An Open-Label Intervention Trial to Reduce Senescence and Improve Frailty in Adult Survivors of Childhood Cancer

Eligible subjects who meet inclusion criteria will be randomized, stratified on sex, 1:1 and age ( ≥40 vs < 40) to receive Dasatinib (100 mg/day) plus Quercetin (500 mg twice daily) on days 1, 2, 3, 30, 31, and 32 taken orally or Fisetin (20 mg/kg/day) alone on days 1, 2, 30 and 31 taken orally. At the visit on day 7, we will assess blood CD3+ T lymphocyte p16^INK4A mRNA and other markers of inflammation and senescence to verify that senescent cells have been cleared by the intervention. Post-treatment follow-up will occur on day 60 (primary endpoints) and day 150 to assess the permanence of change after completion of the trial. Treatment adherence will be confirmed by the study coordinator who will administer the Dasatinib + Quercetin in clinic on days 1, 2, 3, 30, 31, and 32 or Fisetin alone on days 1, 2, 30 and 31.

Inclusion criteria

• Participant in SJLIFE and > 5 years from diagnosis.
• ≥18 years of age.
• Frail (2 of 4 objectively measured Fried criteria adapted,(excluding self-reported fatigue as a criteria), including abnormal walking speed; muscle strength; activity level; and muscle mass). See Section 5 for details.
• CD3+ T lymphocytes: p16INK4A detected at <34 cycles by RT PCR.
• Agrees to use contraception as Dasatinib is teratogenic.
• Female participant has a negative pregnancy test.
• QTc <450 milliseconds in electrocardiogram.
• Able to take oral medications.

Exclusion criteria

• Currently has HIV, Hepatitis B/C, invasive fungal infection
• Anemia or as per clinical judgement.
• Hypersensitivity to study drugs
• New/active malignancy/taking chemotherapy and/or radiation except non-melanoma skin cancers
• Currently taking medications that inhibit or induce CYP3A4 or that are sensitive to substrates or substrates with a narrow therapeutic range for CYP2C8, CYP2C9, or CYP2D6.
• Taking anticoagulants or antimicrobial agents
• Currently taking Quercetin or Fisetin
• Pregnant or nursing at time of enrollment/during the study
• Impaired cognition or motor performance due to congenital defects
• Currently participating in another research intervention to aid walking speed or other measures of frailty including muscle strength; low activity; muscle mass or exhaustion/fatigue
• Participant is a Non-English Speaker
• Uncontrolled pleural/pericardial effusion or ascites
• Subjects on anticoagulant or antiplatelet agents (Warfarin, Clopidogrel [Plavix]; Dipyridamole + Aspirin [Aggrenox]; Ticagrelor [Brilintal]; Prasugrel [Effient]; Ticlopidine [Ticlid]; or other) who are unable or unwilling to reduce or hold therapy prior to and during the 2-3 day drug dosing. Subjects may continue their previous regimen after drug dosing is complete.
• Cognitive impairment defined by IQ <80
• Diagnosis of a psychotic disorder
• Laboratory tests as indicated or as per clinical judgement
• Severe hepatic dysfunction with ALT/AST > 3 times upper limit of normal.
• Total bilirubin > 2 times upper limit of normal.
• eGFR <25 ml/min/1.73m2 or as per clinical judgement.
• Hemoglobin < 7 g/dl; white blood cell count ≤2,000/mm3 (≤2.0 x 109/L) or ≥20,000/mm3 (≥20 x 109/L); platelet count ≤40,000/μL (≤40 x 109/L); absolute neutrophil count ≤1 x 109/L; lymphocyte count <0.3 x 109/L at screening as a marker of poor nutrition
• Fasting glucose >300.
• Participant is unable to ambulate