Conditions: Breast Cancer
Keywords: HER2 pertuzumab trastuzumab docetaxel paclitaxel carboplatin crofelemer chemotherapy induced diarrhea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: no

Brief summary:
Chemotherapy induced diarrhea is seen in up to 40-80% of patients receiving this treatment for HER2 positive locally advanced or metastatic breast cancer. This diarrhea can significantly impact a patient's quality of life and ability to tolerate chemo/anti-HER2 therapy. This study will look at the efficacy of the drug crofelemer in preventing diarrhea in breast cancer patients.

Detailed description:
Various anti-diarrheal agents, such as loperamide, codeine, octreotide, are available for diarrhea management, but few are used in the prophylactic setting and none provide a targeted approach for treating chemotherapy induced diarrhea (CID).

Pre-clinical studies have suggested that blocking EGFR results in excess chloride secretion and thus diarrhea. Crofelemer is an extract from the blood red bark of Croton lechleri that inhibits luminal chloride efflux by blocking the calcium activated chloride channel (CaCC) and cystic fibrosis transmembrane regulator (CFTR) chloride channels. Due to its size and polarity, it acts only luminally and is not systemically absorbed. It is currently FDA approved for use in preventing diarrhea in HIV/AIDS patients on anti-retroviral therapy.

Arms:
arm 1: Patients on the treatment arm will take one tablet of crofelemer twice a day (each tablet is 125 mg), to be swallowed whole without chewing or crushing, during cycles 1-2 of chemotherapy with THP or TCHP. Patient will be monitored off crofelemer during cycle 3 of chemotherapy. arm 2: Patients on the control arm will be on the study for cycles 1-3 of THP or TCHP. Patients on the control arm will not receive crofelemer at any time on this study.

Interventions: intervention 1: Crofelemer
Intervention descriptions: intervention 1: Crofelemer 125 mg BID during cycles 1-2 of THP or TCHP

Protocol document:
Prot_SAP_000.pdf: 
 
TITLE: DIARRHEA PREVENTION AND PROPHYLAXIS WITH 
CROFELEMER IN HER2 POSITIVE BREAST CANCER PATIENTS 
RECEIVING TRASTUZUMAB, PERTUZUMAB, AND DOCETAXEL OR 
PACLITAXEL WITH OR WITHOUT CARBOPLATIN 
NCT: NCT02910219 
 
Current Protocol Date  June 7, 2021 


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HALT-D 
 
 
DIARRHEA PREVENTION AND PROPHYLAXIS WITH CROFELEMER IN HER2 POSITIVE 
BREAST CANCER PATIENTS RECEIVING TRASTUZUMAB, PERTUZUMAB, AND 
DOCETAXEL OR PACLITAXEL WITH OR WITHOUT CARBOPLATIN 
 
 
 
Sponsor  
Sandra M. Swain, MD, FACP, FASCO 
4000 Reservoir Road NW 
120 Building D 
Washington, DC 20057 
Phone: 202-687-4600  
Fax: 202-687-1110 
Email: sandra.swain@georgetown.edu 
  
 
Biostatistician  
Lombardi Comprehensive Cancer Center 
Biostatistics and Bioinformatics Shared Resource 
 
Study Drug  
Crofelemer 
 
Funding Source(s)  
Genentech 
Napo Pharmaceuticals 
MedStar Health Research Institute 
 
Current Protocol Date 
 
 
 
June 7, 2021 
 
 


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SIGNATURE PAGE  
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according 
to local legal and regulatory requirements and applicable U.S. federal regulations and 
International Conference on Harmonization guidelines.  
 
 
 
 
Sponsor 
 
 
 
Dr. Sandra M. Swain, MD, FACP, FASCO 
 
 
 
 
Sponsor Signature  
 
_______________________________ 
 
 
 
 
 
Date 
 
 
 
 
_______________________________  
 


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SCHEMA 
 
Figure 1: Flow chart of patient enrollment  
 
 
 


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Figure 2: Treatment group schema 
cycle 
1 
2 
3 
4 
pertuzumab 
  
  
  
  
trastuzumab 
  
  
  
  
  
    
            
            
            
docetaxel or paclitaxel 
  
        
  
        
  
        
  
carboplatin (if using) 
  
  
  
  
crofelemer 
  
            
          
  
    
            
            
            
crofelemer diary 
  
            
          
rescue medication diary 
  
            
            
          
bowel movement diary 
  
            
            
          
clinic visit 
X 
X 
X 
X 
FACIT-D 
X 
X 
X 
X 
  
    
            
            
            
Pertuzumab: 840 mg load -> 420 mg q3 weeks 
Trastuzumab: 8 mg/kg load -> 6 mg/kg q3 weeks 
Paclitaxel: 80 mg/m2 q1 week 
Docetaxel: 75 mg/m2 q3 weeks 
Carboplatin: AUC 6 q3 weeks (if using) 
Crofelemer: 125 mg BID daily for cycles 1 and 2 
 


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Figure 3: Control group schema 
cycle 
1 
2 
3 
4 
pertuzumab 
  
  
  
  
trastuzumab 
  
  
  
  
  
    
            
            
            
docetaxel or paclitaxel 
  
        
  
        
  
        
  
carboplatin (if using) 
  
  
  
  
no prophylaxis 
  
    
            
            
            
rescue medication diary 
  
            
            
          
bowel movement diary 
  
            
            
          
clinic visit 
X 
X 
X 
X 
FACIT-D 
X 
X 
X 
X 
  
    
            
            
            
Pertuzumab: 840 mg load -> 420 mg q3 weeks 
Trastuzumab: 8 mg/kg load -> 6 mg/kg q3 weeks 
Paclitaxel: 80 mg/m2 q1 week 
Docetaxel: 75 mg/m2 q3 weeks 
Carboplatin: AUC 6 q3 weeks (if using) 
 


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STUDY SYNOPSIS 
 
Title: 
Diarrhea prevention and prophylaxis with crofelemer in HER2 positive breast cancer patients 
receiving trastuzumab, pertuzumab, and docetaxel or paclitaxel with or without carboplatin: 
HALT-D 
 
Investigators:  
Sponsor: Sandra M. Swain, MD, FACP, FASCO 
 
Study Center(s):  
This study will be open at multiple sites in the United States. 
 
Concept and Rationale:  
Chemotherapy induced diarrhea (CID) occurs in 40-80% of breast cancer patients who receive 
HER2 directed therapy with trastuzumab, pertuzumab, and a taxane, with most patients 
experiencing grade 1-2 diarrhea. In the CLEOPATRA trial, in which patients received a median 
of 8 cycles of trastuzumab, pertuzumab, and docetaxel, 67% had all grade diarrhea and 8% 
experienced grade 3 diarrhea. Patients on the TRYPHAENA trial received 6 cycles of 
neoadjuvant trastuzumab, pertuzumab, and docetaxel, with 72.4% of patients experiencing all 
grade diarrhea and 11.8% experiencing grade 3 diarrhea; the results were similar in the patients 
who also received carboplatin.  In a phase 2 trial of trastuzumab and pertuzumab with weekly 
paclitaxel, in which patients received a median of 10 cycles of treatment, 81% of patients had all 
grade and 3% had grade 3-4 diarrhea.  
 
