Rifaximin for the Treatment of Gastrointestinal Toxicities Related to Pertuzumab-Based Therapy in Patients With Stage I-III HER2 Positive Breast Cancer

Phase II Trial of Rifaximin in Patients With Early Stage HER2 Positive Breast Cancer With Gastrointestinal Toxicities Related to Pertuzumab-Based Therapy

This phase II trial studies how well rifaximin works for the treatment of gastrointestinal toxicities related to pertuzumab-based therapy in patients with stage I-III HER2 positive breast cancer. Rifaximin may reduce the incidence and severity of pertuzumab induced gastrointestinal toxicities without interrupting or delaying the chemotherapy schedule.

Study Overview

• Status: Active, not recruiting
• Conditions: Anatomic Stage I Breast Cancer AJCC v8; Anatomic Stage IA Breast Cancer AJCC v8; Anatomic Stage IB Breast Cancer AJCC v8; Anatomic Stage II Breast Cancer AJCC v8; Anatomic Stage IIA Breast Cancer AJCC v8; Anatomic Stage IIB Breast Cancer AJCC v8; Anatomic Stage III Breast Cancer AJCC v8; Anatomic Stage IIIA Breast Cancer AJCC v8; Anatomic Stage IIIB Breast Cancer AJCC v8; Anatomic Stage IIIC Breast Cancer AJCC v8; Prognostic Stage I Breast Cancer AJCC v8; Prognostic Stage IA Breast Cancer AJCC v8; Prognostic Stage IB Breast Cancer AJCC v8; Prognostic Stage II Breast Cancer AJCC v8; Prognostic Stage IIA Breast Cancer AJCC v8; Prognostic Stage IIB Breast Cancer AJCC v8; Prognostic Stage III Breast Cancer AJCC v8; Prognostic Stage IIIA Breast Cancer AJCC v8; Prognostic Stage IIIB Breast Cancer AJCC v8; Prognostic Stage IIIC Breast Cancer AJCC v8; HER2 Positive Breast Carcinoma
• Intervention / Treatment: Other: Questionnaire Administration; Drug: Rifaximin; Other: Best Practice

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate the reduction rate of grade >= 2 abdominal toxicities, including abdominal distension, abdominal pain, diarrhea, dyspepsia, stomach pain, and typhlitis according to the National Cancer Institute Common Terminology for Adverse Events version 5.0 (NCI CTCAE v5.0) with the use of rifaximin in stage II-III HER-2 positive breast cancer patients with pertuzumab induced gastrointestinal toxicities.

SECONDARY OBJECTIVES:

I. Evaluate dose reductions, dose delays and discontinuation of treatment with pertuzumab due to gastrointestinal side effects.

II. Evaluate and measure the change in the Bristol stool scale before and after rifaximin treatment.

III. Evaluate and measure the change in the 4-point Likert scale patient questionnaire before and after rifaximin treatment.

CORRELATIVE STUDY OBJECTIVES:

I. Evaluate changes in the fecal microbiome, hydrogen breath test, and permeability test before and after rifaximin.

II. Evaluate changes in the fecal microbiome, hydrogen breath test, and permeability test before and after pertuzumab-based chemotherapy.

III. Evaluate the difference in the fecal microbiome, hydrogen breath test, and permeability test among patients with or without pertuzumab induced gastrointestinal toxicities (PIGT).

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I (GRADE >= 2 PIGT): Patients that experience PIGT after receiving first standard of care cycle of pertuzumab-based chemotherapy receive rifaximin orally (PO) twice daily (BID) on days 1-5 and standard of care pertuzumab-based chemotherapy on day 1. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

ARM II (GRADE =< 1 PIGT): Patients that do not experience PIGT after receiving first standard of care cycle of pertuzumab-based chemotherapy continue receiving standard of care pertuzumab-based chemotherapy on day 1. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• PRE-REGISTRATION INCLUSION CRITERIA
• Age >= 18 years
• Histological confirmation of HER2 positive breast cancer stage I-III per American Joint Committee on Cancer (AJCC) staging 8th edition
• Provide written informed consent
• Breast cancer patients who will be receiving pertuzumab-based chemotherapy with either TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) or docetaxel/paclitaxel, trastuzumab, and pertuzumab
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• Hemoglobin >= 10.0 g/dL (obtained =< 30 days prior to pre-registration)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained =< 30 days prior to pre-registration)
• Platelet count >= 100 x 10^9/L (obtained =< 30 days prior to pre-registration)
• Total bilirubin =< 1.5 x ULN (institutional upper limit of normal) (obtained =< 30 days prior to pre-registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (obtained =< 30 days prior to pre-registration)
• Serum or plasma creatinine =< 1.5 x ULN (obtained =< 30 days prior to pre-registration)
• Calculated creatinine clearance >= 45 ml/min using the Cockcroft-Gault formula (obtained =< 30 days prior to pre-registration)
• Negative serum pregnancy test done =< 30 days prior to pre-registration, for person of childbearing potential only
• Willingness to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• Willingness to provide mandatory stool specimen for correlative research
• Ability to complete questionnaire(s) by themselves or with assistance
• REGISTRATION INCLUSION CRITERIA
• Received pertuzumab based regimens in the adjuvant or neoadjuvant setting
• Hemoglobin >= 8.0 g/dL (obtained =< 14 days prior to registration)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained =< 14 days prior to registration)
• Platelet count >= 100 x 10^9/L (obtained =< 14 days prior to registration)
• Total bilirubin =< 1.5 x ULN (institutional upper limit of normal) (obtained =< 14 days prior to registration)
• AST (SGOT)/ALT (SGPT) =< 2.5 x ULN (obtained =< 14 days prior to registration)
• Serum or plasma creatinine =< 1.5 x ULN (obtained =< 14 days prior to registration)
• Calculated creatinine clearance >= 45 ml/min using the Cockcroft-Gault formula (obtained =< 14 days prior to registration)

