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

• Status: Not yet recruiting
• Trial end date: 2024-07-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: St. Jude Children's Research Hospital
• Collaborators: National Cancer Institute (NCI); National Institutes of Health (NIH)
• Treatments: Dasatinib; Quercetin

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.