Single-arm, Open-label, Dose-escalating Phase I Clinical Study of PA3-17 Injection in Children and Adolescents With Relapsed/Refractory T-lymphoblastic Leukemia/Lymphoma
Single-arm, Open-label, Dose-escalating Phase I Clinical Study of PA3-17 Injection in Children and Adolescents With Relapsed/Refractory T-lymphoblastic Leukemia/Lymphoma
This is a phase I, open-label, dose-escalation clinical trial. The primary objectives are to assess the safety of PA3-17 injection in pediatric and adolescent participants with relapsed/refractory T-lymphoblastic leukemia/lymphoma, and determine the recommended phase II dose of PA3-17 injection for this patient population.
Secondary objectives include evaluating the pharmacokinetics/pharmacodynamics, preliminarily assessing clinical efficacy, and evaluating the immunogenicity of the injection.
In the dose-escalation phase of this phase I trial, the conventional 3+3 design is adopted with three dose cohorts. The starting dose is 1×10^6 CAR-T cells/kg, followed by incremental doses of 2×10^6CAR-T cells/kg and 4×10^6CAR-T cells/kg. A total of 9 to 18 pediatric and adolescent participants with relapsed/refractory T-lymphoblastic leukemia/lymphoma will be enrolled.
In the first and second cohorts, subsequent participants may receive treatment after the prior subject completes a minimum 14-day safety observation period. For the third cohort, dosing of the next subject can proceed only after a 28-day safety monitoring period for the previous participant.
After the final subject in each cohort finishes the 28-day dose-limiting toxicity (DLT) assessment post single administration, enrollment for the next cohort can commence upon approval from the Safety Review Committee based on clinical safety data.
If one DLT occurs among 3 subjects in a cohort, 3 additional participants will be enrolled in the same cohort, bringing the total assessed subjects to 6. No further dose escalation will be conducted if one or more DLTs are observed in the supplementary subjects. Enrollment will then resume at the preceding lower dose level with another 3 subjects for DLT evaluation.
During the dose expansion phase of the phase I trial, the Safety Review Committee will review available safety, efficacy, pharmacokinetic and immunogenicity data to comprehensively determine the recommended phase II dose. At least 3 additional participants will be enrolled at this dose level. No dosing interval restriction or DLT assessment is required for expanded enrollment, so as to further confirm the preliminary efficacy and safety of the recommended phase II dose.
Inclusion Criteria:
(1) Aged from 3 to 18 years (inclusive), with no restriction on gender. (2) Expected survival time ≥ 3 months. (3) At screening, Karnofsky Performance Status score (for subjects aged ≥ 16 years) or Lansky Performance Score (for subjects aged < 16 years) > 60 points (see Appendix 4).
(4) Diagnosed with T-ALL or T-LBL (including ETP-ALL and ETP-LBL) by local laboratories based on the classification criteria of WHO Classification of Haematolymphoid Tumours, 5th Edition: Lymphoid Neoplasms, confirmed via MICM classification (morphology, immunology, cytogenetics and molecular genetics), and/or pathological and imaging examinations.
For subjects diagnosed with T-LBL: bone marrow smear shows blasts between 5% (inclusive) and 20% (exclusive), or focal infiltration is observed on bone marrow biopsy indicating bone marrow involvement of T-LBL.
(5) Subjects with relapsed or refractory disease after failure of standard treatment or without available effective treatment options:
① Refractory disease: Failure to achieve remission after completion of at least 2 cycles of standard induction chemotherapy*.
② Relapsed disease: New extramedullary lesions or bone marrow recurrence occurring in subjects who have achieved complete remission (CR).
Early relapse (< 12 months) after complete remission; Late relapse (≥ 12 months) after complete remission with no response to one cycle of standard induction chemotherapy*.
Definition of bone marrow recurrence: If the percentage of blasts/immature lymphocytes in bone marrow smear is ≥ 5% and < 20%, evidence of molecular recurrence is required. In the absence of molecular recurrence evidence, at least two consecutive test results (both ≥ 5%) are required.
