Results of a phase I dose escalation study of eltrombopag in patients with advanced soft tissue sarcoma receiving doxorubicin and ifosfamide

BMC Cancer

Yasser Mostafa Kamel¹  Rita Patwardhan⁴  Conrad A Messam⁴  Andrew Hendifar²  Arthur Staddon³  Sant P Chawla² 

[1]GlaxoSmithKline, Stockley Park, UK

[2]Sarcoma Oncology Center, Santa Monica, CA, USA

[3]University of Pennsylvania School of Medicine, Pennsylvania Hospital, Philadelphia, PA, USA

[4]GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA, USA

关键词: Chemotherapy-induced thrombocytopenia;    Myelosuppression;    Chemotherapy;    Thrombopoietin receptor agonists;    Platelets;    Sarcoma;   

Others  :  1079869
DOI  :  10.1186/1471-2407-13-121

 received in 2012-04-12, accepted in 2013-03-06,  发布年份 2013

【 摘 要 】

Background

The objective of this Phase I dose escalation study was to explore the safety and tolerability of eltrombopag, an oral, nonpeptide, thrombopoietin receptor agonist, in patients with advanced soft tissue sarcoma (STS) and thrombocytopenia due to treatment with doxorubicin and ifosfamide (AI) combination chemotherapy.

Methods

Patients aged 18 or older with histologically confirmed, locally advanced or metastatic STS were treated with 1 cycle of AI followed by AI with eltrombopag starting at Cycle 2, using 2 different dosing schedules. The study design included an eltrombopag dose escalation phase starting at 75 mg daily to determine the optimal biological dose (OBD).

Results

Eighteen patients were enrolled and 15 received at least 1 dose of chemotherapy; 3 patients withdrew prior to receiving eltrombopag. Seven, 4, and 1 patients received 75 mg, 100 mg, and 150 mg eltrombopag daily, respectively. No dose-limiting toxicities were reported. Due to slow recruitment, the study was closed prior to identifying an OBD. The most common hematologic adverse events (AEs) were thrombocytopenia (80%), neutropenia (73%), and anemia (67%). The most common nonhematologic AEs were fatigue (53%), alanine aminotransferase increased, constipation, and nausea (47% each). Eleven of 12 patients who received eltrombopag completed at least 2 chemotherapy cycles; all had increased platelet counts on Day 1 of Cycle 2 (cycle with eltrombopag) compared to Day 1 of Cycle 1 (cycle without eltrombopag).

Conclusions

Although data are limited, safety data were consistent with the known toxicities of AI combination chemotherapy or the side effect profile of eltrombopag seen in other studies. Available data suggest a potential pre- and post-chemotherapy dosing scheme for eltrombopag when administered with AI chemotherapy, and support further investigation of eltrombopag treatment in patients with chemotherapy-induced thrombocytopenia.

