Abstract CT310: First-in-man (FIM) pharmacodynamic (PD) and pharmacokinetic (PK) phase I trial of PQR309 in advanced solid tumors
Authors: Wicki Andreas , Sessa Cristiana , Childs Alexa , Stathis Anastasios , Hess Dagmar , Joerger Markus , von Moos Roger , Rodon Jordi , Hierro Cinta , Cmiljanovic Natasa , Bize Vincent , Berardi Simona , Xyrafas Alexandros , Kristeleit Rebecca 
Published: August 2015

Abstract
Background: PQR309 is a novel, oral, balanced pan-PI3K, mTORC1 and mTORC2 inhibitor. Preclinical experiments show promising anti-cancer activity. The primary objectives of this FIM trial of PQR309 were definition of maximal tolerated dose (MTD), and safety.
Methods: The trial was designed as an accelerated 3+3 study. Patients with advanced solid tumors with no standard management options were eligible. Dose-limiting toxicity (DLT) was defined as either grade 4 neutropenia &gt;7 days, febrile neutropenia, grade 4 thrombocytopenia, non-hematological toxicity of either grade 4, uncontrolled grade 3 &gt;7 days or dose-limiting grade 2, or treatment delay &gt;14 days. The DLT period was 21 days. Starting dose of PQR-309 was 10mg once daily (OD) continuously, based on preclinical data and a No observed adverse effect level (NOAEL) of 4 mg/kg in non-rodent species. The predefined dose levels were 10, 20, 40, 80, 120mg adjusted by dose banding method to the patient weight. Additional flat doses at 80 and 100 mg were investigated. The highest dose reached with this schedule was 150mg OD. Toxicities were assessed throughout dose escalation. 21 patients were included in the trial.
Results: No DLT has been observed to date. Drug-related adverse events (AE) included hyperglycemia, rash, loss of appetite, weight loss, nausea, diarrhea, and fatigue. The most common AE ≥ grade 3 was hyperglycemia in 5 patients. Blood sugar levels were manageable with oral antidiabetic drugs or insulin. Preliminary PK evaluation estimates a half-life of about 20 hours. Cmax and AUC show dose proportionality. Preliminary PD assessment of 16 phospho-proteins involved in PI3K and MAPK signaling in fresh-frozen tumor biopsies, indicates downregulation of p-Akt, pS6 and p4EPB from 40mg OD. In addition, moderate inhibition of p-Erk was also observed. This correlates with preclinical data. Preliminary signs of clinical anti-cancer activity include 1 patient with clear cell cancer of the Bartholin's gland experiencing stable disease for over 16 weeks. No DLT has been observed up to doses of 150mg OD. Based on these data, further dose escalation in this study will continue with intermittent dosing schedules. Trials of PQR309 in combination with other anti-cancer agents are planned.
Citation Format: Andreas Wicki, Cristiana Sessa, Alexa Childs, Anastasios Stathis, Dagmar Hess, Markus Joerger, Roger von Moos, Jordi Rodon, Cinta Hierro, Natasa Cmiljanovic, Vincent Bize, Simona Berardi, Alexandros Xyrafas, Rebecca Kristeleit. First-in-man (FIM) pharmacodynamic (PD) and pharmacokinetic (PK) phase I trial of PQR309 in advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT310. doi:10.1158/1538-7445.AM2015-CT310