Study of TBI-1501 for Relapsed or Refractory Acute Lymphoblastic Leukemia

Sponsor

Takara Bio Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03155191

Collaborator

(none)

Enrollment

Locations

Arm

213.9

Anticipated Duration (Months)

1.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Evaluate the safety (P-I), pharmacokinetics and anti-tumor effect of immunotherapy of autologous T cells genetically modified to express anti-CD19 chimeric antigen receptor (CAR) (TBI-1501) for relapsed or refractory CD19+ B-cell acute lymphoblastic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Lymphoblastic Leukemia, Acute Adult	Biological: TBI-1501	Phase 1/Phase 2

Detailed Description

Enroll patients after confirming eligibility. Following enrollment, peripheral blood mononuclear cells and blood plasma will be obtained from each subject by apheresis to start the manufacturing of TBI-1501.

Before TBI-1501 administration, it is necessary to pass the quality tests. Subject will be hospitalized from Day -3 to Day 28, and administered Cyclophosphamide (1,000 mg/m2/day×2 days) on Day -3 and Day -2.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

21 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Peripheral blood will be collected from a subject after obtaining a written informed consent. 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 retroviral vector. Cyclophosphamide will be administered after obtaining a written informed consent and completing registration. CD19-CAR-T will be administered in the split dose. Phase 2 recommended dose will be applied for phase 1 portion. The investigator assesses efficacy of CD19-CAR-T in accordance with study-specific criteria, at 8 week after the 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 infusion of CD19-CAR-T in reference to guidelines of FDA.Peripheral blood will be collected from a subject after obtaining a written informed consent. 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 retroviral vector. Cyclophosphamide will be administered after obtaining a written informed consent and completing registration. CD19-CAR-T will be administered in the split dose. Phase 2 recommended dose will be applied for phase 1 portion. The investigator assesses efficacy of CD19-CAR-T in accordance with study-specific criteria, at 8 week after the 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 infusion of CD19-CAR-T in reference to guidelines of FDA.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multicenter Phase I/II Study for Relapsed or Refractory CD19+ B-acute Lymphoblastic Leukemia

Actual Study Start Date :

Jun 1, 2017

Anticipated Primary Completion Date :

Mar 31, 2035

Anticipated Study Completion Date :

Mar 31, 2035

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Level -1 to 2 0.3 to 3 x 10^6 autologous CD19-CAR-T cells/kg per patient will be administered intravenously after a conditioning chemotherapy with cyclophosphamide. cohort -1: 3×10^5 cells/kg cohort 1: 1×10^6 cells/kg cohort 2: 3×10^6 cells/kg.	Biological: TBI-1501 Phase-I portion: Cyclophosphamide is administered for conditioning medication of TBI1501, that is CD19-CAR-T cells, (cohort -1: 3×10^5 cells/kg, cohort 1: 1×10^6 cells/kg, cohort 2: 3×10^6 cells/kg). Phase-II portion: Recommended dose of Phase-II part will be administered. Cyclophosphamide will be administered as conditioning. The end of study will be Week 52 after administration of TBI-1501.

Arm

Intervention/Treatment

Experimental: Dose Level -1 to 2

0.3 to 3 x 10^6 autologous CD19-CAR-T cells/kg per patient will be administered intravenously after a conditioning chemotherapy with cyclophosphamide. cohort -1: 3×10^5 cells/kg cohort 1: 1×10^6 cells/kg cohort 2: 3×10^6 cells/kg.

Biological: TBI-1501

Phase-I portion: Cyclophosphamide is administered for conditioning medication of TBI1501, that is CD19-CAR-T cells, (cohort -1: 3×10^5 cells/kg, cohort 1: 1×10^6 cells/kg, cohort 2: 3×10^6 cells/kg). Phase-II portion: Recommended dose of Phase-II part will be administered. Cyclophosphamide will be administered as conditioning. The end of study will be Week 52 after administration of TBI-1501.

Outcome Measures

Primary Outcome Measures

Phase-I portion: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [One year]
Adverse event (frequency, seriousness, duration, causality, severity, classification), mortality, severe adverse event, discontinuation due to adverse event.
Phase-II portion: Anti-tumor effect (CR+CRi rate) [56 days]
Complete Remission (CR)+Complete Remission with Incomplete Blood Count Recovery (CRi) , as determined by assessments of peripheral blood and bone marrow.

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

In phase-1 study, patients must be ≥ 18 years of age. In phase-2 study, patients must be ≥ 16 years of age.
Patients with relapse or refractory CD19+ acute B-cell lymphoblastic leukemia
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
Patients must have adequate key organ function (bone marrow, heart, lung, liver, renal, etc), as defined below

Total bilirubin level ≤1.5xULN (Upper limit of normal)
AST(GOT)/ALT(GPT) level ≤5.0xULN
Serum creatinine ≤2.0mg/dL
SpO2 ≧ 92%
LVEF ≥50%

Patients must be able to understand and willing to sign a written informed consent document (for patients <20 years of age their legal guardian must give informed consent).

Exclusion Criteria:

White blood cell counts ≧ 50,000/uL
Received expected antitumor therapy (chemotherapy or radiation therapy, etc) within 2 weeks.
Received HSCT within 12 weeks before enrollment.
Under treatment for GVHD.
lymphocytes except for blasts ≦ 500/uL
Presence of active CNS-3
Concurrent use of systemic steroids or immunosuppressive agents (except for replacement therapy and local administration. e.g. inhalation, application and so on).
HBs Ag positive ,or either HBc Ab positive or HBs positive with HBV-DNA > 1.3LogIU/ml
Presence of active hepatitis C infection
HIV Ab or anti-HTLV-1 Ab positive
History of allergy about component of investigational product or animal(cattle and/or mouse)-derived additives
Hypersensitivity to antibiotics.
Presence of symptomatic cardiac arrhythmias or serious heart disease.
Presence of another malignant tumor.
Psychiatric disorder, alcohol addiction or drug addiction that affects the ability of informed consent.
Active or serious infection.
Both men and women who have generative functions, and who cannot agree with using contraceptive devices from the day of the consent to the end of study.
Pregnant or lactating women.
Any other patients judged by the investigators to be inappropriate for the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Of Fukui Hospital	Yoshida	Fukui	Japan	910-1193
2	Kyushu University Hospital	Higashi-ku	Fukuoka	Japan	812-8582
3	Hokkaido University Hospital	Sapporo-shi	Hokkaido	Japan	060-8648
4	Kobe City Medical Center General Hospital	Kobe	Hyogo	Japan	650-0047
5	Mie University Hospital	Tsu-shi	Mie	Japan	514-8507
6	Tohoku University Hospital	Sendai	Miyagi	Japan	980-8574
7	Jichi Medical University hospital	Shimotsuke-shi	Tochigi	Japan	329-0498
8	Cancer Institute Hospital Of JFCR	Kōto	Tokyo	Japan	135-8550
9	The Institute of Medical Science, The University of Tokyo	Minato-ku	Tokyo	Japan	108-8639
10	Akita University Hospital	Akita		Japan	010-8543
11	Okayama University Hospital	Okayama		Japan	700-8558