Overview

This is an open-label, multi-cohort, investigator-initiated clinical study designed to evaluate the safety, tolerability, and preliminary efficacy of GI001 in adult patients with relapsed or refractory B-cell Non-Hodgkin Lymphoma (R/R B-NHL) and B-cell Acute Lymphoblastic Leukemia (R/R B-ALL).

GI001 is an exploratory, in vivo chimeric antigen receptor T-cell (CAR-T) therapy targeting the CD19 antigen. Unlike traditional CAR-T cell therapies that require extensive in vitro cell manufacturing, GI001 is administered directly to the patient via intravenous infusion, aiming to generate CAR-T cells directly within the patient's body.

The study consists of two main phases:

• Dose-Escalation Phase: This phase will evaluate four ascending dose levels to assess safety, identify any Dose-Limiting Toxicities (DLTs), determine the Maximum Tolerated Dose (MTD), and establish the Recommended Dose for Expansion (RDE). It utilizes an accelerated titration design for the initial doses, followed by a standard "3+3" dose-escalation design.
• Dose-Expansion Phase ： Once the RDE is identified, additional patients will be enrolled to further evaluate the safety, clinical efficacy, pharmacokinetics, and pharmacodynamics of GI001 at the selected dose(s).

The primary focus of the study is to continuously monitor adverse events and evaluate the overall safety profile. Secondary objectives include assessing clinical response rates (such as Objective Response Rate and Complete Response Rate), survival outcomes, and the expansion levels of CAR-T cells in the peripheral blood.

Eligibility

Inclusion Criteria:

1\. Age 18 to 75 years, inclusive.

• 2\. Diagnosis of CD19-positive relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) or R/R B-cell acute lymphoblastic leukemia (B-ALL):
• 2.1 CD19-positive R/R B-NHL meeting the following:
• Histopathologic diagnosis of indolent NHL (iNHL), including but not limited to follicular lymphoma (FL) and marginal zone lymphoma (MZL), or small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL); or aggressive B-cell lymphoma, including but not limited to diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed follicular lymphoma (TFL), and T-cell/histiocyte-rich large B-cell lymphoma (TCRBCL).
• Refractory disease defined as: (a) best response of progressive disease (PD) to first-line standard therapy, or stable disease (SD) after at least 4 cycles of first-line therapy with SD duration not exceeding 6 months after the last treatment; or (b) no response to second-line or later therapy, including best response of PD to the most recent therapy, or SD after at least 2 cycles of the most recent therapy with SD duration not exceeding 6 months after the last treatment; or (c) disease progression within 12 months after autologous hematopoietic stem cell transplantation (ASCT) or biopsy-confirmed relapse, or no remission or relapse (SD or PD) after salvage therapy following ASCT.
• Relapse defined as PD after achieving a response (partial response \[PR\] or complete response \[CR\]) to adequate prior therapy.
• Note: participants must have received adequate prior therapy; participants with CD20-positive disease must have failed or relapsed after anti-CD20 monoclonal antibody therapy.
• 2.2 CD19-positive R/R B-ALL meeting the following:
• Relapse defined as: (a) hematologic relapse: reappearance of blasts (\>=5%) in peripheral blood or bone marrow, or extramedullary disease, in a participant who had achieved CR; or (b) molecular relapse: reappearance of measurable residual disease (MRD) positivity after hematologic CR (HCR) and CR MRD negativity, with an increase in MRD level of \>=1 log between two positive specimens.
• Refractory disease defined as: (a) failure to achieve CR after at least 2 cycles of standard chemotherapy, or late relapse (\>=12 months) after CR with failure to achieve CR after at least 1 additional cycle; or (b) relapse after hematopoietic stem cell transplantation, or failure to achieve remission with the last therapy in participants receiving salvage therapy after HSCT; or (c) failure to achieve CR or relapse after at least 2 tyrosine kinase inhibitors (TKIs) (participants with TKI-resistance mutations such as T315I/A, V299L, F317L/V/I/C, G250E, Y253H, E255K/V, or F359V/C/I are not required to have received at least 2 TKIs), or intolerance to or contraindication for TKIs, in Philadelphia chromosome-positive (Ph+) B-ALL.
• 2.3 Participants who are not eligible for stem cell transplantation, or whose medical records document refusal of other available therapies, may also be enrolled.
• 3\. CD19 expression positivity confirmed by immunohistochemistry (IHC) or flow cytometry (FACS) on tumor specimen, bone marrow, or peripheral blood at screening.
• 4\. Measurable disease per Lugano 2014 criteria for B-NHL participants (nodal lesion LDi \> 1.5 cm, extranodal lesion LDi \> 1.0 cm); bone marrow blasts and immature lymphocytes \>=5% for B-ALL participants at screening.
• 5\. ECOG performance status 0 to 2.
• 6\. Expected survival \>=12 weeks.
• 7\. Adequate organ function meeting all of the following laboratory results before enrollment:
• Hematology: bone marrow reserve for R/R B-NHL participants must meet: absolute neutrophil count (ANC) \> 0.5 x 10\^9/L (no short-acting G-CSF within 7 days and no long-acting G-CSF within 14 days before testing); absolute lymphocyte count (ALC) \>= 0.5 x 10\^9/L; platelet count \>= 30 x 10\^9/L (no platelet transfusion within 7 days before testing); hemoglobin \>= 80 g/L (no red blood cell transfusion within 7 days before testing; recombinant erythropoietin permitted). All participants (B-NHL and B-ALL) require absolute CD3+ T cell count \>= 150/uL.
• Hepatic: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<= 3 x upper limit of normal (ULN); total serum bilirubin \<= 2 x ULN.
• Renal: creatinine clearance (CrCl) \>= 60 mL/min (Cockcroft-Gault formula).
• Coagulation: fibrinogen \>= 1.0 g/L; activated partial thromboplastin time \<= 1.5 x ULN; prothrombin time (PT) \<= 1.5 x ULN.
• Cardiac: left ventricular ejection fraction (LVEF) \>= 55%; oxygen saturation \> 91%.
• 8\. Therapeutic-dose steroids must be discontinued 72 hours before GI001 infusion (physiologic replacement-dose steroids are permitted).
• 9\. CNS disease prophylaxis (e.g., intrathecal methotrexate) must be discontinued 1 week before GI001 infusion.
• 10\. Participants and their partners agree to use effective barrier or pharmacologic contraception (excluding calendar/rhythm methods) from the time of informed consent through 1 year after GI001 administration.
• 11\. Written informed consent approved by the ethics committee must be obtained before initiating any screening procedures.

