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

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

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, HER2 Positive Breast Carcinoma, 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

Intervention / Treatment
-----------------
* Other: Best Practice
* Other: Questionnaire Administration
* Drug: Rifaximin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (rifaximin, pertuzumab-based chemotherapy)<br>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: Best Practice<br>* Given standard of care pertuzumab-based chemotherapy<br>* Other names: standard therapy;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Rifaximin<br>* Given PO<br>* Other names: Xifaxan;|
| Active Comparator: Arm II (pertuzumab-based chemotherapy)<br>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: Best Practice<br>* Given standard of care pertuzumab-based chemotherapy<br>* Other names: standard therapy;Other: Questionnaire Administration<br>* Ancillary studies<br>|

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 |