A Pilot Study of Dociparstat Sodium (ODSH) in Acute Myeloid Leukemia

Summary

This was an open-label pilot study that evaluated the safety and preliminary evidence of a therapeutic effect of dociparstat in conjunction with standard induction and consolidation therapy for acute myeloid leukemia (AML).

Timeline

Start

2013-12

Primary completion

2015-02

Completion

2015-06

Publications

• Background Greer JP, Baer MR, Kinney MC. Acute Myelogenous Leukemia in Adults. In Wintrobe's Clinical Hematology. Lee GR et al ed. Williams and Wilkins, Baltimore, 2098-2142, 2004.
• Background Stroncek DF, Rebulla P. Platelet transfusions. Lancet. 2007 Aug 4;370(9585):427-38. doi: 10.1016/S0140-6736(07)61198-2.
• Background Kuter DJ. What is the potential for thrombopoietic agents in acute leukemia? Best Pract Res Clin Haematol. 2011 Dec;24(4):553-8. doi: 10.1016/j.beha.2011.09.002. Epub 2011 Nov 4.
• Background Trafalis DT, Poulakidas E, Kapsimali V, Tsigris C, Papanicolaou X, Harhalakis N, Nikiforakis E, Mentzikof-Mitsouli C. Platelet production and related pathophysiology in acute myelogenous leukemia at first diagnosis: prognostic implications. Oncol Rep. 2008 Apr;19(4):1021-6.
• Background Stasi R, Bosworth J, Rhodes E, Shannon MS, Willis F, Gordon-Smith EC. Thrombopoietic agents. Blood Rev. 2010 Jul-Sep;24(4-5):179-90. doi: 10.1016/j.blre.2010.04.002. Epub 2010 May 20.
• Background Majka M, Janowska-Wieczorek A, Ratajczak J, Kowalska MA, Vilaire G, Pan ZK, Honczarenko M, Marquez LA, Poncz M, Ratajczak MZ. Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis. Blood. 2000 Dec 15;96(13):4142-51.
• Background Lambert MP, Rauova L, Bailey M, Sola-Visner MC, Kowalska MA, Poncz M. Platelet factor 4 is a negative autocrine in vivo regulator of megakaryopoiesis: clinical and therapeutic implications. Blood. 2007 Aug 15;110(4):1153-60. doi: 10.1182/blood-2007-01-067116. Epub 2007 May 10.
• Background Lambert MP, Reznikov A, Grubbs A, Nguyen Y, Xiao L, Aplenc R, Rauova L, Poncz M. Platelet factor 4 platelet levels are inversely correlated with steady-state platelet counts and with platelet transfusion needs in pediatric leukemia patients. J Thromb Haemost. 2012 Jul;10(7):1442-6. doi: 10.1111/j.1538-7836.2012.04767.x. No abstract available.
• Background Lambert MP, Xiao L, Nguyen Y, Kowalska MA, Poncz M. The role of platelet factor 4 in radiation-induced thrombocytopenia. Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1533-40. doi: 10.1016/j.ijrobp.2011.03.039.
• Background Joglekar MV, Quintana Diez PM, Marcus S, Qi R, Espinasse B, Wiesner MR, Pempe E, Liu J, Monroe DM, Arepally GM. Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH). Thromb Haemost. 2012 Apr;107(4):717-25. doi: 10.1160/TH11-11-0795. Epub 2012 Feb 8.
• Background Lambert MP, Sharma SS, Xiao L, Marcus S et al. 2-O, 3-O-Desulfated Heparin (ODSH) Mitigates Chemotherapy-Induced Thrombocytopenia (CIT) by Blocking the Negative Paracrine Effect of Platelet Factor 4 (PF4) On Megakaryopoiesis. Proceedings of the 54th Annual Meeting of the American Society of Hematology. Abstract 386, 2012.
• Background Yang L, Yu Y, Kang R, Yang M, Xie M, Wang Z, Tang D, Zhao M, Liu L, Zhang H, Cao L. Up-regulated autophagy by endogenous high mobility group box-1 promotes chemoresistance in leukemia cells. Leuk Lymphoma. 2012 Feb;53(2):315-22. doi: 10.3109/10428194.2011.616962. Epub 2011 Nov 15.
• Background Kang R, Tang D, Schapiro NE, Livesey KM, Farkas A, Loughran P, Bierhaus A, Lotze MT, Zeh HJ. The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ. 2010 Apr;17(4):666-76. doi: 10.1038/cdd.2009.149. Epub 2009 Oct 16.
