Efficacy and Safety of TKI Combined With Chemotherapy and Sequential CAR-T Cells in ND Adult Patients With Ph+ ALL

Official title

Efficacy and Safety of Molecular Targeted Therapy Combined With Chemotherapy and Sequential CAR-T Cells in Newly Diagnosed Adult Patients With Philadelphia Chromosome-Positive B-cell Acute Lymphoblastic Leukemia

Overview

In recent years, immunotherapy (eg. blinatumomab, inotuzumab ozogamicin, CAR-T cells) has demonstrated a high safety and efficacy profile in relapsed/refractory (R/R）B-ALL. The available data suggest that the advancement of immunotherapy from R/R field to the frontline setting may be an important approach to increase the depth of remission, which ultimately translates into a survival benefit. In this study, the investigators propose a treatment regimen using CAR-T cell therapy as a consolidation method for Ph+ ALL patients achieving complete remission (CR) with overembatinib, venetoclax and reduced-intensity chemotherapy, aiming to reduce the total cycles of chemotherapy and related toxicities, shorten length of hospitalization, and ultimately improve patients' survival and quality of life.The study endpoints include 2-year disease-free survival (DFS) rate, overall survival (OS) rate, event-free survival (EFS) rate, cumulative molecular remission rate, immune repertoire-minimal residual disease (MRD) remission rate, cumulative relapse rate, treatment-related toxicities, and quality of life. Additionally, an interim analysis will be conducted, with the 1-year DFS rate as the key index for this analysis.

Detailed description

The CAR-T cells were murine-derived second-generation CD19 CAR-T with a co-stimulation domain of 4-1BB, and the infusion dose was 1×10\^6/kg CAR+ cells in a single infusion.

Interventions

• Combination product CAR-T cells
  CAR-T cells as consolidation therapy
• Drug Venetoclax
  BCL2 inhibitor
• Drug Olverembatinib
  TKI

Primary outcome measures

• Disease-free Survival (DFS) [Time frame: Up to 2 years post-registration]

Secondary outcome measures (6)

• Overall survival (OS) [Time frame: Up to 5 years post-registration]
• Event-free survival (EFS) [Time frame: Up to 5 years post-registration]
• Cumulative rate of complete molecular response [Time frame: Up to 1 year post-registration]
• MRD-negative complete remission rate measured by NGS tracking clonal IG/TR rearrangements [Time frame: Up to 1 year post-registration]
• Cumulative incidence of relapse (CIR) [Time frame: Up to 2 years post-registration]
• The rate of adverse [Time frame: Up to 5 years post-registration]

Eligibility criteria

Inclusion criteria

• Male or female patients aged 18 years or older
• Newly diagnosed Philadelphia chromosome positive(either t(9;22) and/or BCR-ABL positive and/ or FISH positive) acute lymphoblastic leukemia
• CD19 expression on blasts
• Expected survival time greater than 3 months
• Adequate end organ function as defined by: Total bilirubin ≤ 1.5 x upper limit of normal（ULN）; serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) ≤ 2.5 x ULN or ≤5 x ULN if leukemic involvement of the liver is present; Creatinine ≤ 1.5 x ULN; Serum amylase and lipase ≤ 1.5 x ULN; Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related; normal electrolytes: Potassium ≥ LLN; Magnesium ≥ LLN; Phosphorus ≥ LLN; Cardiac color Doppler ultrasound ejection fraction ≥ 45%
• Subject has provided written informed consent prior to any screening procedure

Exclusion criteria

• Lymphoid blast crisis of chronic myelocytic leukemia (CML)
• Previous or ongoing systemic anti-ALL therapy (including but not restricted to TKI and/or radiotherapy, except for appropriate pre-treatment)
• Patients with a history of myocardial infarction within 12 months or clinically significant cardiac disorders disease (e.g., unstable angina, congestive heart failure, uncontrollable hypertension, uncontrollable arrhythmia, etc.)
• Uncontrolled active serious infections that could, in the investigator's opinion, potentially interfere with the completion of treatment
• Known HIV seropositivity
• History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis
• Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)
• Another malignancy diagnosed and treated within 5 years prior to diagnosis or previously diagnosed with another malignancy with evidence of residual disease. Patients with non-melanoma skin cancer or any type of carcinoma in situ that has been completely excised should not be excluded
• Female patients who are pregnant or breast feeding
• Clinical manifestations of active CNS or extramedullary involvement with ALL
• Poorly controlled diabetes, defined as glycosylated hemoglobin (HbA1c) values of >7.5%. Patients with preexisting, well-controlled diabetes are not excluded
• Any serious psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment
• Other conditions assessed by the investigators to be inappropriate for this study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Institute of Hematology & Blood Diseases Hospital — Tianjin

Identifiers

NCT: NCT06481228 · IIT2024019

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