Abstract 2287: Final results of the pharmacodynamic (PD) data of PQR309-001, a first-in-human trial of a combined PI3K/mTOR inhibitor in advanced solid tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.2287-2287
• Main Authors: Wicki, Andreas, Prêtre, Vincent, Ritschard, Reto, Brown, Nicholas, Bize, Vincent, Fabbro, Thomas, Cmiljanovic, Natasa, Dimitrijevic, Sasa, Schmitz, Deborah, Stumm, Michael, Kristeleit, Rebecca
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-2287

Background: PQR309 is a novel, oral, balanced pan-class 1 PI3K, mTORC1 and mTORC2 inhibitor. PQR309-001 was a first-in-man dose escalation study evaluating PQR309 in patients with advanced solid tumours. The primary objective of the study was to establish the maximum tolerated dose (MTD) of PQR309, its safety and tolerability. Secondary objectives included characterization of PQR309 pharmacokinetics (PK) and pharmacodynamics (PD). Methods: We investigated PQR309 treatment-induced PD, including changes of 16 PI3K-mTOR and MAPK associated phospho-proteins, and 84 mRNAs in serial tumor biopsies obtained from patients enrolled in study PQR309-001. 13 patients were eligible for PD analysis after histologic evaluation of fresh-frozen tissue. A solid-phase assay with phospho-specific antibodies was used for the investigation of PI3K/mTOR and MAPK signalling. RNA analysis was performed with an RTK/PI3K-specific RNA array. Results: Under treatment with PQR309, phospho-Akt (p_T308 and p_S473), phospho-mTOR and phospho-S6 were significantly downregulated compared to baseline (p