Phase I/IIA open-label study presents encouraging results on hard-to-treat AML subtypes

Novel menin-KMT2A inhibitor appears to be safe and well-tolerated. FLT3 inhibitor plus low-dose chemotherapy shows promising efficacy and safety. Results represent encouraging news on hard-to-treat AML subtypes.

Eunice Wang, MD, Chief of Leukemia and Director of Infusion Services at Roswell Park Comprehensive Cancer Center, is leading multiple research efforts focused on different treatment approaches for acute myeloid leukemia (AML) patients.

Today, during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, which is being held virtually, she is presenting data on two ongoing studies incorporating new treatment options.

KOMET-001 (NCT04067336) is an ongoing phase I/IIA open-label study evaluating KO-539, a once-daily oral drug, in adult AML patients at Roswell Park and select other sites in the U.S. and Europe. KO-539 is a novel experimental inhibitor of the menin-KMT2A complex, which is dysregulated in acute leukemias characterized by rearrangements in the MLL gene and mutations in the NPM1 gene.

The phase I dose-escalation aims to assess safety and tolerability, characterize the pharmacokinetics, and determine a recommended phase II dose. Researchers will examine anti-leukemic activity, pharmacokinetics, safety and tolerability in patients with select genetic subtypes of AML during the phase IIA dose expansion.

"Preliminary results demonstrate that the drug appears to be safe and well-tolerated in adult patients with relapsed/refractory AML failing 3-7 prior lines of therapy," says Dr. Wang. "None of 12 patients treated to date have discontinued therapy due to toxicity. Moreover, six of eight evaluable patients to date have shown some evidence of anti-leukemic activity, with two individuals achieving complete remissions on therapy. This promising trial continues to enroll."

Dr. Wang will also present early findings from the randomized, multicenter, open-label phase III LACEWING study exploring the efficacy of gilteritinib, a FLT3 inhibitor, combined with low-dose chemotherapy compared to low-dose chemotherapy alone. Eligible patients include those with newly diagnosed FLT3 mutant AML who are considered unfit for intensive chemotherapy.

The primary objective of this study was overall survival. Secondary endpoints included event-free survival, best response, remission rates and duration, transfusion conversion and maintenance rates, leukemia-free survival, patient-reported fatigue, and safety/tolerability.

Patients in an initial safety cohort received gilteritinib (80-120 mg daily) plus the low-dose chemotherapy azacitidine. Mature data presented today show that 10 of 15 patients (67%) achieved a complete response or complete response, with incomplete count recovery on therapy with a median overall survival of 10.4 months.

The adverse events observed by researchers were hematologic and no new safety signals have been associated with gilteritinib (120 mg daily) when combined with azacitidine.

Enrollment in the randomized portion of the LACEWING trial is ongoing, with 136 of 250 anticipated patients accrued to date. Patients in this group will be randomized 2:1 to receive oral gilteritinib in combination with azacitidine. Based on data from the safety cohort, patients will receive a gilteritinib dose of 120 mg daily alongside low-dose chemotherapy.

It's encouraging to see signals of efficacy and evidence of good tolerability in these emerging treatment options, especially for subgroups of patients with AML whose cancers have been especially resistant to other therapies."

Eunice Wang, MD, Chief of Leukemia and Director of Infusion Services, Roswell Park Comprehensive Cancer Center

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