Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings.
Vol 23, No 16S (June 1 Supplement), 2005: 9068
© 2005 American Society of Clinical Oncology

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Abstract

A phase II study of AP23573 (an mTOR inhibitor) in patients (pts) with advanced sarcomas

The Cancer Ctr of Midway Hosp, Los Angeles, CA; Keck Sch of Medicine of USC, Los Angeles, CA; UCLA David Geffen Sch of Medicine, Los Angeles, CA; ARIAD Pharmaceuticals, Inc, Cambridge, MA; Dana-Farber Cancer Inst, Boston, MA

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Background: AP23573 (AP) is a non-produg rapamycin analog, which potently inhibits mTOR, a downstream effector of the PI3K/Akt pathway. AP has demonstrated some anti-tumor activity in sarcomas in a phase I study. Methods: Advanced sarcoma patients are being enrolled into a phase II trial, comprising 4 histological cohorts, employing a Simon’s 2-stage design with a minimum of 16 evaluable patients/cohort and up to 176 patients overall. AP is dosed at 12.5 mg IV daily X 5 days every 2 weeks (1 course). Tumor response is being assessed by RECIST criteria after 4 courses of treatment. Pharmacodynamic and biomarker endpoints were chosen based on mTOR/glycolytic pathway relationships, and include [¹⁸F] 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) performed before and 5 days after starting AP dosing. Percent difference in sum of maximum standard uptake values on targeted lesions is calculated on the PET scans for this evaluation. Results: 25 pts (14M/11F) were enrolled (age 18–76 yrs, median 57 yrs). Histological subtypes included bone sarcomas (5), leiomyosarcoma (5), liposarcoma (1) and others (14). All but 2 pts received extensive prior therapy. A total of 64 courses of AP were administered (25 pts received 1 course, 19 pts 2 courses, 11 pts 3 courses and 9 pts 4 courses). Among 23 pts with tumor-associated uptake of FDG at baseline, a decrease in overall uptake 25% was observed in 9 pts (39%), the remaining 14 pts exhibited an overall uptake change of <25%. Symptomatic improvement in pain, cough and dyspnea was noted in 13 pts. Response assessment by RECIST criteria is pending. The main related adverse events of AP have included mucositis (16 pts), anemia (10 pts), thrombocytopenia (8 pts) and maculopapular rash (5 pts). Most of these events were mild or moderate in severity. One pt with advanced abdominal liposarcoma died of rapidly progressive disease after receiving one course of AP. Conclusions: At this early assessment, 18 of 23 patients demonstrated decrease in overall uptake on PET imaging during the first course of AP. Symptomatic clinical improvement has been observed in 13 pts. These early findings are consistent with promising clinical activity and enrollment is continuing.

Author Disclosure

Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ariad Ariad Ariad, Cambridge, MA

Abstract presentation from the 2005 ASCO Annual Meeting