Defibrotide TMA Prophylaxis Pilot Trial

NCT03384693 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 17-23356
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

Thrombotic microangiopathy (TMA) is a common complication in the stem cell transplant population. Certain populations within the hematopoietic stem cell transplant (HSCT) population are at a higher risk than others. Defibrotide is an endothelial stabilizing agent which may prevent the endothelial damage that triggers TMA in HSCT patients. The feasibility, safety, and efficacy of defibrotide prophylaxis in a pediatric transplant population is unknown. Twenty five patients age 0 to 30 years receiving autologous or allogeneic hematopoeitic stem cell transplant who meet TMA high risk criteria will be enrolled. Patients will receive Defibrotide for 28-35 days starting before conditioning, and will be closely monitored for any adverse events up through 6 months post-transplant. The feasibility of administering defibrotide will be evaluated as well as incidence of TMA.

Conditions

Thrombotic Microangiopathies

Keywords

hematopoeitic stem cell transplant; prophylactic defibrotide

Outcome Measures

Primary Outcomes (4)

• Percent of Total Doses of Defibrotide That Were Missed [Feasibility]

  Feasibility will be determined with regard to administration concurrently with chemotherapy and supportive medications before, during, and after stem cell infusion.

  From first treatment with study drug to day +21 post Transplant

• Participants With Reportable Serious Adverse Events [Safety] Per CTACAE v5 Grade 3 or Higher

  Safety was assessed by evaluating drug-related Serious Adverse Events per CTACAE v5 that occur after prophylactic administration of defibrotide. Analyses will be performed for all patients having received at least one dose of study drug.

  From first treatment with study drug to 6 months post-transplant

• Participants With Clinically Significant Bleeding Requiring Discontinuation of Therapy [Safety]

  Bleeding was assessed using Common Toxicity Criteria for Adverse Events version 4.03. (CTCAE). Study drug was permanently discontinued at grade 3 bleeding or higher. Analyses will be performed for all patients having received at least one dose of study drug.

  From first treatment with study drug to 6 months post-transplant

• Participants With Hypersensitivity Reaction Requiring Discontinuation of Therapy [Safety]

  Hypersensitivity reaction will be assessed using Common Toxicity Criteria for Adverse Events version 4.03. For grade 2 hypersensitivity reaction, study drug will be held until it resolves to grade 1 or lower. Study drug will be permanently discontinued at grade 3 hypersensitivity reaction or higher. Analyses will be performed for all patients having received at least one dose of study drug.

  From first treatment with study drug to 6 months post-transplant

Secondary Outcomes (2)

• Number of Patients With TMA Enrolled on the Study

  6 months post-transplant

• Number of Patients With Severe TMA

  6 months post-transplant

Other Outcomes (3)

• Incidence of Elevation of Single or Combination of Biomarkers Predictive of Development of TMA

  6 months post-transplant

• Incidence of TMA

  Day 30, day 100 and day 180 post-transplant

• Non Relapse Mortality

  Day 100 and day 180 post-transplant

Study Arms (1)

Prophylactic Defibrotide

EXPERIMENTAL

6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated.

Drug: Defibrotide

Interventions

Defibrotide DRUG

Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.

Also known as: Defitelio

Prophylactic Defibrotide

Eligibility Criteria

• Age: Up to 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age 0-30 years of age
• Life expectancy \> 6 months
• Eastern Cooperative Oncology Group or Karnofsky Performance Status \>40
• Meets minimum organ function requirements per institutional standard of care guiding clearance for autologous or allogeneic stem cell transplantation.
• Patients must meet TMA High-Risk criteria 5A or 5B below:
• A. Patients undergoing tandem autologous transplant with thiotepa in one or more of the conditioning regimens
• OR:
• B. . Patients with at least 3 of the following characteristics:
• \>10 years of age
• Non-Caucasian race/ Hispanic ethnicity
• Undergoing haploidentical transplant
• Minor ABO blood group mismatch

You may not qualify if:

• Age \>30 years
• Life expectancy \< 6 months
• Known bleeding diathesis or bleeding risk deemed by the treating physician to be a contraindication to administration of anticoagulants.
• Known hypersensitivity reaction to defibrotide
• Any patient not meeting TMA High-Risk criteria
• Pregnant women are excluded from this study because they will be receiving teratogenic therapy as part of the stem cell transplant.

