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Golvatinib is a highly potent, small-molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family as well as c-Kit and Ron, based on isolated kinase assays. Golvatinib showed preclinical evidence of anti-tumor activity. Two phase 1 studies were conducted: a once daily (QD) dosing study in UK and a twice daily (BID) dosing study in JP to evaluate the MTD, safety, PK, PD and preliminary activity.


Golvatinib was administered orally, QD or BID, continuously to patients with advanced solid tumors. Blood samples for PK and PD analysis were collected at multiple time-points. Tumor tissues were collected pre- and post-cycle 1 for PD analysis in an expanded MTD cohort.


34 patients were treated at 6 QD doses levels (100, 200, 270, 360, 450 and 400 mg QD) and 16 patients were treated at 4 BID doses levels (50, 100, 200 and 300 mg BID). In the QD dosing, 3 DLTs occurred: Gr3 GGT and alkaline phosphatase (n = 1; 200 mg QD) and repeated Gr2 (n = 1) and Gr3 (n = 1) fatigue, both at 450 mg QD. In the BID dosing, one DLT (Gr3 ALT) and one equivalent DLT (Gr2 vomiting, nausea and anorexia) occurred, both at 300 mg BID. The MTDs were determined to be 400 mg QD and 200 mg BID. Frequently occurring AEs (of which, all ≤G3) across both dosing regimens (n = 50) were fatigue 58% (G3: 10%), nausea 56% (G3: 2%), diarrhea 54%, vomiting 48%, decreased appetite 48% (G3: 8%), ALT increase 44% (G3: 2%) and AST increase 32%. Best response included 6 SDs (>84 days) and 4 SDs (>84 days) in the QD and the BID dosing, respectively. PK showed high variability and plasma concentration increased with dose. The Cmax was reached at a median time of 2–4 h, and declined with a t1/2 of ∼40 h. Plasma PD analysis showed a significant increase in soluble c-Met levels after golvatinib treatment. Tumour tissue PD analysis in five patients at 400 mg QD demonstrated a baseline elevated MET gene copy number, with c-Met over-expression and post-treatment decline phospho (p)-c-Met expression in 1 patient, post-treatment decline in p-c-Met in the second patient, and post-treatment decline in p-ERK in the third patient.


The MTD of golvatinib was achieved at 400 mg QD and 200 mg BID. Preliminary PD analysis demonstrated evidence of c-Met target modulation. QD dosing was selected for further evaluation of golvatinib in phase 2 studies.

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