title: A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors.
abstract: Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.
authors.affiliation: Division of Hematology/Oncology, University of North Carolina Lineberger Comprehensive Cancer Center, 3rd Fl. Physicians Office Building, CB7305, 170 Manning Drive, Chapel Hill, NC, 27599-7305, USA. juneko_grilley-olson@med.unc.edu.
authors.forename: J E
authors.initials: JE
authors.lastname: Grilley-Olson
authors.affiliation: University Health Network- Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada.
authors.forename: P L
authors.initials: PL
authors.lastname: Bedard
authors.affiliation: Unità Nuovi Farmaci e Terapie Innovative Dept. Medical Oncology 1Q-A Ospedale San Raffaele, IRCCS Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Fasolo
authors.affiliation: GlaxoSmithKline Plc, Collegeville, PA, USA.|RTP, Durham, NC, USA.|Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cornfeld
authors.affiliation: GlaxoSmithKline Plc, Collegeville, PA, USA.|RTP, Durham, NC, USA.|UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cartee
authors.affiliation: University Health Network- Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada.
authors.forename: A R Abdul
authors.initials: AR
authors.lastname: Razak
authors.affiliation: University Health Network- Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada.
authors.forename: L-A
authors.initials: LA
authors.lastname: Stayner
authors.affiliation: GlaxoSmithKline Plc, Collegeville, PA, USA.|RTP, Durham, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.affiliation: GlaxoSmithKline Plc, Collegeville, PA, USA.|RTP, Durham, NC, USA.|Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: R
authors.initials: R
authors.lastname: Greenwood
authors.affiliation: GlaxoSmithKline Plc, Collegeville, PA, USA.|RTP, Durham, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.affiliation: Division of Hematology/Oncology, University of North Carolina Lineberger Comprehensive Cancer Center, 3rd Fl. Physicians Office Building, CB7305, 170 Manning Drive, Chapel Hill, NC, 27599-7305, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Lee
authors.affiliation: Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bendell
authors.affiliation: Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: Unità Nuovi Farmaci e Terapie Innovative Dept. Medical Oncology 1Q-A Ospedale San Raffaele, IRCCS Scientific Institute, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Del Conte
authors.affiliation: Unità Nuovi Farmaci e Terapie Innovative Dept. Medical Oncology 1Q-A Ospedale San Raffaele, IRCCS Scientific Institute, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.affiliation: Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Infante
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011724:Pyridazines; D011728:Pyridones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011804:Quinolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D055815:Young Adult; D000096926:Benzenesulfonamides
chemical_list: D014408:Biomarkers, Tumor; D048369:MAP Kinase Kinase 1; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011728:Pyridones; D011744:Pyrimidinones; D011804:Quinolines; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C561454:omipalisib; D000096926:Benzenesulfonamides; C560077:trametinib; C546842:MTOR protein, human; C482125:MAP2K1 protein, human
keywords: GSK2126458; MEK inhibitor; PI3K inhibitor; Phase I clinical trial; Trametinib