BP-U-004, Phase I/II study of CaspaCide T cells from an HLA-partially matched family donor after negative selection of TCR αβ+T cells in pediatric patients affected by hematological disorders

Trial Design This is a phase 1/2 multi-center, open label study. The Phase 1 trial design consists of 3 cohorts, receiving escalating doses of BPX-501 of 2.5 x 105, 5 x105, and 1x106 cells/kg, respectively. Dose escalation will occur according to a 3+3 design. if none of the initial 3 patients in a cohort experiences a dose-limiting toxicity, another 3 patients will be treated at the next higher dose level. if one of the first three patients experiences a dose limiting toxicity (DLT), three more patients will be treated at the same dose level. Dose escalation will continue until at least 2 patients in a cohort of 3 to 6 patients experience dose limiting toxicities. a Phase 2 extension will occur after dose escalation, enrolling at the highest tolerated dose for a maximum of 60 pediatric patients total, enrolled over 36 months and the minimum active study follow-up for each patient will be 2 years. The maximum duration of the active study period will be approximately 5 years. Phase 1 primary end-points 1. To evaluate the safety of infusion of BPX-501 at 3 different escalating doses (2.5 x 105/kg, 5 x 105 and 1 x 106cells/kg recipient ideal body weight) to be administered within 21 + 14 days after transplantation of partially mismatched T cell depleted hematopoietic stem cell transplant (HSCT). To determine the pediatric maximum tolerated and/or recommended phase 2 dose of BPX-50. 2. To evaluate the safety of the infusion of dimerizer drug, aP1903, to subjects who received BPX 501 and have developed Grade iii-iV acute Graft Versus Host Disease (GVHD), as well as to those subjects with Grade ii gut/liver acute GVHD or with Grade i/ii acute GVHD (skin only) who progress or do not respond within 7 days to standard of care treatment. 3. To determine the optimal dose of BPX-501 resulting in improved immune reconstitution without a significant impact on incidence on GHVD Phase 2 primary end-points 1. To demonstrate the safety of the approach, using the Maximum Tolerated Dose (MTD) defined during the phase i portion of the study; 2. To maintain the cumulative incidence of non-Relapse Mortality (nRM) at 180 days and 1 year of subjects given the MTD defined during the phase i portion of the study comparable to that of the historical cohort of patients given the alpha/beta T-cell depleted HSCT without any T-cell add-back (i.e., below 10%). Phase 1 and 2 secondary end-points 1. Disease-free survival rates after transplantation; 2. Cumulative incidence of relapse; 3. Cumulative incidence of neutrophil and platelet engraftment; 4. Kinetics of donor cell engraftment; 5. Cumulative incidence of both primary and secondary graft failure; 6. Cumulative incidence and severity of acute and chronic GVHD; 7. Time to resolution of acute GVHD after administration of aP1903 8. Rates of infectious complications, with particular regards to HCMV reactivation or other viral or invasive fungal infections. in detail, we will estimate the rate of subjects experiencing any HCMV reactivation, as well as that of subjects who will need antiviral treatment because of a clinically significant viral load increase; 9. Duration of hospitalization and rehospitalization; 10. T-cell immune reconstitution (time to reach an alpha/beta positive, on day 180, as measure by CD3+, CD4+, and CD8+ cell counts); 11. Research evaluations of T cell function will include some or all of the following: diversity of T cell receptor repertoire, virus-specific immunity, quantitation of CD4 and CD8 subsets and response to polyclonal activators or nominal antigens will be the objective of ancillary biological studies; 12. Rehospitalization due to viral infection.