Exclusion Criteria:

• PRE-REGISTRATION EXCLUSION CRITERIA
• History of myocardial infarction =< 6 months prior to pre-registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

• Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment

  • EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 3 months since completion of prior treatment

• Uncontrolled intercurrent non-cardiac illness including, but not limited to:

  • Ongoing or active infection
  • Psychiatric illness/social situations
  • Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
  • Any other conditions that would limit compliance with study requirements

• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy

  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm (adjust to protocol if applicable)

• Any of the following because this study involves an agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown

  • Pregnant women
  • Nursing women
  • Women of childbearing potential who are unwilling to employ adequate contraception
• Current colostomy or ileostomy
• History of inflammatory bowel disease
• History of irritable bowel syndrome
• History of arteriovenous malformations
• History of gastrointestinal bleeds
• Previous surgical resection of the small bowel or colon
• Previous allergy to rifaximin or its derivatives

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (rifaximin, pertuzumab-based chemotherapy); Patients that experience PIGT after receiving first standard of care cycle of pertuzumab-based chemotherapy receive rifaximin PO BID on days 1-5 and standard of care pertuzumab-based chemotherapy on day 1. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.	Other: Questionnaire Administration; Ancillary studies; Drug: Rifaximin; Given PO; Other Names: Xifaxan; Other: Best Practice; Given standard of care pertuzumab-based chemotherapy; Other Names: standard of care; standard therapy
Active Comparator: Arm II (pertuzumab-based chemotherapy); Patients that do not experience PIGT after receiving first standard of care cycle of pertuzumab-based chemotherapy continue receiving standard of care pertuzumab-based chemotherapy on day 1. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.	Other: Questionnaire Administration; Ancillary studies; Other: Best Practice; Given standard of care pertuzumab-based chemotherapy; Other Names: standard of care; standard therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction rate of >= grade 2 abdominal toxicities including abdominal distension, abdominal pain, diarrhea, dyspepsia, stomach pain, and typhlitis	Based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner (1987).	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose reductions of treatment with pertuzumab	Descriptive statistics (frequency table) and histogram will be used to summarize dose reductions, dose delays and discontinuation of treatment with pertuzumab due to gastrointestinal side effects.	Up to 3 years
Dose delays of treatment with pertuzumab	Descriptive statistics (frequency table) and histogram will be used to summarize dose reductions, dose delays and discontinuation of treatment with pertuzumab due to gastrointestinal side effects.	Up to 3 years
Discontinuation of treatment with pertuzumab	Descriptive statistics (frequency table) and histogram will be used to summarize dose reductions, dose delays and discontinuation of treatment with pertuzumab due to gastrointestinal side effects.	Up to 3 years
Change in the Bristol stool scale before and after rifaximin treatment	Descriptive statistics (frequency table) and histogram will be used to summarize the Bristol stool scale during the study.	Baseline up to 3 years
Other pertuzumab induced gastrointestinal toxicities (PIGT) such as abdominal pain, bloating and flatulence	Descriptive statistics (frequency table) and histogram will be used to summarize other PIGT such as abdominal pain, bloating and flatulence as measured by a 4 point Likert scale during the study.	Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in the fecal microbiome, hydrogen breath test, and permeability test	Descriptive statistics (mean, sd, median, iqr) and longitudinal plots (raw value, change, change in percentage) will be used to the fecal microbiome, hydrogen breath test, and permeability test among patients with or without PIGT. The study is not powered to detect any differences between the two arms; the main purpose is to quantify and evaluate differences descriptively between patients who develop and do not develop PIGT (between arm 1 and arm 2) to inform subsequent research.	Up to 3 years
Changes in the fecal microbiome, hydrogen breath test, and permeability test - rifaximin	Descriptive statistics (mean, standard deviation [sd], median, interquartile range [iqr]) and longitudinal plots (raw value, change, change in percentage) will be used to summarize the baseline levels of hydrogen/methane peak by hydrogen breath test , diversity of gut microbiome(number of species) and specific species by fecal microbiome, and levels of urine mannitol and lactulose by permeability test before and after rifaximin.	Baseline up to 3 years
Changes in the fecal microbiome, hydrogen breath test, and permeability test - pertuzumab	Descriptive statistics (mean, sd, median, iqr) and longitudinal plots (raw value, change, change in percentage) will be used to summarize the baseline levels of hydrogen/methane peak by hydrogen breath test, diversity of gut microbiome (number of species) and specific species by fecal microbiome, and levels of urine mannitol and lactulose by permeability test before and after pertuzumab-based chemotherapy.	Baseline up to 3 years

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Saranya Chumsri, M.D., Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2020
• Primary Completion (Actual): December 27, 2022
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: January 27, 2020
• First Submitted That Met QC Criteria: January 28, 2020
• First Posted (Actual): January 31, 2020

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 16, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Anti-Infective Agents; Gastrointestinal Agents; Anti-Bacterial Agents; Rifaximin
• Other Study ID Numbers: MC18C3 (Other Identifier: Mayo Clinic in Florida); P30CA015083 (U.S. NIH Grant/Contract); NCI-2020-00332 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

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