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Eltrombopag for People With Fanconi Anemia

This study is not yet open for participant recruitment.
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Verified June 28, 2017 by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ) Identifier:
First received: June 30, 2017
Last updated: July 20, 2017
Last verified: June 28, 2017


Fanconi anemia is a genetic disease. Some people with it have reduced blood cell counts. This means their bone marrow no longer works properly. These people may need blood transfusions for anemia (low red blood cells) or low platelet counts or bleeding. Researchers want to see if a new drug will help people with this disease.


To find out if a new drug, eltrombopag, is effective in people with Fanconi anemia. To know how long the drug needs to be given to improve blood counts.


People at least 4 years old with Fanconi anemia with reduced blood cell counts.


Participants will be screened with blood and urine tests. They will repeat this before starting to take the study drug.

Participants will take eltrombopag pills by mouth once a day for 24 weeks. They will be monitored closely for side effects.

Participants will have blood tests every 2 weeks while on eltrombopag.

Participants will visit NIH 3 months and 6 months after starting eltrombopag. At these visits, participants will:

Answer questions about their medical history, how they are feeling, and their quality of life

Have a physical exam

Have blood and urine tests

Have a bone marrow sample taken by needle from the hip. The area will be numbed.

If participants blood cell counts improve, they might join the extended access part of the study. They will continue taking eltrombopag for 3 years and sign a different consent.

After 24 weeks of treatment, if there is no improvement in blood cell counts, participants will stop taking eltrombopag. They will return for an optional follow-up visit that repeats the study visits.

Condition Intervention Phase
Fanconi's Anemia Drug: Eltrombopag Phase 2

National Heart, Lung, and Blood Institute (NHLBI) has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Eltrombopag for Patients With Fanconi Anemia

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):

Primary Outcome Measures:
  • Proportion of drug responders [ Time Frame: 6 months ]
  • Toxicity profile [ Time Frame: 6 months ]

Secondary Outcome Measures:
  • Hematological responses [ Time Frame: At 3 Months ]
  • Relapse [ Time Frame: During 3 years of treatment ]
  • Clonal evolution [ Time Frame: 3 month,6 month (primary endpoint), every 6 month for 3 years after signing the extension part of the protocol. ]
  • Toxicities with extended duration of therapy [ Time Frame: 3 month,6 month (primary endpoint), every 6 month for 3 years after signing the extension part of the protocol. ]
  • Impact of treatment and treatment response on quality of life [ Time Frame: 3 month and 6 month ]
  • Evaluation of DNA repair activity in HSPCs (-H2AX Assay and comet assay) [ Time Frame: At baseline, 3 and 6 months. ]
  • Evaluation of global transcriptome in HSPCs (single cell RNA seq) [ Time Frame: At baseline and 6 months ]
  • Serum cytokine profile, i.e. TNF alpha, IFNgamma, TPO [ Time Frame: At baseline, 3 and 6 months ]
  • Multicolor flow cytometry of bone marrow cells [ Time Frame: At baseline, 3 and 6 months ]
  • Impact of EPAG on other organ systems commonly involved in FA (e.g. skin lesions, endocrine dysfunction, and incidence of new head/neck, oropharyngeal, gastrointestinal, anogenital or skin cancers by clinical assessment) [ Time Frame: At baseline, 3 and 6 months ]

Estimated Enrollment: 25
Anticipated Study Start Date: July 26, 2017
Estimated Study Completion Date: January 1, 2020
Estimated Primary Completion Date: January 1, 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group
Drug: Eltrombopag

Daily dose Non-Asian (greater than or equal to 12): 150 mg Non-Asian (6-11): 75 mg Non-Asian (4-5): 2.5 mg/kg

East Asian, South East Asian (greater than or equal to 12):

75 mg East Asian, South East Asian (6- 11): 37.5 mg

East Asian, South East Asian (4-5):

1.25 mg/kg

Detailed Description:

Fanconi anemia (FA) is a rare genetic disease that often presents as a bone marrow failure (BMF) syndrome but also can affect any other organ. Etiologically, loss of function mutations in more than 21 different gene members of the FA core complex (i.e. FANCA-FANCV) have been associated with FA. The FA core complex is involved in interstrand cross-link DNA damage repair during cell division. Impaired DNA repair causes genomic instability which consequently can cause apoptosis of the cell or malignant transformation. In addition to impaired DNA repair mechanisms, FA cells exhibit increased sensitivity to pro-inflammatory cytokines (e.g. IFN- >=, TNF- ) and elevated levels of these cytokines have been associated with bone marrow failure in subjects with FA and other inherited bone marrow failure syndromes.

