Phase I study evaluating the combination of lapatinib (a Her2/Neu and EGFR inhibitor) and everolimus (an mTOR inhibitor) in patients with advanced cancers: South West Oncology Group (SWOG) Study S0528. Cancer Chemother Pharmacol 2013 Nov;72(5):1089-96
Date
09/24/2013Pubmed ID
24057042Pubmed Central ID
PMC4072025DOI
10.1007/s00280-013-2297-4Scopus ID
2-s2.0-84887187698 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
PURPOSE: Everolimus, an oral inhibitor of mammalian target of rapamycin, can augment the efficacy of HER inhibitors in preclinical studies. This study was conducted to determine the safety and pharmacokinetics (PK) of the combination of lapatinib, a Her1 and 2 inhibitor, and everolimus and to describe its anti-tumor activity in the Phase I setting.
METHODS: In Part I, dose escalation to define the maximum tolerated dose (MTD) was performed. In Part II, PK of both drugs were analyzed to assess drug-drug interaction.
RESULTS: Twenty-three evaluable patients with advanced cancers were treated on six different dose levels in Part I of the study. The dose-limiting toxicities were diarrhea, rash, mucositis, and fatigue. The MTD of the combination was 1,250 mg of lapatinib and 5 mg of everolimus once daily. In Part II of the study, 54 patients were treated with the combination at the MTD. The mean everolimus time to maximum concentration was increased by 44 %, and mean clearance was decreased by 25 % when co-administered with lapatinib, though these differences were not statistically significant. There was no significant influence on the PK of lapatinib by everolimus. Two patients achieved a partial response [thymic cancer (45+ months) and breast cancer (unconfirmed PR; 7 months)]; 11 patients attained stable disease of at least 4 months.
CONCLUSIONS: Lapatinib and everolimus are well tolerated at doses of 1,250 and 5 mg po daily, respectively. Stable disease ≥4 months/PR was achieved in 13 of 78 patients (17 %).
Author List
Gadgeel SM, Lew DL, Synold TW, LoRusso P, Chung V, Christensen SD, Smith DC, Kingsbury L, Hoering A, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Cohort Studies
Dose-Response Relationship, Drug
Drug Interactions
ErbB Receptors
Everolimus
Female
Humans
Incidence
Male
Middle Aged
Neoplasms
Protein Kinase Inhibitors
Quinazolines
Receptor, ErbB-2
Sirolimus
TOR Serine-Threonine Kinases
United States
Young Adult
