TY - JOUR
T1 - Combination of Docetaxel Plus Savolitinib in Refractory Cancer Patients
T2 - A Report on Phase I Trial
AU - Kim, Seung Tae
AU - Lee, Sujin
AU - Park, Minhwa
AU - Park, Se Hoon
AU - Park, Joon Oh
AU - Lim, Ho Yeong
AU - Park, Young Suk
AU - Kang, Won Ki
AU - Gangolli, Esha A.
AU - Shin, Hyeongchan
AU - Kim, Kyoung Mee
AU - Hollingsworth, Simon J.
AU - Mortimer, Peter G.S.
AU - Lee, Jeeyun
N1 - Funding Information:
This work was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2750, HI14C3418).
Funding Information:
This work was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare , Republic of Korea ( HI14C2750 , HI14C3418 ).
Publisher Copyright:
© 2019 The Authors
PY - 2019/4
Y1 - 2019/4
N2 - MET amplification is a frequently observed genomic aberration in solid tumors. We conducted a phase I trial to evaluate dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) for the combination therapy. The following dose levels were tested in this single-arm phase I study: docetaxel as an intravenous infusion over 1 hour at 60 mg/m 2 once every 3 weeks of a 21-day schedule plus savolitinib (level 1, 200 mg qd; level 2, 400 mg qd; level 3, 600 mg qd; level 4800 mg qd). In total, there were 17 patients enrolled on to this study [7 gastric cancer (GC) patients, 5 melanoma patients, 3 sarcoma patients, and 2 rectal cancer patients]. Most of the patients (14 of 17) were heavily pretreated (≥third line or greater lines of treatment). For the first 3 cohorts (200 mg savolitinib + docetaxel 60 mg/m 2 , 400 mg savolitinib + docetaxel 60 mg/m 2 , 600 mg savolitinib + docetaxel 60 mg/m 2 ), there were no DLTs. In the fourth dose cohort (800 mg savolitinib + docetaxel 60 mg/m 2 ), one DLT occurred with generalized edema grade 3 that required intensive management. One GC patient with both MET overexpression (3+) and MET amplification (MET/CEP7 ratio, 7.3) achieved a durable partial response for 297 days, and another MET-amplified GC patient (MET/CEP7 ratio, 7.6) achieved stable disease for 86 days. Due to the higher incidence of G4 neutropenia in cohort 4 (800 mg), we recommend savolitinib 600 mg qd in combination with docetaxel 60 mg/m 2 as the RP2D for phase II trial. The combination therapy demonstrated a very promising antitumor activity with durable responses in MET amplified GC patients.
AB - MET amplification is a frequently observed genomic aberration in solid tumors. We conducted a phase I trial to evaluate dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) for the combination therapy. The following dose levels were tested in this single-arm phase I study: docetaxel as an intravenous infusion over 1 hour at 60 mg/m 2 once every 3 weeks of a 21-day schedule plus savolitinib (level 1, 200 mg qd; level 2, 400 mg qd; level 3, 600 mg qd; level 4800 mg qd). In total, there were 17 patients enrolled on to this study [7 gastric cancer (GC) patients, 5 melanoma patients, 3 sarcoma patients, and 2 rectal cancer patients]. Most of the patients (14 of 17) were heavily pretreated (≥third line or greater lines of treatment). For the first 3 cohorts (200 mg savolitinib + docetaxel 60 mg/m 2 , 400 mg savolitinib + docetaxel 60 mg/m 2 , 600 mg savolitinib + docetaxel 60 mg/m 2 ), there were no DLTs. In the fourth dose cohort (800 mg savolitinib + docetaxel 60 mg/m 2 ), one DLT occurred with generalized edema grade 3 that required intensive management. One GC patient with both MET overexpression (3+) and MET amplification (MET/CEP7 ratio, 7.3) achieved a durable partial response for 297 days, and another MET-amplified GC patient (MET/CEP7 ratio, 7.6) achieved stable disease for 86 days. Due to the higher incidence of G4 neutropenia in cohort 4 (800 mg), we recommend savolitinib 600 mg qd in combination with docetaxel 60 mg/m 2 as the RP2D for phase II trial. The combination therapy demonstrated a very promising antitumor activity with durable responses in MET amplified GC patients.
UR - http://www.scopus.com/inward/record.url?scp=85060467156&partnerID=8YFLogxK
U2 - 10.1016/j.tranon.2018.12.009
DO - 10.1016/j.tranon.2018.12.009
M3 - Article
AN - SCOPUS:85060467156
SN - 1936-5233
VL - 12
SP - 597
EP - 601
JO - Translational Oncology
JF - Translational Oncology
IS - 4
ER -