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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials

Timothy A Yap1,2, Naval Daver3, Mikhila Mahendra4

  • 1Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. TYap@mdanderson.org.

Nature Medicine
|January 19, 2023
PubMed

Insights

Targeting oxidative phosphorylation (OXPHOS) with IACS-010759 showed limited efficacy and significant neurotoxicity in cancer patients. Further research is needed to understand and mitigate OXPHOS inhibitor-related side effects.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Targeting oxidative phosphorylation (OXPHOS) is a promising anticancer strategy.
  • Clinical success with OXPHOS inhibitors remains limited.
  • IACS-010759 is a potent and selective inhibitor of mitochondrial complex I.

Purpose of the Study:

  • To evaluate the safety, tolerability, and preliminary efficacy of IACS-010759 in patients with relapsed/refractory acute myeloid leukemia and advanced solid tumors.
  • To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of IACS-010759.
  • To investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of IACS-010759.

Main Methods:

  • Two Phase I dose-escalation clinical trials (NCT02882321, NCT03291938) were conducted.
  • Patients with relapsed/refractory acute myeloid leukemia and advanced solid tumors received IACS-010759.
  • Safety, tolerability, PK, PD, and preliminary antitumor activity were assessed.

Main Results:

  • IACS-010759 exhibited a narrow therapeutic index with dose-limiting toxicities, including elevated blood lactate and neurotoxicity.
  • No RP2D was established due to toxicity and inability to maintain target exposure.
  • Modest target inhibition and limited antitumor activity were observed at tolerated doses.
  • Reverse translational studies in mice indicated IACS-010759-induced neurotoxicity, partly mitigated by a histone deacetylase 6 inhibitor.

Conclusions:

  • IACS-010759 demonstrated significant toxicity, primarily neurotoxicity, hindering its clinical development as an anticancer agent.
  • The development of complex I inhibitors requires careful consideration of their association with neurotoxicity.
  • Further research is necessary to understand and manage OXPHOS inhibitor-induced neurotoxicity.

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