Safety, tolerability?and antitumour activity of LY2780301 (p70S6K/AKT inhibitor) in combination with gemcitabine in molecularly selected patients with advanced or metastatic cancer: a phase IB dose escalation study

摘要

Abstract Background LY2780301, a dual inhibitor of protein kinase B (AKT) and the downstream effector p70 ribosomal protein S6 kinase (p70S6K), may inhibit progression in tumours relying on phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway activation. This phase IB trial investigated the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK) and antitumour activity of LY2780301 plus gemcitabine in patients with advanced/metastatic solid tumours. Methods This was a non-randomised, open-label, dose escalation and dose expansion trial. Patients harbouring molecular alterations of the PI3K/AKT/mTOR pathway received once daily (QD) oral LY2780301 (400 or 500?mg) in combination with intravenous gemcitabine (750 or 1000?mg/m 2 ) on days 1, 8?and 15 of a 28-d?cycle. Dose escalation followed a 3?+?3 design. Assessments included adverse events (AEs), PK and preliminary antitumour activity. Results Fifty patients (median age, 53 years; 74% female) predominantly with mutations/amplifications of PI3K (60%) and phosphatase and tensin homologue (PTEN) gene/protein inactivation (42%) were treated for up to 14 cycles. The MTD was LY2780301 500?mg QD with gemcitabine 750?mg/m 2 . DLTs during cycle 1 were grade IV thrombocytopenia, grade III skin rash?and grade III increase in alkaline phosphatase, gamma glutamyltransferase?and alanine aminotransferase, occurring in one patient each. Most common AEs were anaemia (84%), fatigue (84%), transaminase increase (74%), thrombocytopenia (74%), nausea/vomiting (70%), neutropenia (68%)?and lymphopenia (56%). Among the efficacy-evaluable population, two patients (5%) had a partial response; the disease control rate was 74% at cycle 2. Conclusions Addition of LY2780301 to gemcitabine showed manageable toxicity and encouraging antitumour activity in patients with molecular alterations of the PI3K/AKT/mTOR pathway. Clinical trial registration number NCT02018874. Highlights ? LY2780301, an oral dual p70S6K/AKT inhibitor, is assessed in advanced solid tumours. ? In molecularly selected patients, LY2780301 plus gemcitabine was tolerable. ? LY2780301 plus gemcitabine shows encouraging antitumour activity.