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

Primary Purpose

Frailty, Childhood Cancer

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Dasatinib plus Quercetin
Fisetin
Sponsored by
St. Jude Children's Research Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Frailty

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • St. Jude Children's Research HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Dasatinib plus Quercetin

Fisetin

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
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.
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.
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
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.
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.

Secondary Outcome Measures

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
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

Full Information

First Posted
December 9, 2020
Last Updated
August 1, 2023
Sponsor
St. Jude Children's Research Hospital
Collaborators
National Institutes of Health (NIH), National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT04733534
Brief Title
An Open-Label Intervention Trial to Reduce Senescence and Improve Frailty in Adult Survivors of Childhood Cancer
Official Title
SEN-SURVIVORS: An Open-Label Intervention Trial to Reduce Senescence and Improve Frailty in Adult Survivors of Childhood Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 6, 2022 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St. Jude Children's Research Hospital
Collaborators
National Institutes of Health (NIH), National Cancer Institute (NCI)

4. Oversight

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
Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Frailty, Childhood Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dasatinib plus Quercetin
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Fisetin
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Dasatinib plus Quercetin
Other Intervention Name(s)
Sprycel, Pentahydroxyflavone, Bioflavonoid,
Intervention Description
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
Intervention Name(s)
Fisetin
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in walking speed
Description
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.
Time Frame
Baseline
Title
Change in Walking Speed
Description
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.
Time Frame
Day 30
Title
Change in Walking Speed
Description
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.
Time Frame
Day 60
Title
Change in Walking Speed
Description
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.
Time Frame
Day 150
Title
Senescent cell abundance in blood (p16INK4A)
Description
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.
Time Frame
Baseline
Title
Senescent cell abundance in blood (p16INK4A)
Description
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.
Time Frame
Day 7
Title
Senescent cell abundance in blood (p16INK4A)
Description
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
Time Frame
Day 30
Title
Senescent cell abundance in blood (p16INK4A)
Description
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.
Time Frame
Day 60
Title
Senescent cell abundance in blood (p16INK4A)
Description
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.
Time Frame
Day 150
Secondary Outcome Measure Information:
Title
Safety of two different senolytic therapies as assessed by treatment-related adverse events using CTCAE v5.0
Description
To test the safety of the combination of Dasatinib plus Quercetin or Fisetin alone
Time Frame
150 days
Title
Tolerability of two different senolytic therapies as assessed by treatment-related adverse events using CTCAE v5.0
Description
To test the tolerability of the combination of Dasatinib plus Quercetin or Fisetin alone
Time Frame
150 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gregory T. Armstrong, MD, MSCE
Phone
866-278-5833
Email
referralinfo@stjude.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gregory T. Armstrong, MD, MSCE
Organizational Affiliation
St. Jude Children's Research Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregory T. Armstrong, MD, MSCE
Phone
866-278-5833
Email
ccss@stjude.org
First Name & Middle Initial & Last Name & Degree
Gregory T. Armstrong, MD, MSCE

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Links:
URL
http://www.stjude.org
Description
St. Jude Children's Research Hospital
URL
http://www.stjude.org/protocols
Description
Clinical Trials Open at St. Jude

Learn more about this trial

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

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