Condy, Mercedes M.

TPS10594 Background: Approximately 13,000 cases of soft tissue and bone are diagnosed annually in the US. Despite primary surgery many patients develop recurrent disease. Response rates to chemotherapy are low and new agents are needed. Gene array studies have shown Aurora Kinase A (AURKA) commonly overexpressed. Inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel and oral, ATP-competitive, selective small-molecule inhibitor of AURKA. We hypothesize that alisertib will be an effective treatment for advanced/metastatic sarcoma. Methods: This CTEP-sponsored, investigator-initiated, multi-center phase II study uses alisertib in patients with advanced/metastatic sarcoma and is conducted through the Alliance for Clinical Trials in Oncology (Alliance A091102). Patients must have adequate performance status, organ function, and measurable disease (RECIST v1.1). Patients are enrolled in one of five cohorts, depending on histology: 1) liposarcoma, 2) leiomyosarcoma, 3) undifferentiated sarcoma, 4) malignant peripheral nerve sheath tumor, or 5) other. Patients are treated with alisertib 50mg PO BID d1-d7 every 21 days until either progressive disease or unacceptable toxicity. The primary endpoint is objective overall response rate (ORR). Secondary endpoints include progression-free survival (PFS) and overall survival (OS). Translational objectives include correlation of ORR, PFS and OS with baseline and post-treatment markers of AURKA inhibition in tumor biopsies and baseline and post-treatment [F-18] FLT-PET scans. A Simon two-stage design is used for each of the 5 cohorts and one confirmed response in the first 9 patients expands enrollment in that cohort to 24. Enrollment began in December 2012. As of January 2013, 14 pts have been enrolled. Funded by the Alliance for Clinical Trials in Oncology. Clinical trial information: NCT01653028.

TPS10592 Background: Angiosarcomas (ASs) are rare, aggressive, malignant endothelial cell tumors that constitute 1% to 2% of all soft tissue sarcomas with 5-year survival of 35%. Cytotoxic agents have demonstrated response rates of about 15%. Gene-array data from MSKCC has revealed up-regulation of endothelial associated genes, including active members of the angiopoietin system e.g., Tie2 and Angiopoietin 2 (Ang2). Trebananib (AMG386) is a novel agent that targets Ang1 and Ang2. We hypothesize that inhibition of angiopoietin 2 with trebananib will be an effective therapy in patients (pts) with AS. Methods: This CTEP sponsored, investigator initiated, multi-center phase II study uses trebananib, in pts with AS having metastatic/unresectable AS and conducted through the Alliance for Clinical Trials in Oncology (Alliance A091103). Pts must have adequate performance status, organ function, and measurable disease (RECIST v1.1). Patients are treated with trebananib 30mg/kg d1, 8, 15, and 22 every 28 days until either progressive disease or unacceptable toxicity. The primary endpoint is objective overall response rate (ORR) via RECIST v1.1. Secondary endpoints include the evaluation of progression-free survival (PFS) and overall survival (OS). Translational objectives include correlation of ORR, PFS and OS with i. baseline and post-treatment expression of Ang2 and Tie2 by immunohistochemistry (IHC), ii. serum levels of Ang1 and Ang2, iii. baseline and post-treatment phospho-receptor tyrosine kinase (p-RTK) status of Tie2, VEGFR-2, PI3K, MEK and MAPK, and iv. mutational status of VEGFR-2 and amplification of MYC/FLT4. A Simon Optimal two-stage phase II study design is used and one confirmed response in the first 12 pts expands enrollment to 25. Pre- and post-treatment biopsies will be performed in up to 10 pts treated at MSKCC. Enrollment began in July 2012. As of January 2013, 7 pts have been recruited. Clinicaltrials.gov#: NCT01623869. Funded by the Alliance Clinical Trials in Oncology. NIH Grant CA-25224. Clinical trial information: NCT01623869.