A Phase I/II, Intra-Patient Dose-Escalation Study of the Selective GlyT1 Inhibitor, Bitopertin for Steroid-Refractory Diamond-Blackfan Anemia.
Background: Diamond-Blackfan anemia (DBA) is an inherited disease that affects the bone marrow. People with DBA have chronic anemia that can be severe. Many must have frequent transfusions of red blood cells. Current treatments for DBA all have risks of serious side effects. Better treatments are needed.
Objective: To test a new drug (bitopertin) in people with DBA.
Eligibility: People aged 18 or older with DBA.
Design: Participants will be screened. They will have a physical exam; they will have blood tests and a test of their heart function. They will have a bone marrow biopsy: An area of their hip will be numbed, and a needle will be inserted to remove a sample of tissue from inside the bone. Bitopertin is a pill taken by mouth. Participants will take the drug once a day every day for 8 months. They will start with a low dose of the drug; the dosage may increase gradually over time. They will keep a diary to record each dose. Participants will have blood tests every 4 weeks. This may be done in the clinic. Participants may also have telehealth visits; they can have blood drawn at a local lab and sent to the researchers. The bone marrow biopsy and other tests will be repeated after 8 months. Participants who have a positive response to bitopertin will be invited to enter an extended phase of the trial. They may continue to take the drug for 3 more years. Those who choose not to continue in the extended phase may have a follow-up visit 6 months after they stop taking the drug.
∙ To be eligible to participate in this study, an individual must meet all of the following criteria:
• Diamond-Blackfan anemia defined as chronic anemia presenting on or before the third year of life, associated with reticulocytopenia and greatly reduced or absent bone marrow erythroid precursors, supported by, but not requiring either:
‣ familial history
⁃ gene mutation testing demonstrating a known disease-causing mutation or a mutation of disease-associated gene in combination with clinical characteristics of DBA
• Patients with late-onset DBA (diagnosed after the third year of life) may also be included if (but only if) gene mutation testing confirms a disease-causing mutation, as above.
• Clinically-significant anemia as defined as either:
‣ hemoglobin less than 9.0 g/dL
⁃ red cell transfusion of at least 2 units PRBC for adults in the eight weeks prior to study enrollment
• Relapsed and/or steroid-refractory disease or patient intolerance of systemic corticosteroids
• Age \>= 18 years at the time of consent
∙ Although all patients without a molecular diagnosis (i.e., genetic testing positive for a disease- causing lesion) will undergo targeted gene panel testing for mutations in all known genes associated with DBA , the diagnosis of DBA is a clinical one, and as such, consent and enrollment does not require results from these genetic tests in the absence of any features that would suggest an alternative diagnosis (e.g., Fanconi Anemia, Dyskeratosis Congenita, etc.).