FDA Lifts Partial Clinical Hold Placed on KOMET-001 Trial Examining KO-539 in AML

The FDA has lifted a partial clinical hold on the phase 1b KOMET-001 trial, which is evaluating KO-539 as a therapeutic option in patients with relapsed or refractory acute myeloid leukemia.

The FDA has lifted a partial clinical hold on the phase 1b KOMET-001 trial (NCT04067336), which is evaluating KO-539 as a therapeutic option in patients with relapsed or refractory acute myeloid leukemia (AML).1

The partial hold was placed on the trial in December 2021 after a report of a patient death from a serious adverse effect that was potentially associated with differentiation syndrome, a known toxicity that is observed with differentiating agents in the treatment of this disease.2

Patients who were enrolled to the trial at the time were permitted to continue to receive the agent, but no additional patients could enroll until the hold was resolved. Kura Oncology, Inc. also suspended guidance regarding the completion of enrollment to the phase 1b portion of the trial, as well as the determination of the recommended phase 2 dose (RP2D) of KO-539.

The recent decision to lift the hold follows an agreement that was made between the company and the regulatory agency to implement a mitigation strategy for differentiation syndrome.

“I am very proud of our team for working diligently with the FDA and site investigators to resolve the partial clinical hold in such a timely manner,” Troy Wilson, PhD, JD, president and chief executive officer of Kura Oncology, Inc., stated in a press release. “Activities to resume patient screening are underway, and we look forward to expediting enrollment of patients in the phase 1b study and determining the RP2D for KO-539 in the coming months.”

The first-in-human, open-label trial was launched to understand the safety, tolerability, and antitumor activity of the menin inhibitor KO-539 in patients with relapsed or refractory AML. The dose-escalation portion of the research followed an accelerated design, with dose selection by modified toxicity probability interval.2

Results showed that KO-539 monotherapy had encouraging activity in an all-comer population of patients with relapsed or refractory disease and in the subsets of patients who harbored NPM1 mutations and KMT2A rearrangements.

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).3 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 at a dose of 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).

The phase 1b portion of the trial comprises 2 expansion cohorts that will explore the agent at a lower dose of 200 mg, and a higher dose of 600 mg. The company plans to enroll 12 patients with NPM1-mutated or KMT2A-rearranged relapsed or refractory AML in each cohort and examine those patients for safety and tolerability, pharmacokinetics, and efficacy to identify the RP2D of KO-539.

“We continue to be encouraged by the safety, tolerability, and clinical activity observed among currently enrolled patients and look forward to sharing a comprehensive update on the phase 1 study at a future medical meeting,” Wilson added in the release.

At the 2021 ASH Annual Meeting, preclinical data spotlighted the molecular correlates linked with the activity of KO-539 against AML and suggested that pairing the menin inhibitor with targeted agents directed against BCL-2, BET, and CDK6 could result in superior efficacy against KMT2A-rearranged and NPM1-mutated disease.4

Specifically, KO-539 induced growth inhibition, differentiation, and loss of viability of AML cells with KMT2A rearrangements or NPM1 mutations in a dose-dependent manner. This was linked with the attenuation levels of MEIS1, FLT3, CDK6, BCL-xL, and BCL-2, as well as an upregulation in MCL1 and CD11b.

The agent also reduced mRNA expression of MLL1 target genes and to reduce their protein expressions in immune-phenotypically–characterized AML stem-progenitor cells. KO-539 destabilized and reduced Menin protein levels, which can be restored by coming the agent with carfilzomib (Kyprolis).

“At the 2021 ASH Annual Meeting, [data on] preclinical combinations of [KO-539] and various other standard-of-care agents in AML [were reported],” Naval Daver, MD, associate professor in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, told OncLive®. “As we have seen over the past 10 to 15 years with FLT3 inhibitors, and in the past 5 to 7 years with IDH inhibitors, although they work well on their own, you can almost double response rates if you combine them with the right agents, whether [that is with] venetoclax [Venclexta], azacitidine [Onureg], or chemotherapy.”

In 2019, the FDA granted an orphan drug designation to KO-539 for the treatment of patients with AML.5


  1. Kura Oncology receives FDA authorization to proceed with phase 1b study of KO-539 in acute myeloid leukemia. News release. Kura Oncology, Inc.; January 20, 2022. Accessed January 22, 2022. https://bit.ly/3FQTxzm
  2. Kura Oncology provides update on phase 1b study of KO-539 in acute myeloid leukemia. News release. Kura Oncology, Inc. November 24, 2021. Accessed January 22, 2022. https://bit.ly/31c5O2A
  3. Wang ES, Altman JK, Pettit KM, et al. Preliminary data on a phase 1/2A first in human study of the menin-KMT2A (MLL) inhibitor KO-539 in patients with relapsed or refractory acute myeloid leukemia. Blood. 2020;136(suppl_1):7-8. doi:10.1182/blood-2020-134942
  4. Davis JA, Fiskus WC, Daver N, et al. Clinical-stage menin inhibitor KO-539 is synergistically active with multiple classes of targeted agents in KMT2A-r and NPM1-mutant AML models. Blood. 2021;138(suppl 1):3357. doi:10.1182/blood-2021-149831
  5. Kura Oncology’s menin-MLL inhibitor KO-539 receives orphan drug designation from FDA for Treatment of acute myeloid leukemia. News release. Kura Oncology, Inc. July 24, 2019. Accessed January 22, 2022. https://bit.ly/3cYSpxt