In addition to impacting kidney function and causing electrolyte imbalance, diarrhea even at 
grades 1-2 can significantly impact a patient’s quality of life. Various anti-diarrheal agents, 
including loperamide, codeine, octreotide, non-absorbed steroids, atropine, antibiotics, opium, 
bismuth, probiotics, and bile acid sequestrants, are available for symptom management.  Of 
these, loperamide is most commonly used and recommended as a first line agent in the 
treatment setting.  Octreotide is generally reserved for refractory diarrhea due to its cost and 
requirement for subcutaneous dosing. However, none of these target the underlying mechanism 
of CID.   
 
Chloride ions and channels play a large role in the underlying mechanism of secretory diarrhea. 
In the luminal side of the colon, chloride efflux is mediated via apical chloride channels, of which 
there are three types: 1) cystic fibrosis transmembrane regulator (CFTR), a cyclic AMP 
stimulated chloride channel; 2) calcium activated chloride channel (CaCC); and 3) chloride 
channel type 2 (ClC2).  Various studies have looked at the role of epidermal growth factor 
receptor (EGFR) targets and the mechanism of diarrhea. These studies have suggested that 
blocking EGFR can cause excess chloride secretion, resulting in impaired gut absorption and a 
resulting secretory diarrhea.  
 
Crofelemer is an extract from the blood red bark of Croton lechleri that inhibits luminal chloride 
efflux by blocking two channels that regulate chloride efflux in the colon, the calcium activated 
chloride channel (CaCC) and the cystic fibrosis transmembrane regulator (CFTR). Due to its 
size and polarity, it acts only luminally and is not systemically absorbed.   
 
In a phase 3 randomized controlled double blinded trial, investigators looked at 376 HIV patients 
with diarrhea for > 1 month. The first part of the study established the optimal dose of 
crofelemer at 125 mg twice a day, which resulted in a 21% reduction in stool frequency. The 


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second part of the study compared crofelemer to placebo with a primary endpoint of ≤ 2 watery 
stools per week. They noted a statistically significant higher response rate of 18% for patients 
on crofelemer versus 8% for those on placebo. When patients initially on placebo crossed over 
to the crofelemer arm, 36% met the criterion of response. Possible side effects included 
dyspepsia, flatulence, constipation, nausea, and increased alanine transferase.  Based on this 
study, crofelemer was approved by the FDA in 2012 for secretory diarrhea in patients with 
HIV/AIDS receiving anti-retroviral therapy.  
We propose a trial of crofelemer versus standard of care (no anti-diarrheal prophylaxis) for 
prevention of CID in HER2 positive breast cancer patients on trastuzumab, pertuzumab, and 
docetaxel or paclitaxel with or without carboplatin.  We hypothesize that crofelemer, which 
targets two of the chloride channels responsible for secretory diarrhea, will be an effective and 
targeted approach to reducing the incidence of CID in this patient population. 
 
Primary Objective(s):  
To determine the efficacy of crofelemer in preventing chemotherapy induced diarrhea (CID) in 
patients with HER2 positive breast cancer receiving chemotherapy with trastuzumab, 
pertuzumab, and docetaxel or paclitaxel (THP) or trastuzumab, pertuzumab, carboplatin, and 
docetaxel (TCHP). 
 
Secondary Objectives: 
If possible, the secondary objectives will be: 
 
To determine the incidence of diarrhea of any grade, as measured by CTCAE v4.0, by 
cycle; 
 
To determine the incidence of diarrhea of grade 3-4, as measured by CTCAE v4.0, by cycle; 
 
To determine the time to onset of first event of diarrhea of any grade, defined as the number 
of days from day one of THP or TCHP until the day in which the first episode of diarrhea 
classified as of grade 1 or higher occurs, or is censored at the date of the last treatment 
cycle for patients who do not experience diarrhea, overall and by stratum; 
 
To determine the duration (days) of any grade diarrhea, by cycle in which the episode 
started and by stratum; 
 
To determine the duration (days) of grade 3-4 diarrhea, by cycle in which the episode 
started and by stratum; 
 
To assess use of anti-diarrheal medications (other than study drug), by cycle, grade of 
diarrhea, and stratum; 
 
To determine the quantitative FACIT-D total score, collected day 1 of each cycle and at the 
time of study completion (defined as cycle 4 day 1, but patients may complete this final 
FACIT-D questionnaire within 5 days of cycle 4 day 1), by cycle and by stratum; 
 
To determine the quantitative FACIT-D diarrhea subset (DS) score, collected day 1 of each 
cycle and at the time of study completion (defined as cycle 4 day 1, but patients may 
complete this final FACIT-D questionnaire within 5 days of cycle 4 day 1), by cycle and by 
stratum; 
 
To determine the frequency table for stool consistency, as measured by the Bristol Stool 
scale, by cycle and stratum for each treatment group. 


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Main Criteria for Inclusion/Exclusion:  
Inclusion Criteria 
1. Willing and able to provide written informed consent; 
2. Men and women ≥18 years of age; 
3. Pathologically confirmed diagnosis of HER2 positive breast cancer of any stage 
(previous treatment is allowed without limits on lines of prior therapy); 
4. Scheduled to receive at least 3 consecutive cycles of THP or TCHP; 
5. Performance status of 0-2 according to the ECOG scale; 
6. Negative pregnancy test within 2 weeks prior to starting THP or TCHP treatment for 
women of childbearing potential; 
7. Able to read, understand, follow the study procedure and complete crofelemer, rescue 
medication, and bowel movement diaries; 
8. Patients may enroll simultaneously on this study and other studies 
9. Patients with brain metastases (including concurrent steroid treatment) are allowed on 
this study. 
10. Left Ventricular Ejection Fraction (LVEF) greater or equal to 50% at baseline as 
determined by either ECHO or MUGA  
 
Exclusion Criteria 
Any patient who at the time of signing consent is/has: 
1. 
Pregnant and/or breastfeeding; 
2. 
Ongoing irritable bowel syndrome (IBS) or colitis (including but not limited to ulcerative 
colitis, Crohn’s disease, microscopic colitis, etc.); 
3. 
Use of investigational drugs within 3 weeks of starting THP or TCHP treatment or 
foreseen use during the study; 
4. 
Use of chemotherapy, trastuzumab, or pertuzumab within the past 2 (two) weeks; 
5. 
Use of laxatives within the past 7 days - deleted; 
6. 
Use of chronic laxatives (≥ 30 consecutive days) - deleted; 
7. 
Use of anti-diarrheal agents (including but not limited to loperamide, octreotide, 
bismuth, tincture of opium, atropine, probiotics in any form other than food) within the 
past 7 days - deleted; 
8. 
Use of antibiotics within the past 7 days (up to 2 prophylactic doses of antibiotic for 
procedures, including but not limited to port placement, is permitted) 
9. 
Any type of ostomy; 
10. Total colectomy; 
11. Fecal incontinence; 
12. Ongoing radiation induced diarrhea or constipation or planned radiotherapy to the 
abdomen or pelvis while on study; 
13. Active systemic infection requiring ongoing intervention, including but not limited to oral 
and intravenous antibiotics, anti-fungals, anti-parasites, anti-virals; 
14. Abdominal or pelvic surgery without recovery of bowel function; 
15. Inadequate organ function for starting THP or TCHP, which may include the following 
laboratory results within 28 days prior to starting THP or TCHP treatment (Please refer 
to the prescribing label instructions on the use of each drug in the setting of abnormal 
organ function): 
 
Serum creatinine > 2.0 mg/dL or 177 μmol/L 
 
Total bilirubin > upper limit of normal (ULN) (unless the patient has documented 
Gilbert’s syndrome) 
 
Exclusion criteria specific for THP with PACLITAXEL (Taxol®) group: 
o Transaminases greater than 10 times ULN  


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 
Exclusion criteria specific for TCHP/THP with DOCETAXEL (Taxotere®) group: 
o AST and/or ALT > 2.5x ULN 
AST and/or ALT > 1.5x ULN with concurrent alkaline phosphatase >2.5 x ULN 
(unless bone metastases are present). 
 
