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

NCT ID: NCT04733534

Last Updated: 2026-01-20

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 110 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-06
• Study Completion Date: 2027-12-31

Brief Summary

This is a first-in survivor pilot study with the goal of establishing preliminary evidence of efficacy, safety, and tolerability of two senolytic regimens to reduce markers of cellular senescence (primary outcome: p16^INK4a) and improve frailty (primary outcome: walking speed) in adult survivors of childhood cancer. If successful, this pilot would provide the preliminary evidence needed for a phase 2, randomized, placebo-controlled trial to establish efficacy.

Primary Objective

• The primary aim of this proposal is to test the efficacy of two, short duration senolytic regimens: 1) combination of Dasatinib plus Quercetin and 2) Fisetin alone, to improve walking speed and decrease senescent cell abundance in blood (p16^INKA):
• Primary endpoints of this trial will be change in walking speed and senescent cell abundance in blood (p16^INK4A) determined at baseline and again at 60 days, within an individual arm. Extended follow up at 150 days will assess the permanence of change after completion of the trial. Secondary endpoints of this trial will be effect of intervention on additional measures of frailty (beyond walking speed; Fried criteria) and on other cell senescence markers, markers of inflammation, insulin resistance, bone resorption, and cognitive function.

Secondary Objectives

The secondary aim is to test the safety and tolerability of two different senolytic therapies.

Exploratory Objectives

• To compare the efficacy of the two senolytic regimens in improving walking speed and decreasing senescent cell abundance
• To evaluate the longitudinal pattern in measures of frailty.

Detailed Description

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.

Conditions

Frailty; Childhood Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Dasatinib plus Quercetin

Day 0 (30 per arm, randomization stratified by sex and age)

At the visit on day 7, blood CD3+ T lymphocyte p16^INK4A mRNA and other markers of inflammation and senescence will be accessed to verify that senescent cells have been cleared by the intervention.

Post-treatment follow-up will occur on days 60 for (primary endpoints) and day 150 for secondary evaluation. Day 150 will assess the permanence of change after completion of the trial.

Group Type: ACTIVE_COMPARATOR

Dasatinib plus Quercetin

Intervention Type: DRUG

Dasatinib (100 mg/day) plus Quercetin (500 mg twice daily) on days 1, 2, 3, 30, 31, 32 taken orally under observation of the study nurse.

Fisetin

Day 0 (30 per arm, randomization stratified by sex and age)

At the visit on day 7, blood CD3+ T lymphocyte p16INK4A mRNA and other markers of inflammation and senescence will be accessed to verify that senescent cells have been cleared by the intervention.

Post-treatment follow-up will occur on days 60 for (primary endpoints) and day 150 for secondary evaluation. Day 150 to will assess the permanence of change after completion of the trial.

Group Type: ACTIVE_COMPARATOR

Fisetin

Intervention Type: DRUG

Fisetin (20mg/kg/day) on days 1, 2, 30 and 31 taken orally under observation of the study nurse. Fisetin will be dispensed based on weight of 20 mg/kg/day on the four separate days.

Interventions

Dasatinib plus Quercetin

Dasatinib (100 mg/day) plus Quercetin (500 mg twice daily) on days 1, 2, 3, 30, 31, 32 taken orally under observation of the study nurse.

Intervention Type: DRUG

Fisetin

Fisetin (20mg/kg/day) on days 1, 2, 30 and 31 taken orally under observation of the study nurse. Fisetin will be dispensed based on weight of 20 mg/kg/day on the four separate days.

Intervention Type: DRUG

Other Intervention Names

Sprycel; Pentahydroxyflavone; Bioflavonoid,

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

St. Jude Children's Research Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gregory T. Armstrong, MD, MSCE

Role: PRINCIPAL_INVESTIGATOR

St. Jude Children's Research Hospital

Locations

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Countries

United States

Related Links

http://www.stjude.org

St. Jude Children's Research Hospital

http://www.stjude.org/protocols

Clinical Trials Open at St. Jude

Other Identifiers

U01CA246510

Identifier Type: NIH

Identifier Source: secondary_id

View Link

SENSURV

Identifier Type: -

Identifier Source: org_study_id