Nucleoside Therapy in Patients With Telomere Biology Disorders

NCT06817590 | Recruiting Phase 1 FDA Drug

• 1 other identifier: IRB-P00049530
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Revesz Syndrome; Telomere Biology Disorders With Bone Marrow Failure; Pulmonary Fibrosis, Familial (Telomere Biology Disorder); Dyskeratosis Congenita; Hoyeraal Hreidarsson Syndrome; Telomere Biology Disorders; Interstitial Lung Disease Due to Systemic Disease (Telomere Biology Disorder)

Keywords

nucleoside; phase I; deoxycytidine; deoxythymidine; telomere biology disorders; safety; tolerability; pharmacokinetics; telomere lengths; bone marrow; clonal hematopoiesis; bone marrow failure; pulmonary fibrosis

Outcome Measures

Primary Outcomes (2)

• Incidence of treatment-related diarrhea [Tolerability]

  Proportion of study participants with grade 3 or higher treatment-related diarrhea refractory to dose adjustments

  8 weeks from study drug initiation

• Incidence of treatment-related adverse events [Safety]

  Proportion of patients with grade 3 or higher treatment-related adverse events refractory to dose adjustments

  8 weeks from study drug initiation

Secondary Outcomes (7)

• Change in hemoglobin

  From pre-treatment baseline to end of treatment

• Change in platelet count

  From pre-treatment baseline to end of treatment

• Change in absolute neutrophil count

  From pre-treatment baseline to end of treatment

• Maximal plasma concentration [Cmax] of dC

  24 weeks

• Maximal plasma concentration [Cmax] of dT

  24 weeks

Other Outcomes (2)

• Change in forced vital capacity (FVC)

  Up to 24 weeks

• Change in diffusing capacity of the lungs for carbon monoxide (DLCO)

  Up to 24 weeks

Study Arms (1)

dC/dT

EXPERIMENTAL

Participants will take study therapy three times daily over 24 weeks with dose escalation.

Drug: deoxycytidine; Drug: deoxythymidine

Interventions

deoxycytidine DRUG

Oral administration, in combination with deoxythymidine

Also known as: dC

dC/dT

deoxythymidine DRUG

Oral administration, in combination with deoxycytidine

Also known as: thymidine, dT

dC/dT

Eligibility Criteria

• Age: 1 Year - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 m2.
• 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.

Sponsors & Collaborators

• Suneet Agarwal: lead

Study Sites (1)

Boston Childrens Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

Related Publications (1)

• Mannherz W, Agarwal S. Thymidine nucleotide metabolism controls human telomere length. Nat Genet. 2023 Apr;55(4):568-580. doi: 10.1038/s41588-023-01339-5. Epub 2023 Mar 23.

  PMID: 36959362 BACKGROUND

MeSH Terms

Conditions

Dyskeratosis Congenita; Revesz Debuse syndrome; Hoyeraal Hreidarsson syndrome; Pulmonary Fibrosis; Bone Marrow Failure Disorders

Interventions

Deoxycytidine; Thymidine

Condition Hierarchy (Ancestors)

Congenital Bone Marrow Failure Syndromes; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Skin Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Skin Diseases, Genetic; Skin Diseases; Skin and Connective Tissue Diseases; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Helen Reed, MD, MPH

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Helen Reed, MD, MPH

CONTACT

857-218-4578; helen.reed@childrens.harvard.edu

Elizabeth Korn, BS

CONTACT

857-218-4578; elizabeth.korn@childrens.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Physician

Study Record Dates

• First Submitted: January 30, 2025
• First Posted: February 10, 2025
• Study Start: September 29, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2029
• Last Updated: March 18, 2026

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)