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

Acute Myeloid Leukemia Clinical Trial

— PGX-AML  

Official title:

A Pilot Study to Evaluate the Safety and Preliminary Evidence of an Effect of ODSH (2 O, 3-O Desulfated Heparin) in Accelerating Platelet Recovery in Patients Receiving Induction or Consolidation Therapy for Acute Myeloid Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02056782
• Other study ID #: PGX-ODSH-2013-AML-1
• Status: Completed
• Phase: Phase 1
• Start date: December 2013
• Est. completion date: June 2015

Study information

• Verified date: May 2022
• Source: Chimerix
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Description:

The primary objectives of this study were the following: 1. To evaluate the safety and tolerability of dociparstat in patients with acute myeloid leukemia (AML) receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy. 2. To determine whether there is preliminary evidence of an effect of dociparstat on time to transfusion-independent platelet recovery in AML patients receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy. The secondary objectives of this study were the following: 1. To determine whether there is preliminary evidence of an effect of dociparstat on remission rate following cytarabine and idarubicin induction in AML patients. 2. To determine whether there is preliminary evidence of an effect of dociparstat on improving platelet nadir counts in AML patients receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy. 3. To determine whether there is preliminary evidence of an effect of dociparstat on decreasing the number of platelet transfusions in AML patients receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy. 4. To determine whether there is preliminary evidence of an effect of dociparstat on reducing overall side effects of chemotherapy in AML patients receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy. This study enrolled patients with newly diagnosed, previously untreated AML; subjects with acute promyelocytic leukemia and acute megakaryoblastic leukemia subtypes were excluded. All patients were to receive standard induction chemotherapy with cytarabine 100 mg/m2/day by continuous intravenous (IV) infusion over 24 hours daily for 7 days (Days 1-7) plus idarubicin 12 mg/m2/day by IV injection daily for 3 days (Days 1-3). For consolidation, patients younger than 60 were to receive cytarabine at a dose of 3 grams/m2 over 3 hours, every 12 hours on days 1, 3, and 5. Induction cycle: dociparstat 4 mg/kg IV bolus Day 1, 30 minutes after completion of administration of the first dose of idarubicin, then dociparstat 0.25 mg/kg/hour for 24 hours daily by continuous IV infusion Days 1-7. Consolidation cycle: dociparstat mg/kg IV bolus Day 1 administered 30 minutes after completion of infusion of the first dose of cytarabine then dociparstat 0.25 mg/kg/hour for 24 hours daily by continuous IV infusion Days 1-5 In total, there were 7 days in the induction cycle and 5 days in the consolidation cycles.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: June 2015
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

All patients had to meet the following criteria to be eligible for this study:

1. Had newly diagnosed, previously untreated acute myeloid leukemia (AML). Acute promyelocytic leukemia and acute megakaryoblastic leukemia subtypes were excluded

2. Had no prior chemotherapy for AML; however, prior hydroxyurea to control white blood cell count was allowed

3. Was aged 18 years or older.

4. Had an Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2.

5. Had a cardiac ejection fraction = 50% (echocardiography or Multi-Gated Acquisition Scan [MUGA]).

6. Had adequate hepatic and renal function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin and creatinine < 2.5 x upper normal limit).

7. Was able to provide informed consent and signed an approved consent form that conformed to federal and institutional guidelines. Exclusion Criteria: Patients who met any of the following criteria were not eligible to be enrolled in this

study:

1. Had acute promyelocytic leukemia.

2. Had acute megakaryoblastic leukemia.

3. Had central nervous system (CNS) leukemia

4. Had the presence of uncontrolled bleeding.

5. Had the presence of significant active infection that was uncontrolled, as judged by the Investigator.

6. Had a history of severe congestive heart failure or other cardiac disease that contraindicated the use of anthracyclines, including idarubicin.

7. Had pre-existing liver disease.

8. Had renal insufficiency, which, in the opinion of the Investigator, might have adversely affected the schedule and dose of therapy with cytarabine, as well as the management of tumor lysis syndrome. Patients with creatinine levels =2 mg/dL were not eligible.

9. Had use of recreational drugs or history of drug addiction, within the prior 6 months.

10. Had known history of positive hepatitis B surface antigens or hepatitis C virus (HCV) antibodies.

11. Had known history of positive test for human immunodeficiency virus (HIV) antibodies

12. Had psychiatric or neurologic conditions that could have compromised patient safety or compliance, or interfered with the ability to give proper informed consent.

13. Had history of other active malignant disease within 5 years, other than cured basal cell carcinoma of the skin, cured in situ carcinoma of the cervix, or localized prostate cancer that had received definitive therapy. Such prostate cancer patients who were receiving hormonal therapy were eligible.

14. Had the presence of disseminated intravascular coagulation, as confirmed by laboratory studies demonstrating evidence of both increased thrombin generation (decreased fibrinogen, prolonged prothrombin time [PT] and partial thromboplastin time [aPTT]), as well as increased fibrinolysis (elevated D-dimer level).

15. Had received any form of anticoagulant therapy.

16. Had the presence of a known bleeding disorder or coagulation abnormality.

17. Had received treatment with any other investigational agent within 7 days prior to study entry. All prior toxicities should have been resolved to no greater than Grade 1 (with the exception of alopecia).

18. Were pregnant or breast-feeding patients.

19. Were of childbearing potential and were not using adequate contraception.

20. Had any condition that required maintenance of platelet counts at 50,000/µL or higher.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Dociparstat sodium
The following induction regimen was administered: Cytarabine (100 mg/m2/day) via continuous intravenous (IV) infusion 24 hours daily for 7 days. Idarubicin (12 mg/m2/day) IV on Days 1, 2, and 3. Dociparstat (4 mg/kg) given over 5 minutes IV, immediately after the idarubicin dose on Day 1, followed by a continuous IV infusion (0.25 mg/kg/hr for 24 hours daily) for a total of 7 days.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Chimerix	Translational Drug Development

References & Publications (31)

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. — View Citation

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. Erratum In: J Clin Oncol. 2004 Feb 1;22(3):576. LoCocco, Francesco [corrected to Lo-Coco, Francesco]. — View Citation

Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26;404-413, 1934.

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. — View Citation

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.

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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.

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Stroncek DF, Rebulla P. Platelet transfusions. Lancet. 2007 Aug 4;370(9585):427-38. doi: 10.1016/S0140-6736(07)61198-2. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 31 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time (Days) to Transfusion-independent Platelet Recovery (Platelet Counts Values = 20,000/µL and = 50,000/µL Without a Platelet Transfusion)	A primary endpoint of this study was evidence of an effect of dociparstat on transfusion independent platelet recovery time. The time (days) to transfusion-independent platelet recovery will be defined as the number of days from the first day of chemotherapy until the first of 5 consecutive days with platelet counts values = 20,000/µL and = 50,000/µL without a platelet transfusion.	Day 1 to Day 35 (35 days)
Secondary	Number of Subjects Who Achieved a Morphologic Complete Remission	A secondary endpoint of this study was to determine whether there was preliminary evidence of an effect of dociparstat on remission rate following cytarabine and idarubicin induction in acute myeloid leukemia (AML) patients, which included complete remission (CR) rate (with neutrophil and platelet count recovery) after the first induction cycle.; Morphologic CR was defined as absolute neutrophil count (ANC) >1000/µL, platelet count >100,000/µL, <5% bone marrow blasts, no Auer rods, and no evidence of extramedullary disease.	Day 1 to Day 35 (35 days)