LY3023414

Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer

LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor targeting class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase, currently in clinical development. Here, we present results from a Phase 1, 3 + 3 dose-escalation study evaluating twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to assess the tolerability and safety of LY3023414, while secondary objectives included pharmacokinetics and preliminary antitumor activity.

A total of 12 patients were enrolled, receiving either 150 mg (n = 3) or 200 mg (n = 9) BID. Dose-limiting toxicities occurred in two patients at the 200 mg dose level, both experiencing Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea (41.7%), and decreased platelet count (41.7%), most of which were mild to moderate in severity. Grade ≥3 treatment-related AEs reported in at least one patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (each in 2 patients, 16.7%). Two patients discontinued treatment due to AEs (interstitial lung disease and stomatitis). No fatal events were observed.

Pharmacokinetic analysis revealed rapid absorption and elimination of LY3023414. Of the 12 patients, five achieved a best overall response of stable disease (150 mg: n = 3; 200 mg: n = 2), resulting in a disease control rate of 55.6%. These findings indicate that LY3023414 at doses up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.