Dyskeratosis Congenita, Hoyeraal Hreidarsson Syndrome, Interstitial Lung Disease Due to Systemic Disease (Telomere Biology Disorder), Pulmonary Fibrosis, Familial (Telomere Biology Disorder), Revesz Syndrome, Telomere Biology Disorders, Telomere Biology Disorders With Bone Marrow Failure
Conditions
Keywords
nucleoside, phase I, deoxycytidine, deoxythymidine, telomere biology disorders, safety, tolerability, pharmacokinetics, telomere lengths, bone marrow, clonal hematopoiesis, bone marrow failure, pulmonary fibrosis
Brief summary
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.
Detailed description
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.
Interventions
DRUGdeoxycytidine
Oral administration, in combination with deoxythymidine
DRUGdeoxythymidine
Oral administration, in combination with deoxycytidine
Sponsors
Suneet Agarwal
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* 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: 1. 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 OR 2. 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.
Exclusion criteria
* 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of treatment-related diarrhea [Tolerability] | 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] | 8 weeks from study drug initiation | Proportion of patients with grade 3 or higher treatment-related adverse events refractory to dose adjustments |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in hemoglobin | From pre-treatment baseline to end of treatment | Change in hemoglobin (in grams per deciliter) |
| Change in platelet count | From pre-treatment baseline to end of treatment | Change in platelet count (in thousands of cells per microliter) |
| Change in absolute neutrophil count | From pre-treatment baseline to end of treatment | Change in absolute neutrophil count (in thousands of cells per microliter) |
| Maximal plasma concentration [Cmax] of dC | 24 weeks | Maximal plasma concentration \[Cmax\] of dC will be obtained during pharmacokinetic profiling of dC at starting dose and maximum dose in some subjects |
| Maximal plasma concentration [Cmax] of dT | 24 weeks | Maximal plasma concentration \[Cmax\] of dT will be obtained during pharmacokinetic profiling of dT at starting dose and maximum dose in some subjects |
| Plasma half-life [T1/2] of dC | 24 weeks | Plasma half-life \[T1/2\] of dC will be obtained during pharmacokinetic profiling of dC at starting dose and maximum dose in some subjects |
| Plasma half-life [T1/2] of dT | 24 weeks | Plasma half-life \[T1/2\] of dT will be obtained during pharmacokinetic profiling of dC at starting dose and maximum dose in some subjects |
Countries
United States
Contacts
CONTACTHelen Reed, MD, MPH
CONTACTBrichelle Pena, BS
PRINCIPAL_INVESTIGATORHelen Reed, MD, MPH
Boston Children's Hospital
Outcome results
None listed