Trial Underway for Potential First Treatment Option of Newly Diagnosed NPM1-Mutant AML

The first patient with NPM1-mutant acute myeloid leukemia (AML) was dosed in a phase 3 clinical trial of entospletinib in combination with anthracycline and cytarabine chemotherapy, which is the current standard of care. The combination will be given to patients with AML who are fit for intensive induction.

The trial is the first to use measurable residual disease (MRD) — or how much disease is detectable during or after treatment — as its primary goal. Other clinical trials have shown patients with this mutation who achieve MRD-negative complete response (CR) — as measured by molecule detection of mutant NPM1 alleles in bone marrow — following induction chemotherapy tended to survive longer than those who achieve CR with detectable MRD.

The results may also support an accelerated approval for entospletinib by the Food and Drug Administration (FDA) for this patient population and would be the first using MRD as the basis for approval in AML.

“Even with current therapies, about half of people newly diagnosed with NPM1-mutated AML will die from the disease within five years,” said Norbert Bischofberger, president and chief executive officer of Kronos Bio, which is the manufacturer of entospletinib, in a news release. “The use of the novel endpoint of MRD provides a pathway to potentially bring entospletinib to patients more quickly.”

The NPM1 mutation is present in roughly 30% of all adult patients with AML.

“Patients with NPM1-mutated AML are in need of better treatment options, and we are excited that we are the first center to begin treating a patient in this trial,” said Dr. Karamjeet S. Sandhu, assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope in Duarte, California, in the release.

The trial is also intended to be conducted at Mount Sinai Health System in New York and St. Francis Cancer Center in Greenville, South Carolina. Researchers plan to randomly dose 180 adult patients who are newly diagnosed and have NPM1-mutated AML, with results assessing the safety and efficacy of entospletinib.

Trial plans are for the patients to be assessed for remission and MRD status after two initial cycles of chemotherapy, though they may receive up to a total of five cycles. Event-free survival, or the length of time after that the patient remains free of certain complications, is a secondary goal, with mature data potentially being used to seek full approval of the drug.

The trial is based on previous findings from the phase 2 clinical data, which suggest that the NPM1 mutation leads to dependency on the signaling of spleen tyrosine kinase (SYK) — which is a non-receptor tyrosine kinase.

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