WP4 Phase I/IIa clinical study with EURE-CART cell
Objectives of WP4
- To conduct a Phase I/IIa clinical study with EURE-CART cells in acute myeloid leukemia and multiple mieloma patients.
- To evaluate and manage potential early toxicities.
WP4 represents the central work package of EURE-CART, and will consist of the phase I/IIa clinical trial on acute myeloid leukemia (AML) and multiple myeloma (MM) patients. OSR, together with other EURE-CART clinical centres (UKW, PAU and UHO) will select chemorefractory patients with elevated CD44v6 expression on tumor cells. T cells from such patients will be retrieved and engineered in MLM GMP laboratories to express anti-CD44v6 CAR, and then reinfusedIn the first part of the study the maximum tolerated dose will be investigated (phase I). In case of dose-dependent side effects, patients will be given ganciclovir, capable of ablating CAR-T cell through activation of the thymidine kinase (TK) suicide gene machinery.After determining the maximum tolerated dose, OSR and other EURE-CART clinical centres (UKW, PAU and UHO), including the paediatric centre OPBG, will proceed to Phase IIa, whose objective is the early detection of anti-tumour activity. Peripheral blood will be studied at different time points for the presence of transduced cells.
The main project tasks are the following
Task 4.1 Patient treatment in EURE-CART Phase I.
Workflow: at OSR and at other adult EURE-CART clinical centres (UKW, PAU and UHO), patients (18-65 yrs) suffering from chemorefractory AML and MM will be screened for CD44v6 expression on tumour cells isolated from the bone marrow or the peripheral blood by FACS. In case of demonstrated expression (RFI: >2), patients will be evaluated at baseline for additional inclusion/exclusion criteria and eventually infused with autologous EURE-CART cells, following leukapheresis for PBMC procurement and lymphodepleting chemotherapy with cyclophosphamide and fludarabine. The aim of Phase I will be to determine the maximum tolerated dose (MTD). After CAR-T cell infusion, patients will be carefully monitored for vital signs for at least 72hrs. In case of any dose limiting toxicity (DLT), patients will be given ganciglovir (GCV) for CAR-T cell ablation through activation of the TK suicide gene machinery (Ciceri et al, Lancet Oncol 2009). Severe CRS will be managed with anticonvulsants, corticosteroids and the IL-6R antagonist tocilizumab and, in case of cardiovascular collapse, with vasopressors in the ICU. Screening, baseline and treatment procedures, as well as DLTs for EURE-CART Phase I will be reported on dedicated Case Report Form (CRFs; treatment sections) prepared and monitored by ACROmion.
Task 4.2 Patient treatment in EURE-CART Phase IIa.
Workflow: after determining the MTD, OSR and other EURE-CART clinical centres (UKW, PAU and UHO), including the paediatric centre OPBG, will proceed to Phase IIa, whose objective is the early detection of anti-tumour activity. To this aim, additional patients (1-65 yrs) will be treated at the MTD or at the maximal dose used in Phase I. The Phase IIa foresees the inclusion of paediatric patients, which is however conditional upon Data Safety Monitoring Board (DSMB) recommendations. The projections are that at least two patients will be treated at each centre. The primary efficacy endpoint measure will be the rate of haematological complete remission according to standard criteria at day 90 day post-infusion. Since another primary endpoint is EURE-CART cell engraftment, peripheral blood will be studied at different time points for the presence of transduced cells (see WP5, Task 1.1). Screening, baseline and treatment procedures, as well as DLTs for EURE-CART Phase IIa will be reported on dedicated CRFs (treatment sections) prepared and monitored by ACROmion.