Phase I study of a novel pro-apoptotic drug R-etodolac in patients with B-cell chronic lymphocytic leukemia
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R-etodolac is a novel pro-apoptotic agent with potential antitumor activity against B-cell chronic lymphocytic leukemia (B-CLL). This phase I clinical trial was conducted to determine the tolerability, safety, and maximum tolerated dose (MTD) of R-etodolac, administered orally twice a day (BID), in patients with B-CLL. Secondary objectives included evaluating clinical response, pharmacodynamic activity (reduction of lymphocytes), and pharmacokinetic (PK) profile. Forty-three patients were enrolled in the study. The most frequently reported adverse events were diarrhea, rash, pruritus, and headache. Increases in alanine aminotransferase (ALT) were also observed. Adverse events were generally mild and self-limiting, although in an apparent dose–response relationship, grade 2 and 3 gastrointestinal toxicities and grade 3 skin toxicities were reported with the highest dose regimens (1,800 and 2,400 mg BID). Hematologic toxicity was rare. The MTD was determined to be 1,200 mg BID. PK results indicated that oral absorption of R-etodolac was rapid (time to maximum concentration ranged from 2 to 4 h), and the half-life ranged from 5 to 7 h. The increase in maximum concentration, however, was not proportional to the increase in dose. R-etodolac significantly reduced absolute lymphocyte count (ALC) in B-CLL patients in a dose-dependent manner up to 1,800 mg BID and caused partial responses in 2 patients. Further study of R-etodolac as a possible new maintenance therapy or as a part of combination therapy of B-CLL appears warranted.
KeywordsR-etodolac CLL Antileukemic activity NSAID Safety
We thank Jennifer Wright Oliver, MD, for assistance with data interpretation and editorial guidance. We thank Margret Platz, Achim Rothe, and Sven Trelle for indispensable help in patient management and data collection. We also acknowledge the literature research and editorial contributions of Bridget O’Keeffe, Ph.D., and Mona Lee, Ph.D., of Helix Medical Communications LLC in the development of this manuscript. Dr. Österborg received research support from Salmedix, Inc.
- 7.O’Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M (1993) Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 82:1695–1700PubMedGoogle Scholar
- 8.Wierda W, O’Brien S, Faderl S, Ferrajoli A, Wang X, Do KA, Garcia-Manero G, Thomas D, Cortes J, Ravandi-Kashani F, Giles F, Lerner S, Kantarjian H, Keating M (2006) A retrospective comparison of three sequential groups of patients with Recurrent/Refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer 106:337–345PubMedCrossRefGoogle Scholar
- 9.Keating MJ, Chiorazzi N, Messmer B, Damle RN, Allen SL, Rai KR, Ferrarini M, Kipps TJ (2003) Biology and treatment of chronic lymphocytic leukemia. Hematology (Am Soc Hematol Educ Program) 153–175Google Scholar
- 14.Brocks DR, Jamali F (1990) The pharmacokinetics of etodolac enantiomers in the rat. Lack of pharmacokinetic interaction between enantiomers. Drug Metab Dispos 18:471–475Google Scholar
- 21.Kolluri SK, Corr M, James SY, Bernasconi M, Lu D, Liu W, Cottam HB, Leoni LM, Carson DA, Zhang XK (2005) The R-enantiomer of the nonsteroidal antiinflammatory drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis. Proc Natl Acad Sci U S A 102:2525–2530PubMedCrossRefGoogle Scholar
- 23.Yasui H, Hideshima T, Hamasaki M, Roccaro AM, Shiraishi N, Kumar S, Tassone P, Ishitsuka K, Raje N, Tai YT, Podar K, Chauhan D, Leoni LM, Kanekal S, Elliott G, Munshi NC, Anderson KC (2005) SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma. Blood 106:706–712PubMedCrossRefGoogle Scholar
- 30.Elter T, Borchmann P, Schulz H, Reiser M, Trelle S, Schnell R, Jensen M, Staib P, Schinkothe T, Stutzer H, Rech J, Gramatzki M, Aulitzky W, Hasan I, Josting A, Hallek M, Engert A (2005) Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol 23:7024–7031PubMedCrossRefGoogle Scholar
- 33.Lindhagen E, Nissle S, Leoni L, Elliott G, Chao Q, Larsson R, Åleskog A (2006) R-etodolac (SDX-101) and the related indole–pyran analogues SDX-308 and SDX-309 potentiate the antileukemic activity of standard cytotoxic agents in primary chronic lymphocytic leukaemia cells. Cancer Chemother Pharmacol 60:545–553PubMedCrossRefGoogle Scholar