The goal of this Phase I/II, single arm, prospective, open label, dose escalation trial is to assess safety, feasibility and efficacy of ex vivo expanded autologous T cells genetically modified to express a T cell receptor (TCR) specific for dNPM1 peptides restricted to human leukocyte antigen (HLA) A\*02:01 in patients with relapsed or refractory AML.
The investigational medicinal product (IMP) MB-dNPM1-TCR.1 is designed to effectively target malignant myeloid cells in patients suffering from relapsed or refractory Acute Myeloid Leukemia (AML) with mutated Nucleophosmin. Autologous T cells will be genetically engineered using a lentiviral vector to express a T cell receptor (TCR) specific for certain dNPM1 peptides restricted to human leukocyte antigen (HLA) A\*02:01. The dNPM1-TCR transduced T cells target specifically the HLA/dNPM1 peptide complex on the cell surface of leukemic myeloid cells and eliminate these. During the treatment, the patients will undergo a leukapheresis, a lymphodepleting chemotherapy and an administration of the expanded dNPM1-TCR transduced T cells. Phase I: Since this is a first in human trial the primary goal in phase I is to establish the recommended dose of MB-dNPM1-TCR.1 for phase II. We assess the maximum tolerated dose (MTD) with toxicity defined as patients experiencing dose limiting toxicity (DLT) until day 28 after infusion of MB-dNPM1-TCR.1. Therefore a BOIN trial design will be used to guide dose escalation and de-escalation decisions in phase I. Phase II: The second phase will evaluate the efficacy and safety in patients treated with the recommended dose from phase I. The phase II part follows a Simon's 'minimax' two stage design.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
29
T Cell Receptor (TCR) T cell therapy
Leiden University Medical Center
Leiden, Netherlands
RECRUITINGPrimary endpoint Phase I
Maximum tolerated dose (MTD), as identified by a Bayesian Optimal Interval (BOIN) design at a target toxicity rate of 30%, with toxicity defined as patients experiencing dose limiting toxicity (DLT) until day 28 (week 4) after infusion of MB-dNPM1-TCR.1.
Time frame: day 28
Primary endpoint Phase II
BOR rate to the treatment with MB-dNPM1-TCR.1 assessed at any time within the first 3 months (12 weeks) after infusion as described above.
Time frame: week 12
Persistence
Percentage and total number of MB-dNPM1-TCR+ cells in peripheral blood and/or bone marrow over time.
Time frame: from day 6 to week 96
Best objective response (BOR)
Best objective response (BOR) during 12 weeks after infusion of MB-dNPM1-TCR.1. BOR is defined in relation to disease activity before thawing the leukapheresis for manufacturing (day -18 and -15).
Time frame: week 12
Overall survival (OS)
Overall survival (OS) defined as the time between the date of infusion of MB-dNPM1-TCR.1 and the date of death from any cause.
Time frame: up to week 96
Progression-free survival (PFS)
Progression-free survival (PFS) defined as the time between the date of infusion of MB-dNPM1-TCR.1 and the date of objective disease progression or death from any cause whichever occurs first.
Time frame: up to week 96
Duration of response (DOR)
Duration of response (DOR), defined as the time between the date of the first objective response (CRMRD- CR, CRi, MLFS, PR, SD) and the date of assessment of relapse or the date of death due to AML, whichever occurs first.
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Time frame: up to week 96
Safety and toxicity
Safety and toxicity assessment of MB-dNPM1-TCR.1 per (serious) adverse events ((S)AE) reporting.
Time frame: up to week 96
Feasibility to manufacture
Proportion of thawed apheresis products, from which MB-dNPM1-TCR.1 drug products are produced.
Time frame: Day 0