• Background Rao NV, Argyle B, Xu X, Reynolds PR, Walenga JM, Prechel M, Prestwich GD, MacArthur RB, Walters BB, Hoidal JR, Kennedy TP. Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands. Am J Physiol Cell Physiol. 2010 Jul;299(1):C97-110. doi: 10.1152/ajpcell.00009.2010. Epub 2010 Apr 7.
• Background Abe R, Shimizu T, Sugawara H, Watanabe H, Nakamura H, Choei H, Sasaki N, Yamagishi S, Takeuchi M, Shimizu H. Regulation of human melanoma growth and metastasis by AGE-AGE receptor interactions. J Invest Dermatol. 2004 Feb;122(2):461-7. doi: 10.1046/j.0022-202X.2004.22218.x.
• Background Logsdon CD, Fuentes MK, Huang EH, Arumugam T. RAGE and RAGE ligands in cancer. Curr Mol Med. 2007 Dec;7(8):777-89. doi: 10.2174/156652407783220697.
• Background Krauel K, Hackbarth C, Furll B, Greinacher A. Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies. Blood. 2012 Feb 2;119(5):1248-55. doi: 10.1182/blood-2011-05-353391. Epub 2011 Nov 2.
• Background Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. doi: 10.1200/JCO.2011.36.5742. Epub 2011 Oct 3.
• Background Ellerman JE, Brown CK, de Vera M, Zeh HJ, Billiar T, Rubartelli A, Lotze MT. Masquerader: high mobility group box-1 and cancer. Clin Cancer Res. 2007 May 15;13(10):2836-48. doi: 10.1158/1078-0432.CCR-06-1953.
• Background Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol. 2010;28:367-88. doi: 10.1146/annurev.immunol.021908.132603.
• Background Takada M, Hirata K, Ajiki T, Suzuki Y, Kuroda Y. Expression of receptor for advanced glycation end products (RAGE) and MMP-9 in human pancreatic cancer cells. Hepatogastroenterology. 2004 Jul-Aug;51(58):928-30.
• Background Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature. 2000 May 18;405(6784):354-60. doi: 10.1038/35012626.
• Background Tang D, Kang R, Cheh CW, Livesey KM, Liang X, Schapiro NE, Benschop R, Sparvero LJ, Amoscato AA, Tracey KJ, Zeh HJ, Lotze MT. HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene. 2010 Sep 23;29(38):5299-310. doi: 10.1038/onc.2010.261. Epub 2010 Jul 12.
• Background Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, Hoppe G, Bianchi ME, Tracey KJ, Zeh HJ 3rd, Lotze MT. Endogenous HMGB1 regulates autophagy. J Cell Biol. 2010 Sep 6;190(5):881-92. doi: 10.1083/jcb.200911078.
• Background Tang D, Loze MT, Zeh HJ, Kang R. The redox protein HMGB1 regulates cell death and survival in cancer treatment. Autophagy. 2010 Nov;6(8):1181-3. doi: 10.4161/auto.6.8.13367.
• Background Kang R, Tang D, Loze MT, Zeh HJ. Apoptosis to autophagy switch triggered by the MHC class III-encoded receptor for advanced glycation endproducts (RAGE). Autophagy. 2011 Jan;7(1):91-3. doi: 10.1038/cdd.2009.149. Epub 2011 Jan 1.
• Background Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. doi: 10.1200/JCO.2003.04.036.
• Background Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26;404-413, 1934.
• Background Harrill AH, Roach J, Fier I, Eaddy JS, Kurtz CL, Antoine DJ, Spencer DM, Kishimoto TK, Pisetsky DS, Park BK, Watkins PB. The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers. Clin Pharmacol Ther. 2012 Aug;92(2):214-20. doi: 10.1038/clpt.2012.40. Epub 2012 Jun 27.
• Background Liu L, Yang M, Kang R, Wang Z, Zhao Y, Yu Y, Xie M, Yin X, Livesey KM, Lotze MT, Tang D, Cao L. HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells. Leukemia. 2011 Jan;25(1):23-31. doi: 10.1038/leu.2010.225. Epub 2010 Oct 7.
• Background Tang D, Kang R, Zeh HJ 3rd, Lotze MT. High-mobility group box 1 and cancer. Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):131-40. doi: 10.1016/j.bbagrm.2009.11.014.

Drugs

Indications