TY - JOUR
T1 - A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors
AU - Soria, J. C.
AU - Gan, H. K.
AU - Blagden, S. P.
AU - Plummer, R.
AU - Arkenau, H. T.
AU - Ranson, M.
AU - Evans, T. R.J.
AU - Zalcman, G.
AU - Bahleda, R.
AU - Hollebecque, A.
AU - Lemech, C.
AU - Dean, E.
AU - Brown, J.
AU - Gibson, D.
AU - Peddareddigari, V.
AU - Murray, S.
AU - Nebot, N.
AU - Mazumdar, J.
AU - Swartz, L.
AU - Auger, K. R.
AU - Fleming, R. A.
AU - Singh, R.
AU - Millward, M.
N1 - Publisher Copyright:
© 2016 European Society for Medical Oncology
PY - 2016/12/1
Y1 - 2016/12/1
N2 - This paper presents results from the phase I study of the focal adhesion kinase inhibitor GSK2256098 in patients with advanced solid tumors. The MTD was identified as 1000 mg, oral BID. Treatment with GSK2256098 showed a good tolerability, evidence of target engagement, and clinical activity in patients with recurrent, merlin-negative mesothelioma. Background: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. Patients and methods: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. Results: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21–84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1–2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4–9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (−26%) and three patients with mesothelioma (−13%, −15%, and −17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). Conclusions: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.
AB - This paper presents results from the phase I study of the focal adhesion kinase inhibitor GSK2256098 in patients with advanced solid tumors. The MTD was identified as 1000 mg, oral BID. Treatment with GSK2256098 showed a good tolerability, evidence of target engagement, and clinical activity in patients with recurrent, merlin-negative mesothelioma. Background: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. Patients and methods: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. Results: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21–84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1–2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4–9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (−26%) and three patients with mesothelioma (−13%, −15%, and −17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). Conclusions: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.
KW - focal adhesion kinase
KW - merlin
KW - mesothelioma
KW - NF2
KW - pharmacodynamics
KW - phase I
UR - http://www.scopus.com/inward/record.url?scp=85016954705&partnerID=8YFLogxK
U2 - 10.1093/annonc/mdw427
DO - 10.1093/annonc/mdw427
M3 - Article
C2 - 27733373
AN - SCOPUS:85016954705
SN - 0923-7534
VL - 27
SP - 2268
EP - 2274
JO - Annals of Oncology
JF - Annals of Oncology
IS - 12
ER -