Patients with FA may present with congenital anomalies, such as microcephaly or short stature. However, the failure of the hematopoietic stem cell (HSC) compartment to produce sufficient numbers of peripheral blood cells, and progression to myelodysplastic syndrome (MDS) and acute myelogenous leukemia are the greatest risk factors for morbidity and mortality, particular in young patients with FA In a few reported cases, spontaneous somatic reversion of inherited mutations has resulted in a selective growth advantage of corrected HSCs that subsequently restored hematopoiesis. However, therapeutic options are limited in FA. Although HSC transplantation outcomes have significantly improved over the past two decades, donor availability, graft failure, and FA-specific transplant toxicities are still significant hurdles towards a curative treatment of FA-associated BMF. Moreover, attempts at genetic correction of FA are not yet ready for patient care.

The thrombopoietin (TPO) mimetic eltrombopag (EPAG) has recently been shown to be effective in restoring tri-lineage hematopoiesis in patients with treatment refractory acquired severe aplastic anemia (SAA). Of particular interest for patients with FA is the observation that EPAG also improves the repair of double strand DNA breaks, a mechanism that is impaired in patients with FA. Additionally, our pre-clinical studies indicate that EPAG evades INF- >= blockade of signal transduction from the TPO receptor (c-MPL) resulting in improved survival and proliferation of HSCs. Based on these clinical and pre-clinical studies, we hypothesize that EPAG will improve peripheral blood cell counts in patients with FA and thus positively affect morbidity and mortality.

This phase II clinical trial proposes to treat patients with FA for 6 months with EPAG to assess safety and efficacy at improving hematological manifestations of FA. Responders at 6 months will be able to continue EPAG on the extension part of this protocol for an additional 3 years. During this time frame we anticipate further improvement of peripheral blood cells counts that will eventually result in the discontinuation of EPAG after a tapering period. Translational studies will explore EPAG effects on DNA repair activity, apoptosis, global transcriptome and TPO signaling pathways in patient s hematopoietic stem and progenitor cells (HSPCs).


Ages Eligible for Study:   4 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • Confirmed diagnosis of Fanconi anemia. Diagnosis is confirmed by a positive chromosome breakage analysis in lymphocytes and/or skin fibroblasts (for mosaicism), and biallelic mutation in a known FANC gene.
  • One or more of the following three clinically-significant cytopenias: platelet count less than 50,000/microliters or platelet-transfusion-dependence (requiring at least 4 platelet transfusions in the 8 weeks prior to study entry, see definition of platelet transfusion units at 8.2.1); neutrophil count less than 500/microliters; hemoglobin less than 9.0 g/dL or red cell transfusion-dependence (requiring at least 4 transfusions of PRBCs (adult patient 4 units PRBC, pediatric patients at least 10ml/kg/transfusion) in the eight weeks prior to study entry.
  • Failed or declined treatment with androgens (danazol or oxymetholone).
  • Age > 4 years old.
  • Weight >12kg.


  • Infection not adequately responding to appropriate therapy.
  • Evidence for MDS or AML as defined by WHO criteria.
  • Any cytogenetic abnormality associated with poor prognosis in FA, including gains of chromosome 3q, deletions of chromosome 7, and complex cytogenetics (72, 73) identified from bone marrow aspirate. Patients with known biallelic mutations in BRCA2 (FANCD1).
  • Active malignancy or likelihood of recurrence of malignancies within 12 months
  • Moribund status such that death within 7 to 10 days is likely. Comorbidities of such severity that in the view of the investigator it would likely preclude the patient's ability to tolerate eltrombopag.
  • Treatment with androgens (danazol or oxymetholone) less than 4 weeks prior to initiating eltrombopag.
  • Creatinine > 2.5 times ULN
  • Direct Bilirubin > 1.5 times ULN
  • SGOT or SGPT >5 3 times the ULN normal
  • Hypersensitivity to EPAG or its components
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 30 days after the last dose of eltrompobag. Highly effective contraception methods include:

    • Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Male sterilization (at least 6 months prior to screening). For female patients on the study the vasectomized male partner should be the sole partner for that patient.
    • Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
    • In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
    • Women are considered post-menopausal and not of child bearing potential if they have had over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile age appropriate (e.g. generally 40-59 years), history of vasomotor symptoms (e.g. hot flushes) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

Sexually active males unless they use a condom during intercourse while taking the study treatment and for 30 days after stopping study treatment and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via seminal fluid.

  • History of thromboembolic events.
  • Unable to take oral medication
  • History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:

    • Recent myocardial infarction (within last 6 months),
    • Uncontrolled congestive heart failure,
    • Unstable angina (within last 6 months),
    • Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker.)
    • Long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome or additional risk factors for cardiac repolarization abnormality, as determined by the investigator.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT03206086

Contact: Sophia Grasmeder, R.N. (301) 827-0367

United States, Maryland
National Institutes of Health Clinical Center Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Thomas Winkler, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI) Identifier: NCT03206086     History of Changes
Other Study ID Numbers: 170121
Study First Received: June 30, 2017
Last Updated: July 20, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
DNA Repair
Bone Marrow

Additional relevant MeSH terms:
Fanconi Anemia
Fanconi Syndrome
Hematologic Diseases
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Bone Marrow Diseases
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Metabolism, Inborn Errors processed this record on July 21, 2017