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (1)

Benioff Children's Hospital at UCSF Medical Center

San Francisco, California, 94143, United States

Location

Related Publications (18)

• Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Kim DW, Lee JW, Min WS, Park CW. Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010 Oct 27;90(8):918-26. doi: 10.1097/TP.0b013e3181f24e8d.

  PMID: 20717073 BACKGROUND

• Choi CM, Schmaier AH, Snell MR, Lazarus HM. Thrombotic microangiopathy in haematopoietic stem cell transplantation: diagnosis and treatment. Drugs. 2009;69(2):183-98. doi: 10.2165/00003495-200969020-00004.

  PMID: 19228075 BACKGROUND

• Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, Boelens JJ, Hewitt A, Schrum J, Schulz AS, Muller I, Stein J, Wynn R, Greil J, Sykora KW, Matthes-Martin S, Fuhrer M, O'Meara A, Toporski J, Sedlacek P, Schlegel PG, Ehlert K, Fasth A, Winiarski J, Arvidson J, Mauz-Korholz C, Ozsahin H, Schrauder A, Bader P, Massaro J, D'Agostino R, Hoyle M, Iacobelli M, Debatin KM, Peters C, Dini G. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012 Apr 7;379(9823):1301-9. doi: 10.1016/S0140-6736(11)61938-7. Epub 2012 Feb 23.

  PMID: 22364685 BACKGROUND

• Corti P, Uderzo C, Tagliabue A, Della Volpe A, Annaloro C, Tagliaferri E, Balduzzi A. Defibrotide as a promising treatment for thrombotic thrombocytopenic purpura in patients undergoing bone marrow transplantation. Bone Marrow Transplant. 2002 Mar;29(6):542-3. doi: 10.1038/sj.bmt.1703414. No abstract available.

  PMID: 11960280 BACKGROUND

• Jodele S, Dandoy CE, Myers KC, El-Bietar J, Nelson A, Wallace G, Laskin BL. New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Transfus Apher Sci. 2016 Apr;54(2):181-90. doi: 10.1016/j.transci.2016.04.007. Epub 2016 Apr 25.

  PMID: 27156964 BACKGROUND

• Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, Myers K, Grimley M, Bleesing J, El-Bietar J, Wallace G, Chima RS, Paff Z, Laskin BL. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014 Jul 24;124(4):645-53. doi: 10.1182/blood-2014-03-564997. Epub 2014 May 29.

  PMID: 24876561 BACKGROUND

• Jodele S, Zhang K, Zou F, Laskin B, Dandoy CE, Myers KC, Lane A, Meller J, Medvedovic M, Chen J, Davies SM. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. 2016 Feb 25;127(8):989-96. doi: 10.1182/blood-2015-08-663435. Epub 2015 Nov 24.

  PMID: 26603840 BACKGROUND

• Kim SS, Patel M, Yum K, Keyzner A. Hematopoietic stem cell transplant-associated thrombotic microangiopathy: review of pharmacologic treatment options. Transfusion. 2015 Feb;55(2):452-8. doi: 10.1111/trf.12859. Epub 2014 Sep 11.

  PMID: 25209960 BACKGROUND

• Kojouri K, George JN. Thrombotic microangiopathy following allogeneic hematopoietic stem cell transplantation. Curr Opin Oncol. 2007 Mar;19(2):148-54. doi: 10.1097/CCO.0b013e3280148a2f.

  PMID: 17272988 BACKGROUND

• Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood. 2011 Aug 11;118(6):1452-62. doi: 10.1182/blood-2011-02-321315. Epub 2011 May 19.

  PMID: 21596850 BACKGROUND

• Obut F, Kasinath V, Abdi R. Post-bone marrow transplant thrombotic microangiopathy. Bone Marrow Transplant. 2016 Jul;51(7):891-7. doi: 10.1038/bmt.2016.61. Epub 2016 Mar 14.

