CD19 CAR-T Consolidation Therapy for Acute Lymphoblastic Leukemia
- Conditions
- Acute Lymphoblastic Leukemia, Adult B-Cell
- Interventions
- Biological: ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion
- Registration Number
- NCT03984968
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 34
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description FTCs: High dose (Phase 1) ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion - FTCs: Medium dose (Phase 1) ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion - FTCs: Low dose (Phase 1) ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion - FTCs: High dose (Phase 2) ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion -
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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.
Trial Locations
- Locations (1)
The First Affliated Hospital of Soochow University
🇨🇳Suzhou, Jiangsu, China