Αρχειοθήκη ιστολογίου

Τρίτη 10 Απριλίου 2018

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

Purpose: The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (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.  Experimental Design: A 3+3 dose escalation for QD and BID 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 (PK)/pharmacodynamics, and antitumor activity. Results: Forty-seven patients with solid tumors received LY3023414 at QD (20-450 mg) or BID dosing (150-250 mg). Dose-limiting toxicities were observed at 450 mg QD (thrombocytopenia, hypotension, hyperkalemia) in 3/3 patients, 250 mg BID dosing (hypophosphatemia, fatigue, mucositis) in 3/4 patients, and in 1/15 patients at 200 BID mg (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 an endometrial cancer patient harboring PIK3R1 and PTEN truncating mutations and 13 additional patients (28%) had 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 BID based on safety, tolerability, and PK/Pharmacodynamic data.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader https://ift.tt/2IJAPwy

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