Low Dose Danazol for the Treatment of Telomere Related Diseases

180004

Background: DNA is a structure in the body. It contains data about how the body develops and works. Telomeres are found on the end of chromosomes in DNA. Some people with short telomeres or other gene changes can develop diseases of the bone marrow, lung, and liver. Researchers want to see if low doses of the hormone drug danazol can help. Objective: To study the safety and effect of low dose danazol. Eligibility: People ages 3 and older with a telomere disease who have either very short telomeres and a specific gene change. They must also show signs of aplastic anemia, lung, or liver disease. Design: Participants will be screened in another protocol. Participants will have: * Medical history * Physical exam * Blood tests * Lung exam. They will breathe into an instrument that records the amount and rate of air breathed in and out over a period of time. 6-minute walking test. * Abdominal ultrasound and liver scan. These tests use sound waves to measure the fibrosis in the liver. Some participants will have: * Pregnancy test * Small sample of the liver removed * Bone marrow biopsy. The bone will be numbed and a small needle will take a sample of the marrow. All participants will have hormone levels checked. All child participants will see a pediatric endocrinologist. Children may need to have a hand x-ray. We will monitor patients for 6 months before starting danazol. Participants will take danazol by mouth twice a day for 1 year. Participants must return to the clinic at 6 months and 12 months while on danazol and 6 months after stopping it. They will have blood and urine tests, a lung exam, abdominal ultrasound, and liver scan.

2018-02-08

2026-04-29

2027-10-29

Recruiting

Early phase I

40

* INCLUSION CRITERIA: 1. Age-adjusted telomere length less than or equal to the first percentile by flow-FISH method. In patients with a known pathogenic or likely pathogenic mutation in a telomere maintenance gene, age adjusted telomere length less than or equal to the 10th percentile is sufficient. 2. A mutation in telomere maintenance genes (TERT, TERC, DKC1, TINF2, NHP2, NOP10, WRAP53, TERF2, PARN, RTEL1, ACD, CTC1, USB1) as tested in a CLIA (or international equivalent) certified laboratory 3. Age greater than or equal to 3 years 4. Weight greater than or equal to 12 Kg AND 5. At least one of the following criteria: 1. Anemia with a hemoglobin less than or equal to 10 g/dL without red blood cell transfusion 2. Thrombocytopenia with a platelet count less than or equal to 50,000/microliter without transfusion 3. Neutropenia with an absolute neutrophil count less than or equal to 1,000/ microliter OR Pulmonary fibrosis diagnosed by either a lung biopsy or computed tomography scan of the chest according to guidelines from the American Thoracic Society and European Respiratory Society. OR 6. Hepatic fibrosis diagnosed by Transient Elastography by Fibroscan value greater than 10 kpa or US evidence of cirrhotic liver or splenomegaly, or transjugular liver biopsy demonstrating fibrosis. EXCLUSION CRITERIA: 1. Patients on androgen hormones to include testosterone or high dose estrogen (estradiol 0.5 mg/day or greater) for the12 months prior to enrollment 2. Patients with active thrombosis or thromboembolic disease and history of such events, undiagnosed abnormal genital bleeding, porphyria, androgendependent tumor, or prostatic hypertrophy 3. Patients with pulmonary fibrosis who are receiving anti-fibrotic drug treatment, such as pirfenidone or nintedanib unless stable on anti-fibrotic drug for at least 6 months prior to starting on danazol as demonstrated by PFTs. 4. Patients with active hepatitis B or C 5. Patients who have received a bone marrow transplant 6. Patient with other hereditary bone marrow failure syndromes such as Fanconi anemia or Diamond Blackfan anemia 7. Patients with infections not adequately responding to appropriate therapy 8. Current pregnancy, or unwillingness to take oral contraceptives or use the barrier methods of birth control or practice abstinence to refrain from pregnancy if of childbearing potential during the course of the study 9. Lactating women, due to the potentially harmful effects on the nursing child 10. Patients with cancer who are actively receiving systemic chemotherapeutic treatment or who take drugs with hematological effects 11. Patients with decompensated liver disease to include persistent ascites, encephalopathy, variceal hemorrhage, or MELD score of 10 or greater 12. Inability to understand the investigational nature of the study or to give informed consent or without a legally authorized representative or surrogate that can provide informed consent 13. Inability to swallow a capsule

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2024-02-23