TY - JOUR
T1 - First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors
T2 - Safety, Pharmacokinetics, and Antitumor Activity
AU - Gan, Hui K.
AU - Millward, Michael
AU - Hua, Ye
AU - Qi, Chuan
AU - Sai, Yang
AU - Su, Weiguo
AU - Wang, Jian
AU - Zhang, Lilin
AU - Frigault, Melanie M.
AU - Morgan, Shethah
AU - Yang, Liu
AU - Lickliter, Jason D.
PY - 2019/8/15
Y1 - 2019/8/15
N2 - Purpose: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib).Patients and Methods: This open-label, multicenter doseescalation and-expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity.Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mgN = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, C-max was 2,414.8 ng/mL, AUC was 17053.9 h.ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks.Conclusions: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.
AB - Purpose: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib).Patients and Methods: This open-label, multicenter doseescalation and-expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity.Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mgN = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, C-max was 2,414.8 ng/mL, AUC was 17053.9 h.ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks.Conclusions: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.
KW - RENAL-CELL CARCINOMA
KW - GROWTH
KW - TRIAL
KW - AMPLIFICATION
KW - CABOZANTINIB
KW - CRIZOTINIB
KW - RESISTANCE
KW - SUNITINIB
KW - DISCOVERY
KW - VOLITINIB
U2 - 10.1158/1078-0432.CCR-18-1189
DO - 10.1158/1078-0432.CCR-18-1189
M3 - Article
C2 - 30952639
SN - 1078-0432
VL - 25
SP - 4924
EP - 4932
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -