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.
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.
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.
Sequential
GI001
Biological/VaccineGI001 is an in vivo CD19-targeted CAR-T therapy. It is a lentiviral vector-based product using a third-generation self-inactivating lentiviral vector system with a five-plasmid packaging design. GI001 is administered by intravenous injection and delivers the CD19 CAR gene directly into the patient, reprogramming the patient's own T cells in situ to express CD19 CAR without ex vivo cell manufacturing. No lymphodepleting conditioning is required, and a single injection is given. GI001 is supplied as a colorless to slightly opaque liquid, 1 mL per vial, stored at -70 +/- 10 degrees C. Infusion duration does not exceed 2 hours. Dose levels evaluated in this study are 3.5x10\^8 TU, 7.0x10\^8 TU and 1.0x10\^9 TU (TU = transducing units). Recommended premedication is intramuscular promethazine 25 mg or diphenhydramine 20 mg given 15-30 minutes before infusion. Dose modification is not permitted (a +/-20% dose range is acceptable).
Incidence and severity of adverse events (AEs)
Incidence, severity, seriousness, and relationship to GI001 of treatment-emergent adverse events and serious adverse events. Severity graded per NCI CTCAE v6.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) graded per ASTCT 2019 consensus criteria; immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) graded per ASTCT 2023 criteria.
Change from baseline in body temperature
Change from baseline in body temperature, measured in degrees Celsius, at each scheduled post-dose assessment.
Percentage of participants with dose-limiting toxicities (DLTs)
Percentage of participants in the DLT analysis set who experience at least one protocol-defined DLT within 28 days after GI001 administration. The analysis set includes participants who complete DLT assessment or experience a DLT during the assessment period. DLTs are treatment-related toxicities defined in Protocol Section 4.1.4, including qualifying cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, infusion-related hypersensitivity, non-hematologic toxicities, neutropenia with severe infection, thrombocytopenia with qualifying bleeding, and grade 5 toxicity. Protocol-specified severity thresholds, recovery criteria, and exclusions apply. The number and percentage of participants with DLTs will be summarized.
Maximum tolerated dose (MTD)
The highest GI001 dose level, expressed in transducing units (TU), at which no more than 1 of 6 evaluable participants experiences a protocol-defined dose-limiting toxicity (DLT) during the 28-day observation period after administration. If only 3 participants have been enrolled at the candidate MTD, 3 additional participants are enrolled for confirmation. The MTD is determined from the dose-escalation cohort data.
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