Intervention and Mode of Delivery: 
Treatment group: crofelemer 125 mg orally twice a day daily during cycles 1-2 of THP or TCHP 
chemotherapy. 
Control group: no prophylaxis (current standard of care). 
 


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Study Design:  
This is a randomized, 1:1, stratified, open-label phase II study in patients with HER2 positive 
breast cancer receiving THP or TCHP in any setting.    Randomization will be stratified 
according to TCHP with docetaxel vs. THP with paclitaxel vs. THP with docetaxel. 
 
Patients randomized to the treatment group will receive oral crofelemer 125 mg twice daily 
during cycles 1-2 of THP or TCHP chemotherapy.  The primary endpoint is the total number of 
patients with all grade diarrhea for two or more consecutive days that is definitely, probably, or 
possibly due to THP or TCHP during cycles 1 and 2.  All patients will keep a daily diary of bowel 
movement number and consistency.   
 
Statistical Methods:  
Definition of primary endpoint:  
The primary endpoint is incidence of diarrhea of any grade for two or more consecutive days felt 
to be definitely, probably, or possibly due to THP or TCHP, as assessed by NCI CTCAE v4.0, 
during cycle 1 and cycle 2 of chemotherapy. The CTCAE v4.0 coding for diarrhea is 10012727. 
 
Definition of secondary endpoints:  
If possible, the secondary endpoints will be: 
 
 
Incidence of diarrhea of any grade, as measured by CTCAE v4.0, by cycle and by stratum; 
 
Incidence of diarrhea of grade 3-4, as measured by CTCAE v4.0, by cycle and by stratum; 
 
Time to onset of first episode of diarrhea of any grade, defined as the number of days from 
day one of THP or TCHP until the day in which the first episode of diarrhea classified as of 
grade 1 or higher occurs, or is censored at the date of the last treatment cycle for patients 
who do not experience diarrhea, overall and by stratum; 
 
Duration (days) of any grade diarrhea, by cycle in which the episode started and by stratum; 
 
Duration (days) of grade 3-4 diarrhea, by cycle in which the episode started and by stratum; 
 
Use of anti-diarrheal medications (other than study drug), by cycle and grade; 
 
Quantitative FACIT-D total score, collected day 1 of each cycle and at the time of study 
completion (defined as cycle 4 day 1, but patients may complete this final FACIT-D 
questionnaire within 5 days of cycle 4 day 1), by cycle and by stratum; 
 
Quantitative FACIT-D diarrhea subset (DS) score, collected day 1 of each cycle and at the 
time of study completion (defined as cycle 4 day 1, but patients may complete this final 
FACIT-D questionnaire within 5 days of cycle 4 day 1), by cycle and by stratum; 
 
Frequency table of stool consistency, as measured by the Bristol Stool scale, by cycle 
stratum between treatment groups. 
 
Analytic plan for primary objective:   
The number and percent of patients who experience diarrhea of any grade for two or more 
consecutive days (felt to be definitely, probably, or possibly due to THP or TCHP) during cycle 1 
and 2 will be summarized with two-sided 90% confidence interval overall and by treatment 
assignment, and compared between treatment arms using a Fisher’s exact test.  The analysis 
population is defined as all randomized patients who complete 2 cycles of THP or TCHP 
chemotherapy.  
 
Analytic plan for secondary objectives:  
We plan on using the following analytic plan for secondary objectives and endpoints, if possible. 
 
According to treatment group, for each of the cycles and stratum, we will summarize: 1) the 


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number and percent of patients (and 95% CI) who experience diarrhea of any grade; 2) the 
number and percent of patients (and 95% CI) who experience diarrhea of grade 3-4; 3) the 
median, range, and interquartile range of the duration of the episodes; and 4) the number (%) of 
patients requiring anti-diarrheal rescue medication. 
 
The time to onset of first episode of diarrhea will be summarized using the Kaplan-Meier 
method, and compared between treatment groups and stratum using log-rank test. 
 
The FACIT-D and FACIT-D DS scores will be summarized descriptively and graphically by 
cycle, treatment assignment, and stratum. The change in FACIT-D and FACIT-D DS scores 
between day 1 of cycles 1-3 and end of study (within 5 days of cycle 4 day 1) will be compared 
at each time point between treatment groups using a Wilcoxon rank sum-test. 
 
The stool consistency, as measured by the Bristol Stool scale, will be summarized in frequency 
tables by cycle and stratum and compared between treatment groups using a Wilcoxon rank 
sum-test. 
 
Adverse events will be summarized by type, grade, and stratum, according to treatment arm. 
 
Sample size justification:   
With a sample size of 46 patients (23 per treatment group), the study has 81% power to detect a 
40% absolute decrease (from 60% to 20%) in incidence of all grade diarrhea for two or more 
consecutive days that is definitely, probably, or possibly due to THP or TCHP during cycles 1 
and 2 of chemotherapy, with a two sided significance level of 0.10 based on Fisher’s exact test.   
Funding:  
Genentech 
Napo Pharmaceuticals 
MHRI 


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TABLE OF CONTENTS 
 
1 
LIST OF ABBREVIATIONS ..............................................................................................14 
2 
BACKGROUND AND RATIONALE ..................................................................................15 
2.1 
NORMAL INTESTINAL FUNCTION....................................................................................15 
2.2 
TYPES OF DIARRHEA ...................................................................................................15 
2.3 
DIARRHEA GRADING ....................................................................................................15 
2.4 
ASSESSING QUALITY OF LIFE WITH DIARRHEA ...............................................................15 
2.5 
CHEMOTHERAPY INDUCED DIARRHEA: BREAST CANCER ................................................15 
2.6 
CHEMOTHERAPY INDUCED DIARRHEA: GUIDELINES AND MANAGEMENT ..........................19 
2.7 
ANTI-DIARRHEAL AGENTS ............................................................................................20 
3 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................22 
3.1 
PRIMARY OBJECTIVE ...................................................................................................22 
3.2 
SECONDARY OBJECTIVES ............................................................................................22 
3.3 
PRIMARY ENDPOINT ....................................................................................................22 
3.4 
SECONDARY ENDPOINTS .............................................................................................23 
4 
PATIENT ELIGIBILITY .....................................................................................................23 
4.1 
INCLUSION CRITERIA ...................................................................................................23 
4.2 
EXCLUSION CRITERIA ..................................................................................................24 
4.3 
INCLUSION OF WOMEN, MINORITIES, AND OTHER UNDERREPRESENTED POPULATIONS ...24 
5 
REGISTRATION PROCEDURES .....................................................................................24 
5.1 
STUDY SITES ..............................................................................................................24 
5.2 
STUDY COORDINATORS AND PHARMACISTS ..................................................................24 
5.3 
PATIENT ENROLLMENT.................................................................................................24 
5.4 
INFORMED CONSENT ...................................................................................................26 
6 
DRUG FORMULATION AND ADMINISTRATION ............................................................26 
6.1 
CROFELEMER ACQUISITION AND STORAGE ...................................................................26 
6.2 
DRUG ACCOUNTABILITY ...............................................................................................27 
6.3 
TRASTUZUMAB, PERTUZUMAB, DOCETAXEL, PACLITAXEL, AND CARBOPLATIN 
ADMINISTRATION ....................................................................................................................27 
7 
EXPECTED TOXICITIES AND DOSING DELAYS AND MODIFICATIONS ......................27 
7.1 
CHEMOTHERAPY DOSE MODIFICATIONS AND DELAYS ....................................................27 
7.2 
CROFELEMER SIDE EFFECTS .......................................................................................27 
7.3 
CROFELEMER DOSE MODIFICATIONS ............................................................................28 
8 
TREATMENT PLAN .........................................................................................................28 
8.1 
CROFELEMER ARM ......................................................................................................28 
8.2 
CONTROL ARM ............................................................................................................29 
8.3 
DIARRHEA GRADING ....................................................................................................29 
8.4 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ...................30 
9 
FOLLOW-UP PLAN ..........................................................................................................31 
9.1 
DURATION OF FOLLOW UP ...........................................................................................31 
9.2 
CRITERIA FOR REMOVAL FROM STUDY ..........................................................................31 
9.3 
CRITERIA TO TERMINATE THE STUDY ............................................................................31 
10 STUDY CALENDAR .........................................................................................................31 
11 QUALITY OF LIFE ASSESSMENT...................................................................................32 


