Efficacy and Safety of CD19-CAR.p40-T in Patients With Relapsed/Refractory CD19-Positive Hematologic Malignancies

Official title

Efficacy and Safety of Autocrine p40-Expressing CD19-Targeted Chimeric Antigen Receptor T Cells (CD19-CAR.p40-T) in Patients With Relapsed/Refractory CD19-Positive Hematologic Malignancies

Overview

1. Study Title: A Study on the Efficacy and safety of Autocrine p40-Expressing CD19-Targeted Chimeric Antigen Receptor T Cells (CD19-CAR.p40-T) in Patients With Relapsed/Refractory CD19-Positive Hematologic Malignancies 2. Study Objectives: 2.1.1 Primary Objective To evaluate the safety of autocrine p40-expressing CD19-targeted chimeric antigen receptor T cells (CD19-CAR.p40-T) in the treatment of patients with relapsed/refractory CD19-positive hematologic malignancies. 2.1.2 Secondary Objective To evaluate the efficacy of autocrine p40-expressing CD19-targeted chimeric antigen receptor T cells (CD19-CAR.p40-T) in the treatment of patients with relapsed/refractory CD19-positive hematologic malignancies. 2.1.3 Exploratory Objective To evaluate the in vivo expansion and persistence of CD19-CAR.p40-T cells. 3. Participant Intervention: Participants will receive lymphodepleting chemotherapy (FC regimen: Fludarabine + Cyclophosphamide) on Days -5, -4, and -3 relative to the planned CD19-CAR.p40-T cell infusion. The CD19-CAR.p40-T cell infusion will be administered 72 hours after the completion of the FC chemotherapy.

Detailed description

CD19-directed CAR-T cell therapy has demonstrated significant antitumor activity in B-cell hematologic malignancies; however, relapse, insufficient persistence, and limited durability of response remain important clinical challenges. CD19-CAR.p40-T is a genetically modified autologous T-cell product designed to target CD19-positive malignant cells while incorporating autocrine p40 expression, with the aim of enhancing T-cell expansion, persistence, and antitumor activity in vivo.

This study is a prospective, single-arm, Phase I/II clinical trial in patients with relapsed or refractory CD19-positive hematologic malignancies. After screening and leukapheresis, eligible participants will undergo manufacture of autologous CD19-CAR.p40-T cells. Before infusion, participants will receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide to promote in vivo expansion and activity of the infused CAR-T cells. CD19-CAR.p40-T cells will then be administered as a single intravenous infusion.

Following infusion, participants will undergo close safety monitoring, including evaluation for cytokine release syndrome, immune effector cell-associated neurotoxicity, hematologic toxicity, infections, and other treatment-emergent adverse events. Disease assessments will be performed according to applicable disease-specific response criteria. In addition, serial blood samples will be collected to characterize the pharmacokinetic and cellular kinetic profile of CD19-CAR.p40-T cells, including expansion and persistence over time.

The purpose of this study is to characterize the safety profile of CD19-CAR.p40-T, evaluate its preliminary antitumor activity, and generate clinical and translational data to support further development of this investigational cell therapy in CD19-positive hematologic malignancies.

Interventions

• Combination product CAR-T cell
  Participants will receive lymphodepleting chemotherapy (FC regimen: Fludarabine + Cyclophosphamide) on Days -5, -4, and -3 relative to the planned CD19-CAR.p40-T cell infusion. The CD19-CAR.p40-T cell infusion will be administered 72 hours after the completion of the FC chemotherapy.

Primary outcome measures

• TEAEs [Time frame: From date of initial treatment to the 30 days after treatment]

Secondary outcome measures (1)

• Disease-related clinical responses [Time frame: From date of enrollment until the date of clinical responses,up to 2 years]

Eligibility criteria

Inclusion criteria

Subjects must meet all of the following criteria to be enrolled:

• • Aged 18 to 75 years, male or female;
• • Histologically or cytologically diagnosed with relapsed/refractory CD19-positive hematologic malignancy according to the 2022 World Health Organization (WHO) diagnostic criteria;
• • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
• • Life expectancy of at least 3 months;
• • No contraindications to peripheral blood leukapheresis;
• • CD19 expression on tumor cells confirmed by flow cytometry and/or immunohistochemistry;
• • No severe cardiac, pulmonary, hepatic, or renal dysfunction;
• • Able to understand and willing to provide written informed consent. Exclusion Criteria

Subjects who meet any of the following criteria should be excluded from enrollment:

• History of allergy to any component of the cellular product;
• Complete blood count meeting any of the following criteria: white blood cell count (WBC) ≤1 × 10⁹/L, absolute neutrophil count (ANC) ≤0.5 × 10⁹/L, absolute lymphocyte count (ALC) ≤0.5 × 10⁹/L, or platelet count (PLT) ≤25 × 10⁹/L;
• Laboratory abnormalities including, but not limited to, serum total bilirubin ≥1.5 mg/dL; serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 times the upper limit of normal; or serum creatinine ≥2.0 mg/dL;
• Class III or IV cardiac insufficiency according to the New York Heart Association (NYHA) functional classification, or left ventricular ejection fraction (LVEF) <50% by echocardiography;
• Abnormal pulmonary function, with oxygen saturation <92% on room air;
• History of myocardial infarction, cardiac angioplasty or stent placement, unstable angina, or other clinically significant severe cardiac disease within 12 months prior to enrollment;
• Grade 3 hypertension with poor blood pressure control despite medication;
• History of traumatic brain injury, disturbance of consciousness, epilepsy, severe cerebral ischemia, or cerebral hemorrhagic disease;
• Autoimmune disease, immunodeficiency, or other conditions requiring treatment with immunosuppressive agents;
• Uncontrolled active infection;
• Prior treatment with any CAR-T cell product or other genetically modified T-cell therapy;
• Receipt of a live vaccine within 4 weeks prior to enrollment;
• Positive test results for HIV, HBV, HCV, or TPPA/RPR, or HBV carrier status;
• History of alcohol abuse, drug abuse, or psychiatric illness;
• Participation in any other clinical study within 3 months prior to enrollment in this clinical study;
• Female subjects who meet any of the following conditions:

• Pregnant or breastfeeding;
• Planning to become pregnant during the study; or
• Of childbearing potential and unwilling or unable to use effective contraception;
• Any other condition that, in the investigator's opinion, makes the subject unsuitable for participation in 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

Health services research

Study locations

China · 1 center

• Shenzhen University General Hospital — Shenzhen

Identifiers

NCT: NCT07584889 · 114 · 114

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