Clinical trial NCT03984968: CD19 CAR-T Consolidation Therapy for Acute Lymphoblastic Leukemia
Official title: Evaluation of the Safety and Efficacy of CD19 CAR-T Combined With Autologous T Cells Engineered to Express CD19 (CD19+ Feeding T Cells, FTCs) for Consolidation Treatment for Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Lymphoblastic Leukemia, Adult B-Cell
Keywords: feeding T cell
CD19 CAR-T therapy
Lead sponsor: The First Affiliated Hospital of Soochow University
Sponsor class: OTHER
First posted: 2019-06-13
Enrollment: 34
Sex: ALL
Minimum age (years): 15
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Phase 1 Incidence of adverse events (AEs) and abnormal laboratory test results
timeFrame: 6 months after ssCART-19 consolidation termination (CAR-T4; each cycle is 3 months)
measure: Phase 2 Molecular response after CD19 CAR-T consolidation therapy combined with CD19+ feeding T cells
timeFrame: 3 months after each cycle of ssCART-19 consolidation termination (each cycle is 3 months)
Secondary outcomes:
measure: Phase 1 Molecular response after CD19 CAR-T consolidation therapy combined with CD19+ feeding T cells.
timeFrame: 3 months after each cycle of ssCART-19 consolidation termination (each cycle is 3 months)
measure: Phase 1 The range of biologically active doses and optimal biological doses of CD19+ feeding T cells.
timeFrame: 6 months after ssCART-19 consolidation termination (CAR-T4; each cycle is 3 months)
measure: Phase 1 Overall survial (OS)
timeFrame: 2 years
measure: Phase 1 Relapse free survival（RFS）
timeFrame: 2 years
measure: Phase 2 Incidence of adverse events (AEs) and abnormal laboratory test results
timeFrame: 6 months after ssCART-19 consolidation termination (the specific date depending how many cycles the participants received; each cycle is 3 months)
measure: Phase 2 Overall survial (OS)
timeFrame: 2 years
measure: Phase 2 Relapse free survival（RFS）
timeFrame: 2 years
Other outcomes:
measure: Phase 1 exploratory endpoints
timeFrame: 3 months after ssCART-19 consolidation termination (CAR-T4; each cycle is 3 months)
measure: Phase 1 exploratory endpoints
timeFrame: Two weeks during each cycle of ssCART-19 (CAR-T1-4; each cycle is 3 months)
Locations:
city: Suzhou
country: China
facility: The First Affliated Hospital of Soochow University
state: Jiangsu
Study officials:
References: