Therapy resistance remains the major obstacle to cure in many types of cancer. In particular in leukemia, therapy resistance depends on leukemic stem cells (LSC) that exhibit inherent therapy resistance to multiple drugs and contribute to overt leukemic relapse. Cellular therapies alone or in combination with other targeted or chemotherapeutic approaches can overcome drug mediated therapy resistance and induce long lasting remissions. Several trials have shown that adoptive transfer of allogeneic NK cells can induce clinical remission in patients with myeloid malignancies. In addition, the antileukemic efficacy of alloreactive NK cells has been shown to facilitate cure after T cell depleted haploidentical stem cell transplantation. Recently, it was demonstrated that absence of NKGD2 ligand expression on leukemic stem cells determines therapy resistance and immune escape towards NK cells in AML. PARP1 inhibitors can induce re-expression of NKG2D ligands. This phase I/II clinical trial will evaluate the combination of NK cell therapy and PARP inhibition by Talazoparib in patients with poor prognosis AML as characterized by Minimal Residual Disease (MRD) or overt relapse with less than 20% bone marrow blasts. The hypothesis that allogeneic NK cell therapy combined with PARP inhibition will increase the response rate (CR/CRi for relapsed/ refractory patients and MRD-response for MRD positive patients) from 35% to 60% will be tested. The co-primary endpoints are i) response to treatment defined as complete remission (CR) for patients with overt leukemia at time of inclusion and MRD decrease \>1log10 for patients with rising MRD at time of inclusion as well as ii) safety and feasibility of the protocol. Key secondary endpoints are event free survival and overall survival. Two cohorts will be assessed independently: patients with i) overt leukemia and ii) patients with rising MRD at time of inclusion. Safety and feasibility will be analyzed continuously during the entire trial. The NAKIP-AML trial will analyze efficacy and feasibility of NK cell transplantation together with PARP1 inhibition.
Patients with confirmed diagnosis of AML according to WHO-2016 (Arber, Orazi et al. 2016) (except acute promyelocytic leukemia) with either de novo AML, AML after preceding myelodysplastic or myeloproliferative syndrome (MDS/MPD), and therapy- related AML (t-AML) after previous cytotoxic therapy or radiation are eligible.
Patients who received at least one line of AML therapy. This is defined as either stem cell transplantation or intensive AML therapy or palliative AML therapy containing at least one of the following drugs Azacitidine, Decitabine, Cytarabine, Venetoclax or an FLT3 inhibitor..
Discontinuation of prior AML treatment before the start of study treatment for at least 107 days for cytotoxic agents and ≥ 53 half-lives for non-cytotoxic / investigational drug treatment preceding the first dose of trial medications.
Age ≥ 18 years
Acute promyelocytic leukemia (AML M3)
AML in which less than 10% of the blasts express the CD34 surface marker expression as analyzed at the local laboratory.
Known central nervous system manifestation of AML
Heart failure NYHA class 3 or 4
Single group
NK cells
Biological/VaccineNK cells will be given as a single intravenous infusion.
Talazoparib 1 MG [Talzenna]
DrugSubjects will receive treatment with Talazoparib capsules 1 mg/day (4 days) with subsequent intravenous NK cell infusion.
complete remission (CR/CRi)
response defined as complete remission (CR/CRi) for patients with overt leukemia at time of inclusion and MRD decrease \>1log10 for patients with rising MRD at time of inclusion.
EFS - Event-free survival
Event-free survival
RFS -Relapse-free survival
RFS is defined only for patients achieving CR or CRi
OS - Overall survival
Overall survival
MRD
Measurable Residual Disease
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