Gut Microbiome, Adverse Effects, and Markers Through MEtabolic Reprogramming (GAMMER)

Gut Microbiome, Adverse Effects, and Markers Through MEtabolic Reprogramming (GAMMER) Study in Early Stage Breast Cancer Receiving Chemotherapy

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Early-stage Breast Cancer
• Intervention / Treatment: Behavioral: Fasting

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jennifer Sheng, MD; Phone Number: 202-537-4000; Email: jsheng7@jhmi.edu

Study Locations

• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20016
      • Recruiting
      • Sibley Memorial Hospital
      • Contact: Azka Tariq; Phone Number: 202-660-5712; Email: atariq6@jhmi.edu
      • Contact: Aliya Lalji; Phone Number: 202-243-2294; Email: alalji1@jhmi.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fasting prior to chemotherapy; Prior to chemotherapy administration, a trial of a 24-hour water-only fast will be conducted; at least 1 successful 24-hour fast is required to proceed with the fasting intervention during chemotherapy. A total of 3 trials is allowed (for a maximum of 48 hours fasting).	Behavioral: Fasting; The dietician will review the patient's chemotherapy schedule, and confirm the fasting window (as windows may be 24, 26 or 48 hours; and chemotherapy start times can vary from patient to patient).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with self-reported adherence to the fasting regimen	Determine the feasibility of water-only fasting during chemotherapy in patients with invasive ESBC receiving cytotoxic chemotherapy.	6 -8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of high-grade adverse effects	Evaluate the rate of any high-grade adverse effects (severe/very severe) during chemotherapy	6-8 months
Rate of Hematologic Toxicities	Evaluate the rate of high-grade hematologic toxicities during chemotherapy	6-8 months
Number of Dose Reductions or Dose Delays	Evaluate the total number of dose reductions or delays	6-8 months
Percent Change in Quality of Life Questionnaire The European Organisation for Research and Treatment Cancer C30 score	Participants will complete the Quality of Life Questionnaire C30 The Quality of Life Questionnaire-C30, which includes 30 items. The 30 items assess physical, role, emotional, cognitive and social functioning, global health status or Quality Of Life scales, fatigue, pain, nausea and vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties. The Quality of Life Questionnaire-C30 is scored on the basis of classical test theory (CTT), and uses the total item score as the scale score. All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient). The percent change in Patient Reported Outcome scores from baseline is accessed at 6 and 12 months.	6 months, 12 months
Percent change in Functional Assessment of Chronic Illness Therapy-Fatigue Scale	Participants will complete the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue) which includes 13 items. The 13 items assess self-reported fatigue and its impact upon daily activities and function. Response scale is 5 point Likert-type scale with manual scoring template, some items are reverse scored. Scale range is 0 to 52 with O being most fatigue and 52 indicating no fatigue. The percent change in fatigue scores from baseline is accessed at 6 and 12 months.	6 months, 12 months
Changes in Key Inflammatory Cytokines/Chemokines	Compare changes in key inflammatory cytokines/chemokines (IL4, IL6, IL22, IL17, CXCL5, and CXCL11), adipokines (Leptin, Adiponectin, Lipocalin, retinol-binding protein 4 (RBP4), Resistin, Ghrelin, and Omentin) from baseline to after each fast	Baseline, 6-8 months
Compare Changes in Tumor Cells	Compare changes in tumor cells (AMPK, TSC1/2, STK11, mTOR) and intratumoral b-hydroxybutyrate from baseline to after each fast (if receiving neoadjuvant chemotherapy)	Baseline, 6-8 months
Compare Modulation of Gut Microbiome	Examine the modulation of gut microbiome in response to fasting (for cycles 1 and 3) and compare it to baseline composition.	Baseline, 6-8 months
Compare the Composition of Gut Microbiome	Compare the composition of the gut microbiome from baseline to after fasting (for Cycles 1 and 3) in individuals whose labs are consistent with fasting versus individuals whose labs are inconsistent with fasting (elevated b-hydroxybutyrate, low insulin, glucose and insulin like growth factor 1 (IGF-1))	Baseline, 6-8 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Percentage Change in Ki-67	Compare the absolute percentage change in Ki-67 and pathologic complete response prior to and following neoadjuvant chemotherapy	Pre neoadjuvant chemotherapy, post neoadjuvant chemotherapy up to 2 years
Prevalence of AA Genotype	Assess prevalence of AA genotype of MnSOD in patient with early stage breast cancer and if a greater proportion of women with the AA genotype have fewer side effects and improvement in biomarkers after fasting compared to the women who do not.	1-2 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: The Commonwealth Fund; Maryland Cigarette Restitution Fund
• Investigators: Principal Investigator: Jennifer Sheng, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2024
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): May 1, 2029

Study Registration Dates

• First Submitted: July 31, 2024
• First Submitted That Met QC Criteria: July 31, 2024
• First Posted (Actual): August 5, 2024

Study Record Updates

• Last Update Posted (Actual): August 21, 2026
• Last Update Submitted That Met QC Criteria: August 19, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Angptl4 protein, mouse
• Other Study ID Numbers: J2362; IRB00390964 (Other Identifier: JHM IRB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No