Evaluation the safety and efficacy of Pembrolizumab (PEM) when administered in combination with standard Azacitidine (AZA) in nucleophosmin (NPM1) mutated AML patients with molecular relapse defined by the presence of measurable residual disease (MRD).
Azacitidine is an effective and well established therapy in patients with acute myeloid leukemia (AML). In fact, in previous measurable residual disease (MRD) triggered studies, azacitidine allowed for a delay towards an overt hematological relapse in the majority of patients. However, the majority of patients ultimately relapsed even though they received multiple cycles of preemptive therapy. Hypomethylating agents (HMA) can enhance antitumor immune responses by upregulating tumor antigene expression, class 1 major histocompatibility complex, and co-stimulatory molecules, while concurrently dampening this antitumor effect by upregulating expression of checkpoint receptors or ligands, including programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Upregulation of these immune checkpoint molecules might be a mechanism of resistance to hypomethylating drugs. It has been shown that PD-L1 Messenger ribonucleic acid (mRNA) is up-regulated acute myeloid leukemia cluster of differentiation 34 (CD34+) cells and importantly, patients resistant to treatment with hypomethylating agents such as azacitidine have an up-regulated expression compared to responding patients. In addition, it is known that PD-1 promoter demethylation correlates with a higher PD-1 expression and a worse response rate to hypomethylating agents as well as a shorter overall survival. In this context it is of note that PD-1 promoter demethylation can be caused by hypomethylating agents and hence the mode of action of the drug itself could cause resistance to therapy in these patients. This might also explain why hypomethylating agents are not curative and can not eradicate early leukemic progenitor cells. The investigators, therefore, perform a phase II trial evaluating a combination therapy of pembrolizumab and azacitidine in nucleophosmin (NPM1) mutated AML patients with MRD and impending hematological relapse after conventional chemotherapy. This trial aims at improving response rates observed with single agent azacitidine within the studies NCT00422890 and NCT01462578.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
26
Pembrolizumab (IMP): 200mg i.v. (fixed dose), every 3 weeks (Q3W), 8 doses
Azacitidine (SOC): 75 mg/m2 s.c., day 1-7 every 4 weeks (Q4W), 6 cycles
Klinikum Chemnitz
Chemnitz, Germany
Universitätsklinikum Dresden
Dresden, Germany
Universitätsklinikum Heidelberg
Heidelberg, Germany
Universitätsklinikum Jena
Jena, Germany
Proportion of event-free patients
Events are: * First hematological relapse after start of combined therapy * Death from any cause * AML-treatment other than Pembrolizumab and Azacitidine or hypomethylating agents only
Time frame: after 24 weeks of combination treatment (i.e. after up to 6 cycles of AZA for 7 days every 4 weeks and up to 8 PEM infusions every 3 weeks)
Overall survival (OS)
Overall survival is defined as the number of days between date of first visit (AZA) and date of death from any cause.
Time frame: through study completion, an average of 1 year
Proportion of event-free patients
For this endpoint apply the same definitions as for the primary endpoint.
Time frame: after 12 weeks of combined therapy
Treatment-related mortality
Any death without preceding hematologic relapse is considered to be treatment related.
Time frame: during 24 weeks of combined therapy
Course of MRD-burden measured as quantitative NPM1/Abelson murine leukemia viral oncogene homolog 1 (ABL) ratio
The NPM1/ABL-ratio will be log-transformed with base 10. With the log transformation a near normal distributed variable will be derived to be able to use parametric methods for analysis. Values below limit of detection (LOD) will be substituted by LOD/2 before log-transformation.
Time frame: through study completion, an average of 1 year
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Universitätsklinikum Leipzig
Leipzig, Germany
Kliniken Maria Hilf
Mönchengladbach, Germany
Klinikum r. d. I.
München, Germany
Universitätsklinikum Münster
Münster, Germany
Robert-Bosch-Krankenhaus
Stuttgart, Germany
Universitätsklinikum Würzburg
Würzburg, Germany