Abstract CT205: A phase I dose-escalation study of trametinib (T) in combination with continuous or intermittent GSK2126458 (GSK458) in patients (pts) with advanced solid tumors
Authors: Bedard Philippe L. , Grilley-Olson Juneko E. , Cornfeld Mark , Cartee Leanne , Warwick Susan , Razak Albiruni A.R. , Stayner Lee-Anne , Wu Yuehui , Greenwood Rebecca , Viana-Gilmartin Veronica , Lee Carrie B. , Bendell Johanna , Burris Howard A. , Gianni Luca , Sessa Cristiana , Infante Jeffrey R. , Fasolo Angelica 
Published: May 2015

Abstract
Objectives: The primary objectives were to assess safety, tolerability and the maximum tolerated dose (MTD) for the combination of the PI3K/mTOR inhibitor GSK458 and the MEK inhibitor T.
Methods: Pts with selected advanced solid tumors enriched for MAPK and PI3K pathway alterations, ECOG PS 0/1, with no history of diabetes, retinopathy or uncontrolled CNS disease were eligible. Three dosing schedules were evaluated: continuous (cont) once daily (QD) GSK458 and T; cont twice daily (BID) GSK458 and QD T; and intermittent (int) BID GSK458 (4 days on/10 days off) and cont QD T. Dose escalation followed a 3+3 design with dose limiting toxicity (DLT) evaluation during the first 28 days (NCT01248858).
Results: From Dec/10-Oct/13, 69 pts were enrolled. The most frequent tumor types were colorectal (CRC) 29%, breast 16%, non-small cell lung (NSCLC) 10%, and pancreas 10%. A total of 12 dose levels were explored and 8 pts experienced DLTs that were reversible (Table). The MTD was exceeded at 0.5mg QD GSK458/2.0mg QD T and 0.5mg BID GSK458/1.5 mg QD T. Dose escalation was stopped before the MTD was defined for int GSK458 dosing because the tolerability of the combination was not improved. The most commonly reported drug-related AEs (≥20%) included rash 72%, diarrhea 54%, vomiting 33%, fatigue 30%, decreased appetite 23%, and stomatitis 22%, with dose interruptions for 51% of pts treated. No RECIST responses were observed. Stable disease &gt;22 weeks occurred in 7 pts (KRASmt CRC, ocular melanoma, renal cell, KRASmt ovary (2), KRASmt small bowel, and KRASmt NSCLC).
Conclusion: The MTDs of cont QD dosing are 1.0mg GSK458/1.5mg T and 2.0mg GSK458/1.0mg T. Tolerability of the combination was limited by rash, GI toxicity, fatigue and anorexia. A recommended phase 2 dose and schedule was not defined despite exploring alternative schedules including twice daily and intermittent dosing of GSK458. No further clinical development of the combination is planned.
CohortGSK458TDLT(s)/EvaluableDLT event(s)10.5mg QD0.5mg QD0/320.5mg QD1.0mg QD0/431.0mg QD0.5mg QD0/440.5mg QD1.5mg QD0/551.0mg QD1.0mg QD1/6G2 folliculitis61.5mg QD1.0mg QD1/8G3 diarrhea70.5mg QD2.0mg QD3/5G3 stomatitis; G3 hypertension & G1 elevated troponin; G3 hypophosphatemia & G2 diarrhea82.0mg QD1.0mg QD0/691.0mg QD1.5mg QD0/7100.5mg BID1.5mg QD2/6Asymptomatic20% decrease LVEF; G3 mucositis110.5mg BID int1.5mg QD1/7G3 central serousretinopathy120.75mg BID int1.5mg QD0/5
Citation Format: Philippe L. Bedard, Juneko E. Grilley-Olson, Mark Cornfeld, Leanne Cartee, Susan Warwick, Albiruni A.R. Razak, Lee-Anne Stayner, Yuehui Wu, Rebecca Greenwood, Veronica Viana-Gilmartin, Carrie B. Lee, Johanna Bendell, Howard A. Burris, Luca Gianni, Cristiana Sessa, Jeffrey R. Infante, Angelica Fasolo. A phase I dose-escalation study of trametinib (T) in combination with continuous or intermittent GSK2126458 (GSK458) in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT205. doi:10.1158/1538-7445.AM2014-CT205