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12 STATISTICAL CONSIDERATIONS ..................................................................................32 
12.1 
SAMPLE SIZE/ACCRUAL RATE ......................................................................................33 
12.2 
FUTILITY .....................................................................................................................33 
12.3 
RANDOMIZATION AND STRATIFICATION FACTORS ...........................................................33 
12.4 
PATIENT ACCRUAL ......................................................................................................33 
12.5 
ANALYTIC PLAN FOR PRIMARY OBJECTIVE ....................................................................33 
12.6 
ANALYTIC PLAN FOR SECONDARY OBJECTIVES .............................................................33 
13 SAFETY REPORTING OF ADVERSE EVENTS ...............................................................34 
13.1 
ASSESSMENT OF SAFETY .............................................................................................34 
13.2 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES ................35 
13.3 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS .............36 
13.4 
STUDY CLOSE-OUT .....................................................................................................40 
13.5 
REPORTING TO THE SPONSOR .....................................................................................41 
13.6 
COMPLIANCE WITH LAWS AND REGULATIONS ................................................................42 
13.7 
Information regarding Genentech Product Complaints ...............................................42 
14 DATA SAFETY MONITORING COMMITTEE ...................................................................42 
14.1 
COLLECTION OF PRIVATE INFORMATION ON INDIVIDUALS OTHER THAN STUDY SUBJECT ..43 
14.2 
SUBJECT COMPENSATION ............................................................................................43 
14.3 
PRIVACY AND CONFIDENTIALITY OF DATA RECORDS ......................................................43 
14.4 
PRIVACY AND CONFIDENTIALITY OF DATA RECORDS – DATA SECURITY ..........................43 
15 STUDY MANAGEMENT ...................................................................................................44 
15.1 
CONFLICT OF INTEREST ...............................................................................................44 
15.2 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT ....................................44 
15.3 
REQUIRED DOCUMENTATION ........................................................................................44 
15.4 
ADHERENCE TO THE PROTOCOL ...................................................................................44 
15.5 
AMENDMENTS TO THE PROTOCOL ................................................................................45 
15.6 
RECORD RETENTION ...................................................................................................45 
15.7 
OBLIGATIONS OF INVESTIGATORS .................................................................................45 
15.8 
STUDY CLOSE-OUT .....................................................................................................45 
16 APPENDICES ...................................................................................................................46 
16.1 
APPENDIX A: FACIT-D AND SCORING GUIDELINES (VERSION 4) ..........................46 
16.2 
APPENDIX B: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ...................................................................................................51 
16.3 
APPENDIX C: CROFELEMER DIARY .......................................................................52 
16.4 
  APPENDIX D: RESCUE MEDICATION DIARY .......................................................55 
16.5 
APPENDIX E: BOWEL MOVEMENT DIARY AND BRISTOL STOOL SCALE .............56 
16.6 
APPENDIX F: ELIGIBILITY CHECKLIST ...................................................................58 
16.7 
APPENDIX G: SAFETY REPORTING FAX COVER SHEET ......................................60 
16.8 
APPENDIX H: CROFELEMER FLOWSHEET FOR C1D1 ..........................................61 
16.9 
APPENDIX I: PATIENT RANDOMIZATION FORM ....................................................62 
16.10 
APPENDIX J: INVESTIGATIONAL DRUG ORDER FORM .....................................63 
16.11 
APPENDIX K: ADDITIONAL ELIGIBILITY INFORMATION ....................................64 
16.12 
APPENDIX L: QAO PATIENT REGISTRATION FORM ..........................................65 
16.13 
 APPENDIX M: HALT-D BOWEL MOVEMENT ENDPOINT FORM ........................67 
17 REFERENCES ..................................................................................................................70 
 
 


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1 
LIST OF ABBREVIATIONS 
 
AD  
 
 
Associate Director 
ADL 
 
 
Activities of Daily Living 
ADEERS 
 
Adverse Events Expedited Reporting System 
AE 
 
 
Adverse event(s) 
AIDS  
 
Acquired Immunodeficiency Syndrome 
ALT 
 
 
Alanine aminotransferase 
AST 
 
 
Aspartate aminotransferase 
CaCC  
 
Calcium activated chloride channel 
CFTR  
 
Cystic fibrosis transmembrane regulator 
CI 
 
 
Confidence Interval 
CID 
 
 
Chemotherapy induced diarrhea 
ClC2  
 
Chloride channel type 2 
CRC 
 
 
Clinical Research Committee 
CRF 
 
 
Case Report Form 
CTCAE 
 
Common Terminology Criteria for Adverse Event(s) 
DS 
 
 
Diarrhea Subscale 
DSMC  
 
Data and Safety Monitoring Committee 
EGFR  
 
Epidermal Growth Factor Receptor 
EST 
 
 
Eastern Standard Time 
FACIT  
 
Functional Assessment of Chronic Illness Therapy 
FACIT-D 
 
Functional Assessment of Chronic Illness Therapy – Diarrhea 
FDA   
 
Food and Drug Administration 
GCP 
 
 
Good Clinical Practice 
G-CSF  
 
Granulocyte-colony stimulating factor 
GI 
 
 
Gastrointestinal 
HER2  
 
Human Epidermal Growth Factor Receptor 2 
HIV 
 
 
Human Immunodeficiency Virus 
HJWCI  
 
Harry and Jeanette Weinberg Cancer Institute 
IBS 
 
 
Irritable bowel syndrome 
IND 
 
 
Investigational New Drug 
IRB 
 
 
Institutional Review Board 
IV 
 
 
Intravenous 
LCCC  
 
Lombardi Comprehensive Cancer Center 
MHRI  
 
MedStar Health Research Institute 
MMMC 
 
MedStar Montgomery Medical Center 
MUMH  
 
MedStar Union Memorial Hospital 
NCI 
 
 
National Cancer Institute 
PHI 
 
 
Protected Health Information 
PO 
 
 
By mouth 
SAE 
 
 
Serious adverse event 
 
TCHP  
 
Trastuzumab, pertuzumab, carboplatin, and docetaxel  
THP 
 
 
Trastuzumab, pertuzumab, docetaxel or paclitaxel 
 


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2 
BACKGROUND AND RATIONALE 
2.1 
Normal Intestinal Function  
Approximately 9000 cc of fluid passes through the human small intestine on a daily basis, a 
combination of ingested fluid (~ 2000 cc), saliva (~ 1500 cc), gastric secretions (~ 2000 cc), 
pancreatic secretions (~ 1500 cc), bile (~ 500 cc), and intestinal secretions (~ 1500 cc).  The 
small intestine reabsorbs approximately 90% of this fluid, passing about 1000 cc into the large 
intestine.  The large intestine reabsorbs an additional 90% of fluid, ultimately leaving only 
approximately 100 cc of fluid to be excreted in feces.  A decrease in 1-2% of intestinal water 
absorption, as little as 50 cc, will increase stool weight to more than 200 g per 24 hours (the 
upper limit of normal) and result in diarrhea. [1] 
 
