A Pilot Study of the Thrombopoietin-Receptor Agonist Eltrombopag in Refractory Aplastic Anemia Patients

NCT00922883 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 09015409-H-0154
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

Severe aplastic anemia (SAA) is a life-threatening blood disease which can be effectively treated with immunosuppressive drug regimens or allogeneic stem cell transplantation. However, 20-40% of patients without transplant options do not respond to immunosuppressive therapies, and have persistent severe cytopenias, requiring regular platelet transfusions, which are expensive and inconvenient, and are a risk for further serious bleeding complications. Thrombopoietin (TPO) is the principal endogenous regulator of platelet production and also stimulates hematopoietic stem and progenitor cells. A small molecule oral TPO-agonist, eltrombopag has been shown to increase platelets in healthy subjects and in patients with immune thrombocytopenic purpura (ITP), and received FDA approval in 2008 for the treatment of thrombocytopenia in ITP. This Phase 2, non-randomized pilot study of eltrombopag in aplastic anemia patients with immunosuppressive therapy refractory thrombocytopenia will test the safety and potential efficacy of eltrombopag treatment patients with refractory thrombocytopenia following immunosuppression for aplastic anemia. Subjects will initiate study medication at an oral dose of 50 mg/day, which will be increased up to 150 mg/day as clinically indicated to the lowest dose that maintains a stable platelet count 20,000/(micro)L above baseline while maximizing tolerability. Response will be assessed at 3-4 months. Platelet response is defined as platelet count increases to 20,000/L above baseline at three months. or stable platelet counts with transfusion independence for a minimum of 8 weeks. Erythroid response for subjects with a pretreatment hemoglobin of less than 9 g/dL will be defined as an increase in hemoglobin by greater than or equal to 1.5g/dL without packed red blood cell (PRBC) transfusion support, or a reduction in the units of transfusions by an absolute number of at least 4 PRBC transfusions for eight consecutive weeks compared with the pretreatment transfusion number in the previous 8 weeks. Neutrophil response will be defined in those with a pretreatment absolute neutrophil count (ANC) of less than 0.5 times 10(9)/L as at least a 100 percent increase or an absolute increase greater than 0.5 times 10(9)/L. Subjects with response at 3-4 months may continue study medication (extended access) until they meet an off study criteria. The primary objective is to assess the safety and efficacy of the oral thrombopoietin receptor agonist (TPO-R agonist) eltrombopag in aplastic anemia patients with immunosuppressive-therapy refractory thrombocytopenia. Secondary objectives include the analysis of the incidence and severity of bleeding episodes, and the impact on quality of life.

Conditions

Anemia, Aplastic; Anemia, Hypoplastic; Thrombocytopenia

Keywords

Promacta; SAA; Aplastic Anemia; Thrombocytopenia

Outcome Measures

Primary Outcomes (1)

• The Portion of Drug Responders as Defined by Hematologic Improvements

  Defined as unilineage or multilineage recovery by 1 or more of the following: 1) platelet response (increase to 20 × 103/μL above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks in those who were transfusion dependent on entry into the protocol); (2) erythroid response (when pretreatment hemoglobin was \<9 g/dL, defined as an increase in hemoglobin by 1.5 g/dL or, in transfused patients, a reduction in the units of packed red blood cell transfusions by an absolute number of at least 4 transfusions for 8 consecutive weeks, compared with the pretreatment transfusion number in the previous 8 weeks); and (3) neutrophil response (when pretreatment absolute neutrophil count \[ANC\] of \<0.5 × 103/μL as at least a 100% increase in ANC, or an ANC increase \>0.5 × 103/μL, and the toxicity profile as measured using Common Terminology Criteria for Adverse Events).

  12-16 weeks

Study Arms (1)

Eltrombopag

EXPERIMENTAL

Eltrombopag (Promacta): Subjects commenced eltrombopag at a dose of 50 mg, which was increased by 25 mg every 2 weeks if the platelet count had not increased by 20 × 103/µL, to a maximum dose of 150 mg.

Drug: Eltrombopag

Interventions

Eltrombopag DRUG

Also known as: Promacta

Eltrombopag

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of aplastic anemia, with refractory thrombocytopenia following at least one treatment course of horse or rabbit ATG/cyclosporine.
• Platelet count less than or equal to 30,000/microL
• Age greater than or equal to 12 years old

You may not qualify if:

• Diagnosis of Fanconi anemia
• Infection not adequately responding to appropriate therapy
• Patients with a PNH clone size in neutrophils of greater than or equal to 50%
• HIV positivity
• Creatinine \> 2.5
• Bilirubin \> 2.0
• SGOT or SGPT \> 5 times the upper limit of normal
• Hypersensitivity to eltrombopag or its components
• Female subjects who are nursing or pregnant or are unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential
• History of malignancy other than localized tumors diagnosed more than one year previously and treated surgically with curative intent (for instance squamous cell or other skin cancers, stage 1 breast cancer, cervical carcinoma in situ, etc)
• Unable to understand the investigational nature of the study or give informed consent
• History of congestive heart failure arrhythmia requiring chronic treatment, arterial or venous thrombosis (not excluding line thrombosis) within the last 1 year, or myocardial infarction within 3 months before enrollment
• ECOG Performance Status of 3 or greater
• Treatment with horse or rabbit ATG or Campath within 6 months of study entry. Concurrent stable treatment with cyclosporine or G-CSF is permitted.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006 Oct 15;108(8):2509-19. doi: 10.1182/blood-2006-03-010777. Epub 2006 Jun 15.

  PMID: 16778145 BACKGROUND

• Emmons RV, Reid DM, Cohen RL, Meng G, Young NS, Dunbar CE, Shulman NR. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996 May 15;87(10):4068-71.

  PMID: 8639762 BACKGROUND

• Desmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, Bevans M, Parikh AR, Broder K, Calvo KR, Wu CO, Young NS, Dunbar CE. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014 Mar 20;123(12):1818-25. doi: 10.1182/blood-2013-10-534743. Epub 2013 Dec 17.

  PMID: 24345753 RESULT

• Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, Parikh AR, Soto S, Biancotto A, Feng X, Lozier J, Wu CO, Young NS, Dunbar CE. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012 Jul 5;367(1):11-9. doi: 10.1056/NEJMoa1200931.

  PMID: 22762314 RESULT

• Winkler T, Fan X, Cooper J, Desmond R, Young DJ, Townsley DM, Scheinberg P, Grasmeder S, Larochelle A, Desierto M, Valdez J, Lotter J, Wu C, Shalhoub RN, Calvo KR, Young NS, Dunbar CE. Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag. Blood. 2019 Jun 13;133(24):2575-2585. doi: 10.1182/blood.2019000478. Epub 2019 Apr 16.

  PMID: 30992268 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Aplastic; Thrombocytopenia

Interventions

eltrombopag

Condition Hierarchy (Ancestors)

Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Bone Marrow Diseases; Blood Platelet Disorders; Cytopenia

Results Point of Contact

• Title: Cynthia E Dunbar
• Organization: NHLBI

dunbarc@nhlbi.nih.gov

301-496-5093

Study Officials

• Cynthia E Dunbar, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: June 16, 2009
• First Posted: June 17, 2009
• Study Start: May 29, 2009
• Primary Completion: May 7, 2013
• Study Completion: April 24, 2018
• Last Updated: October 20, 2020
• Results First Posted: July 16, 2018

Record last verified: 2020-09

Locations

US (1)