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

• ClinicalTrials.gov Identifier: NCT04733534
• Recruitment Status: Recruiting
• First Posted: February 2, 2021
• Last Update Posted: June 9, 2022
• Sponsor: St. Jude Children's Research Hospital
• Collaborators: National Institutes of Health (NIH); National Cancer Institute (NCI)
• Information provided by (Responsible Party): St. Jude Children's Research Hospital

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 (Clinical Trial)
• Estimated 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: June 6, 2022
• Estimated Primary Completion Date: July 2023
• Estimated Study Completion Date: July 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.

Outcome Measures

Primary Outcome Measures :

1. Change in walking speed [ Time Frame: 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.
2. Change in Walking Speed [ Time Frame: 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.
3. Change in Walking Speed [ Time Frame: 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.
4. Change in Walking Speed [ Time Frame: 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.
5. Senescent cell abundance in blood (p16INK4A) [ Time Frame: 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.
6. Senescent cell abundance in blood (p16INK4A) [ Time Frame: 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.
7. Senescent cell abundance in blood (p16INK4A) [ Time Frame: 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
8. Senescent cell abundance in blood (p16INK4A) [ Time Frame: 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.
9. Senescent cell abundance in blood (p16INK4A) [ Time Frame: 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 :

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

Eligibility Criteria

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

Criteria

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

Contacts

Contact: Gregory T. Armstrong, MD, MSCE; 866-278-5833; referralinfo@stjude.org

Locations

United States, Tennessee

St. Jude Children's Research Hospital; Recruiting

Memphis, Tennessee, United States, 38105

Contact: Gregory T. Armstrong, MD, MSCE 866-278-5833 ccss@stjude.org

Principal Investigator: Gregory T. Armstrong, MD, MSCE

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

More Information

Additional Information:

St. Jude Children's Research Hospital 

Clinical Trials Open at St. Jude 

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT04733534
• Other Study ID Numbers: SENSURV; U01CA246510 ( U.S. NIH Grant/Contract )
• First Posted: February 2, 2021
• Last Update Posted: June 9, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Data will be made available at the time of article publication.
• 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.

• 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

Additional relevant MeSH terms:

Frailty; Pathologic Processes; Dasatinib; Quercetin; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antioxidants; Protective Agents; Physiological Effects of Drugs