The FDA has placed a partial clinical hold on the phase 1b KOMET-001 trial, which is examining KO-539 in patients with relapsed or refractory acute myeloid leukemia.
The FDA has placed a partial clinical hold on the phase 1b KOMET-001 trial (NCT04067336), which is examining KO-539 in patients with relapsed or refractory acute myeloid leukemia (AML), according to a statement from the drug’s developer Kura Oncology, Inc.
The hold comes following a recent report of a patient death from a serious adverse effect (AE) that was potentially associated with differentiation syndrome, a known AE related to differentiating agents in the treatment of patients with AML. Patients currently enrolled on the study may continue to receive KO-539, but no additional patients may be enrolled until the hold is resolved.
Kura Oncology will also suspend guidance on the completion of enrollment in the phase 1b portion of the KOMET-001 study, as well as the determination of the recommended phase 2 dose of KO-539.
“We share the FDA’s commitment to patient safety, and we appreciate our ongoing dialogue as we work diligently to address their questions,” Troy Wilson, PhD, JD, president and chief executive officer of Kura Oncology, said in a press release. “Differentiation syndrome is known to be an on-target effect associated with therapeutic agents that induce differentiation, and we want to ensure physicians are fully informed and prepared to address these events if they occur. Based on the totality of preclinical and clinical data, we continue to believe that KO-539 has the potential to address the significant unmet medical need of AML patients, including those with NPM1 mutations and KMT2A rearrangements.”
The KOMET-001 study is a first-in-human, phase 1/2a study of the Menin-KMT2A (MLL) inhibitor KO-539 in patients with relapsed and refractory AML. The phase 1, dose-escalation portion followed an accelerated design, with dose selection by modified toxicity probability interval.2 The phase 2 dose-expansion portion included a cohort of patients with NPM1-mutant AML, as well as a cohort of patients with KMT2A/MLL-rearranged AML.
The primary end points of the phase 1 portion include safety and tolerability, determination of a recommended phase 2 dose and/or maximum-tolerated dose, pharmacokinetics, and early evidence of antitumor activity. In the phase 2 portion, primary end points include safety, tolerability, and antitumor activity.
In total, 12 patients were enrolled to 1 of 4 dosing cohorts; 50 mg (n = 1), 100 mg (n = 1), 200 mg (n = 6), and 400 mg (n = 4). Preliminary results from the study, which were presented at the 2020 ASH Annual Meeting, showed that among 8 evaluable patients, single-agent KO-539 demonstrated activity in 6 patients across dose levels. This included 3 patients receiving KO-539 at a dose of 200 mg, 1 at 400 mg, 1 100 mg, and 1 at a dose of 50 mg.
The clinical activity demonstrated in the 3 patients enrolled in the 200-mg dosing cohort included stable disease (n = 1), morphological leukemia-free state (n = 1), and complete response and minimal residual disease negativity (n = 1).
KO-539 was previously granted an orphan drug designation by the FDA in 2019 for the treatment of patients with AML.3