Fisetin and Exercise to Prevent Frailty in Breast Cancer Survivors

Summary

Objectives

PRIMARY OBJECTIVE:
I. To determine the effect of fisetin and/or exercise on physical function, as assessed using the 6-minute walk distance (6MWD), in chemotherapy-treated postmenopausal breast cancer survivors.

SECONDARY OBJECTIVES:
I. To determine the effect of fisetin and/or exercise on heart rate, step count, and sleep quality, as measured by wearable device.
II. To determine the effect of fisetin and/or exercise on other measures of physical function beyond 6MWD (short physical performance battery [SPPB], grip strength, frailty phenotype, physical function component of the 36-item short form survey [SF-36]).
III. To determine the effect of fisetin and/or exercise on fatigue (Borg Rating of Perceived Exertion [RPE]).
IV. To determine the effect of fisetin and/or exercise on health-related quality of life (SF-36).
V. To determine the effect of fisetin and/or exercise on patient-reported activity level (e.g., Godin Leisure Time Exercise [GLTE]) and physical and mental health (2 item Patient Reported Outcomes Measurement Information System [PROMIS] global physical and mental health scales [PROMIS Global]).
VI. To determine the effect of fisetin and/or exercise on cognition (PROMIS Cognitive Function short form 8a [PROMIS Cog 8a]).
VII. To determine the effect of fisetin and/or exercise on neuropathy (Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 [QLQ-CIPN20]).
VIII. To determine the effect of fisetin and/or exercise on sleep (Insomnia Severity Index [ISI]).
IX. To determine the effect of fisetin and/or exercise on anxiety (Generalized Anxiety Disorder [GAD]-7).
X. To determine the effect of fisetin and/or exercise on depression (Patient Health Questionnaire [PHQ]-8).
XI. To determine the effect of fisetin and/or exercise on cardiometabolic health, as measured by glycosylated hemoglobin measurement (hemoglobin A1C), fasting glucose, fasting insulin, fasting lipid profile, central adiposity (waist circumference), body weight, body mass index (BMI), and body composition data from digital scale.
XII. To determine the effect of fisetin and/or exercise on local and distant recurrence free survival (RFS).
XIII. To determine the effect of fisetin and/or exercise on breast cancer-specific survival and overall survival.
XIV. To evaluate the safety and tolerability of fisetin and/or exercise (physician and patient-reported Common Terminology Criteria for Adverse Events [CTCAEs]).
XV. To estimate rates of adherence to fisetin and/or exercise regimen.

EXPLORATORY OBJECTIVES:
I. To determine the effect of fisetin and/or exercise on p16 expression in peripheral CD3+ T-cells.
II. To determine the effect of fisetin and/or exercise on circulating senescence-associated secretory phenotype (SASP) inflammatory factors in blood and urine.

OUTLINE: Patients are randomized to 1 of 4 arms.

ARM AB: Patients receive fisetin orally (PO) on days 1-3 of each cycle. Treatment repeats every 14 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive individually tailored supervised exercise training consisting of 30-45 minutes of aerobic training and 20-30 minutes of resistance training three times a week over 16 weeks. Patients undergo collection of blood samples on study.

ARM A: Patients receive fisetin PO on days 1-3 of each cycle. Treatment repeats every 14 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive handout on the importance of physical activity during baseline. Patients undergo collection of blood samples on study.

ARM B: Patients receive placebo PO on days 1-3 of each cycle. Treatment repeats every 14 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive individually tailored supervised exercise training consisting of 30-45 minutes of aerobic training and 20-30 minutes of resistance training three times a week over 16 weeks. Patients undergo collection of blood samples on study.

ARM C: Patients receive placebo PO on days 1-3 of each cycle. Treatment repeats every 14 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive handout on the importance of physical activity during baseline. Patients undergo collection of blood samples on study.

Following completion of study intervention, patients are followed up on days 120 and 180 and then annually for up to 3 years.