In a first-in-human phase I trial reported in the Journal of Clinical Oncology, Salamero et al identified toxicities and activity associated with iadademstat, an oral first-in-class lysine-specific histone demethylase 1A (LSD1) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (AML).

Study Details

The study enrolled 27 patients in a dose-escalation phase, with patients receiving iadademstat at 5 to 220 µg/m²/d on days 1 to 5 of each week in 28-day cycles. An additional 14 patients were treated in an extension cohort limited to patients with MLL gene rearrangements or erythroleukemia. Patients were enrolled between February 2014 and May 2016.

Key Findings

Serious adverse events possibly related to iadademstat were observed at a dose of 220 µg/m²/d in the dose-escalation cohort. The recommended dose for the extension cohort was 140 µg/m²/d.

Adverse events were as expected in patients with relapsed or refractory AML and included myelosuppression and nonhematologic adverse events; the most common nonhematologic adverse events of any grade were infection, gastrointestinal symptoms, hemorrhagic manifestations, asthenia, musculoskeletal pain, mucositis, edema, skin rash, and anorexia.

A total of six treatment-related grade 3 or 4 adverse events occurred in patients in the dose-escalation cohort, including fever of an unknown origin or neutropenic fever in one patient, thrombocytopenia in three, and neutropenia in two. A total of 10 treatment-related adverse events occurred in the extension cohort, including asthenia in 2 patients, anorexia in 2, fever of an unknown origin or neutropenic fever in 3, respiratory infection or pneumonia in 1, and thrombocytopenia in 2.

One patient exhibited complete remission with incomplete blood cell count recovery. Reductions in blood and bone marrow blast percentages were observed in several patients, along with induction of blast cell differentiation in some. Among five evaluable patients with an MLL gene rearrangement, four exhibited morphologic and molecular blast cell differentiation in blood or bone marrow, with the remaining patient exhibiting clearance of circulating blasts.

The investigators concluded: “Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with relapsed or refractory AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).”

Tim C.P. Somervaille, MBBS, PhD, of Cancer Research UK Manchester Institute, of The University of Manchester, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was supported by Oryzon Genomics and others. For full disclosures of the study authors, visit ascopubs.org.