Phase 3 Trial Initiated for Entospletinib in Patients With NPM1-mutated AML After Positive FDA Meeting

“As the first AML trial to use MRD negative CR as a primary endpoint, our trial is breaking new ground that may help deliver effective, targeted therapies more expeditiously to patients living with this devastating disease,” Bischofberger said.

Kronos Bio confirmed that the company will proceed with a phase 3 trial analyzing measurable residual disease (MRD)–negative complete response (CR) in patients receiving entospletinib to treat newly diagnosed NPM1-mutated acute myeloid leukemia (AML), according to a Kronos Bio press release.1

The company announced the plans after completing a positive end-of-phase 2 meeting with the FDA, with this phase 3 trial necessary to support a potential accelerated approval for entospletinib in this indication.

“Even with current therapies, about half of patients with newly diagnosed NPM1-mutated AML will die from the disease within five years,” Norbert Bischofberger, PhD, president and CEO of Kronos Bio, said in a press release. “Given this urgent need, we are pleased with the outcome of the FDA meeting and look forward to initiating our phase 3 trial to establish the benefit of entospletinib, in combination with chemotherapy, as a frontline treatment for NPM1-mutated AML.”

The randomized, double-blind, placebo-controlled trial will recruit approximately 180 adult patients with newly diagnosed NPM1-mutated AML to assess the safety and efficacy of entospletinib.

The trial will randomize the cohort of patients to receive either entospletinib or placebo for at least 2 cycles in combination with standard induction and consolidation chemotherapy.

The primary end point of the research is MRD-negative CR measured by next-generation sequencing (NGS). Measurement via NGS allows for a high degree of sensitivity to detect MRD. The focal secondary end points include event-free survival, with mature event-free survival data helping to support the pending approval of entospletinib.

“MRD has been used as a surrogate endpoint for approvals in other forms of leukemia but not for AML, in part due to the requirement for a unique marker that can be used to track rare residual leukemia cells. In the case of NPM1-mutated AML, the mutated gene itself provides that unique marker,” John Byrd, MD, professor at The Ohio State University Comprehensive Cancer Center and chief medical officer of the Leukemia & Lymphoma Society’s Beat AML Master Trial, said in a press release.

Entospletinib is a selective inhibitor that targets a critical node in a “dysregulated transcription regulatory network within AML” known as a spleen tyrosine kinase. The drug has already been investigated with over 700 patients and the clinical data from this research support further exploration of the therapy.

Recently reported results of the phase 1b/2 trial of entospletinib (NCT02343939) were reported in Clinical Cancer Research and showed that when added to intensive chemotherapy, the agent was well tolerated in patients with previously untreated de novo or secondary AML. Moreover, patients with mutations in NPM1 (n = 15) had a noticeably higher response rate than that of the whole patient population, at 87% and 70%, respectively.2

“The association between MRD negativity and improved survival in patients with NPM1-mutated AML is well established in the literature. Based on this body of evidence, AML experts around the world recommend monitoring MRD in patients with NPM1 mutation to guide treatment decisions,” said Byrd. “The best opportunity to achieve long-lasting remission and extend survival is to achieve MRD negativity with the first attempt at treatment.”


1. Kronos Bio Announces Positive End-of-Phase 2 Meeting with FDA for Entospletinib in Newly Diagnosed NPM1-mutated Acute Myeloid Leukemia (AML). News release. Kronos Bio. Published March 4, 2021. Accessed March 12, 2021.

2. Walker AR, Byrd JC, Blachly JS, et al. entospletinib in combination with induction chemotherapy in previously untreated acute myeloid leukemia: response and predictive significance of HOXA9 and MEIS1 expression. Clin Cancer Res. 2020;26(22):5852-5859. doi: 10.1158/1078-0432.CCR-20-1064