这里有一个ARQ197与多吉美联用的临床试验，有效率67%。
意思是c-met抑制剂与多吉美联用也很好。
A phase I dose-escalation trial evaluating ARQ 197 administered in combination with sorafenib in adult patients (pts) with advanced solid tumors.
Meeting:
2010 ASCO Annual Meeting
Abstract No:3024
Citation:
J Clin Oncol 28:7s, 2010 (suppl; abstr 3024)
Author(s):
A. A. Adjei, J. A. Sosman, G. K. Dy, W. Ma, G. J. Fetterly, D. Skupien, J. A. Means, R. Savage, F. Chai, I. Puzanov; Roswell Park Cancer Institute, Buffalo, NY; Vanderbilt University Medical Center, Nashville, TN; ArQule, Woburn, MA
Abstract:
Background: ARQ 197 (A) is a selective non-ATP competitive inhibitor of c-MET, a RTK implicated in tumor cell proliferation, invasion and angiogenesis. Maximum tolerated dose (MTD) and recommend phase II dose (RP2D) of A in monotherapy and in combination with erlotinib were reported previously. Based on preclinical synergy of A in combination with sorafenib (S) in a number of cell lines, a phase I study was undertaken to define safety and RP2D of A+S combination. Secondary objectives include evaluation of pharmacokinetics (PK) and biomarkers (HGF, VEGF, soluble c-MET). Methods: A traditional 3+3 dose escalation schema was employed. An initial cohort was treated at dose level (DL) 1 (A 360 mg PO BID + S 200 mg PO BID). With no DLT observed at this DL, dosing was escalated to DL2 (A 360 mg BID + S 400 mg BID), which represents full single-agent doses of both drugs. Results: To date, 14 pts (2 F/12 M; mean age: 58.7 yrs) have been treated at the 2 DLs, 5 in DL1 w/o DLT and 9 in DL2 with 1 experiencing 2 DLTs [grade (G) 3 fatigue and G3 dyspnea]. Accordingly, DL2 is the RP2D. No A-related serious adverse events (AEs) or G4 AEs were reported. G3 A-related AEs have been reported in 4/14 pts (29%) (fatigue, dyspnoea, dry skin, musculoskeletal chest pain, hyperbilirubinaemia 1 each); G1/2 in 7 pts (50%) (2 fatigue, thrombocytopenia, lymphopenia, diarrhea, nausea, vomiting, abdominal tenderness, AST increased, anorexia, nipple pain, and rash 1 each). PK analysis of A showed that on day 1 mean Cmax(n=8) was 1766 ± 1452 ng/mL and mean AUC(0-12) was 14053 ± 13736 hr*ng/mL. On day 29 mean Cmax (n=6) was 1986 ± 1487 ng/mL and mean AUC(0-12) was 15,003 ± 13428 hr*ng/mL. Nine of 14 pts are evaluable for efficacy with 6/9 (67%) demonstrating a best RECIST response of stable disease (8+ to 29+ wks) including 1 renal cell carcinoma pt with 22% tumor regression. Conclusions: The combination of A + S is safe and well tolerated, with 360 mg PO BID A + 400 mg PO BID S recommended for subsequent phase II evaluation. PK parameters indicated that S had no effect on the disposition of A. Preliminary evidence of anticancer activity has been observed, indicating that the combined inhibition of c-MET and angiogenic signaling has therapeutic potential.Fictional
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