Quercetin Dyskeratosis Congenita (DC)/Telomere Biology Disorders (TBD)

The purpose of this study is to see if a vitamin-like substance called quercetin is safe for people who have a rare condition called Dyskeratosis congenita (DC) or telomere biology disorders (TBD). This study is a single arm, open-label pilot study. There is no randomization. This study will enroll approximately 12 patients with DC/TBD who will be treated with quercetin for 24 weeks.

• Quercetin (Drug): Quercetin (3, 30, 40, 5, 7-pentahydroxyflavone) is a naturally occurring antioxidant that belongs to a group of polyphenolic compounds known as flavonoids. Quercetin is routinely available as an over-the-counter product due to it being a nutritional supplement. However, for the purpose of the study, it will be purchased in the powder form from PCCA (supplied as 96% quercetin dihydrate) and stored and distributed by the investigational pharmacy at CCHMC using standard operational procedures. Quercetin is administered as an oral medication, supplied in powder form. Quercetin will be stored at room temperature. The product will be dispensed for home administration. Each packet will be labeled in accordance with applicable regulatory requirements. Patients or parents will be instructed to mix it with a small amount of yogurt or other preferred food for ingestion.

Primary outcomes

• Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0 [24 weeks]: Participants will be evaluated by monitoring treatment-emergent adverse events, physical exam, and labs throughout the study treatment period.
• Number of Participants who Discontinue Quercetin Due to Lack of Feasibility as defined in the protocol [24 weeks]: Participants will keep a log of medication administration and bring the same to their follow-up study visits, to demonstrate the feasibility of administering the supplement to patients consistently for a prolonged period of time (24 weeks). If ≥3 out of the first 6 patients miss ≥2 weeks of continuous therapy during the 24 weeks of treatment, without medical reason for the same, study will pause and findings will be discussed with the medical monitor.

Sex: All, ages: 2 Years to any

Inclusion Criteria:

1. Diagnosis of DC/TBD deficiency as defined by at least one of the following:

   * Age adjusted mean-telomere length of <1 percentile in all tested peripheral blood cells such as granulocytes, lymphocytes, B-cells, naïve T-cells, memory T-cells, and NK cells
   * A pathogenic or likely pathogenic mutation in DKC1, TERC, TERT, NOP10, NHP2, TINF2, CTC1, PARN, RTEL1, ACD, NAF1, ZCCHC8, or WRAP53
2. Patients ≥ 2.0 years of age*

   * The first three enrolled patients must be ≥ 10.0 years of age
3. Able to take medication orally

Exclusion Criteria:

1. Renal failure requiring dialysis
2. Total bilirubin >3 mg/dl and/or SGPT >300 at time of enrollment, unless elevation thought to be related to DC/TBD
3. Patients who have received quercetin or any over-the-counter antioxidant supplementation within last 1 month
4. Patients currently taking androgen therapy
5. Patients receiving digoxin therapy, who are unable to discontinue treatment due to medical reasons
6. Patients receiving fluoroquinolone therapy, who are unable to discontinue treatment due to medical reasons
7. Patients who are pregnant or breastfeeding or are at risk of pregnancy and are unable to use acceptable methods of birth control during the length of the study
8. Patients with morphologic or cytogenetic evidence of myelodysplasia or leukemia.
9. Patients needing to start or actively receiving radiation therapy, chemotherapy or immunotherapy for treatment of SCC or other cancers.
10. Patients with unstable disease status or other medical issues requiring hospitalization or rapid escalation of medical care
11. Participating in another therapeutic study for DC/TBD
12. Patients who are in the early post-stem cell transplant period (i.e. first 6 months post-transplant)

• Parinda Mehta, MD, Principal investigator, Children's Hospital Medical Center, Cincinnati