1. 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
- Author
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Lee-Anne Stayner, Yuehui Wu, G. Del Conte, Johanna C. Bendell, Rajeshwar Singh, Philippe L. Bedard, Albiruni Ryan Abdul Razak, Cornfeld Mark J, R. Greenwood, Leanne Cartee, Cristiana Sessa, Angelica Fasolo, Juneko E. Grilley-Olson, H. A. Burris, Carrie B. Lee, and J. R. Infante
- Subjects
Male ,0301 basic medicine ,Oncology ,MAP Kinase Kinase 1 ,Phases of clinical research ,Pharmacology ,0302 clinical medicine ,Neoplasms ,Tissue Distribution ,Pharmacology (medical) ,Phosphoinositide-3 Kinase Inhibitors ,Trametinib ,Sulfonamides ,TOR Serine-Threonine Kinases ,MEK inhibitor ,Middle Aged ,Prognosis ,Rash ,Pyridazines ,Survival Rate ,Tolerability ,030220 oncology & carcinogenesis ,Quinolines ,Drug Therapy, Combination ,Female ,medicine.symptom ,Adult ,medicine.medical_specialty ,Maximum Tolerated Dose ,Pyridones ,Pyrimidinones ,Article ,Young Adult ,03 medical and health sciences ,Pharmacokinetics ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Dosing ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,Neoplasm Staging ,business.industry ,030104 developmental biology ,business ,Follow-Up Studies - 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.
- Published
- 2016