Steroid-refractory Diamond-Blackfan Anemia (DBA) Clinical Trial
Official title:
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.
Study Description: Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by selective erythroid defects. In DBA, a defect in erythroid ribosome biosynthesis creates an asynchrony between protein synthesis of globin chains and heme, wherein the continued production of free heme without sufficient globin is toxic to cells. Bitopertin prevents the uptake of glycine through the GlyT1 transporter reducing the synthesis of 5- aminolevulinic acid, the rate-limiting step in heme synthesis, which in turn leads to a significant reduction in intracellular heme. We hypothesize that bitopertin will rescue DBA by rebalancing heme and globin chain production and reducing the toxicity to the hematopoietic cells that the excess heme causes. Thus, we propose a phase I/II (pilot), single-arm, intra-patient dose-escalation trial of bitopertin for the treatment of steroid-refractory DBA. Objectives: Primary Objective: Efficacy of bitopertin in treating Diamond- Blackfan anemia Secondary Objectives: - Examine the safety and tolerability of bitopertin in treating Diamond-Blackfan anemia. - Examine the maintenance of response and relapse rates of Diamond-Blackfan anemia during long-term bitopertin use - Examine the effects of long-term treatment of Diamond-Blackfan anemia with bitopertin on clonal evolution, survival, and health- related quality of life metrics Tertiary/Exploratory Objectives: - Evaluate the impact of bitopertin on stem cell and erythroid cell dynamics in the Diamond-Blackfan anemia through correlative and translational studies - Examine the pharmacology of bitopertin in Diamond-Blackfan anemia Endpoints: Primary endpoint: -response rate from drug initiation until 8 months (32 weeks) as measured by an increase in pre-transfusion hemoglobin and/or either decrease in transfusion rate or transfusion-independence Secondary endpoints: - toxicity profile at 8 months (CTCAE criteria) - intra-patient maximum tolerated dose at 8 months (32 weeks) from drug initiation - response rate after 3 months (12 weeks) at the maximum tolerated dose - response rate 3 years post-primary endpoint (extension) - rate of relapse ongoing for up to 3 years, beginning 8 months (32 weeks) from drug initiation as demonstrated by new or increasing transfusion requirements and/or according to clinical outcome - rate of clonal evolution on bitopertin annually for up to 3 years, beginning 8 months (32 weeks) from drug initiation as measured by karyotypic, histologic, and flow cytometric changes - rate of overall survival ongoing for up to 3 years, beginning 8 months (32 weeks) from drug initiation according to clinical outcomes - Health-related quality of life (HRQL) annually for up to 3 years, beginning 8 months (32 weeks) from drug initiation based on questionnaire-based inventory of HRQL ;