2.2 
Types of Diarrhea  
When evaluating diarrhea, both the duration and underlying mechanism are important to 
ascertain.  Acute diarrhea is defined as greater than or equal to three stools daily of decreased 
form, with symptoms lasting less than 14 days.  Persistent diarrhea occurs when the symptoms 
last more than 14 days but less than 1 month.  If the symptoms persist more than 1 month, then 
the diarrhea is considered chronic. [1-3] 
 
There are many different mechanisms of diarrhea.  Secretory diarrhea is due to decreased 
reabsorption or increased secretion of fluid and electrolytes within the gastrointestinal (GI) tract.  
Osmotic diarrhea occurs when osmotically active, poorly absorbed solutes inhibit the 
reabsorption of fluid and electrolytes.  Various forms of colitis, including microscopic, ischemic, 
and autoimmune, can also cause diarrhea due to inflammation and mucosal damage.  If the 
cause of diarrhea is a direct consequence of chemotherapy, then the diarrhea is called 
chemotherapy induced diarrhea (CID). [1-3] 
 
2.3 
Diarrhea Grading 
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 assigns grades to CID depending on the amount of stool produced.  Grade 1 
diarrhea is defined by an increase of less than 4 stools per day over baseline.  Grade 2 diarrhea 
is an increase of 4-6 stools per day over baseline, but not interfering with activities of daily living 
(ADLs).  Grade 3 diarrhea occurs when there is an increase of 7 or more stools per day over 
baseline, the presence of incontinence, symptoms that limit self care ADLs, or requirement for 
hospitalization.  Finally, grade 4 diarrhea is defined as diarrhea that can cause life-threatening 
consequences, warranting urgent medical intervention.   
 
2.4 
Assessing Quality of Life with Diarrhea  
The Functional Assessment of Chronic Illness (FACIT) is a health related quality of life 
questionnaire that focuses on four primary quality of life domains: physical, social/family, 
emotional, and functional well-being. FACIT has been validated in all cancers.  A FACIT 
questionnaire for diarrhea (FACIT-D) incorporates the original four quality of life domains and 
includes additional questions addressing how diarrhea affects quality of life.   
 
2.5 
Chemotherapy Induced Diarrhea: Breast Cancer  
While chemotherapy and targeted therapy can be highly effective in breast cancer, the side 
effects of each can cause significant problems resulting in loss of quality of life, dose reductions, 
and dose delays.  Diarrhea in particular can be seen in 40- 80% of patients who are on breast 
cancer therapy.  Therapies targeted at HER2 positive breast cancer patients and their diarrhea 
incidences will be discussed below. 
 
2.5.1 Breast Cancer: EGFR Targets  
Human epidermal growth factor receptor 2 (HER2) is a member of the EGFR family.  
Chemotherapy induced diarrhea (CID) occurs in 40-80% of breast cancer patients who receive 


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HER2 directed therapy with trastuzumab, pertuzumab, lapatinib, or neratinib.  Various studies 
have looked at the role of EGFR targets and the mechanism of diarrhea.  In the luminal side of 
the colon, chloride efflux is mediated via apical chloride channels, of which there are three 
types: 1) cystic fibrosis transmembrane regulator (CFTR), a cyclic AMP stimulated chloride 
channel; 2) calcium activated chloride channel (CaCC); and 3) chloride channel type 2 (ClC2).  
These prior studies have suggested that blocking EGFR can cause excess chloride secretion, 
resulting in impaired gut absorption and producing secretory diarrhea. [4-6] 
 
2.5.2 Breast Cancer: Docetaxel and Paclitaxel  
Docetaxel and paclitaxel are chemotherapy agents in the class of taxanes.  Taxanes stabilize 
tubulin in the microtubules, thus preventing mitosis and halting cell division.  Both docetaxel and 
paclitaxel are used in the treatment of breast cancer either in combination chemotherapy, as a 
single agent, or with monoclonal antibodies such as trastuzumab and pertuzumab.  Sparano et 
al. showed that docetaxel given every 3 weeks or paclitaxel given weekly had the best disease 
free survival in the adjuvant setting when used with combination chemotherapy.  Diarrhea was 
more frequent in the docetaxel arm, as well as neutropenia, febrile neutropenia, and infections; 
neuropathy was higher in the paclitaxel arm.  Thus while both docetaxel and paclitaxel are in the 
same class of medications, their side effect profiles do differ. [7]     
 
Hainsworth et al. conducted a phase 1 dose escalation trial of weekly docetaxel in 38 patients 
with solid tumors, seven of whom were breast cancer patients.  The dose limiting toxicity was 
found to be fatigue and asthenia, particularly at the higher dose levels of 43 mg/m2/wk and 52 
mg/m2/wk.  Other toxicities noted at these dose levels included skin and nail changes and 
diarrhea.  In a phase 2 study of docetaxel in 35 patients with metastatic anthracycline resistant 
breast cancer, Valero et al. reported 31 patients developed neutropenia, with 18 experiencing 
febrile neutropenia and one patient dying of resulting sepsis.  Other common side effects 
included stomatitis, myalgia, and fluid retention. [8, 9]   
 
More serious complications in docetaxel include colitis and typhlitis.  Ibrahim et al. reported 6 
cases of ischemic colitis in metastatic breast cancer patients receiving docetaxel based 
regimens.  Typhlitis was noted in 3 patients on vinorelbine and docetaxel, with 2 patients 
ultimately dying of necrotic bowel and neutropenic fever.  The other three patients with colitis 
were receiving docetaxel monotherapy or with pamidronate or cyclophosphamide.  Three out of 
the six patients received dedicated abdominal imaging, all of which were positive for colitis.  
Other case reports published have shown docetaxel induced cecal perforation in a patient being 
treated for gastro-esophageal junctional adenocarcinoma and a patient who died of Clostridium 
perfrigens septic shock, with a source hypothesized to be due to typhlitis. [10]   
 
Phase 1 studies of paclitaxel in patients with metastatic breast and ovarian cancer showed 
neutropenia, diarrhea, mucositis, neuropathy, and myalgia was seen at various doses, with 
neutropenia predominant at higher doses of 90-100 mg/m2.  These results have been 
corroborated by various phase 2 studies in metastatic breast cancer patients.  Seidman et al. 
looked a paclitaxel in 49 patients.  Of the grade 3-4 events, 36% had neutropenia, 16% had 
arthralgia/myalgia, 8% had neuropathy, and 4% had mucositis.  Reichman et al. looked at 
paclitaxel in 28 patients; 20 patients developed neutropenia, of which 6 had febrile neutropenia, 
and 24 had grade 1-2 neuropathy.  Diarrhea was seen in 14, mucositis in 20, nausea in 16, and 
arthralgia/myalgia in 27 patients. [11, 12] 
 
