First-in-human evaluation of the novel mitochondrial complex I inhibitor ASP4132 for treatment of cancer

Filip Janku, Patricia LoRusso, Aaron S. Mansfield, Rita Nanda, Alexander Spira, Tianli Wang, Amal Melhem-Bertrandt, Jennifer Sugg, Howard A. Ball

Research output: Contribution to journalArticlepeer-review


Background We assessed the safety, tolerability, and pharmacokinetics of mitochondrial complex 1 inhibitor ASP4132. Methods This phase I dose-escalation/dose-expansion study enrolled patients with treatment refractory advanced solid tumors to assess safety, dose-limiting toxicities (DLTs), efficacy and pharmacokinetic or oral ASP4132. Results Overall, 39 patients received ASP4132. Acceptable tolerability of ASP4132 5 mg in the first patient led to enrollment in the 10-mg dose cohort. After two DLTs at the 10-mg dose, additional patients were enrolled in the 5-mg cohort; a 7.5-mg cohort and two intermittent-dosing cohorts (ASP4132 10 mg for 3 days, then 4 days off; ASP4132 15 mg for 1 day, then 6 days off). ASP4132 5 mg was well tolerated; however, multiple DLTs such as fatigue, mental status changes, dizziness, lactic acidosis, enteritis, and posterior reversible encephalopathy syndrome were observed in higher dose cohorts (7.5-mg and intermittent 10-mg and 15-mg dose cohorts). Stable disease (+ 4 % to + 15 %) was observed in 8/39 (20.5 %) patients. ASP4132 plasma pharmacokinetics were characterized by high variability, with rapid absorption and accumulation from slow elimination. Conclusions ASP4132 showed limited clinical activity, and DLTs prohibited dose escalation. Further research is required to determine if DLTs will limit clinical activity of other mitochondrial complex I inhibitors. Clinical Trial ID ( NCT02383368, March 9, 2015.

Original languageEnglish (US)
Pages (from-to)1348-1356
Number of pages9
JournalInvestigational New Drugs
Issue number5
StatePublished - Oct 2021


  • ASP4132
  • Clinical trial, phase I
  • Lactic acidosis
  • Mitochondrial complex I inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)


Dive into the research topics of 'First-in-human evaluation of the novel mitochondrial complex I inhibitor ASP4132 for treatment of cancer'. Together they form a unique fingerprint.

Cite this