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.
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
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 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.
Single group
deoxycytidine
DrugOral administration, in combination with deoxythymidine
deoxythymidine
DrugOral administration, in combination with deoxycytidine
Incidence of treatment-related diarrhea [Tolerability]
Proportion of study participants with grade 3 or higher treatment-related diarrhea refractory to dose adjustments
Incidence of treatment-related adverse events [Safety]
Proportion of patients with grade 3 or higher treatment-related adverse events refractory to dose adjustments
Change in hemoglobin
Change in hemoglobin (in grams per deciliter)
Change in platelet count
Change in platelet count (in thousands of cells per microliter)
Change in absolute neutrophil count
Change in absolute neutrophil count (in thousands of cells per microliter)
Maximal plasma concentration [Cmax] of dC
Maximal plasma concentration \[Cmax\] of dC will be obtained during pharmacokinetic profiling of dC at starting dose and maximum dose in some subjects
Change in forced vital capacity (FVC)
Change in forced vital capacity (percent predicted) on pulmonary function testing
Change in diffusing capacity of the lungs for carbon monoxide (DLCO)
Change in diffusing capacity of the lungs for carbon monoxide (percent predicted) by pulmonary function testing
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Suneet Agarwal
Lead sponsor
Boston Children's Hospital
Sponsor institution
