This multicenter phase 1 trial with "3 + 3" dose escalation design seeks to examine the feasibility and safety of the administration of autologous T cells that have been modified through the introduction of chimeric antigen receptors targeting the B cell surface antigens CD19/20/22 following administration of a chemotherapy lymphodepletion regimen in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) or Non-Hodgkin's lymphoma (NHL). The overall goals of this study are to estimate maximum tolerated dose (MTD) level, establish the overall safety profile and evaluate initial efficacy of administering duo-CAR-T cell treatment in this patient population.
Ability of participant to understand this study, and participant willingness to sign a written informed consent
Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to the start of preparatory regimen
Patients with relapsed or refractory disease after allogeneic stem cell transplantation must be >100 days from HSCT to be eligible for study participation. Furthermore, post-HSCT immunosuppressive medications must be discontinued for at least 4 weeks prior to study entry
Prior CAR-T therapy is permissible if ≥ 3 months from therapy completion
Patients with CLL, Richter's transformation, and Burkitt lymphoma
Active CNS involvement by malignancy - CNS3 disease, i.e., patients with WBC count in CSF ≥5 and having blasts in the CSF in patients with ALL or detection of NHL on CSF by flow cytometry or active CNS involvement on imaging)
Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
Investigational medicinal product within the last 30 days prior to screening Note: Investigational therapies must not be used at any time while on study until the first progression following DuoCAR20.19.22-D95 CAR T infusion.
Sequential
DuoCAR20.19.22-D95
DrugPatient derived autologous T cells, lentiviral transduced to generate, using the Miltenyi CliniMACS Prodigy® closed transduction system, a Duo-CAR-T cells targeting cell surface antigens CD19/20/22.
Fludarabine (Conditional therapy)
DrugLymphodepletion chemotherapy
Cyclophosphamide (Conditional therapy)
DrugLymphodepletion chemotherapy
Maximum Tolerated Dose (MTD)
The MTD is defined as the dose level immediately below that in which ≥ 2/6 participants experience a dose limiting toxicity (DLT).
Recommended Phase 2 Dose (RP2D)
Determine using MTD and DLTs.
Safety: Incidence of Serious Adverse Events/Adverse Events
Toxicities of DuoCAR20.19.22-D95 in combination with preceding lymphodepleting chemotherapy regimen As measured with CTCAE v 5.0,
Treatment-related Mortality (TRM)
defined by the absence of progressive disease at the time of death.
Efficacy of DuoCAR 20.19.22-D95
Overall response rate defined by CR/PR rate as determined by WHO defined bone marrow results in ALL and the Lugano response criteria in B-cell NHL.
Safety related to DuoCAR20.19.22-D95
To assess long-term safety risks, per FDA guidelines pertaining to gene therapy, as measured by delayed adverse events of special interest potentially related to DuoCAR20.19.22-D95
Pharmacology (Expansion kinetics)
Expansion kinetics of DuoCAR20.19.22-D95 over time as measured by PCR and/or flow cytometry, WinNonlin 8.4
Manufacturing Feasibility of Miltenyi CliniMACS Prodigy (By number of participants)
To assess the Miltenyi CliniMACS Prodigy® closed transduction system for manufacturing feasibility of DuoCAR20.19.22-D95 throughout dose escalation and efficacy. For evaluation of feasibility, the number of participants which can successfully manufacture the targeted dose number will be determined and reported by dose level for the three enrollment groups.
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