Treatment of Frailty With Fisetin (TROFFi) in Breast Cancer Survivors
Study Details
Study Description
Brief Summary
This phase II trial tests whether fisetin works to improve physical function in postmenopausal women who have received chemotherapy for stage I-III breast cancer treatment. Fisetin is a naturally occurring substance that is found in strawberries and other foods. Fisetin eliminates 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 causes inflammation and damages nearby healthy cells. Studies have shown that chemotherapy causes a build-up of these senescent cells. Giving fisetin may eliminate senescent cells and improve physical function in postmenopausal women who have received chemotherapy for breast cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- To determine the effect of fisetin on physical function, as assessed using the 6-minute walk distance (6MWD), in postmenopausal breast cancer survivors.
SECONDARY OBJECTIVES:
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To determine the effect of fisetin on other measures of physical function (grip strength, short physical performance battery [SPPB], frailty phenotype, activities of daily living [ADL]/instrumental ADL).
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To determine the effect of fisetin on fatigability (Borg Rating of Perceived Exertion [RPE]).
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To determine the effect of fisetin on neuropathy (Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 [QLQ-CIPN20]).
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To determine the effect of fisetin on cognitive function (Montreal Cognitive Assessment [MoCA]).
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To determine the effect of fisetin on health-related quality of life (QLQ-C30).
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To determine the effect of fisetin on local and distant recurrence free survival.
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To determine the effect of fisetin on breast cancer specific survival and overall survival.
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To evaluate the safety and tolerability of fisetin. IX. To estimate rates of adherence to fisetin.
EXPLORATORY OBJECTIVES:
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To determine the effect of fisetin on p16 expression in peripheral CD3+ T-cells.
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To determine the effect of fisetin on circulating senescence-associated secretory phenotype (SASP) inflammatory factors in the plasma and urine.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive fisetin orally (PO) on the trial. Patients also undergo collection of blood throughout the trial.
ARM B: Patients receive placebo PO on the trial. Patients also undergo collection of blood throughout the trial.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm A (fisetin) Patients receive fisetin PO on the trial. Patients also undergo collection of blood throughout the trial. |
Procedure: Biospecimen Collection
Undergo collection of blood
Other Names:
Drug: Fisetin
Given PO
Other Names:
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Other: Questionnaire Administration
Ancillary studies
|
| Placebo Comparator: Arm B (placebo) Patients receive placebo PO on the trial. Patients also undergo collection of blood throughout the trial. |
Procedure: Biospecimen Collection
Undergo collection of blood
Other Names:
Drug: Placebo Administration
Given PO
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
Other: Questionnaire Administration
Ancillary studies
|
Outcome Measures
Primary Outcome Measures
- Change in 6-minute walk distance (6MWD) [Baseline to day 60]
The 6MWD is a validated measure of physical function. Participants walk at their own pace for 6 minutes and distance (in meters) is measured at the end. Will be treated as a continuous variable. Its distribution will be transformed to normality as appropriate, Initially, a simple t-test will be used to compare the means of 6MWD at Day 60 by treatment groups.
Secondary Outcome Measures
- Change in grip strength [From baseline to day 60]
Generalized estimating equation (GEE) models will be fitted. The variables also will be dichotomized (e.g., < median, >= median) and GEE models for binary data used to test treatment effects over time.
- Change in short physical performance battery (SPPB) score [From baseline to day 60]
GEE models will be fitted. The variables also will be dichotomized (e.g., < median, >= median) and GEE models for binary data used to test treatment effects over time.
- Change in frailty phenotype [From baseline to day 60]
GEE models will be fitted. The variables also will be dichotomized (e.g., < median, >= median) and GEE models for binary data used to test treatment effects over time.
- Change in activities of daily living (ADL)/instrumental activities of daily living (IADL) [From baseline to day 60]
GEE models will be fitted. The variables also will be dichotomized (e.g., < median, >= median) and GEE models for binary data used to test treatment effects over time.
- Change in the Borg rating of perceived exertion (RPE) score [From baseline to day 60]
GEE models will be fitted. The variables also will be dichotomized (e.g., < median, >= median) and GEE models for binary data used to test treatment effects over time.
- Change in Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN)20 scores [From baseline to day 60]
GEE models will be fitted. The variables also will be dichotomized (e.g., < median, >= median) and GEE models for binary data used to test treatment effects over time.
- Change in Montreal cognitive assessment (MoCA) score [From baseline to day 60]
GEE models will be fitted. The variables also will be dichotomized (e.g., < median, >= median) and GEE models for binary data used to test treatment effects over time.
- Change in quality of life questionnaire (QLQ)-C30 [From baseline to day 60]
GEE models will be fitted. The variables also will be dichotomized (e.g., < median, >= median) and GEE models for binary data used to test treatment effects over time.
