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 endpoints will be duration of response (DOR), PFS rate at 6 months, PFS, OS, and safety/tolerability. PK/PD and tumor biomarkers will be analyzed as correlative and translational components to determine mechanisms of tumor response and resistance. In agreement with the FDA (DOP2) in a pre-IND meeting, this single-arm study design and statistical considerations may be sufficient to support a marketing application for ABI-009 in advanced PEComa [Appendix - Attachment 2: AADi-FDA Pre-IND Meeting Minutes 7/7/2015] if the primary endpoint of ORR is of sufficient magnitude and duration. As of the date of this grant resubmission, all 9 of the planned US clinical sites have been IRB approved and activated. From April 2016 to October 2016 (date of the resubmission), 7 patients have been enrolled in the study. This program represents a unique opportunity to develop and get approval of a new drug with potentially improved efficacy and safety over existing therapies, for an extremely rare disease and patient population for which there are no approved therapies.

Public Health Relevance

Perivascular epithelioid cell tumors (PEComa) are a rare subset of soft tissue sarcomas with a strong female predominance and a median age of ~43 years. Most PEComas are benign and treated with surgery, but an extremely rare subset are malignant with an aggressive clinical course including distant metastases and ultimate death. This subset, Advanced Malignant PEComa, for which there are no approved treatments, has a poor prognosis with median survival estimated at 12-17 months and has a prevalence of less than 200 patients in the US. Recent case studies have shown mTOR pathway activation often through TSC2 mutations or deletion, making advanced malignant PEComas a promising target for mTOR inhibitors. This prospective phase 2 study (IND 125,669, July 13, 2015) will assess the safety and efficacy of the novel mTOR inhibitor ABI-009, a nanoparticle albumin-bound rapamycin (nab-rapamycin), in patients with advanced malignant PEComa. Based on agreement reached with the FDA in a pre-IND meeting and the outcomes of the trial, this phase 2 study could be sufficient to provide the basis of marketing approval of ABI-009 for this extremely rare indication.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZFD1)
Program Officer
Mueller, Christine
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Aadi, LLC
Pacific Palisades
United States
Zip Code