Clinical trial NCT06536881: Gut Microbiome, Adverse Effects, and Markers Through MEtabolic Reprogramming
Official title: Gut Microbiome, Adverse Effects, and Markers Through MEtabolic Reprogramming (GAMMER) Study in Early Stage Breast Cancer Receiving Chemotherapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Breast Cancer
Early-stage Breast Cancer
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: The Commonwealth Fund
name: Maryland Cigarette Restitution Fund
First posted: 2024-08-05
Enrollment: 30
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Participants undergo a trial of 24-hour water only fasting before starting chemotherapy. At least one successful 24-hour fast is required. A total of 3 trials can be attempted. Participants can also progressively increase by 12 hours each week as tolerated or to a max of 48 hours. If a participant is unable to maintain at least a 24-hour fast during the study, participation in this study will end. Once the tolerated fasting time is established, this will be the starting fasting regimen used for Cycle 1 of 4 of the scheduled chemotherapy.

Investigators also aim to understand the impact of fasting on quality of life, inflammatory markers, and the bacteria in the gut. Participants will complete surveys weekly, blood samples for research and fasting labs with each cycle of chemotherapy (at 4 different time points). Investigators will also collect research bloods at baseline, stool samples 3 times in the study: baseline, and after fasting interventions for Cycle 1 and 3.
Primary purpose: OTHER

Brief summary: This research is being done to test the feasibility of 24-48 hours of water-only fasting to improve delivery of 4 cycles of chemotherapy in those receiving breast cancer treatment either before or after surgery.

Detailed description: Breast cancer is the most common cancer diagnosed among women worldwide. Many women diagnosed with early stage breast cancer (ESBC) will receive systemic therapy consisting of cytotoxic chemotherapy. As therapy-related toxicities are the most common reason for non-completion or dose reduction of chemotherapy, new strategies are needed to mitigate adverse effects. Preclinical studies show that fasting can prevent toxic effects of oxidative stress and chemotherapy without causing chronic weight loss via modulation of key oncogenic pathways. A few studies in women with breast cancer have demonstrated that fasting around chemotherapy is safe and has the same or fewer expected toxicities, although the underlying biological mechanisms for these findings is unknown. A better understanding of the mechanistic underpinnings of fasting interventions can lead to future interventions to enhance tolerability of chemotherapy and ultimately, maintaining intended chemotherapy dosing and schedule.

The primary objective of this study is to determine the feasibility of water-only fasting during chemotherapy (standard of care Taxotere and Cyclophosphamide (TC) every 3 weeks for 4 cycles or dose dense doxorubicin and cyclophosphamide (ddAC) every 2 weeks for 4 cycles) in 30 patients with early stage breast cancer. Concomitant human epidermal growth factor 2 (HER2) therapy is allowed. The investigators designed a bed-to-bench feasibility study called the Gut microbiome, Adverse effects, and Markers through MEtabolic Reprogramming (GAMMER) study. Feasibility will be evaluated by the proportion of participants with self-reported adherence to the fasting regimen. The investigators will consider the fasting intervention to be feasible if there is evidence that at least 70% of patients (corresponding with 24 out of 30 patients) adhere to the intervention for at least 3 of 4 cycles of chemotherapy.

Prior to chemotherapy, patients will undergo a dose finding for fasting. A minimum of one successful 24 hour fast is required during this. A maximum of three trials is allowed. Participants have the option to progressively increase the fasting window by 12 hours each week as tolerated or to a maximum of 48 hours). Patients who are unable to adhere to at least a 24 hour fast during the dose finding phase will be replaced. Once patients have a fasting dose established, this will be the starting dose used for Cycle 1 of 4 of scheduled chemotherapy.

The investigators also aim to understand the impact of short-term fasting on quality of life, as well as key cytokines, metabolites and gut microbiome. Participants will complete patient reported outcomes (PROs) weekly. The investigators will collect fasting labs and research blood with each cycle of chemotherapy (4 instances). The investigators will also collect research bloods at baseline. The investigators will collect stool samples at baseline, and after fasting interventions for Cycle 1 and 3.

Through the proposed investigations the investigators will test the feasibility of a promising strategy to augment delivery of chemotherapy in a population at risk for toxicity for cancer therapy, and explore the mechanisms by which it may function. The long-term goals are to: enhance patient experience during chemotherapy, improve survival outcomes, and reduce disparities in survival between those who received recommended dose of chemotherapy versus those who require a dose reduction due to side effects. The study can potentially move the field forward by (a) identifying key cytokine, microbiome and metabolome changes associated with short-term fasting in ESBC and (b) improving survival outcomes in patients with ESBC.

Eligibility criteria: Inclusion Criteria:

* Diagnosed with histologically-confirmed stage I-III invasive carcinoma of the breast
* Planning for standard neoadjuvant or adjuvant chemotherapy ddAC or TC for 4 cycles (concurrent anti-HER2 therapy is permitted)
* Provider physical exam within 4 weeks of consent
* Eastern Cooperative Oncology Group (ECOG) 0-1 (as per recent provider note or direct confirmation with provider)
* BMI ≥ 19.5 kg/m2 (as per most recent visit documented in medical record)
* Willingness to change diet, and provide fecal sample 3 times during study

Exclusion Criteria:

* BMI \<19.5 kg/m2
* Diabetes
* History of eating disorder
* Serious/uncontrolled medical condition (e.g. end stage renal disease on dialysis, cirrhosis, uncontrolled hypertension, seizure disorder, history of bariatric surgery)
* Pregnant or nursing
* Use of medications that must be taken with food: allopurinol, aspirin, amiodarone, baclofen, bromocriptine, carvedilol, carbamezpine, cimetidine, diclofenac, doxycycline, fenofibrate, fludrocortisone, glyburide, hydrocortisone, iron supplements, ketorolac, lithium, methylprednisolone, naproxen, niacin, potassium salts, prednisone, procainamide, sevelamer, sulfasalazine, trazodone, valproic acid

Primary outcomes:
measure: Proportion of participants with self-reported adherence to the fasting regimen
timeFrame: 6 -8 months
Secondary outcomes:
measure: Rate of high-grade adverse effects
timeFrame: 6-8 months
measure: Rate of Hematologic Toxicities
timeFrame: 6-8 months
measure: Number of Dose Reductions or Dose Delays
timeFrame: 6-8 months
measure: Percent Change in Quality of Life Questionnaire The European Organisation for Research and Treatment Cancer C30 score
timeFrame: 6 months, 12 months
measure: Percent change in Functional Assessment of Chronic Illness Therapy-Fatigue Scale
timeFrame: 6 months, 12 months
measure: Changes in Key Inflammatory Cytokines/Chemokines
timeFrame: Baseline, 6-8 months
measure: Compare Changes in Tumor Cells
timeFrame: Baseline, 6-8 months
measure: Compare Modulation of Gut Microbiome
timeFrame: Baseline, 6-8 months
measure: Compare the Composition of Gut Microbiome
timeFrame: Baseline, 6-8 months
Other outcomes:
measure: Absolute Percentage Change in Ki-67
timeFrame: Pre neoadjuvant chemotherapy, post neoadjuvant chemotherapy up to 2 years
measure: Prevalence of AA Genotype
timeFrame: 1-2 years
Locations:
city: Washington
country: United States
facility: Sibley Memorial Hospital
state: District of Columbia
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Jennifer Sheng, MD
role: PRINCIPAL_INVESTIGATOR
References: