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

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Frailty Childhood Cancer	Drug: Dasatinib plus Quercetin Drug: Fisetin	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 6, 2022

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2024

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Change in walking speed [Baseline]
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.
Change in Walking Speed [Day 30]
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.
Change in Walking Speed [Day 60]
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.
Change in Walking Speed [Day 150]
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.
Senescent cell abundance in blood (p16INK4A) [Baseline]
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.
Senescent cell abundance in blood (p16INK4A) [Day 7]
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.
Senescent cell abundance in blood (p16INK4A) [Day 30]
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
Senescent cell abundance in blood (p16INK4A) [Day 60]
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.
Senescent cell abundance in blood (p16INK4A) [Day 150]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Participant in SJLIFE and > 5 years from diagnosis
≥18 years of age
Frail (3 of 5 Fried criteria, including abnormal walking speed; muscle strength; activity level; muscle mass and exhaustion/fatigue scale).
CD3+ T lymphocytes: p16^INK4A detected at <33 cycles by RT PCR
Agrees to use contraception as Dasatinib is teratogenic
Participant has a negative pregnancy test
QTc <450 milliseconds in electrocardiogram
Participant has hematocrit of >34 for females and >35 for males
Participant has hemoglobin of >11 for females and >12 for males
Able to take oral medications

Exclusion Criteria:

Currently has HIV, Hepatitis B/C, invasive fungal infection
Anemia
Hypersensitivity to study drugs
New/active malignancy/taking chemotherapy and/or radiation except non-melanoma skin cancers
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 antiplatelet agents (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-day drug dosing. Subjects may continue their previous regimen on Day 3.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

St. Jude Children's Research Hospital
National Institutes of Health (NIH)
National Cancer Institute (NCI)

Investigators

Principal Investigator: Gregory T. Armstrong, MD, MSCE, St. Jude Children's Research Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.

Responsible Party:

St. Jude Children's Research Hospital

ClinicalTrials.gov Identifier:

NCT04733534

Other Study ID Numbers:

SENSURV
U01CA246510

First Posted:

Feb 2, 2021

Last Update Posted:

Jun 9, 2022

Last Verified:

Jun 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Yes

Additional relevant MeSH terms:

Frailty

Dasatinib

Quercetin

Study Results

No Results Posted as of Jun 9, 2022