This is a phase I dose-finding trial of an autologous CD22 targeting chimeric antigen receptor (CAR)-T cell product, called CLIC-2201, for participants with relapsed/refractory B cell malignancies. In the proposed trial, eligible enrolled participants will undergo leukapheresis for autologous T cell collection to enable CLIC-2201 manufacturing, followed by lymphodepletion with cyclophosphamide and fludarabine, then intravenous infusion of the autologous CLIC-2201 product. The trial will use the 3+3 design to escalate or de-escalate the dose level of CLIC-2201 administered. Participants will be monitored for safety and tolerability up to day 365 following CLIC-2201 infusion.
The primary objective is to evaluate the safety and tolerability of CLIC-2201 and estimate the maximum tolerated dose (MTD) of CLIC-2201 in B-cell malignancies.
The secondary objectives are to evaluate the (i) feasibility; (ii) anti-tumour activity of CLIC-2201; (iii) and characterize the pharmacokinetic (PK) profile of CLIC-2201.
Exploratory objectives will include: i) characterizing the cellular and humoral immune responses against CLIC-2201 up to 1 year following infusion of CLIC-2201; (ii) characterizing the phenotype and gene expression profile of CLIC-2201 cells; (iii) evaluating immune and tumour cells at baseline and relapse for biomarkers of response or toxicity; (iv) evaluating serum cytokines, circulating tumour DNA (ctDNA) and B cell aplasia as biomarkers of clinical outcomes; and (v) assessing the quality of life.
Participants in the cohort A must be 18 years of age or older of age at time of informed consent.
Participants must provide written informed consent.
diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS),
high grade B cell lymphoma NOS,
Any uncontrolled or serious active infection at the time of enrolment.
Active autoimmune disease requiring immunosuppressive therapy within 4 weeks of enrolment.
Live vaccine ≤6 weeks prior to enrolment
Active Graft Versus Host Disease (GVHD) requiring systemic immunosuppressive therapy within 4 weeks of enrolment.
Single group
CLIC-2201
Biological/VaccineParticipants will undergo (a) lymphodepletion with cyclophosphamide and fludarabine, followed by (b) infusion of autologous CLIC-2201 CAR-T cells. All treatments will be delivered intravenously.
Defining the maximum tolerated dose (MTD) of CLIC-2201
The MTD will be measured by monitoring and recording the AEs experienced by the participant within the first 28 days after the infusion, including the treatment-related death as deemed by the investigator, grade 3 Cytokine Release Syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS), and Immune Effector Cell-Associated Hemophagocytic Lymphocytosis-Like Syndrome (IEC-HS) lasting for more than seven days; grade 4 CRS, ICANS, and IEC-HS; grade 4 non-hematologic toxicity that is not deemed related to CRS, ICANS, IEC-HS (except for Grade 4 transaminases and isolated, asymptomatic laboratory electrolyte abnormalities for seven days or more).
Proportion of participants who experienced any grade of CRS to define the safety of CLIC-2201
The safety will be measured by the proportion of participants who experienced any grade of CRS, ICANS, IEC-HS, any adverse events, and any severe adverse events.
Proportion of participants who experienced any grade of ICANs to define the safety of CLIC-2201
The safety will be measured by the proportion of participants who experienced any grade of CRS, any grade of ICANS, any adverse events, and any severe adverse events.
Proportion of participants who experienced any grade of IEC-HS to define the safety of CLIC-2201
The safety will be measured by the proportion of participants who experienced any grade of CRS, any grade of ICANS, any adverse events, and any severe adverse events.
Proportion of participants achieving achieving and/or maintaining Complete response (CR) or complete response with incomplete count recovery (CRi).
This would be used to measure the anti-tumour activities of the CLIC-2201 treatment within a year after the infusion. The complete response will be assessed on days 28, 90, 180, and 365. Response for lymphoma participants will be defined by Lugano criteria and for B-ALL participants by CIBMTR response criteria.
Proportion of participants with an overall response [achieving a CR or partial remission (PR)]
This would be used to measure the anti-tumour activities of the CLIC-2201 treatment within a year after the infusion.
Proportion of B-ALL participants with B with minimal residual disease (MRD) negative status by next-generation sequencing and/or high-resolution flow cytometry.
This would be used to measure the anti-tumour activities of the CLIC-2201 treatment within a year after the infusion. The partial remission will be assessed on days 28, 90, 180, and 365.
Overall survival rate
This would be used to measure the the anti-tumor activities of the CLIC-2201 treatment within 6 months after the infusion.
Serum cytokine levels before and after CAR-T cell infusion (Mesoscale)
This would be used to evaluate the biomarkers of CLIC-2201 treatment within 28 days after the infusion.
Proportion of participants with B-cell aplasia assessed by flow cytometry (BTNK panel)
This would be used to evaluate the biomarkers of CLIC-2201 treatment within a year after the infusion. This would be assessed on days 28, 60, 90, 180, and 365.
Measurement (quantitative and qualitative) of circulating tumour DNA in peripheral blood.
This would be used to evaluate the biomarkers of CLIC-2201 treatment within a year after the infusion.
Molecular profiling of tumour tissue to explore mechanisms of efficacy and resistance prior to CLIC-2201 infusion and on relapse.
This would be used to evaluate immune and tumour cells at baseline and relapse for biomarkers of response or toxicity of CLIC-2201 treatment.
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