Background: SAR125844 (SAR) is a potent and small molecule inhibitor of the MET kinase (IC50 = 4.2nM; Ki = 2.8nM). This phase I study (NCT01657214) was initiated to address the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity in adult Asian pts with advanced solid tumors.
Methods: Eligible pts received SAR by IV infusion every week. Dose escalation proceeded with an adaptive Bayesian method. At the MTD, pts with advanced c-Met amplified solid tumors including gastric cancer (GC) pts were enrolled in an expansion cohort.
Results: As of 30 June 2015, 32 pts have received SAR, 19 pts in the dose escalation phase over 4 dose levels (DL) ranging from 260 to 570 mg/m2 and 13 pts in the MTD expansion cohort including 8 pts with advanced GC. Of the 32 treated pts, median age was 64 years [28-78], 18M/14F, ECOG-PS 0/1/2: 14/16/2 with various solid tumors including 16 GC, 6 colorectal and 4 lung adenocarcinomas. Pts received a median of 4 infusions [2-20]. No dose-limiting toxicity (DLT) was reported nor MTD was reached. Of the 19 pts treated in dose escalation, blood exposure PK parameters (AUC and Cmax) increased in proportion with the dose with a mean clearance of 34 L/h associated with a large volume of distribution (239 L). Dose expansion was opened at 570 mg/m2 for pts with solid tumor and c-Met-gene amplification determined on local FISH assay. The most commonly reported all-causality AE (≥15% of pts) were: nausea, vomiting, decreased appetite, asthenia/fatigue, constipation, pyrexia, abdominal pains, injection site reaction and back pain. 31.3% of pts had grade ≥3 AEs, none were related to study drug. No relevant severe laboratory abnormality was observed. In the dose escalation part in unselected pts, stable disease (SD) was reported in 8 pts at the 4 week assessment. Of the 13 pts treated so far in dose expansion, 2 pts with GC achieved confirmed partial response and 5 pts had SD (4GC and 1sarcoma).
Conclusions: SAR administered as single agent at the dose of 570mg/m2 has a tolerable and manageable safety profile and encouraging anti-tumor activity is seen in pts with c-Met -amplified GC. Accrual of pts with c-Met-gene amplified GC is still ongoing.
Sponsored by Sanofi; NCT01657214
Citation Format: Kohei Shitara, Do-Youn Oh, Tomoya Yokota, Tae Won Kim, Toshihiko Doi, Satoshi Hamauchi, Jin-Hee Ahn, Corinne Gomez, Marzia Harnois, Yung Jue Bang. A phase I study of MET TKI SAR125844 in Asian patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A167.