A Study of MGCD516, a receptor tyrosine kinase (RTK) inhibitor, in molecularly selected patients with NSCLC or other advanced solid tumors.
Werner T, Heist R, Carvajal R, Adkins D, Alva A, Goel S, Hong D, Bazhenova L, Saleh M, Siegel R, Kyriakopoulos C, Blakely C, Eaton K, Lauer R, Wang D, Schwartz G, Neuteboom S, Potvin D, Faltaos D, Chen I, Christensen J, Levisetti M, Chao R, and Bauer T. A Study of MGCD516, a receptor tyrosine kinase (RTK) inhibitor, in molecularly selected patients with NSCLC or other advanced solid tumors. J Thorac Oncol 2017; 12(1):S1068-S1069.
J Thorac Oncol
Background: MGCD516 (Sitravatinib), is an oral, potent small molecule inhibitor of a closely related spectrum of RTKs including RET, the split RTKs (VEGFR, PDGFR and KIT), TRK family, DDR2, MET and AXL. RTKs inhibited by sitravatinib are genetically altered in NSCLC and other cancers, where they function as oncogenic drivers, promoting cancer development and progression. Alterations in these RTKs have also been implicated in tumor resistance mechanisms. Sitravatinib has demonstrated antitumor activity in nonclinical cancer models harboring genetic alterations of sitravatinib targets, including rearrangement of RET, NTRK, or CHR4q12 amplification. Phase 1 dose escalation has been completed, showing dose proportional increases in exposure. PK and preliminary PD data indicate inhibition of the targets at the 150 mg dose administered orally once per day. Methods: This phase 1b study includes enrollment of molecularly selected patients (pts) with unresectable or metastatic NSCLC or other advanced solid tumor malignancies in patient cohorts characterized by activating alterations in sitravatinib RTK targets (RET, KDR, PDGFRA, KIT, TRK, DDR2, MET, AXL) or by loss of function mutations in CBL, a negative regulator for MET, AXL and PDGFR/KIT signaling. Pts receive sitravatinib at 150 mg once daily in 21-day cycles. Study endpoints include safety and tolerability, PK/PD, and clinical activity assessed by objective disease response per RECIST 1.1, duration of response and survival. A two stage optimal Simon design of up to 24 pts (8 pts in first stage and 16 pts in second stage) will be applied to those cohorts defined by a specific tumor gene alteration assuming p0=0.15 and p1=0.35, with an additional expansion of a cohort up to a total of 70 pts in order to provide a more precise estimate of ORR. PD biomarkers, including sMET, sVEGFR2, VEGFA and sAXL, are being explored in plasma samples for prognostic potential and possible relationship with clinical outcome. The study is open for enrollment, and recruitment is ongoing.