Patients with relapsed or refractory CD19-positive B-cell acute lymphoblastic leulemia
Conditions
Interventions
Phase 1 part: Autologous T cells expressing a chimeric antigen receptor (CAR) against CD19 (CAR-T cells) will be administered in two separate doses at a maximum of 5.0 x 10^6 million cells per kg of b
Sponsors
Takahashi Yoshiyuki
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients with relapsed or refractory CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) who meet any of the following criteria: 1) Refractory patients: Patients under 65 years of age who have undergone two or more lines of chemotherapy at the time of initial diagnosis but have not achieved remission Patients aged 65 years or older who have undergone one or more lines of chemotherapy at the time of initial diagnosis but have not achieved remission 2) Relapsed patients: Patients who have undergone one or more lines of chemotherapy at the time of relapse but have not achieved remission 3) Patients who are not eligible for allogeneic HSCT (hematopoietic stem cell transplantation) or who have relapsed after allogeneic HSCT and for whom at least 100 days have elapsed since the allogeneic HSCT at the time of enrollment. 4) Patients who are Ph (Philadelphia chromosome) positive and are intolerant to TKI (tyrosine kinase inhibitor) therapy, have not responded to two types of TKI therapy, or are contraindicated for TKI therapy. 2. Patients who meet any of the following criteria: 1) Patients with 5% or more lymphoblasts in the bone marrow in the morphological evaluation at screening. 2) If 1) is not met, patients with CNS3 (presence of leukemia cells in the cerebrospinal fluid and leukemia cell count of 5/microL or more) in the central nervous system (CNS) classification at the time of screening, or patients with leukemia cells in either flow cytometry or histopathological diagnosis of a biopsy specimen other than bone marrow (Phase 1 part and Phase 2 part Cohort B). 3. Patients aged 1 year or older: However, only those aged 18 years or older will be included at the start of the clinical trial. After the start of the clinical trial and the accumulation of three cases of administration of the investigational product, the Efficacy and Safety Evaluation Committee will determine that changes are possible, and then patients aged 1 year or older will be allowed to register. 4. Patients must have confirmed expression of CD19 antigen in bone marrow or peripheral blood blast cells by flow cytometry within 3 months prior to enrollment in this clinical trial. For patients in 2-2), patients must have confirmed expression of CD19 antigen in cerebrospinal fluid or leukemia cells obtained by biopsy. 5. Patients who are expected to survive for 90 days or more after the scheduled date of first administration of the investigational drug. 6. Patients who meet the criteria for general condition and organ function at the time of screening.
Exclusion criteria
Exclusion criteria: 1. Patients with Burkitt's lymphoma/leukemia (mature B-ALL, leukemia with B-ALL positive for surface immunoglobulin (sIg) limited to kappa or lambda, FAB classification L3 and/or MYC translocation ALL) 2. Patients with a hereditary syndrome associated with bone marrow failure (Fanconi anemia, Kostmann syndrome, Schwachmann syndrome, other bone marrow failure syndromes). Note that patients with Down's syndrome are not excluded. 3. Patients with active concurrent malignancy (i.e., synchronous malignancy or malignancy with a disease-free interval of less than 5 years after curative treatment).However, patients who have undergone curative treatment for intraepithelial carcinoma of the skin or uterus and have no evidence of current active disease may be enrolled even if less than 5 years have elapsed since curative treatment. 4. Patients with severe or uncontrollable infections 5. Patients with Grade 2-4 acute or widespread chronic GVHD 6. Patients with active CNS infiltration (>=5 white blood cells/microL in cerebrospinal fluid and blasts) who suffer from the following: Seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, autoimmune disease involving the CNS, reversible posterior encephalopathy syndrome, cerebral edema, and other CNS disorders 7. Patients with psychiatric disorders or symptoms that are deemed difficult to participate in this clinical trial 8. Patients with a history of optic neuritis, immunological disease, or inflammatory disease affecting the central nervous system 9. Patients with primary immunodeficiency 10. Patients with NYHA Class III/IV cardiovascular disorders 11. Patients with a history of myocardial infarction, unstable angina, or other clinically significant cardiac disease within 12 months prior to enrollment, or who have undergone cardiac angioplasty or stent placement. 12. Patients with a history of symptomatic deep vein thrombosis or pulmonary embolism within 6 months prior to enrollment. 13. Patients with a history of autoimmune disease requiring systemic immunosuppressants or systemic disease-modifying agents due to end-organ damage within the past 2 years. 14. Patients who have received an investigational drug within 6 months prior to screening. 15. Patients who have previously received anti-CD19 CAR-T cell therapy (excluding Phase 2 part cohort A). 16. Pregnant or breastfeeding female patients. 17. Males or females of childbearing potential who are willing to completely abstain from heterosexual intercourse or use appropriate contraception during the clinical trial and for 12 months after administration of the investigational product. 18. Patients with a history of allergies to bovine or mouse-derived proteins. 19. Patients who are deemed inappropriate by the investigator, etc.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 1: Incidence of Dose-limiting toxicity within 28 days after the second dose of the investigational product. Phase 2: Overall remission rate (ORR) up to 90 days after first dose of investigational product. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Safety: Phase 1 and phase 2: 1) Incidence of adverse events 2) Number and incidence of significant adverse events 3) Occurrence of defects 2. Efficacy Phase 1: 1) ORR within 90 days after administration of the investigational product 2) MRD response rate within 90 days after administration of the investigational product 3) Duration of response (DOR) 4) Relapse-free survival (RFS) 5) Overall survival (OS) Phase 2: 1) Minimal Residual Disease (MRD) response rate within 90 days after administration of the investigational product 2) Duration of response (DOR) 3) Relapse-free survival (RFS) 4) Event-free survival (EFS) 5) Overall survival (OS) | — |
Contacts
Public ContactYoshiyuki Takahashi
Nagoya University Hospital
Outcome results
None listed