As in docetaxel, typhlitis is also seen in patients receiving paclitaxel.  In a phase 2 trial of 63 
patients with small cell lung cancer on paclitaxel, topotecan, and etoposide, one patient died of 
febrile neutropenia and one of febrile neutropenia and typhlitis.  In a phase 1/2 trial of 42 
patients with metastatic breast cancer, Fisherman et al. reported that all three patients who had 
received the highest dose of a 72 hour infusional regimen of paclitaxel and doxorubicin 


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experienced typhlitis with radiographic corroboration.  All 42 patients had grade 4 neutropenia 
with an absolute neutrophil count of less than 500.  The dose limiting toxicity was diarrhea.  
There have also been case reports of patients experiencing acute transient encephalopathy 
while receiving paclitaxel; this has not been reported with docetaxel. [13]   
 
While typhlitis, colitis, and acute transient encephalopathy are rarer side effects of docetaxel 
and paclitaxel, neutropenia (including febrile neutropenia), neuropathy, and gastrointestinal 
symptoms are well established and in some studies, diarrhea is even the dose limiting toxicity. 
[7-10, 13-18] 
 
2.5.3 Breast Cancer: Trastuzumab and Pertuzumab  
Trastuzumab is a monoclonal antibody that binds to the extracellular segment of the HER2 
receptor, causing cell cycle arrest and antibody-dependent cell-mediated cytotoxicity (ADCC).  
Pertuzumab is a monoclonal antibody that binds to the extracellular dimerization domain of 
HER2, thus inhibiting HER signaling pathways and ultimately also resulting in ADCC.   
 
The BCIRG 006 study looked at patients with early stage HER2 positive breast cancer.  Patients 
were randomized to doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks 
(AC-T), AC-T with 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and 
carboplatin plus 52 weeks of trastuzumab (TCH).  Overall, grade 3 or 4 diarrhea was seen in 
3.0% (32/1050) of patients who received AC-T, 5.6% (60/1068) of patients who received AC-T 
plus trastuzumab, and 5.4% (57/1056) of patients who received TCH. [19]   
 
The CLEOPATRA study launched the combination of trastuzumab, pertuzumab, and docetaxel  
(THP) into the forefront of treatment for advanced or metastatic HER2 positive breast cancer.  
Patients on this regimen saw a benefit not only in progression free survival (PFS), but also 
overall survival (OS).  However, 66.8% (272/407) of patients experienced all grade diarrhea, 
and 7.9% (32/407) had grade 3-4.  In subsequent trials using this three drug regimen, authors 
report a similar incidence of diarrhea.  In the TRYPHAENA study, patients who received six 
cycles of THP experienced 72.4% (55/76) all grade diarrhea and 11.8% (9/76) grade 3-4 
diarrhea.  Similarly, in the NEOSPHERE study, patients who received THP experienced 46% 
(49/107) all grade diarrhea and 6% (6/107) grade 3-4 diarrhea.  Patients who received 
trastuzumab and docetaxel experienced 34% (36/107) all grade and 4% (4/107) grade 3 or 
higher diarrhea.  Patients who received pertuzumab plus trastuzumab experienced 28% 
(30/108) all grade diarrhea and no patients had grade 3 or higher diarrhea.  Finally, patients 
who received pertuzumab plus docetaxel experienced 54% (51/94) all grade and 4% (4/94) 
grade 3 or higher diarrhea.  In a recent publication looking at paclitaxel with trastuzumab and 
pertuzumab, Dang et al. reported 81% (56/69) all grade diarrhea and 3% (2/69) grade 3-4, 
showing that both patients on docetaxel and paclitaxel have similar incidences of diarrhea when 
combined with trastuzumab and pertuzumab. [20-23]    
 
Prior studies of pertuzumab and trastuzumab suggest that while pertuzumab can cause a high 
incidence of diarrhea, trastuzumab usually does not.  A phase 1 study of pertuzumab of 21 
patients showed 43% (9/21) experienced all grade diarrhea and 5% (1/21) had grade 3-4.  In a 
phase 2 study of trastuzumab monotherapy, only two grade 2 diarrhea events occurred out of 
768 administrations of trastuzumab in 46 patients, and no grade 3 events occurred.  Finally, a 
study of pertuzumab with or without trastuzumab in patients who had previously progressed on 
trastuzumab showed that in the pertuzumab monotherapy arm, 48.3% (14/29) had all grade 
diarrhea and 3% (1/29) had grade 3-4.  Interestingly in the two drug pertuzumab-trastuzumab 
arm, 29% (5/17) had all grade diarrhea and 6% (1/17) had grade 3-4. [20, 22-27] 
 


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2.5.4 Breast Cancer: Carboplatin 
Carboplatin is a platinum-based antineoplastic agent that interferes with DNA repair.  It is 
related to cisplatin, although carboplatin has less nephrotoxicity.  Cisplatin is currently not 
routinely used in the treatment of breast cancer.   
 
Isakoff et al. conducted a phase 2 study of carboplatin or cisplatin in the first or second line 
setting in patients with metastatic triple negative breast cancer.  Both groups of patients 
experienced fatigue, nausea, electrolyte abnormalities, and hematologic toxicities.  Patients in 
the carboplatin arm had more thrombocytopenia, while patients on the cisplatin arm had more 
anemia, neutropenia, hypomagnesemia, tinnitus, and anorexia. [28] 
 
Von Minckwitz et al. looked at patients with untreated, non-metastatic triple negative and HER2 
positive breast cancer who received paclitaxel and non-pegylated liposomal doxorubicin as their 
chemotherapy backbone, with or without carboplatin in the neoadjuvant setting.  Triple negative 
cancer patients also received bevacizumab and HER2 positive cancer patients also received 
trastuzumab and lapatinib.  Patients who received carboplatin had a statistically higher 
incidence of anemia, neutropenia, thrombocytopenia, nausea, anorexia, hand-foot syndrome, 
nail changes, and pneumonitis. [29]  
 
The BCIRG 007 Study was a phase 3 randomized trial comparing TH (docetaxel and 
trastuzumab) versus TCH (docetaxel, trastuzumab, carboplatin) as first line treatment for 
patients with HER2 positive metastatic breast cancer.  Patients who received carboplatin had 
increased thrombocytopenia, motor neuropathy, myalgia, rash, nail changes, nausea, and 
vomiting compared to the patients who did not receive carboplatin.  All grade diarrhea was seen 
in 51.1% (67/131) of patients on the TH arm and 56.5% (74/131) in the patients on TCH.  Grade 
3 or 4 diarrhea was seen in 2.3% (3/131) of the patients who received TH and 9.9% (13/131) of 
the patients who received TCH.  The difference in diarrhea was not statistically significant. [9] 
 
2.5.5 Breast Cancer: Neratinib and Lapatinib  
Neratinib and lapatinib are oral tyrosine kinase inhibitors of HER2 and EGFR; neratinib is an 
irreversible inhibitor that targets cysteine in the ATP-binding pocket of the receptors and 
lapatinib is a reversible inhibitor that blocks the phosphorylation of the receptors.  Lapatinib has 
also been shown to inhibit cyclin D in human tumor cell lines in vitro.     
 