【 授权许可】

   
2013 Chawla et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Ang JE, Shah RN, Everard M, Keyzor C, Coombes I, Jenkins A, Thomas K, A’Hern R, Jones RL, Blake P, et al.: A feasibility study of sequential doublet chemotherapy comprising carboplatin-doxorubicin and carboplatin-paclitaxel for advanced endometrial adenocarcinoma and carcinosarcoma. Ann Oncol 2009, 20(11):1787-1793.
• [2]Blay JY, von Mehren M, Samuels BL, Fanucchi MP, Ray-Coquard I, Buckley B, Gilles L, Lebedinsky C, Elsayed YA, Le Cesne A: Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma. Clin Cancer Res 2008, 14(20):6656-6662.
• [3]Hensley ML, Sill MW, Scribner DR Jr, Brown J, Debernardo RL, Hartenbach EM, McCourt CK, Bosscher JR, Gehrig PA: Sunitinib malate in the treatment of recurrent or persistent uterine leiomyosarcoma: a gynecologic oncology group phase II study. Gynecol Oncol 2009, 115(3):460-465.
• [4]Kantarjian H, Coutre PL, Cortes J, Pinilla-Ibarz J, Nagler A, Hochhaus A, Kimura S, Ottmann O: Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer 2010, 116(11):2665-2672.
• [5]Sleijfer S, Seynaeve C, Verweij J: Using single-agent therapy in adult patients with advanced soft tissue sarcoma can still be considered standard care. Oncologist 2005, 10(10):833-841.
• [6]Worden FP, Taylor JM, Biermann JS, Sondak VK, Leu KM, Chugh R, McGinn CJ, Zalupski MM, Baker LH: Randomized phase II evaluation of 6 g/m2 of ifosfamide plus doxorubicin and granulocyte colony-stimulating factor (G-CSF) compared with 12 g/m2 of ifosfamide plus doxorubicin and G-CSF in the treatment of poor-prognosis soft tissue sarcoma. J Clin Oncol 2005, 23(1):105-112.
• [7]Tascilar M, Loos WJ, Seynaeve C, Verweij J, Sleijfer S: The pharmacologic basis of ifosfamide use in adult patients with advanced soft tissue sarcomas. Oncologist 2007, 12(11):1351-1360.
• [8]Lashkari A, Chow WA, Valdes F, Leong L, Phan V, Twardowski P, Kapoor N, Molina A, Al-Kadhimi Z, Frankel P, et al.: Tandem high-dose chemotherapy followed by autologous transplantation in patients with locally advanced or metastatic sarcoma. Anticancer Res 2009, 29(8):3281-3288.
• [9]Maurel J, Lopez-Pousa A, de Las PR, Fra J, Martin J, Cruz J, Casado A, Poveda A, Martinez-Trufero J, Balana C, et al.: Efficacy of sequential high-dose doxorubicin and ifosfamide compared with standard-dose doxorubicin in patients with advanced soft tissue sarcoma: an open-label randomized phase II study of the Spanish group for research on sarcomas. J Clin Oncol 2009, 27(11):1893-1898.
• [10]Sleijfer S, Ouali M, van Glabbeke M, Krarup-Hansen A, Rodenhuis S, Le Cesne A, Hogendoorn PC, Verweij J, Blay JY: Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: an exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). Eur J Cancer 2010, 46(1):72-83.
• [11]Schiffer CA, Anderson KC, Bennett CL, Bernstein S, Elting LS, Goldsmith M, Goldstein M, Hume H, McCullough JJ, McIntyre RE, et al.: Platelet transfusion for patients with cancer: clinical practice guidelines of the american society of clinical oncology. J Clin Oncol 2001, 19(5):1519-1538.
• [12]Vadhan-Raj S: Management of chemotherapy-induced thrombocytopenia: current status of thrombopoietic agents. Semin Hematol 2009, 46(1 Suppl 2):S26-32.
• [13]Gordon MS, McCaskill-Stevens WJ, Battiato LA, Loewy J, Loesch D, Breeden E, Hoffman R, Beach KJ, Kuca B, Kaye J, et al.: A phase I trial of recombinant human interleukin-11 (neumega rhIL-11 growth factor) in women with breast cancer receiving chemotherapy. Blood 1996, 87(9):3615-3624.
• [14]Brown JR, Demetri GD: Challenges in the development of platelet growth factors: low expectations for low counts. Curr Hematol Rep 2002, 1(2):110-118.
• [15]Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, et al.: Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007, 357(22):2237-2247.
• [16]Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, et al.: Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 2009, 373(9664):641-648.
• [17]Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB: Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 2011, 377(9763):393-402.
• [18]Bussel JB, Psaila B, Saleh MN, Vasey S, Mayer B, Stone NL, Arning M: Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood 2008., 112(11) Abstract 3431 http://abstracts.hematologylibrary.org/cgi/content/abstract/112/11/3431?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=bussel&searchid=1&FIRSTINDEX=0&volume=112&issue=11&resourcetype=HWCIT webcite
• [19]Saleh MN, Cheng G, Bussel JB, Sun H, Mayer B, Bailey C, Brainsky A: EXTEND study update: safety and efficacy of eltrombopag in adults with chronic immune thrombocytopenia (ITP) from June 2006 to February 2010. Blood 2010., 116(21) Abstract 67 http://abstracts.hematologylibrary.org/cgi/content/abstract/116/21/67?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=saleh&searchid=1&FIRSTINDEX=0&volume=116&issue=21&resourcetype=HWCIT webcite
• [20]McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, Berg T, Gordon SC, Campbell FM, Theodore D, et al.: Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007, 357(22):2227-2236.
• [21]Afdhal N, Dusheiko G, Giannini EG, Chen P-J, Han K-H, Moshin A, Rodriguez-Torres M, Rugina S, Lawitz E, Shiffman ML, et al.: Final results of ENABLE 1, a phase 3, multicenter study of eltrombopag as an adjunct for antiviral treatment of hepatitis C virus-related chronic liver disease associated with thrombocytopenia. Hepatology 2011, 54(S1):100A. Abstract LB-3
• [22]Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, Patwardhan R, Messam C, Mostafa Kamel Y: A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin 2010, 26(10):2339-2346.
• [23]Cairo MS: Dose reductions and delays: limitations of myelosuppressive chemotherapy. Oncology (Williston Park) 2000, 14(9 Suppl 8):21-31.
• [24]Wu Y, Aravind S, Ranganathan G, Martin A, Nalysnyk L: Anemia and thrombocytopenia in patients undergoing chemotherapy for solid tumors: a descriptive study of a large outpatient oncology practice database, 2000–2007. Clin Ther 2009, 31(Pt 2):2416-2432.