Clinical trial NCT06113016: Prevention of Frailty with Fisetin and Exercise (PROFFi) in Breast Cancer Survivors
Official title: A Phase II Randomized Placebo-Controlled Study of Fisetin and Exercise to Prevent Frailty in Breast Cancer Survivors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Anatomic Stage I Breast Cancer American Joint Committee on Cancer (AJCC) V8
Anatomic Stage II Breast Cancer AJCC V8
Anatomic Stage III Breast Cancer AJCC V8
Early Stage Breast Carcinoma
Lead sponsor: Jonsson Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Cancer Institute (NCI)
First posted: 2023-11-02
Enrollment: 164
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief 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.

Detailed description: 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 and step count, as measured by wearable device.

II. To determine the effect of fisetin on other measures of physical function beyond 6MWD (short physical performance battery \[SPPB\], grip strength, frailty phenotype, physical activity).

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 neuropathy (Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 \[QLQ-CIPN20\]).

V. To determine the effect of fisetin and/or exercise on cognition (Patient Reported Outcomes Measurement Information System \[PROMIS\] cognitive function short form).

VI. To determine the effect of fisetin and/or exercise on health-related quality of life (Short Form \[SF\]-36).

VII. To determine the effect of fisetin on local and distant recurrence free survival (RFS).

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

IX. To evaluate the safety and tolerability (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]5.0) of fisetin.

X. 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 criteria: Inclusion Criteria:

* Women who are postmenopausal at the start of study treatment

  * Postmenopausal status will be established as follows: Women who are 50 years or older and who are not menstruating for greater than 12 months will be considered postmenopausal. Women who are less than 50 years with an intact uterus and ovaries must have chemically induced menopause (e.g., ovarian suppression) to be considered postmenopausal
* 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
* No evidence of active/recurrent breast cancer or other serious chronic illnesses
* Have evidence of pre-frail health, defined as a 6-minute walk distance (400-480m) 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 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 (gastrostomy \[g\]-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

Primary outcomes:
measure: Change in 6 minute walk distance (6MWD)
timeFrame: From baseline to day 120
Secondary outcomes:
measure: Change in heart rate
timeFrame: From baseline to day 120
measure: Change in step count
timeFrame: From baseline to day 120
measure: Change in short physical performance battery (SPPB)
timeFrame: From baseline to day 120
measure: Change in grip strength
timeFrame: From baseline to day 120
measure: Change in frailty phenotype
timeFrame: From baseline to day 120
measure: Change in physical function subsection of Short Form (SF)-36
timeFrame: From baseline to day 120
measure: Change in the Borg Rating of Perceived Exertion (RPE)
timeFrame: From baseline to day 120
measure: Change in Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20) scores
timeFrame: From baseline to day 120
measure: Change in Patient Reported Outcomes Measurement Information System (PROMIS) cognitive function short form score
timeFrame: From baseline to day 120
measure: Change in SF-36 scores
timeFrame: From baseline to day 120
measure: Local and distant recurrence free survival
timeFrame: Up to 3 years
measure: Breast cancer specific survival
timeFrame: Up to 3 years
measure: Overall survival
timeFrame: Up to 3 years
measure: Incidence of adverse events
timeFrame: Up to day 120
measure: Adherence rate
timeFrame: Up to day 120
Other outcomes:
Locations:
city: Alhambra
country: United States
facility: UCLA Health Cancer Care in Alhambra
state: California
city: Beverly Hills
country: United States
facility: UCLA Health Beverly Hills Primary & Specialty Care
state: California
city: Burbank
country: United States
facility: UCLA Health Burbank Primary & Specialty Care
state: California
city: Los Angeles
country: United States
facility: UCLA / Jonsson Comprehensive Cancer Center
state: California
city: Marina del Rey
country: United States
facility: UCLA Health Primary Care in Marina del Rey
state: California
city: Pasadena
country: United States
facility: UCLA Health Primary Care in Pasadena
state: California
Study officials:
affiliation: UCLA / Jonsson Comprehensive Cancer Center
name: Mina S Sedrak
role: PRINCIPAL_INVESTIGATOR
References: