Phase 2 Study of Abi-009 Treatment of Advanced Pecoma-ind 125669; 7/13/2015

PROJECT SUMMARYPerivascular epithelioid cell tumors (PEComa) are a rare subset of soft tissue sarcomas. PEComasarise most commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, andabdominopelvic sites. Most PEComa lesions are benign and slow-progressing, however, a small subsetof them are malignant PEComas, with an aggressive clinical course including distant metastases andultimate 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 advancedmalignant 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, asignificant 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 studiessuggest that the mTOR pathway is frequently deregulated in sporadic malignant PEComa (mostly withmutation or loss of TSC2), making mTOR inhibition a promising therapeutic strategy. Rapamycin blocksmTORC1 signaling, resulting in decreased protein translation and G1 cell cycle arrest. In some casestudies, 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-limitingGI toxicities and require therapeutic monitoring of blood levels to ensure adequate dosing. A novelalbumin-bound nanoparticle rapamycin (sirolimus) was developed (nab-rapamycin, ABI-009; originallyby 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 ofresponses and stable disease in a variety of solid tumors. Albumin bound drugs have shown enhancedtumor penetration, and ABI-009 shows significantly improved activity in animal models at equal doseand superior pharmacological properties with significantly higher Cmax and AUC without compromisingsafety 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 Jul13, 2015 and approved Aug 13, 2015) to conduct a single arm phase 2 clinical study (NCT02494570) toassess 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 willbe 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 beanalyzed as correlative and translational components to determine mechanisms of tumor response andresistance. In agreement with the FDA (DOP2) in a pre-IND meeting, this single-arm study design andstatistical considerations may be sufficient to support a marketing application for ABI-009 in advancedPEComa [Appendix - Attachment 2: AADi-FDA Pre-IND Meeting Minutes 7/7/2015] if the primaryendpoint of ORR is of sufficient magnitude and duration. As of the date of this grant resubmission, all 9of the planned US clinical sites have been IRB approved and activated. From April 2016 to October2016 (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 withpotentially improved efficacy and safety over existing therapies, for an extremely rare disease andpatient population for which there are no approved therapies.