Tier 4 — mechanistic

A phase II randomized placebo-controlled study of fisetin to improve physical function in breast cancer survivors: the TROFFi study rationale and trial design

Ji J, Crespi CM, Yee L, Zekster YA, Al-Saleem A, Petersen L, Lee C, Son N, Smith C, Evans T, Tchkonia T, Kirkland JL, Kuchel GA, Cohen HJ, Sedrak MS

Therapeutic Advances in Medical Oncology 2026 18:17588359261424668

Bibliography

PubMed: PMID 41835341
PubMed Central: PMC12979913
DOI: 10.1177/17588359261424668
Trial registry: View on ClinicalTrials.gov Registered trial — results not yet published in a peer-reviewed journal.
Funding: NIH-funded. Full acknowledgement: National Institute on Aging K76AG074918 (Sedrak) and R33AG61456 (NIH Translational Geroscience Network; Kirkland, Tchkonia, Evans); National Cancer Institute R21CA277660 (Sedrak). Additional investigator support: R01CA280088 (Sedrak), Breast Cancer Research Foundation BCRF 25-228 (Sedrak), ASCO Young Investigator Award 2023YIA-3100001264 (Ji), ASCO Career Development Award 2025CDA-8346891688 (Ji), NIA P30AG094848 (Sedrak), NCI P30CA016042 (Crespi, Sedrak). Institutional support from Cedars-Sinai Medical Center, the Connor Fund, and Robert J. and Theresa W. Ryan (all Kirkland-affiliated). REDCap infrastructure funded by CTSI UL1TR001881. Per the authors' note, funders had no role in study design, data collection/analysis/interpretation, manuscript writing, or the decision to publish.
Competing interests: The authors declare that there is no conflict of interest (per Declarations).

Study snapshot

Design	Multicentre, Phase II, randomised, double-blind, placebo-controlled trial. NCT05595499.
Model	Postmenopausal women with early-stage, high-risk breast cancer who completed neo/adjuvant chemotherapy within the past 12 months and have diminished physical function (6-minute walk distance under 400m).
Sample	88 (planned, 1:1 randomisation)
Intervention	Fisetin 20 mg/kg/day on days 1-3 of a 14-day cycle, for four cycles, versus matched placebo. Fisetin/placebo supplied in 100 mg capsules under an FDA Investigational New Drug (IND) application, manufactured under Good Manufacturing Practice by Sharp Clinical Services; drug supply funded by NIH at no cost to participants; dose rounded to the nearest 100 mg capsule based on body weight measured at each visit.
Duration	4 cycles (approximately 56 days) of treatment; primary endpoint assessed at end of treatment.
Endpoints	Change in 6-minute walk distance from baseline to end of treatment (primary)

What the study showed, in plain terms

TROFFi is a new, actively recruiting Phase II trial testing whether fisetin can improve physical function in postmenopausal breast cancer survivors who still have reduced walking capacity after finishing chemotherapy. Chemotherapy is known to accelerate cellular senescence, and the trial's premise is that clearing senescent cells with a pulsed senolytic dose might help physical function recover.

Eighty-eight women with a 6-minute walk distance under 400 metres will be randomised to fisetin (20 mg/kg/day on days 1-3 of a 14-day cycle, four cycles total, roughly 8 weeks) or matched placebo. The primary outcome is the change in walking distance from baseline to the end of treatment.

This is a design and rationale paper only — no results are available yet. It is a close sibling to the PROFFi trial (also fisetin in breast cancer survivors, same UCLA-affiliated investigator group) but with a different design: TROFFi tests fisetin alone against placebo with a shorter treatment course, while PROFFi uses a 2x2 factorial design adding a supervised-exercise arm over a longer course. The two should not be conflated as the same trial.

Key findings

This is a trial rationale and design publication — no efficacy results are available yet.
88 postmenopausal breast cancer survivors with reduced physical function (6MWD <400m) will be randomised 1:1 to fisetin 20 mg/kg/day (days 1-3 of a 14-day cycle, 4 cycles) or placebo.
Primary endpoint is change in 6-minute walk distance from baseline to end of treatment (approximately 8 weeks).
TROFFi is a distinct trial from PROFFi, not a rename — same investigator network and population type, different design (no exercise arm, shorter 4-cycle course vs PROFFi's 2x2 factorial, 8-cycle course).

What this study can and cannot tell us

Design/rationale paper only — no efficacy or safety results to report yet; results should not be assumed either way.
Single population (postmenopausal breast cancer survivors post-chemotherapy) — findings, whenever they arrive, may not generalise to other frailty or ageing populations.
No supervised-exercise comparison arm, unlike the parallel PROFFi trial, so TROFFi alone cannot address whether fisetin adds benefit on top of exercise.

Tier 4

Prevention of Frailty With Fisetin and Exercise in Breast Cancer Survivors (PROFFi)

PROFFi Trial et al. · Not applicable - trial registered on ClinicalTrials.gov (not yet published in a peer-reviewed journal) · 2023

Tier 4

Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Women (AFFIRM)

AFFIRM Trial et al. · ClinicalTrials.gov (trial registry record — not yet published in a peer-reviewed journal) · 2018

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Last verified 02 September 2026

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction

Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability