Phase II Study of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus in Patients With Advanced Bone and Soft Tissue Sarcomas Sant P. Chawla, Arthur P. Staddon, Laurence H. Baker, Scott M. Schuetze, Anthony W. Tolcher, Gina Z. D’Amato, Jean-Yves Blay, Monica M. Mita, Kamalesh K. Sankhala, Lori Berk, Victor M. Rivera, Tim Clackson, John W. Loewy, Frank G. Haluska, and George D. Demetri See accompanying article doi: 10.1200/JCO.2011.37.9701 Sant P. Chawla, International Institute of Clinical Studies, Sarcoma Oncology Center, Santa Monica, CA; Arthur P. Staddon, Pennsylvania Oncology Hema- tology Associates, Philadelphia, PA; Laurence H. Baker and Scott M. Schue- tze, University of Michigan School of Medicine, Ann Arbor, MI; Anthony W. Tolcher, South Texas Accelerated Research Therapeutics; Monica M. Mita and Kamalesh K. Sankhala, Cancer Therapy Research Center, Institute for Drug Development, San Antonio, TX; Gina Z. D’Amato, H. Lee Moffitt Cancer Center, Tampa, FL; Jean-Yves Blay, Centre Leon Berard, Lyon, France; Victor M. Rivera, Tim Clackson, John W. Loewy, and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge; and George D. Demetri, Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. Submitted February 26, 2011; accepted August 3, 2011; published online ahead of print at www.jco.org on November 7, 2011. Supported by ARIAD Pharmaceuticals, Cambridge, MA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: George D. Demetri, MD, Ludwig Center at Dana- Farber Cancer Institute, Dana 1212, 450 Brookline Ave, Boston, MA 02215; e-mail: gdemetri@partners.org. © 2011 by American Society of Clinical Oncology 0732-183X/11/2999-1/$20.00 DOI: 10.1200/JCO.2011.35.6329 A B S T R A C T Purpose Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas. Patients and Methods Patients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease  16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated. Results A total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue. Conclusion Single-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas. J Clin Oncol 29. © 2011 by American Society of Clinical Oncology INTRODUCTION Sarcomas represent a heterogeneous group of un- common malignancies arising from mesenchymal cells and connective tissues. If surgically incurable, systemic therapy for most metastatic and/or unre- sectable sarcomas has been limited to cytotoxic chemotherapy. However, the successes of molecu- larly targeted agents, such as imatinib and sunitinib, in the treatment of defined sarcoma subtypes, such as gastrointestinal stromal tumors (GIST) 1 and dermatofibrosarcoma protuberans (DFSP), 2 have demonstrated clinical benefits from inhibition of oncogenic signaling pathways critical to the patho- biology of sarcoma. 3 The mammalian target of rapamycin (mTOR) is a serine/threonine kinase, a central regulator in the phosphatidyl 3-kinase (PI3K)/AKT pathway. Deregulation of the PI3K/AKT pathway occurs frequently in human cancer. 4,5 Ridaforolimus (AP23573, MK-8669, formerly deforolimus) is a nonprodrug analog of rapamycin and an inhibitor of mTOR. Ridaforolimus reduces phosphorylation of the mTOR effector proteins S6K and 4E-BP1 and has potent antitumor activity against a wide range of cancer cell lines. 6-8 In a phase I study, ridaforolimus administered intravenously (IV) was well-tolerated by patients with advanced solid tumors. 9 Seven patients with sarcoma participated in the study, and potential JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T © 2011 by American Society of Clinical Oncology 1 http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2011.35.6329 The latest version is at Published Ahead of Print on November 7, 2011 as 10.1200/JCO.2011.35.6329 Copyright 2011 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on March 10, 2016. For personal use only. No other uses without permission. 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