- Local and distant recurrence free survival [Up to 3 years]
Will be compared between fisetin and placebo using the stratified log-rank test. The stratified Cox regression model will be used to obtain the estimate of the hazard ratio and the 95% confidence interval. The distributions of various survival endpoints will be estimated using the Kaplan-Meier method.
- Breast cancer specific survival and overall survival [Up to 3 years]
Will be compared between fisetin and placebo using the stratified log-rank test. The stratified Cox regression model will be used to obtain the estimate of the hazard ratio and the 95% confidence interval. The distributions of various survival endpoints will be estimated using the Kaplan-Meier method.
- Adverse events rates [Up to 90 days]
Measured by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5. Adverse events will be determined at each time point per patient as the presence (Y/N) of toxicities (CTCAE v 5.0) of grade >= 2. The number of patients with adverse events will be compared by treatment arms using Fisher's exact test. GEE models for binary data will also be used to compare the proportion of patients with adverse events over time by treatment.
- Adherence rate [From baseline up to 30 days]
Measured by pill diary. Treatment adherence (Yes/No) for each patient at each time point will be determined. A patient will be considered adherent (coded 1) if she took all the required capsules within the allotted time, and non-adherent (coded 0) otherwise. The number of capsules taken in the allotted time out of the total required will also be recorded. Will then compare between treatments the proportion of adherent patients and the average proportion of capsules taken within the allotted time across patients at each time point using the t-test. Time point-specific analysis will be performed since conditions for pill-taking differ between the clinic (supervised) and patients' home (self-administered).
Eligibility Criteria
Criteria
Inclusion Criteria:
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Documented informed consent of the participant and/or legally authorized representative
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Age: >= 50 years at the time of cancer diagnosis
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Female
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Baseline diminished 6-minute walk distance (< 400m). Must be able to ambulate without assistance from another individual. Supportive devices such as a cane or walker are allowed
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History of resected stage I-III breast cancer treated with neo/adjuvant chemotherapy
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Must have completed chemotherapy within at least 3 months but no more than 6 months
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Must have been postmenopausal at the time of cancer diagnosis
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Platelets > 60,000/mm^3
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White blood cell count > 2,000/mm^3
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Absolute neutrophil count > 500/mm^3
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Hemoglobin >= 7.0 g/dL
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Total bilirubin =< 3.0 X upper limit of normal (ULN)
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Aspartate aminotransferase (AST) =< 4.0 x ULN
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Alanine aminotransferase (ALT) =< 4.0 x ULN
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Estimated glomerular filtration rate (eGFR) of >= 30mL/min/1.73m^2 per the Modification of Diet in Renal Disease (MDRD) calculation
Exclusion Criteria:
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Chemotherapy, biological therapy, or immunotherapy within 3 months prior to the start of study treatment. Exceptions include: trastuzumab, pertuzumab, pembrolizumab, tamoxifen, and aromatase inhibitors
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Surgery and/or radiation within the last 30 days (Exception: invasive non- major procedures such as an outpatient biopsy)
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Subjects taking medications that cannot be stopped 2 days prior to the start of study that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus or sirolimus) within 14 days prior to the start of study treatment. If antifungals are absolutely necessary from an infectious disease perspective, then they will be allowed only if the levels are therapeutic. Azole antifungals are not allowed (fluconazole, miconazole, voriconazole, itraconazole, posaconazole, isavuconazole)
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On herbal and natural medications (Exception: cannabidiol (CBD) and unable or unwilling to hold its administration 2 days prior to and during study treatment dosing
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On proton pump inhibitors and unable or unwilling to hold therapy 2 days prior to the start of study treatment and during study treatment dosing
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Subjects taking potentially senolytic agents within the last year: fisetin, quercetin, luteolin, dasatinib or imatinib (or other tyrosine kinase inhibitors), piperlongumine, or navitoclax
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Subjects on therapeutic doses of anticoagulants (e.g., warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc.)
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Subjects taking the following antimicrobial agents within 2 days prior to the start of study: aminoglycosides, macrolides (clarithromycin, erythromycin), antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir), rifampin
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Issues with tolerating oral medication (such as but not limited to, inability to swallow pills (g-tubes not allowed), malabsorption issues, ongoing nausea or vomiting during screening, history of Crohn's, gastric bypass/reduction, or celiac disease)
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Untreated endocrine disorder such as hypoparathyroidism, hyperparathyroidism, acromegaly, Cushing's syndrome, hypopituitarism. Treated conditions are allowed
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Active infection requiring antibiotics
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Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
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Currently participating in another intervention research study seeking to improve functional status, alleviate frailty, muscle strength, exhaustion/fatigue, or cognitive function
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Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope Medical Center | Duarte | California | United States | 91010 |
Sponsors and Collaborators
- City of Hope Medical Center
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Mina Sedrak, City of Hope Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 22239
- NCI-2022-08061
- 22239
- P30CA033572