SYNCAR-100 治疗急性淋巴细胞白血病：早期 I 期临床试验

Inclusion Criteria:

* 1.Aged 18 to 75 years (inclusive), of any gender.
* 2.Karnofsky Performance Status score ≥ 70.
* 3.Estimated life expectancy ≥ 12 weeks.
* 4.Positive CD19 expression on tumor cells confirmed by flow cytometry in bone marrow or peripheral blood.
* 5.Confirmed diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) by bone marrow examination, and meeting one of the following criteria:
* ① Refractory B-ALL: Failure to achieve complete remission (CR) after 2 courses of standard induction chemotherapy, or failure to achieve CR after first-line/multiline salvage chemotherapy.
* ② Relapsed B-ALL: Relapse within 12 months after the first remission, or relapse after first-line/multiline salvage chemotherapy.
* ③Relapse after autologous or allogeneic hematopoietic stem cell transplantation (HSCT).
* ④ For Philadelphia chromosome-positive (Ph+) patients: At least 2 lines of tyrosine kinase inhibitor (TKI) therapy have failed, or the patient is intolerant to TKI therapy, or the patient harbors the T315I mutation and is resistant to TKIs.
* 6.Proportion of blasts and immature lymphocytes in bone marrow \> 5% confirmed by bone marrow morphologic examination.
* 7.No prior hematopoietic stem cell transplantation (HSCT) within 6 months before enrollment.
* 8.Adequate organ function reserve, as defined by all of the following:
* ① Creatinine clearance (calculated by the Cockcroft-Gault formula) \> 60 mL/min: Male: Creatinine Clearance = \[(140 - Age) × Body Weight (kg)\] / \[0.818 × Serum Creatinine (μmol/L)\] Female: Creatinine Clearance = \[(140 - Age) × Body Weight (kg) × 0.85\] / \[0.818 × Serum Creatinine (μmol/L)\]
* ② Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 times the upper limit of normal (ULN) ; for patients with hepatic metastasis, AST and ALT ≤ 5 times the upper limit of normal (ULN) .
* ③Serum total bilirubin \< 1.5 times the upper limit of normal (ULN) ; for patients with Gilbert's syndrome, total bilirubin ≤ 3 times the upper limit of normal (ULN) .
* ④ Absolute lymphocyte count (ALC) ≥ 0.1 × 10\^9/L.
* ⑤Left ventricular ejection fraction (LVEF) \> 50% confirmed by echocardiography, with no clinically significant pericardial effusion on echocardiography.
* ⑥ No clinically significant pleural effusion.
* ⑦ Baseline peripheral oxygen saturation (measured at the fingertip) \> 92% while breathing room air.
* 9.For women of childbearing potential: Non-lactating; negative result of highly sensitive serum or urine pregnancy test during screening. All women of childbearing potential must use medically accepted contraceptive methods (e.g., intrauterine device, oral contraceptives) throughout the treatment period and for 2 years after the first treatment. For males of childbearing potential: Sperm donation is prohibited during the same period.
* 10.Ability to communicate effectively with investigators; willingness and ability to comply with the study protocol, complete all study-related procedures as required, and provide written informed consent (signed voluntarily by the patient or their legal guardian).

Exclusion Criteria:

* 1.Isolated extramedullary leukemia or isolated extramedullary relapse.
* 2.Central nervous system (CNS) involvement of leukemia at CNS2 stage.
* 3.A history of other malignant tumors, except for the following: cured non-melanoma skin cancer, carcinoma in situ of the uterine cervix, localized prostate cancer, superficial bladder cancer, ductal carcinoma in situ, or other malignant tumors with disease-free survival for more than 5 years.
* 4.Positive test results for any of the following infectious diseases: HIV; HCV; HBsAg; positive HBcAb with concurrent positive HBV DNA copy number; TPPA.
* 5.Administration of live or attenuated live vaccines within 4 weeks prior to enrollment.
* 6.Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with tyrosine kinase inhibitor (TKI) therapy within 1 week prior to enrollment.
* 7.Prior receipt of CD19-targeted therapy, CAR-T cell therapy, or other gene-edited T cell therapy.
* 8.Grade ≥2 acute graft-versus-host disease (GVHD) (per Glucksberg criteria) requiring treatment, or extensive chronic GVHD (per Seattle criteria) within 4 weeks prior to enrollment; or patients judged by the investigator to potentially require anti-GVHD therapy during the study period.
* 9.Comorbidities judged by the investigator to require systemic corticosteroid therapy or other immunosuppressive therapy during the study period; or receipt of allogeneic cellular therapy (e.g., donor lymphocyte infusion \[DLI\]) within 4 weeks prior to enrollment.
* 10.Receipt of CNS-directed radiotherapy within 4 weeks prior to enrollment.
* 11.Unresolved acute toxicities from prior therapy (excluding hematologic toxicities and alopecia) that have not recovered to Grade 1 or lower.
* 12.Known life-threatening hypersensitivity or other intolerance to the study drug, or a history of severe atopy.
* 13.Active autoimmune diseases (including but not limited to systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Hashimoto's thyroiditis, etc.), excluding hypothyroidism that is controllable solely with hormone replacement therapy.
* 14.Receipt of major surgery requiring general anesthesia within 4 weeks prior to enrollment; or failure to recover and achieve clinical stability from prior surgical treatment; or anticipated major surgery requiring general anesthesia during the study period.
* 15.Use of other investigational drugs within 28 days prior to enrollment.
* 16.A history of any unstable cardiovascular disease within 6 months prior to enrollment, including but not limited to unstable angina pectoris, myocardial infarction, heart failure (New York Heart Association \[NYHA\] Class ≥III), severe cardiac arrhythmias requiring pharmacologic treatment; or receipt of percutaneous transluminal coronary angioplasty, coronary stenting, or coronary artery bypass grafting within 6 months prior to enrollment.
* 17.A history of central nervous system (CNS) disease or disorders (e.g., seizure disorders, cerebral vascular ischemia/hemorrhage, dementia, cerebellar disease) or any autoimmune disease involving the CNS.
* 18.Uncontrolled active infection at screening (e.g., sepsis, bacteremia, fungemia, viremia).
* 19.Any other condition judged by the investigator to make the patient unsuitable for participation in this clinical study.

主要终点：Adverse events（AE） · Evaluated through laboratory investigations, 12-lead electrocardiography, and vital signs. · within 48 weeks post-dose
次要终点：Overall Response Rate（ORR）；Minimal Residual Disease（MRD）；Duration of Response（DOR）；Progression-Free Survival（PFS）；Overall Survival（OS）；Pharmacokinetics（PK）；Pharmacodynamics（PD）；Anti-Drug Antibody（ADA）

• SYNCAR-100 Treatment Group · EXPERIMENTAL · Weekly intravenous (IV) administration for 4 doses. The investigator and sponsor may determine the dosing interval and number of doses for subsequent dose cohorts based on the safety/tolerability, pharmacokinetic parameters, clinical efficacy and prior clinical study experience of the 0.02 mg/kg dose cohort.

The purpose of this study is to assess the safety, tolerability, and preliminary efficacy of SYNCAR-100 in patients with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Participants who have signed the informed consent form will undergo screening against the inclusion and exclusion criteria. Eligible participants will receive study drug administration once weekly for a total of four doses, followed by a 1-year safety and efficacy follow-up observation period. After the completion of the study, long-term follow-up may be required for participants to monitor their health and survival status until 15 years post-treatment, or until the occurrence of patient death, loss to follow-up, or withdrawal of consent.