Acute Lymphoblastic Leukemia, Adult B-Cell
Conditions
Keywords
feeding T cell, CD19 CAR-T therapy
Brief summary
This is a single-arm, open-label, single-center, phase I/II study to determine the safety and efficacy of CD19 CAR-T(ssCART-19) combined with autologous T cells engineered to express CD19, namely CD19+ feeding T cells (FTCs), as consolidation therapy in patients diagnosed with de novo Philadelphia chromosome-positive CD19+ B-ALL. The study will contain the following sequential phases: screening, lymphocyte apheresis, induction, and consolidation chemotherapies combined with tyrosine kinase inhibitors. Once in complete response, patients will receive two to four cycles of ssCART-19s, namely one cycle of ssCART-19 infusion (CAR-T1) followed by one to three cycles of ssCART-19 and CD19+ FTC infusion (CAR-T2-4). The role of CD19+ FTCs is to mimic leukemia cells. Therefore, they are expected to stimulate in vivo expansion and persistence of ssCART-19. Considering the limited number of lymphocytes obtained by a single apheresis from patients and cost-efficacy, in addition to safety, we will explore the range of biologically active doses of FTCs in a phase I study. Based on preclinical data, FTCs' stimulation of ssCART-19 at a ratio of 1:1 could achieve the best activation response, so a 5×10\^6/kg dosage of FTCs was set as the initial dosage in the study, and lower doses were also evaluated. In phase I, FTCs will be administered at the dose of 5×10\^6/kg, 3.25×10\^6/kg, or 2×10\^6/kg two hours after ssCART-19 infusion on day 1 and once again administered at the same dose on day 8. After ssCART-19 and FTCs infusion, adverse events (AEs) as the primary endpoints will be recorded for 6 months; efficacy as the secondary endpoint will be assessed by detecting molecular response for 6 months, PFS, and OS for 2 years. In phase II, we will expand the study at optimal biological doses of FTCs and further evaluate the efficacy and safety of the innovative combination therapy of ssCART-19 and FTCs. The primary endpoint was the complete molecular response (CMR). The secondary endpoints were RFS, OS, and adverse events (AEs) of the patients.
Interventions
BIOLOGICALssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion
Phase 1: Optimal biological doses of feeding T cells (FTCs) identification. ssCART-19 cells combined with CD19+ FTCs were administered to Philadelphia chromosome-positive B-ALL patients with remission. ssCART-19 was infused at the dose of 5×10\^6/kg on days 1 to 3 of the first cycle and on day 1 of the second to fourth cycle. CD19+ FTCs (5×10\^6 cells/kg) were infused two hours after the infusion of ssCART-19 cells on day 1 and at the same dose alone on day 8 of the second to fourth cycle. Five patients were enrolled in this arm, and all the patients received four cycles of ssCART-19 consolidation.
Sponsors
The First Affiliated Hospital of Soochow University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 15-65 years of age at the time of signing informed consent * Diagnosed as de novo Philadelphia chromosome-positive CD19+ B-ALL * Karnofsky performance status ≥ 60 or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Unable to find a suitable donor or for other reasons to undergo allogeneic hematopoietic stem cell transplantation during the study * Ability and willingness to adhere to the study visit schedule and all protocol requirements * Voluntarily sign informed consent forms
Exclusion criteria
* Unable to tolerate any kind of TKIs (including the first- and second-generation tyrosine kinase inhibitors) for a long period. * Subjects who have positive mutation(s) of the ABL kinase domain and require the third-generation tyrosine kinase inhibitors for long-term therapies. * Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 3 × upper limit of normal (ULN) and direct bilirubin \> 1.5 × ULN * Inadequate renal function defined by serum creatinine \> 1.6 mg/dL * International ratio (INR) or partial thromboplastin time (PTT) \> 1.5 x ULN * Left ventricular ejection fraction \< 50% * Ongoing treatment with chronic immunosuppressants * Significant comorbid conditions or diseases which, in the judgment of the investigator, would place the subject at undue risk or interfere with the study; examples include, but are not limited to, cirrhotic liver disease, sepsis, recent significant traumatic injury, and other conditions * Known human immunodeficiency virus (HIV) positivity * Subjects with a history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control * Subjects with second malignancies in addition to ALL * Pregnant or lactating women, or subjects refusing to take effective contraception measures * Other contraindications that are considered inappropriate to participate in this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 Incidence of adverse events (AEs) and abnormal laboratory test results | 6 months after ssCART-19 consolidation termination (CAR-T4; each cycle is 3 months) | AEs will be assessed according to the Common Terminology Criteria for Adverse Events 5.0 (CTCAE5.0). |
| Phase 2 Molecular response after CD19 CAR-T consolidation therapy combined with CD19+ feeding T cells | 3 months after each cycle of ssCART-19 consolidation termination (each cycle is 3 months) | Complete molecular response (CMR) was defined as the absence of a detectable BCR-ABL1 transcript with a sensitivity of 0.01%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 Molecular response after CD19 CAR-T consolidation therapy combined with CD19+ feeding T cells. | 3 months after each cycle of ssCART-19 consolidation termination (each cycle is 3 months) | Complete molecular response (CMR) was defined as the absence of a detectable BCR-ABL1 transcript with a sensitivity of 0.01%. |
| Phase 1 The range of biologically active doses and optimal biological doses of CD19+ feeding T cells. | 6 months after ssCART-19 consolidation termination (CAR-T4; each cycle is 3 months) | The range of biologically active doses and optimal biological doses of CD19+ feeding T cells will be determined. |
| Phase 1 Overall survial (OS) | 2 years | It is measured from the date of entry into this trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive. |
| Phase 1 Relapse free survival（RFS） | 2 years | It is measured from the date of achievement of a remission until the date of relapse from CR, or CRi, or death from any cause; patients not known to have any of these events are censored on the date they were last examined. |
| Phase 2 Incidence of adverse events (AEs) and abnormal laboratory test results | 6 months after ssCART-19 consolidation termination (the specific date depending how many cycles the participants received; each cycle is 3 months) | AEs will be assessed according to the Common Terminology Criteria for Adverse Events 5.0 (CTCAE5.0). |
| Phase 2 Overall survial (OS) | 2 years | It is measured from the date of entry into this trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive. |
| Phase 2 Relapse free survival（RFS） | 2 years | It is measured from the date of achievement of a remission until the date of relapse from CR, or CRi, or death from any cause; patients not known to have any of these events are censored on the date they were last examined. |
Countries
China
Outcome results
None listed