Summary

This phase II trial tests how well fisetin and exercise works in preventing frailty in breast cancer survivors. Fisetin is a natural substance found in strawberries and other foods and is available as a nutritional supplement. Nutritional supplements may be useful in eliminating cells that have undergone a process called senescence. Senescence is when a cell ages and permanently stops dividing but does not die. Over time, large numbers of these cells build up in tissues throughout the body and can release harmful substances that cause inflammation and damage nearby healthy cells. Giving fisetin may eliminate senescent cells in patients with breast cancer undergoing physical activity.

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.

Eligibility

1. Women who are postmenopausal at the start of study treatment * Postmenopausal status will be established as follows: ** Women aged = 60 years OR ** Women aged < 60 years AND one of the following conditions is met: *** They have not had any menstrual periods for at least 12 months in the absence of exogenous hormonal treatments, chemotherapy, and/or tamoxifen AND have serum estradiol and follicle-stimulating hormone (FSH) levels confirmed as being within the standard laboratory reference range for postmenopausal females *** They have documented irreversible bilateral oophorectomy *** They are receiving ovarian suppression with their breast cancer endocrine therapy
2. Women with a diagnosis of early-stage breast cancer (stage I, II, III) treated with neo/adjuvant chemotherapy within 12 months of starting study treatment
3. No evidence of active/recurrent breast cancer or other serious chronic illnesses
4. Have evidence of pre-frail health, defined as a 6-minute walk distance (400-480m) at baseline
5. Platelets > 60,000/mm^3
6. White blood cell count > 2,000/mm^3
7. Absolute neutrophil count > 500/mm^3
8. Hemoglobin = 8.0 g/dL
9. Total bilirubin = 3.0 X upper limit of normal (ULN)
10. Aspartate aminotransferase (AST) = 4.0 x ULN
11. Alanine aminotransferase (ALT) = 4.0 x ULN
12. Estimated glomerular filtration rate (eGFR) of = 30mL/min/1.73m^2 per the Modification of Diet in Renal Disease (MDRD) calculation
13. Ability to understand and the willingness to sign a written informed consent document

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