A first-in-human phase 1 study of LY3023414, an Oral PI3K/mTOR dual inhibitor, in patients with advanced cancer

Johanna C. Bendell, Anna M. Varghese, David M. Hyman, Todd M. Bauer, Shubham Pant, Sophie Callies, Ji Lin, Ricardo Martinez, Enaksha Wickremsinhe, Aaron Fink, Volker Wacheck, Kathleen N. Moore

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Purpose: The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414. Patients and Methods: A 3þ3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug–drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity. Results: Forty-seven patients with solid tumors received LY3023414 at once-daily (20–450 mg) or twice-daily dosing (150–250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with 90% target inhibition at doses 150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%. Conclusions: LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data.

Original languageEnglish (US)
Pages (from-to)3253-3262
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number14
DOIs
StatePublished - Jul 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'A first-in-human phase 1 study of LY3023414, an Oral PI3K/mTOR dual inhibitor, in patients with advanced cancer'. Together they form a unique fingerprint.

Cite this