymphoma" J Clin Oncol. 25: 579-586 (2007).	12 weeks	No
Secondary	Lymphocyte subset analysis of CD19-CAR-T	Confirm the state of immune mechanism by flow cytometry.	12 weeks	No
Secondary	Human anti-mouse antibody (HAMA) test	Examine HAMA with ELISA.	12 weeks	Yes