Cancer Therapy: Clinical A First-in-Man Phase I and Pharmacokinetic Study on CHR-2797 (Tosedostat), an Inhibitor of M1 Aminopeptidases, in Patients with Advanced Solid Tumors

Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary therapeutic activity profile of CHR-2797 (tosedostat), a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases with antiproliferative and antiangiogenic activity in vitro. Experimental Design: A phase I study of accelerated titration design that escalated through nine doses (10-320 mg) in patients (Eastern Cooperative Oncology Group performance status, ≤2) with advanced solid tumors. CHR-2797 was administered once daily. Results: Forty patients (median age, 60 years; range, 24-80 years; male, 27; female, 13) were treated in 12 cohorts with once daily doses (10-320 mg). Dose-limiting toxicities were thrombocytopenia, dizziness, and visual abnormalities in one patient, and anemia, blurred vision, and vomiting in a second patient at 320 mg, resulting in an inability to complete 28 days of study drug. The most commonly observed toxicities were fatigue, diarrhea, peripheral edema, nausea, dizziness, and constipation. One patient had a partial response (renal cell carcinoma) and four patients had stable disease for >6 months. CHR-2797 and its active metabolite, CHR-79888, show dose-proportional increases in plasma AUC and Cmax. The terminal half-life for CHR-2797 is ∼1 to 3.5 hours and between 6 and 11 hours for CHR-79888. Intracellular (packed blood cells) exposure to CHR-79888 is consistent with intracellular levels that proved to be efficacious in xenograft models. Conclusion: CHR-2797 is well tolerated and can be safely administered at doses that result in intracellular levels of CHR-79888 that are associated with activity in preclinical models. The recommended dose for single agent therapy in solid tumors is 240 mg/d. CHR-2797 (tosedostat) is a metalloenzyme inhibitor with pleiotropic activity against a range of human cancer cells in vitro and in vivo. Exposure of cells to the ester, CHR-2797, causes intracellular accumulation of its acid metabolite, CHR-79888, which exerts a powerful inhibitory effect on intracellular aminopeptidases, resulting in antiproliferative, proapoptotic, and antiangiogenic effects. Although the most important intracellular metalloenzyme targets for CHR-2797 have not been fully elucidated, there is a substantial body of evidence indicating that they are likely to be members of the M1 family of aminopeptidases, for example, puromycin-sensitive aminopeptidase, leukotriene A4 hydrolase, or the M17 family member, leucine aminopeptidase (IC50 values of CHR-2797 and CHR-79888 for these aminopeptidases are detailed in Fig. 1A, all of which are often overexpressed in human cancers; refs. 1–5). The antiproliferative effects of CHR-2797 likely depend on the simultaneous inhibition of more than one intracellular aminopeptidase. The M1 class of aminopeptidases plays a critical role in the final steps of protein recycling downstream of proteasomal degradation (6), and inhibition of aminopeptidases by CHR-2797 and/or CHR-79888 may, like proteasome inhibition, disrupt the turnover of cell cycle intermediates, affecting cancer cell survival or proliferation (Fig. 1B). In addition, inhibition of aminopeptidases by CHR-2797 and its metabolite in transformed cells of the hematopoietic lineage seems to lead to an accumulation of small peptides and results in a deficiency of free amino acids for new protein synthesis (1). Authors' Affiliations: The Royal Marsden Hospital NHS Foundation Trust, The Institute of Cancer Research, Sutton, Surrey, United Kingdom, The Churchill Hospital, Headington, Oxford, United Kingdom, and Chroma Therapeutics Ltd., Abingdon, Oxon, United Kingdom Received2/9/09; revised4/15/09; accepted4/30/09; publishedOnlineFirst 7/28/09. Grant support: Chroma Therapeutics. The costs of publication of this article were defrayed in part by the payment of page charges. This articlemust therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Previously presented in abstract form at the 2006 ASCO and ESMO annual meetings and in an oral presentation at 2007 ASCO annual meeting Requests for reprints: Johann S. de Bono, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom. Phone: 44-20-8722-4302; Fax: 44-20-8642-7979; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0306 4978 Clin Cancer Res 2009;15(15) August 1, 2009 www.aacrjournals.org Research. on May 1, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst July 28, 2009; DOI: 10.1158/1078-0432.CCR-09-0306