Burstein et al. looked at neratinib monotherapy in patients with advanced HER2 positive breast 
cancer both with and without previous trastuzumab therapy.  All grade diarrhea was seen in 
93% (126/136) of patients and grade 3-4 diarrhea in 21% (29/136).  At the American Society of 
Clinical Oncology (ASCO) meeting in 2015, the results of the ExteNET study looking at with 
localized HER2 positive cancer treated with neratinib versus placebo for one year showed 
patients had 95.4% (1343/1408) all grade diarrhea and 39.9% (562/1408) grade 3-4 diarrhea on 
the neratinib arm.  In comparison, 35.4% (499/1408) had all grade diarrhea and 1.6% (23/1408) 
had grade 3-4 diarrhea for patients on the placebo arm.  Patients on this study did not receive 
prophylactic anti-diarrheal agents and diarrhea resulted in dose reduction in 26.4% and drug 
discontinuation in 16.8% of patients.  In the NEfERT-T trial, patients received either 
neratinib+paclitaxel or trastuzumab+paclitaxel.  In the neratinib+paclitaxel arm, 92.5% (222/240) 
had all grade diarrhea, and 30.4% (73/240) had grade 3-4; patients on the 
trastuzumab+paclitaxel arm had 33.3% (78/234) all grade diarrhea and 3.8% (9/234) grade 3-4. 
[30-32]   
 
Lapatinib has a similar diarrhea side effect profile as compared to neratinib.  In a phase 1 study 
of single agent lapatinib in breast cancer patients, 80% (32/40) had all grade diarrhea and 20% 
(8/40) had grade 3-4.  In the NeoALTTO study, a phase 3 trial looking at lapatinib, trastuzumab, 
or lapatinib plus trastuzumab in the neoadjuvant setting, the incidence of diarrhea was much 


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higher in the arms that contained lapatinib.  In the lapatinib with or without trastuzumab arm, 
approximately 85% experienced all grade diarrhea and 25% had grade 3-4 diarrhea.  In 
comparison, the trastuzumab monotherapy arm had 35% all grade diarrhea and 3% grade 3-4. 
[30-34] 
 
2.5.6 Breast Cancer: Immunotherapy  
Immunotherapy agents such as ipilimumab, nivolumab, and pembrolizumab have been 
approved in melanoma and lung cancer; studies into these agents as well as other checkpoint 
inhibitors are underway in the field of breast cancer.   
 
PD-1 is present on activated T cells.  The binding of PD-L1 to PD-1 results in inactivation of T 
cells.  Nivolumab and pembrolizumab are anti-PD1 antibodies that inhibit PD-L1 from binding to 
PD1, thereby stopping the inhibitory signal.  Both agents have been shown to have a high 
incidence of diarrhea, ranging from 11-37% in nivolumab, 13-16% in pembrolizumab, and up to 
45% in combination therapy with nivolumab and pembrolizumab. In a phase 1 study of 
nivolumab of 39 patients, only one grade 3 adverse event, inflammatory colitis, was reported, 
which resolved with infliximab and steroids.  There have been no reports of pembrolizumab 
associated colitis. [6, 35-44] 
 
Ipilimumab is a monoclonal antibody targeting CTLA-4, a protein receptor on the surface of T 
cells that downregulates the immune system; ipilimumab blocks this downregulatory signal.  
Pooled analyses in melanoma patients have shown that the toxicities are primarily due to 
activation of the immune system.  Twenty-seven to thirty-one percent of patients on ipilimumab 
developed diarrhea, with 5% of cases at grade 3-4; treatment is primarily with steroids, with one 
case report of a patient who required infliximab to stop the diarrhea.  Other serious side effects 
of ipilimumab include colonic perforation, necrotic and hemorrhagic colitis, hypohysitis, and 
uveitis.  In a recent publication looking at nivolumab, ipilimumab, or nivolumab plus ipilimumab 
in melanoma, diarrhea and colitis were seen much more frequently in the combination arm.  All 
grade diarrhea was reported in 19.2% of patients on nivolumab, 33.1% on ipilimumab, and 
44.1% on nivolumab plus ipilimumab.  All grade colitis was seen in 1.3% on nivolumab, 11.6% 
on ipilimmab, and 11.8% on nivolumab plus ipilimumab. [6, 35-44] 
 
Anti-PDL1 agents are also currently being studied.  Brahmer et al. conducted a study looking at 
the safety and activity of the anti-PDL1 agent BMS-936559 in 207 cases of advanced solid 
tumors, 4 of which were breast.  The three most common side effect were an infusion reaction 
(seen in 10% of patients), diarrhea (seen in 9% of patients), and pruritus (seen in 6% of 
patients). [6, 35-44] 
 
2.6 
Chemotherapy Induced Diarrhea: Guidelines and Management  
Currently, there are no guidelines for prophylactically treating CID in patients on regimens 
known to have high incidences of diarrhea.  Guidelines do exist for treating diarrhea once it 
occurs. 
 
Loperamide is an opioid receptor agonist and the most commonly used anti-diarrheal 
medication in the front line setting.  It decreases both colonic mass movements and activity of 
the myenteric plexus, thereby increasing transit time and water reabsorption.  For grade 1-2 
diarrhea, the guidelines recommend a 4 mg loading dose and then 2 mg either on a scheduled 
basis or after every loose stool with a maximum of 16 mg daily.  Once the diarrhea reaches 
grade 3-4, hospitalization is needed to aggressively control symptoms and avoid dehydration.  
Loperamide can be continued and adding other agents, such as octreotide, fluoroquinolone 
antibiotics, or other anti-diarrheal agents should be considered.  Stool studies and imaging 
should also be considered if there is an indication. [4, 5, 45] 
 


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2.7 
Anti-Diarrheal Agents 
2.7.1 Loperamide  
While guidelines recommend loperamide as a first line agent against CID after the diarrhea 
occurs, there have been very few studies looking at loperamide in the prophylactic setting.  A 
case report published in Korea documents the use of loperamide in a 72-year-old gentleman on 
treatment with cisplatin and docetaxel for stage 4 non-small cell lung cancer.  The patient 
developed grade 3 docetaxel induced diarrhea during cycle 2 on days 4-10.  With prophylactic 
loperamide 2 mg every 8 hours and fasting during cycle 3, the patient experienced no diarrhea. 
[46, 47] 
 
Jankowitz et al. looked at neratinib and trastuzumab with paclitaxel in a phase 1 dose-escalation 
study of 21 patients with metastatic breast cancer. Patients were started on loperamide 4 mg 
after the first episode of diarrhea and then 2 mg after each loose stool; however, the authors 
found that patients still consistently had diarrhea during the first week of therapy.  Therefore, the 
authors amended the protocol to include prophylactic loperamide for all patients.  During cycle 
1, patients received 4 mg of loperamide with the first dose of neratinib, followed by 2 mg every 4 
hours for 3 days.  During the remaining 3 weeks of cycle 1, patients received 2 mg of 
loperamide every 6-8 hours.  In total, 90% patients had all grade diarrhea and 38% had grade 3.  
The authors did not state how many patients who received anti-diarrhea prophylaxis 
experienced diarrhea. [46, 47] 
 
Currently, there is a phase 2 underway looking at the incidence and severity of diarrhea in 
patients receiving neratinib and prophylactic high dose loperamide (NCT02400476). [48]   
 
2.7.2 Octreotide  
Octreotide is a somatostatin analog that works by inhibiting secretion of gastrointestinal 
hormones (such as gastrin, glucagon, growth hormone, etc.), reducing fluid secretion in the 
intestines, and reducing gastrointestinal motility.  It is administered subcutaneously (SQ) under 
the skin with a starting dose of 100-150 mcg three times a day, up to a maximum tolerated dose 
of 2000 mcg three times a day.   
 