  PMID: 26974272 BACKGROUND

• Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D, Elias AD, Antin JH, Soiffer R, Spitzer T, Avigan D, Bearman SI, Martin PL, Kurtzberg J, Vredenburgh J, Chen AR, Arai S, Vogelsang G, McDonald GB, Guinan EC. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood. 2002 Dec 15;100(13):4337-43. doi: 10.1182/blood-2002-04-1216. Epub 2002 Aug 1.

  PMID: 12393437 BACKGROUND

• Rosenthal J. Hematopoietic cell transplantation-associated thrombotic microangiopathy: a review of pathophysiology, diagnosis, and treatment. J Blood Med. 2016 Sep 2;7:181-6. doi: 10.2147/JBM.S102235. eCollection 2016.

  PMID: 27621680 BACKGROUND

• Uderzo C, Bonanomi S, Busca A, Renoldi M, Ferrari P, Iacobelli M, Morreale G, Lanino E, Annaloro C, Volpe AD, Alessandrino P, Longoni D, Locatelli F, Sangalli H, Rovelli A. Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation. 2006 Sep 15;82(5):638-44. doi: 10.1097/01.tp.0000230373.82376.46.

  PMID: 16969286 BACKGROUND

• Uderzo C, Fumagalli M, De Lorenzo P, Busca A, Vassallo E, Bonanomi S, Lanino E, Dini G, Varotto S, Messina C, Miniero R, Valsecchi MG, Balduzzi A. Impact of thrombotic thrombocytopenic purpura on leukemic children undergoing bone marrow transplantation. Bone Marrow Transplant. 2000 Nov;26(9):1005-9. doi: 10.1038/sj.bmt.1702648.

  PMID: 11100281 BACKGROUND

• Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, Sorror ML, Horowitz MM, Bolwell B, Rizzo JD, Socie G. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011 Jun 1;29(16):2230-9. doi: 10.1200/JCO.2010.33.7212. Epub 2011 Apr 4.

  PMID: 21464398 BACKGROUND

• Yeates L, Slatter MA, Bonanomi S, Lim FLWI, Ong SY, Dalissier A, Barberi W, Shulz A, Duval M, Heilmann C, Willekens A, Hwang WHY, Uderzo C, Bader P, Gennery AR. Use of defibrotide to treat transplant-associated thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation. Bone Marrow Transplant. 2017 May;52(5):762-764. doi: 10.1038/bmt.2016.351. Epub 2017 Jan 16. No abstract available.

  PMID: 28092354 BACKGROUND

• Higham CS, Shimano KA, Melton A, Kharbanda S, Chu J, Dara J, Winestone LE, Hermiston ML, Huang JN, Dvorak CC. A pilot trial of prophylactic defibrotide to prevent serious thrombotic microangiopathy in high-risk pediatric patients. Pediatr Blood Cancer. 2022 May;69(5):e29641. doi: 10.1002/pbc.29641. Epub 2022 Mar 6.

  PMID: 35253361 DERIVED

MeSH Terms

Conditions

Thrombotic Microangiopathies

Interventions

defibrotide

Condition Hierarchy (Ancestors)

Thrombocytopenia; Blood Platelet Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cytopenia

Limitations and Caveats

Limitations include: Small single institution non-randomized trial. Combination of two separate patient populations at high-risk for TA-TMA allowed for a more robust study, but smaller numbers of patients in each of the groups limits sub-analysis. Some interesting preliminary findings with study biomarkers but the study is too small to draw definitive conclusions regarding utility. No current CLIA-approved lab measuring ANG-2, limiting applicability of this test to the clinical setting.

Results Point of Contact

• Title: Dr. Christine Higham
• Organization: University of California, San Francisco

christine.higham@ucsf.edu

415-476-2188

Study Officials

• Christine Higham, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Defibrotide 6.25mg/kg administered intravenously for 28-35 days

Study Record Dates

• First Submitted: December 11, 2017
• First Posted: December 27, 2017
• Study Start: May 1, 2018
• Primary Completion: July 31, 2020
• Study Completion: July 31, 2020
• Last Updated: September 16, 2021
• Results First Posted: September 16, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Beginning 3 months and ending 5 years following article publication
• Access Criteria: Researchers can submit a request for access to the study Steering Committee. If the proposal is determined to be methodologically sound, data requestors will need to sign a data access agreement prior to gaining access.

Locations

US (1)