A Pilot Study of a Thrombopoietin-Receptor Agonist, Eltrombopag, in Patients With Low to Int-2 Risk Myelodysplastic Syndrome (MDS)

NCT00961064 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 09019909-H-0199
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Myelodysplastic syndromes (MDS) are bone marrow disorders characterized by anemia, neutropenia, and thrombocytopenia (low red blood cell, white blood cell, and platelet counts). Patients with MDS are at risk for symptomatic anemia, infection, and bleeding, as well as a risk of progression to acute leukemia. Standard treatments for MDS have significant relapse rates. MDS patients with thrombocytopenia who fail standard therapies require regular, expensive, and inconvenient platelet transfusions, and are at risk for further serious bleeding complications.
• Eltrombopag is a drug designed to mimic the protein thrombopoietin, which causes the body to make more platelets. Eltrombopag has been able to increase platelet counts in healthy volunteers and in patients with chronic ITP (a disease where patients destroy their own platelets very rapidly and thus develop thrombocytopenia), but researchers do not know if the drug can increase platelet counts in patients with MDS. Objectives:
• To find out whether eltrombopag can improve platelet counts in patients with MDS.
• To determine whether eltrombopag is safe for patients with MDS. Eligibility:
• Patients 18 years of age and older who have consistently low blood platelet counts related to MDS that has not responded to conventional treatment.
• Platelet count ≤ 30,000/μL or platelet-transfusion-dependence (requiring at least 4 platelet transfusions in the 8 weeks prior to study entry); OR hemoglobin less than 9.0 gr/dL or red cell transfusion-dependence (requiring at least 4 units of PRBCs in the eight weeks prior to study entry) OR ANC≤500 Design:
• Treatment with eltrombopag tablets once per day for 16-20 weeks.
• Participants will be monitored closely throughout the initial treatment, with weekly blood tests and separate evaluations at the National Institutes of Health (NIH) treatment center every 4 weeks. Bone marrow biopsies may be conducted to check for abnormalities in bone marrow.
• If patients show signs of improved platelet counts after 90 days, treatment will continue with additional doses of eltrombopag.
• Patients who discontinue taking eltrombopag will be evaluated at the NIH treatment center 4 weeks after ending treatment, and again 6 months after ending treatment to check for potential side effects.

Conditions

Myelodysplastic Syndromes; Thrombocytopenia

Keywords

Hematopoiesis; Thrombocytopenia; Autoimmunity; Megakaryocytes; Bone Marrow Fibrosis; Myelodysplastic Syndrome; MDS

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Response Between Weeks 16 and 20

  The primary endpoint was hematologic response at 16 or 20 weeks, defined as either: (1) an increase in platelet counts =20.000/uL or transfusion independence for a minimum of 8 weeks; (2) hemoglobin (Hb) increase of =1.5g/dL from baseline, or a reduction in red blood cells (RBC) transfusion of at least 50%; or (3) an increase in absolute neutrophil counts (ANC) of =0.5x109/L or by at least 100% in patients with a baseline ANC \<0.5x109/L.

  16 - 20 weeks

Secondary Outcomes (4)

• Changes in Serum Thrombopoietin Level

  16 - 20 weeks

• Number of Participants With Progression to Higher Risk Myelodysplastic Syndrome as Measured by International Working Group Criteria

  up to 5 years

• Number of Participants Who Achieved a Robust Response and Discontinued Eltrombopag

  up to 5 years

• Number of Participants With Grade 2 or Higher Bleeding Events Defined by Common Terminology Criteria for Adverse Events v. 4.0

  up to 5 years

Study Arms (1)

Eltrombopag in Low to Int-2 Risk Myelodysplastic Syndrome (MDS)

EXPERIMENTAL

Eltrombopag will be initiated at 50 mg/day (Asians 25 mg/day) and dose adjusted up to 150mg/day based response and safety in participants with Low to Int-2 Risk Myelodysplastic Syndrome (MDS)

Drug: Eltrombopag

Interventions

Eltrombopag DRUG

Eltrombopag will be initiated at 50 mg/day (Asians 25 mg/day) and dose adjusted up to 150mg/day based response and safety

Also known as: PROMACTA

Eltrombopag in Low to Int-2 Risk Myelodysplastic Syndrome (MDS)