Failure to achieve remission after treatment with two or more lines of chemotherapy regimens*.
Two or more episodes of relapse.
Relapse after hematopoietic stem cell transplantation. * Remission criteria: CR and CRi for T-ALL; CR and PR for T-LBL. (6) At screening: ① Abnormal tumor cells are detected in bone marrow and/or peripheral blood by multi-color flow cytometry, regardless of the presence or absence of extramedullary lesions on imaging. Abnormal tumor cells in bone marrow must be CD7-positive; abnormal tumor cells in peripheral blood must be CD7-positive, CD4-negative and CD8-negative.
No abnormal tumor cells are detected in bone marrow and/or peripheral blood by multi-color flow cytometry, and imaging shows only extramedullary lesions (e.g. lymphadenopathy). Immunohistochemistry of lesion specimens must confirm CD7 positivity with a CD7 positive rate ≥ 70%.
(7) For subjects with only extramedullary lesions: lesions shall be evaluable (by PET-CT) or measurable (by contrast-enhanced CT) per the 2014 Lugano Criteria for efficacy assessment specified in Appendix 5.
(8) Liver, renal, cardiac and pulmonary function shall meet the following criteria:
① Total bilirubin ≤ 2 × ULN; ALT and AST ≤ 2.5 × ULN. If ALT/AST elevation is judged by the investigator to be caused by the underlying disease (e.g. liver infiltration or biliary obstruction), the upper limit may be extended to ≤ 5 × ULN. For subjects diagnosed with Gilbert's syndrome, total bilirubin ≤ 3.0 × ULN with direct bilirubin ≤ 1.5 × ULN.
Creatinine ≤ 1.5 × ULN.
Left ventricular ejection fraction (LVEF) ≥ 45%. ④ Oxygen saturation > 91%. (9) The subject and/or legal guardian fully understands this trial, has signed the informed consent form, and is willing and able to comply with scheduled visits, treatment regimens, laboratory tests and all other study requirements specified in the study schedule.
Exclusion Criteria:
(1) Patients judged by the investigator to require long-term use of immunosuppressants at screening.
(2) Cerebrovascular accident or seizure occurring within 6 months prior to signing the informed consent form.
(3) Uncontrolled graft-versus-host disease (GvHD) or ongoing requirement for systemic treatment for GvHD.
(4) History of other malignancies (other than T-ALL/LBL) within 5 years prior to screening, except for cured carcinoma in situ.
(5) Subjects with positive hepatitis B surface antigen (HBsAg) and abnormal peripheral blood hepatitis B virus (HBV) DNA titer; positive hepatitis B core antibody (HBcAb) with abnormal peripheral blood HBV DNA titer; positive hepatitis C virus (HCV) antibody coupled with positive peripheral blood HCV RNA; positive human immunodeficiency virus (HIV) antibody; positive cytomegalovirus (CMV) DNA; positive syphilis serology; positive Epstein-Barr virus (EBV) DNA.
(6) Severe cardiac diseases, including but not limited to unstable angina, myocardial infarction (within 6 months prior to screening), congestive heart failure (New York Heart Association [NYHA] Class ≥ III), and severe arrhythmia.
(7) Unstable systemic diseases as assessed by the investigator, including but not limited to severe hepatic, renal or metabolic diseases requiring medical treatment.
(8) Presence of chronic progressive neurological diseases. (9) Patients with unresolved acute toxicities from prior treatments. (10) Active or uncontrolled infections requiring systemic therapy (excluding mild genitourinary tract infections and upper respiratory tract infections).
(11) Female subjects of childbearing potential who plan to become pregnant within 2 years after cell infusion; male subjects whose partners plan to become pregnant within 2 years after cell infusion.
(12) Subjects who have received CAR-T therapy or other genetically modified cell therapies prior to screening.
(13) Participation in another clinical trial within 1 month prior to screening (calculated from the last administration of unapproved investigational products).
(14) Evidence of central nervous system (CNS) involvement identified at screening.
(15) Any other conditions deemed ineligible for enrollment by the investigator.
Zhuxiaofan@ihcams.ac.cn13752090418