PROJECT SUMMARY Perivascular epithelioid cell tumors (PEComa) are a rare subset of soft tissue sarcomas. PEComas arise most commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, and abdominopelvic sites. Most PEComa lesions are benign and slow-progressing, however, a small subset of them are malignant PEComas, with an aggressive clinical course including distant metastases and ultimate death. Malignant PEComa is extremely rare, with an estimated incidence of 0.12- 0.24/1,000,000 or approximately 42-84 new patients per year, and an estimated prevalence of 0.22- 0.48/1,000,000 or approximately 77-168 patients in the United States. Currently, no effective medical treatment has been prospectively investigated or approved for advanced malignant PEComa, including metastatic or locally advanced disease where surgery is not an option. The prognosis for these patients is poor, with an estimated median survival of 12-17 months. Chemotherapy and radiotherapy have not demonstrated significant clinical benefit. Therefore, a significant unmet need exists for effective therapies to treat this aggressive and life-threatening disease. The cytosolic kinase mTOR plays a major role in cell survival and proliferation. Limited case studies suggest that the mTOR pathway is frequently deregulated in sporadic malignant PEComa (mostly with mutation or loss of TSC2), making mTOR inhibition a promising therapeutic strategy. Rapamycin blocks mTORC1 signaling, resulting in decreased protein translation and G1 cell cycle arrest. In some case studies, patients with PEComa benefited from treatment with mTOR inhibitors, including oral rapamycin. Oral mTOR inhibitors have low and highly variable oral bioavailability, poor solubility, and dose-limiting GI toxicities and require therapeutic monitoring of blood levels to ensure adequate dosing. A novel albumin-bound nanoparticle rapamycin (sirolimus) was developed (nab-rapamycin, ABI-009; originally by Abraxis Bioscience/Celgene Corporation and licensed to AADi, LLC). In a phase 1 clinical study, ABI-009 administered intravenously showed a promising safety despite high dose with evidence of responses and stable disease in a variety of solid tumors. Albumin bound drugs have shown enhanced tumor penetration, and ABI-009 shows significantly improved activity in animal models at equal dose and superior pharmacological properties with significantly higher Cmax and AUC without compromising safety as compared to the available mTOR inhibitors. AADi, LLC, a small start-up company and applicant for this grant, has filed IND 125,669 (submitted Jul 13, 2015 and approved Aug 13, 2015) to conduct a single arm phase 2 clinical study (NCT02494570) to assess the efficacy and safety of intravenous ABI-009 for advanced (locally advanced and metastatic) malignant PEComa. There are no other ongoing trials for this patient population. Thirty-five patients will be enrolled and the primary endpoint will be ORR; the secondary endpo...