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of MDS, with WHO classification of refractory anemia, refractory cytopenia with unilineage dysplasia (RCUD), RARS, RCMD-RS, or RCMD.
• IPSS risk scores of low, intermediate-1, or intermediate-2.
• Platelet count less than or equal to 30,000/ microL or platelet-transfusion-dependence (requiring at least 4 platelet transfusions in the 8 weeks prior to study entry); or hemoglobin less than 9.0 gr/dL or red cell transfusion-dependence (requiring at least 4 units of PRBCs in the eight weeks prior to study entry) OR ANC less than or equal to 500
• Age greater than or equal to 18 years old
• Treatment naive or off all other treatments for MDS (except stable dosing of filgrastim \[G-CSF\], erythropoietin, and transfusion support) for at least four weeks. G-CSF can be used before, during and after the protocol treatment for subjects with documented neutropenia (\<500/UI) as long as they meet the criteria for other cytopenia as stated above. G-CSF must be held for 3 weeks prior to enrollment bone marrow biopsy and prior to each study assessment bone marrow biopsy, unless clinically indicated to avoid infections per PI discretion.
• Adequate liver function, as evidenced by total serum bilirubin less than or equal to 1.5 times the upper limit of normal patients with Gilbert's disease are eligible, provided intermittent indirect hyperbilirubinemia, AST or ALT less than or equal to 5 times the upper limit of normal.
• A serum creatinine concentration less than or equal to 2 times ULN

You may not qualify if:

• WHO classification of chronic myelomonocytic leukemia (CMML), RAEB-1, RAEB-2, AML
• Treatment with horse or rabbit ATG or Campath within 6 months of study entry
• Subjects with liver cirrhosis including subjects infected with Hepatitis B or C
• Subjects with HIV
• Infection not adequately responding to appropriate therapy
• History of malignancy treated with chemotherapy and cytogenetic abnormalities suggestive of secondary myelodysplasia.
• Moribund status or concurrent hepatic, renal, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy
• Life expectancy of less than 3 months
• 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
• Unable to understand the investigational nature of the study or give informed consent or does not have a legally authorized representative or surrogate that can provide informed consent per section

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)

• Kantarjian H, Giles F, List A, Lyons R, Sekeres MA, Pierce S, Deuson R, Leveque J. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007 May 1;109(9):1705-14. doi: 10.1002/cncr.22602.

  PMID: 17366593 BACKGROUND

• Houwerzijl EJ, Blom NR, van der Want JJ, Vellenga E, de Wolf JT. Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death. Leukemia. 2006 Nov;20(11):1937-42. doi: 10.1038/sj.leu.2404385. Epub 2006 Sep 7.

  PMID: 16990774 BACKGROUND

• Kalina U, Hofmann WK, Koschmieder S, Wagner S, Kauschat D, Hoelzer D, Ottmann OG. Alteration of c-mpl-mediated signal transduction in CD34(+) cells from patients with myelodysplastic syndromes. Exp Hematol. 2000 Oct;28(10):1158-63. doi: 10.1016/s0301-472x(00)00527-0.

  PMID: 11027834 BACKGROUND

• Giudice V, Feng X, Lin Z, Hu W, Zhang F, Qiao W, Ibanez MDPF, Rios O, Young NS. Deep sequencing and flow cytometric characterization of expanded effector memory CD8+CD57+ T cells frequently reveals T-cell receptor Vbeta oligoclonality and CDR3 homology in acquired aplastic anemia. Haematologica. 2018 May;103(5):759-769. doi: 10.3324/haematol.2017.176701. Epub 2018 Feb 1.

  PMID: 29419434 DERIVED

• Hosokawa K, Kajigaya S, Feng X, Desierto MJ, Fernandez Ibanez MD, Rios O, Weinstein B, Scheinberg P, Townsley DM, Young NS. A plasma microRNA signature as a biomarker for acquired aplastic anemia. Haematologica. 2017 Jan;102(1):69-78. doi: 10.3324/haematol.2016.151076. Epub 2016 Sep 22.

  PMID: 27658437 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Myelodysplastic Syndromes; Thrombocytopenia; Autoimmune Diseases; Primary Myelofibrosis

Interventions

eltrombopag

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Blood Platelet Disorders; Cytopenia; Immune System Diseases; Myeloproliferative Disorders

Limitations and Caveats

The first five participants enrolled were entered when eligibility criteria included only thrombocytopenia. They were not included in the efficacy analysis set, as requested by the Institutional Review Board, but were included for secondary endpoint and sensitivity analyses.

Results Point of Contact

• Title: Bhavisha Patel, MD
• Organization: National Heart Lung and Blood Institute

bhavisha.patel@nih.gov

301.402.3477

Study Officials

• Neal S Young, 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: August 15, 2009
• First Posted: August 18, 2009
• Study Start: March 15, 2011
• Primary Completion: August 10, 2017
• Study Completion: December 30, 2021
• Last Updated: November 14, 2023
• Results First Posted: August 22, 2019

Record last verified: 2023-11

Locations

US (1)