Phase 2 study of ABI-009 Treatment of Advanced PEComa-IND 125669, 7/13/2015 - 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 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.
