Fisetin to Improve Physical Function in Stage I-III Breast Cancer Survivors

Anatomic Stage III Breast Cancer AJCC v8 Clinical Trial

Official title:

A Phase II Randomized Double-Blind Placebo-Controlled Study of Fisetin to Improve Physical Function in Breast Cancer Survivors

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05595499
• Other study ID #: 23-001170
• Secondary ID: NCI-2022-08061P3
• Status: Recruiting
• Phase: Phase 2
• Start date: March 27, 2023
• Est. completion date: June 1, 2026

Study information

• Verified date: April 2024
• Source: Jonsson Comprehensive Cancer Center
• Contact: Barbara Kahn-Mills
• Phone: 3108252520
• Email: bkahnmills[@]mednet.ucla.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial tests whether fisetin works to improve physical function in 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.

Description:

PRIMARY OBJECTIVE:

I. To determine the effect of fisetin on physical function, as assessed using the 6-minute walk distance (6MWD), in frail older breast cancer survivors.

SECONDARY OBJECTIVES:

I. To determine the effect of fisetin on other measures of physical function (grip strength, short physical performance battery [SPPB], frailty phenotype, physical function component of the 36 item short form survey [SF-36]).

II. To determine the effect of fisetin on fatigability (Borg Rating of Perceived Exertion [RPE]).

III. To determine the effect of fisetin on neuropathy (Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 [QLQ-CIPN20]).

IV. To determine the effect of fisetin on cognitive function (Patient Reported Outcomes Measurement Information System [PROMIS] cognitive function short form).

V. To determine the effect of fisetin on health-related quality of life (SF-36).

VI. To determine the effect of fisetin on sleep (Insomnia Severity Index [ISI]).

VII. To determine the effect of fisetin on anxiety (GAD-7). VIII. To determine the effect of fisetin on depression (PHQ-8). IX. To determine the effect of fisetin on local and distant recurrence free survival.

X. To determine the effect of fisetin on breast cancer specific survival and overall survival.

XI. To evaluate the safety and tolerability of fisetin (physician and patient-reported Common Terminology Criteria for Adverse Events [CTCAEs]).

XII. To estimate rates of adherence to fisetin (pill diary).

EXPLORATORY OBJECTIVES:

I. To determine the effect of fisetin on p16 expression in peripheral CD3+ T-cells.

II. To determine the effect of fisetin on circulating senescence-associated secretory phenotype (SASP) inflammatory factors.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive fisetin orally (PO) on days 1, 2, and 3. Treatment repeats every 2 weeks for up to 8 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples throughout the trial.

ARM B: Patients receive placebo PO on the trial. on days 1, 2, and 3. Treatment repeats every 2 weeks for up to 8 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up yearly for up to 3 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 88
• Est. completion date: June 1, 2026
• Est. primary completion date: June 1, 2026
• Accepts healthy volunteers: No
• Gender: Female
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• 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

• Women with a diagnosis of early-stage breast cancer (Stage I-III) treated with neo/adjuvant chemotherapy within 12 months of starting study treatment

• No evidence of active/recurrent breast cancer or other serious chronic illnesses

• Have evidence of frail health, defined as a diminished 6-minute walk distance (< 400m) at baseline

• Platelets > 60,000/mm^3

• White blood cell count > 2,000/mm^3

• Absolute neutrophil count > 500/mm^3

• Hemoglobin >= 8.0 g/dL

• Total bilirubin =< 3.0 X upper limit of normal (ULN)

• Aspartate aminotransferase (AST) =< 4.0 x ULN

• Alanine aminotransferase (ALT) =< 4.0 x ULN

• Estimated glomerular filtration rate (eGFR) of >= 30mL/min/1.73m^2 per the Modification of Diet in Renal Disease (MDRD) calculation

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Cancer-directed chemotherapy, biological therapy, or immunotherapy within 30 days prior to the start of study treatment. Exceptions include: trastuzumab, pertuzumab, pembrolizumab, tamoxifen, and aromatase inhibitors

• Surgery and/or radiation within the last 30 days of starting study treatment (Exception: invasive non- major procedures such as an outpatient biopsy)

• Subjects taking medications that are considered prohibited.

• Exception: Subjects taking any of the medications listed in under "Temporary medication adjustment required" may participate if they are otherwise eligible AND the medication can be safely withheld (from immediately before the 1st study agent administration until at least 10 hours after the last study agent administration, for each dosing interval)

• On herbal and natural medications with possible senolytic properties (i.e., curcumin, kava kava, St. John's wort) and are unable or unwilling to hold its administration 2 days prior to and during study treatment dosing. Exceptions include cannabidiol (CBD), vitamins, probiotics, and fish oil. Other herbal and natural medications may be permitted or prohibited per clinician discretion

• Subjects taking potentially senolytic agents within the last year: fisetin, quercetin, luteolin, dasatinib or imatinib (or other tyrosine kinase inhibitors), piperlongumine, or navitoclax

• Subjects on therapeutic doses of anticoagulants (e.g., warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc.)

• 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)

• 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

• Currently participating in another intervention research study seeking to improve functional status, alleviate frailty, muscle strength, exhaustion/fatigue, or cognitive function

Related Conditions & MeSH terms

• Anatomic Stage I Breast Cancer AJCC v8
• Anatomic Stage II Breast Cancer AJCC v8
• Anatomic Stage III Breast Cancer AJCC v8
• Breast Neoplasms

Intervention

Procedure:
• Biospecimen Collection
Undergo collection of blood samples

Drug:
• Fisetin
Given PO
• Placebo Administration
Given PO

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California

Sponsors (3)

Lead Sponsor	Collaborator
Jonsson Comprehensive Cancer Center	National Cancer Institute (NCI), National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in 6-minute walk distance (6MWD)	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.	Baseline to day 60
Secondary	Change in grip strength	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 access change in grip strength.; Grip strength will be obtained using a hand dynamometer.	From baseline to day 60
Secondary	Change in Short Physical Performance Battery score	GEE models will be fitted. The variables also will be dichotomized (e.g., < median, >= median) and GEE models for binary data used to access change in short physical performance battery score.	From baseline to day 60
Secondary	Change in frailty phenotype	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.	From baseline to day 60
Secondary	Change in physical function component of 36-item Short Form (SF-36)	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.	From baseline to day 60
Secondary	Change in the Borg Rating of Perceived Exertion score	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.	From baseline to day 60
Secondary	Change in Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 scores	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.	From baseline to day 60
Secondary	Change in Patient Reported Outcomes Measurement Information System cognitive function short form score	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.	From baseline to day 60
Secondary	Change in composite SF-36 score	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.	From baseline to day 60
Secondary	Change in sleep (Insomnia Severity Index score)	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.	From baseline to day 60
Secondary	Change in anxiety (Generalized Anxiety Disorder-7 score)	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.	From baseline to day 60
Secondary	Change in depression (Patient Health Questionnaire-8 score)	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.	From baseline to day 60
Secondary	Local recurrence free survival	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.	Up to 3 years
Secondary	Distant recurrence free survival	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.	Up to 3 years
Secondary	Breast cancer specific survival and overall survival	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.	Up to 3 years
Secondary	Overall survival	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.	Up to 3 years
Secondary	Adverse events rates	Measured by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5. Adverse events will be determined at each time point per patient as the presence (yes/no) 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.	Up to 90 days
Secondary	Adherence rate	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).	From baseline up to 30 days