NCT03769532

MRD-guided Treatment in NPM1mut AML Patients

MRD-guided Treatment With Pembrolizumab and Azacitidine in NPM1mut AML Patients With an Imminent Hematological Relapse

• Status: Terminated
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 26 (actual)
• Sponsor: Technische Universität Dresden · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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).

Detailed description

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.

Conditions

• Acute Myeloid Leukemia

Interventions

Type	Name	Description
DRUG	Pembrolizumab	Pembrolizumab (IMP): 200mg i.v. (fixed dose), every 3 weeks (Q3W), 8 doses
DRUG	Azacitidine	Azacitidine (SOC): 75 mg/m2 s.c., day 1-7 every 4 weeks (Q4W), 6 cycles

Timeline

• Start date: 2019-08-21
• Primary completion: 2025-02-13
• Completion: 2025-02-13
• First posted: 2018-12-07
• Last updated: 2025-08-24

Locations

10 sites across 1 country: Germany