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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Frailty; Childhood Cancer
• Intervention / Treatment: Drug: Dasatinib plus Quercetin; Drug: Fisetin

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.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: 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.; Other Names: Sprycel; Pentahydroxyflavone; Bioflavonoid,
Active Comparator: 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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in walking speed	Walking speed will be measured by having the participant walk 4 meters as fast as he/she can walk. This test will be measured in meters per second.	Baseline
Change in Walking Speed	Walking speed will be measured by having the participant walk 4 meters as fast as he/she can walk. This test will be measured in meters per second.	Day 30
Change in Walking Speed	Walking speed will be measured by having the participant walk 4 meters as fast as he/she can walk. This test will be measured in meters per second.	Day 60
Change in Walking Speed	Walking speed will be measured by having the participant walk 4 meters as fast as he/she can walk. This test will be measured in meters per second.	Day 150
Senescent cell abundance in blood (p16INK4A)	Following a 12 hour overnight fast, 10 ml blood will be collected in EDTA tubes, processed at St. Jude and shipped to the Kirkland lab for evaluation of CD3+ peripheral blood T lymphocytes (PTBL) p16INK4A mRNA, a biomarker of senescence and chronological aging. CD3+ PTBL will be isolated from whole blood using Whole Blood CD3 Human Microbeads (Miltenyi Biotec, Cat# 130-090-874) by MACS sorting [79]. CD3+ cells will be lysed, mRNA isolated, and p16INK4A expression assayed by RT-PCR using a Taq-man primer-probe system.	Baseline
Senescent cell abundance in blood (p16INK4A)	Following a 12 hour overnight fast, 10 ml blood will be collected in EDTA tubes, processed at St. Jude and shipped to the Kirkland lab for evaluation of CD3+ peripheral blood T lymphocytes (PTBL) p16INK4A mRNA, a biomarker of senescence and chronological aging. CD3+ PTBL will be isolated from whole blood using Whole Blood CD3 Human Microbeads (Miltenyi Biotec, Cat# 130-090-874) by MACS sorting [79]. CD3+ cells will be lysed, mRNA isolated, and p16INK4A expression assayed by RT-PCR using a Taq-man primer-probe system.	Day 7
Senescent cell abundance in blood (p16INK4A)	Following a 12 hour overnight fast, 10 ml blood will be collected in EDTA tubes, processed at St. Jude and shipped to the Kirkland lab for evaluation of CD3+ peripheral blood T lymphocytes (PTBL) p16INK4A mRNA, a biomarker of senescence and chronological aging. CD3+ PTBL will be isolated from whole blood using Whole Blood CD3 Human Microbeads (Miltenyi Biotec, Cat# 130-090-874) by MACS sorting [79]. CD3+ cells will be lysed, mRNA isolated, and p16INK4A expression assayed by RT-PCR using a Taq-man primer-probe system	Day 30
Senescent cell abundance in blood (p16INK4A)	Following a 12 hour overnight fast, 10 ml blood will be collected in EDTA tubes, processed at St. Jude and shipped to the Kirkland lab for evaluation of CD3+ peripheral blood T lymphocytes (PTBL) p16INK4A mRNA, a biomarker of senescence and chronological aging. CD3+ PTBL will be isolated from whole blood using Whole Blood CD3 Human Microbeads (Miltenyi Biotec, Cat# 130-090-874) by MACS sorting [79]. CD3+ cells will be lysed, mRNA isolated, and p16INK4A expression assayed by RT-PCR using a Taq-man primer-probe system.	Day 60
Senescent cell abundance in blood (p16INK4A)	Following a 12 hour overnight fast, 10 ml blood will be collected in EDTA tubes, processed at St. Jude and shipped to the Kirkland lab for evaluation of CD3+ peripheral blood T lymphocytes (PTBL) p16INK4A mRNA, a biomarker of senescence and chronological aging. CD3+ PTBL will be isolated from whole blood using Whole Blood CD3 Human Microbeads (Miltenyi Biotec, Cat# 130-090-874) by MACS sorting [79]. CD3+ cells will be lysed, mRNA isolated, and p16INK4A expression assayed by RT-PCR using a Taq-man primer-probe system.	Day 150

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of two different senolytic therapies as assessed by treatment-related adverse events using CTCAE v5.0	To test the safety of the combination of Dasatinib plus Quercetin or Fisetin alone	150 days
Tolerability of two different senolytic therapies as assessed by treatment-related adverse events using CTCAE v5.0	To test the tolerability of the combination of Dasatinib plus Quercetin or Fisetin alone	150 days

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Collaborators: National Cancer Institute (NCI); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Gregory T. Armstrong, MD, MSCE, St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: December 9, 2020
• First Submitted That Met QC Criteria: January 28, 2021
• First Posted (Actual): February 2, 2021

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Pathological Conditions, Signs and Symptoms; Frailty; Neoplasms; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrans; Thiazoles; Azoles; Pyrimidines; Benzopyrans; Flavonols; Chromones; Dasatinib; Quercetin; fisetin; Flavonoids; peflavit
• Other Study ID Numbers: SENSURV; U01CA246510 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
• IPD Sharing Time Frame: Data will be made available at the time of article publication.
• IPD Sharing Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes