Nucleoside Therapy in Patients With Telomere Biology Disorders
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 36
- 试验地点
- 2
- 主要终点
- Incidence of treatment-related diarrhea [Tolerability]
研究概览
简要总结
The goal of this clinical trial is to learn if a combination therapy of deoxycytidine (dC) plus deoxythymidine (dT) is safe in patients with telomere biology disorders. The main questions it aims to answer are:
- Is the therapy safe with tolerable side effects in patients with telomere biology disorders?
- Are problems with the bone marrow or blood or lungs changed after 6 months of dC+dT treatment in patients with telomere biology disorders?
Participants will:
- Take study drug by mouth three times daily for 24 weeks
- Make approximately 2 visits to Boston Children's Hospital during the 24 weeks: once at the beginning of treatment and once at the end of treatment.
- Go to a lab for a blood draw an additional 6 times during treatment.
- Have 9 phone calls with a research nurse, including one 4 weeks after treatment ends.
- Keep a diary to track doses of study drug that were taken or missed.
详细描述
This is an investigator-initiated, single-arm, single-center phase 1 clinical trial investigating nucleoside therapy in patients telomere biology disorder (TBDs). TBDs are a group of rare, inherited conditions characterized by critically short telomeres which can limit cellular replication resulting in a wide spectrum of clinical manifestations. From a hematologic standpoint, patients with TBDs often present with bone marrow failure. Therapy options for bone marrow failure for patients with TBDs are limited to androgen therapy and hematopoietic cell transplantation, which are associated with significant challenges and toxicities. From a pulmonary standpoint, patients with TBDs can present with low oxygen levels due to hepatopulmonary syndrome or lung fibrosis, which requires organ transplantation. New therapeutic approaches are needed in patients with an underlying TBD. Recent studies emerging from multiple independent human genetic studies have established a critical role for deoxythymidine (dT) metabolism in human telomere maintenance and demonstrated that upregulation of nucleotide metabolism by dT supplementation in vitro led to telomere elongation. The goals of this trial are to (1) assess the safety and tolerability of enteral nucleoside therapy in patients with TBDs and (2) explore the clinical and biologic effects of enteral nucleoside therapy in patients with TBDs. A total of 36 pediatric and adult patients with a diagnosis of a TBD will be enrolled at Boston Children's Hospital. Patients will receive enteral nucleoside therapy for a total of 24 weeks. Drug diary reviews and safety and tolerability assessments will be conducted on a weekly basis during an initial dose-escalation phase (4 weeks) and then monthly until study treatment completion at week 24. Pharmacokinetic studies will be conducted on a subset of participants. Additionally, changes in lymphocyte telomere lengths, peripheral blood counts, bone marrow cellularity, clonal hematopoiesis, pulmonary function tests, and chest CT imaging may be explored pre- and post-treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 70 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 1 year and ≤ 70 years
- •Karnofsky performance status ≥ 50 for participants ≥16 years of age and Lansky performance status ≥ 50 for participants <16 years of age
- •Diagnosis requirement. Participants must meet at least one of the following requirements for a diagnosis of a telomere biology disorder:
- •Age-adjusted mean telomere length < 1%ile in peripheral blood lymphocytes by flow cytometry-fluorescence in situ hybridization (flow-FISH), as reported by a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory
- •Pathogenic or likely pathogenic variant(s) in one of the follow telomere biology associated genes: DKC1, TERC, TERT, NOP10, NHP2, WRAP53/TCAB1, TINF2, CTC1, RTEL1, ACD, PARN, NAF1, STN1, ZCCHC8, POT1, RPA1, DCLRE1B, TYMS, as reported by a CLIA-approved laboratory.
- •Participants must exhibit at least one active clinical manifestation associated with a telomere biology disorder, in the judgment of the PI, which includes but is not limited to the following: one or more peripheral blood cytopenias, bone marrow hypocellular for age, pulmonary abnormalities, liver abnormalities, gastrointestinal bleeding, immunodeficiency or immune dysregulation, ophthalmologic abnormalities, or neurologic abnormalities.
- •Participants must be able to take enteral liquids by mouth or enteral feeding tube.
- •Female participants who are sexually active and could become pregnant must use two effective methods of contraception, at least one of which must be considered a highly effective method.
- •Participants (or parent/legally authorized representative for minors) must demonstrate the ability to understand and willingness to provide informed consent, which will be documented using an institutionally approved informed consent procedure.
排除标准
- •Participants must not have very severe aplastic anemia necessitating bone marrow transplant at the time of enrollment. Very severe aplastic anemia is defined by the presence of at least 2 of the following: ANC <200 cells/microliter, platelets <20,000 cells/microliter, absolute reticulocyte count <40,000 cells/microliter. If individuals with very severe aplastic anemia are not expected to undergo bone marrow transplant either due to the lack of an acceptable donor or medical co-morbidities and otherwise meet the inclusion/exclusion criteria, then they would be eligible for enrollment in this trial.
- •Participants must not otherwise be expected to undergo bone marrow transplantation within 6 months of enrollment.
- •Participants must not be taking concurrent medications intended to improve hematopoiesis such as androgens or growth factors, including granulocyte colony stimulating factor, erythropoietin, or thrombopoietin mimetics. If any of these therapies were taken previously, patients must wait 30 days after cessation of the therapy before enrollment on this trial.
- •Participants must not have chronic diarrhea or an average baseline stool output of more than 4 stools per day.
- •Participants must not have gastrointestinal disorders that may impair enteral absorption of dC/dT, such as inflammatory bowel disease or short bowel syndrome.
- •Participants must not have chronic kidney disease with an estimated glomerular filtration rate < 60 mL/min/1.73 m
- •Participants must not be on other medications or study agents or have other uncontrolled intercurrent illness that could interfere with study interpretation, in the opinion of the study Principal Investigator (PI)
- •Participants must not have high-risk myelodysplastic syndrome or leukemia or other active malignancy.
- •Pregnant individuals will not be eligible for enrollment given the physiological changes in blood counts that occur during pregnancy.
- •Breastfeeding mothers will not be eligible for enrollment due to the unknown risk to nursing infants.
研究组 & 干预措施
dC/dT
Participants will take study therapy three times daily over 24 weeks with dose escalation.
干预措施: deoxythymidine (Drug)
dC/dT
Participants will take study therapy three times daily over 24 weeks with dose escalation.
干预措施: deoxycytidine (Drug)
结局指标
主要结局
Incidence of treatment-related diarrhea [Tolerability]
时间窗: 8 weeks from study drug initiation
Proportion of study participants with grade 3 or higher treatment-related diarrhea refractory to dose adjustments
Incidence of treatment-related adverse events [Safety]
时间窗: 8 weeks from study drug initiation
Proportion of patients with grade 3 or higher treatment-related adverse events refractory to dose adjustments
次要结局
- Maximal plasma concentration [Cmax] of dT(24 weeks)
- Plasma half-life [T1/2] of dT(24 weeks)
- Maximal plasma concentration [Cmax] of dC(24 weeks)
- Plasma half-life [T1/2] of dC(24 weeks)
- Change in platelet count(From pre-treatment baseline to end of treatment)
- Change in hemoglobin(From pre-treatment baseline to end of treatment)
- Change in absolute neutrophil count(From pre-treatment baseline to end of treatment)
研究者
Suneet Agarwal
Physician
Boston Children's Hospital