Phase 2 trial of the novel multi-receptor tyrosine kinase inhibitor sitravatinib in well-differentiated/dedifferentiated liposarcoma.

Abstract

TPS11082 Background: Well-differentiated/dedifferentiated liposarcoma (WD/DD LPS) is a sarcoma subtype of adipocytic origin characterized by amplification of cyclin dependent kinase 4 (CDK4) and MDM2. WD/DD LPS is resistant to chemotherapy and success with CDK4 inhibitors is limited. We recently characterized the landscape of activated receptor tyrosine kinases (RTKs) and intracellular signaling pathways finding marked heterogeneity by sarcoma subtype [Patwardhan et al. Oncotarget 2016;7(4)]. In WD/DD LPS cell lines, phosphorylated (p) IGF1-R, MET and PDGFRb are strongly expressed. Selective siRNA knockdown of expression of 1 or more of these RTKs inhibited growth of WD/DD LPS cell lines. Sitravatinib (S) is a novel inhibitor of a broad panel of related RTKs. We showed that S abrogates expression of p-RTKs, including IGF1-R, MET and PDGFRb, at low nanomolar concentrations and potently inhibits proliferation of WD/DD LPS cell lines, where anti-proliferative effects of S were superior to other RTK inhibitors including imatinib, crizotinib and pazopanib. S suppressed tumor growth in vivo in WD/DD LPS . A phase 1 trial of S in solid tumors showed clinical activity in WD/DD LPS. Recommended phase 2 dose was 150 mg/day. As there are no approved RTK inhibitors for adipocytic sarcomas, and based on these findings, we initiated a phase 2 trial of S in WD/DD LPS. Methods: This is a single-arm open-label multi-center Simon 2 stage phase II trial of S in 29 patients (pts) with advanced WD/DD LPS who failed 1 prior therapy and show disease progression before enrollment. Pts receive S 150 mg orally daily continuously. Primary endpoint is the progression free rate at 12 weeks (PFR12) versus historical controls. The design has power of 85% to show improvement in PFR12 from 20% (inactive) to 40% (active) with α = 0.10. Secondary endpoints are ORR, PFS and safety. A subset of pts undergo baseline and on-treatment biopsies and reverse phase protein array used to measure changes in expression of p-RTKs and signaling pathway proteins with confirmation by immunoblot. Genomic landscape of these tumors will be analyzed by next generation sequencing. The study opened in 1/2017. Clinical trial information: NCT02978859.