Eltrombopag for People With Fanconi Anemia
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.
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 Design:||Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||Eltrombopag for Patients With Fanconi Anemia|
- Proportion of drug responders [ Time Frame: 6 months ]
- Toxicity profile [ Time Frame: 6 months ]
- 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 ]
|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)|
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):
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).
Please refer to this study by its ClinicalTrials.gov identifier: NCT03206086
|Contact: Sophia Grasmeder, R.N.||(301) email@example.com|
|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 firstname.lastname@example.org|
|Principal Investigator:||Thomas Winkler, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|