Exclusion Criteria:

1\. Prior antitumor therapy as follows (except agents proven to enhance CAR-T cell efficacy or not to affect CAR-T cells, after an appropriate washout period):

• Cytotoxic chemotherapy within 2 weeks before dosing.
• Small molecule targeted therapy within 2 weeks before dosing.
• Antibody therapy within 3 weeks before dosing.
• Pegylated asparaginase within 4 weeks before dosing.
• Immunosuppressive therapy within 4 weeks before dosing or requirement for long-term immunosuppression.
• Radiotherapy within 4 weeks before dosing.
• Bendamustine within 6 months before dosing.
• Prior treatment with any gene therapy product, including CAR-T therapy (except participants with no in vivo CAR-T, normal T cell count and function, and CD19-positive tumor).
• Prior treatment with any anti-CD19/anti-CD3 therapy or any other anti-CD19 therapy (except participants with normal T cell count and function and CD19-positive tumor).
• Other investigational drugs or other antitumor therapy within 4 weeks or 5 half-lives (whichever is shorter) before dosing.
• 2\. Other malignancy within 2 years before screening, excluding adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer after radical prostatectomy, ductal carcinoma in situ of the breast after radical surgery, and papillary thyroid carcinoma after radical treatment.
• 3\. History of solid organ transplantation.
• 4\. Use of immunomodulatory agents within 2 weeks before dosing, or likely use during the study, including but not limited to thalidomide, lenalidomide, and pomalidomide.
• 5\. Requirement for long-term therapeutic-dose corticosteroids (defined as prednisone or equivalent \> 15 mg/day); physiologic replacement, topical, and inhaled use are permitted.
• 6\. Prior or current CNS involvement or suspected CNS involvement: leukemia or lymphoma cells detected in cerebrospinal fluid (CSF); or imaging findings of mass, thickening, or enhancement in brain parenchyma, meninges, cranial nerves, or spinal cord supporting a diagnosis of CNS involvement; or neurologic signs or symptoms with abnormal CSF findings suggestive of CNS involvement.
• 7\. Hypertension not controllable with medication.
• 8\. Severe cardiac disease, including but not limited to: myocardial infarction within 6 months before screening; coronary artery bypass grafting or coronary stent placement within 6 months before screening; unstable angina; congestive heart failure (New York Heart Association class \>= III); severe arrhythmia; history of severe non-ischemic cardiomyopathy.
• 9\. Unstable systemic disease as judged by the investigator, including but not limited to severe hepatic, renal, or metabolic disease requiring medication.
• 10\. Uncontrolled active bacterial, fungal, viral, or other infection, or infection requiring intravenous anti-infective therapy (uncontrolled infection defined as persistent infection-related signs or symptoms without improvement after appropriate anti-infective therapy).
• 11\. Stroke, seizure, or other CNS disease unsuitable for this study within 6 months before screening; uncontrolled psychiatric disorder; or any medical or psychiatric history that in the investigator's judgment may increase the risk of study participation or dosing, or may interfere with study results.
• 12\. History of deep vein thrombosis or pulmonary embolism within 6 months before screening.
• 13\. Live vaccine within 6 weeks before screening.
• 14\. Major surgery within 2 weeks before screening, or planned surgery within 2 weeks after dosing (excluding surgery under local anesthesia).
• 15\. Pregnant or breastfeeding women, or women planning pregnancy during or after treatment.
• 16\. Non-hematologic toxicity from prior therapy not resolved to baseline or \<= grade 2 (excluding alopecia, fatigue, and peripheral neuropathy).
• 17\. Prior treatment with a therapeutic pseudotyped with vesicular stomatitis virus glycoprotein (VSVG) or Nipah virus.
• 18\. Positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb) with hepatitis B virus DNA (HBV-DNA) above the lower limit of detection; positive hepatitis C virus (HCV) antibody with HCV-RNA above the lower limit of detection; positive human immunodeficiency virus (HIV) antibody; or positive syphilis serology.
• 19\. Isolated extramedullary relapse of B-ALL.
• 20\. Hypersensitivity to the investigational drug or its excipients, or to tocilizumab.
• 21\. Primary immunodeficiency.
• 22\. Planned hematopoietic stem cell transplantation within 28 days after GI001 infusion.
• 23\. Any other condition that in the investigator's judgment makes the participant unsuitable for enrollment.