There have been many studies looking at octreotide in the setting of CID.  Cascinu et al. 
enrolled 41 patients who experienced grade 2-3 diarrhea on a 5-fluorouracil containing regimen, 
the majority with gastrointestinal cancers.  Patients were randomized to octreotide 100 mcg SQ 
twice a day for 3 days (n=21) or loperamide with a 4 mg loading dose and then 2 mg every 6 
hours for 3 days (n=20).  Seventeen patients on the octreotide arm had diarrhea resolution 
compared with only three patients on the loperamide arm, suggesting a superior efficacy for 
octreotide.  In the STOP trial, 147 patients on 5-fluorouracil or irinotecan based regimens were 
randomized to receive long acting octreotide LAR intramuscularly (IM) at either 30 mg or 40 mg 
with the first dose 7-14 days before cycle 1 and each subsequent dose during the first day of the 
next chemotherapy cycle, with a total of 6 doses.  While fewer patients were noted to have 
severe diarrhea in the 40 mg group compared to the 30 mg group (62% vs. 48%, p=0.14), the 
differences were not statistically significant.  Finally, in the phase 3 LARCID trial, patients 
receiving 5-fluorouracil, capecitabine, or irinotecan containing regimens were randomized to 
receive either octreotide LAR 30 mg IM every 4 weeks or physician’s choice, which was 
primarily loperamide.  The incidence of diarrhea was equal in the two groups, with a 76% 
incidence of diarrhea in the octreotide LAR and 79% incidence in the physician’s choice group, 
with no difference noted in quality of life as assessed based on the FACIT-D score between the 
two groups. [49-52] 
 
2.7.3 Atropine  
Atropine is a muscarinic acetylcholine receptor antagonist and is an anticholineric medication 
given in intravenous (IV) or subcutaneous (SQ) form.  It is not directly an anti-diarrheal agent.  


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However, patients on irinotecan based chemotherapy regimens frequently experience a 
cholinergic syndrome within 1 hour of drug infusion, marked by increased lacrimation and 
salivation, sweating, flushing, rhinitis, and ultimately diarrhea; these symptoms can all be 
avoided with atropine administered before irinotecan.  Thus though atropine is not an anti-
diarrheal agent, it is used prophylactically to prevent irinotecan induced diarrhea. [53] 
 
2.7.4 Lactobacillus  
Lactobacillus is a gram-positive facultative anaerobic rod shaped bacteria that converts lactose 
to lactic acid.  It is present as normal floral in the human gastrointestinal tract and also used in 
food preparation such as bread, yogurt, pickles, and beer.  It has also been studied in cancer 
treatment related diarrhea. 
 
In a study of 490 patients who received adjuvant post-operative radiation therapy for sigmoid, 
rectal, or cervical cancer, patients were randomized to receive one packet of VSL#3 three times 
a day or placebo.  VSL#3 is a combination of 4 strains of lactobacillus, 3 strains of 
bifidobacteria, and 1 strain of streptococcus, with a total of 450 billion bacteria per gram.  
Patients who received VSL#3 had a statistically significant lower incidence of grade 3-4 
diarrhea, fewer daily bowel movements, and a longer time to requiring the anti-diarrheal agent 
loperamide, suggesting an efficacy for treating radiation induced diarrhea.  Another study looked 
at 150 patients with colorectal cancer who were receiving adjuvant 5-fluorouracil based therapy.  
Patients were randomized to lactobacillus capsules twice a day (total of 1-2x1010 daily) plus 
fiber (11 grams guar gum daily) on days 7-14 of each cycle of treatment versus no treatment.  
Those who received lactobacillus and fiber had statistically significant lower incidence of grade 
3-4 diarrhea, abdominal discomfort, and fewer chemotherapy dose reductions.  [54, 55] 
 
2.7.5 Elsiglutide  
Elsiglutide is a synthetic glucagon-like peptide-2 analog (GLP-2) that is administered 
subcutaneously and promotes proliferation of epithelial cells and small intestinal mucosa. A 
phase 2 clinical trial sponsored by Helsinn in colorectal cancer patients receiving 5-fluorousacil 
based chemotherapy in the prophylactic setting showed positive numerical but not statistically 
significant results earlier in 2016.   
 
2.7.6 Crofelemer  
Previous studies have looked at the use of various anti-diarrheal agents in treating 
chemotherapy diarrhea and there are current studies looking at preventing diarrhea in colorectal 
patients on 5-fluorouracil based regimens.  However, none of these previous and ongoing 
studies focused on breast cancer and HER2 regimens, even though 40-90% of patients will 
experience diarrhea on HER2 directed therapies.  
 
Crofelemer (Fulyzaq®) (Mytesi®) is an FDA-approved anti-diarrheal agent that is derived from 
the red sap of the Croton lechleri plant in South America.  It acts luminally in the intestine and is 
not systemically absorbed due to its size and polarity.  In the large intestine, it is a dual inhibitor 
of the calcium activated chloride channel (CaCC) and the cystic fibrosis transmembrane 
regulator (CFTR), two of the three channels that control chloride efflux.   
 
The incidence of diarrhea in HIV/AIDS patients on anti-retroviral therapy is as high as 28%.  In a 
randomized controlled study in HIV/AIDS patients with a history of diarrhea for at least 1 month 
while on anti-retroviral therapy, 180 patients were randomized to crofelemer 125 mg orally twice 
a day versus placebo for 4 weeks.  The primary endpoint was the percentage of patients who 
had two or fewer watery stools per week during at least two out of the four weeks of treatment.  
Patients who received crofelemer had a significant improvement in their daily stool consistency 
and number of daily watery bowel movements. Patients tolerated the drug well with minimal side 


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effects.  Based on this trial, on December 31, 2012, the FDA approved the use of crofelemer in 
HIV patients on anti-retroviral therapy. [56-58] 
 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
To determine the efficacy of crofelemer in preventing chemotherapy induced diarrhea (CID) in 
patients with HER2 positive breast cancer receiving chemotherapy with trastuzumab, 
pertuzumab, and docetaxel or paclitaxel (THP) or trastuzumab, pertuzumab, carboplatin, and 
docetaxel (TCHP). 
 
3.2 
Secondary Objectives 
If possible, our secondary objectives are: 
3.2.1 To determine the incidence of diarrhea of any grade, as measured by CTCAE 
v4.0, by cycle and by stratum 
3.2.2 To determine the incidence of diarrhea of grade 3-4, as measured by CTCAE 
v4.0, by cycle and by stratum 
3.2.3 To determine the time to onset of first event of diarrhea of any grade, defined as 
the number of days from day one of THP or TCHP until the day in which the first 
episode of diarrhea classified as of grade 1 or higher occurs, or is censored at 
the date of the last treatment cycle for patients who do not experience diarrhea, 
overall and by stratum 
3.2.4 To determine the duration (days) of any grade diarrhea, by cycle in which the 
episode started and by stratum 
3.2.5 To determine the duration (days) of grade 3-4 diarrhea, by cycle in which the 
episode started and by stratum 
3.2.6 To assess use of anti-diarrheal medications (other than study drug), by cycle and 
grade of diarrhea and by stratum 
3.2.7 To determine the quantitative FACIT-D total score, collected day 1 of each cycle 
and at the time of study completion (defined as cycle 4 day 1, but patients may 
complete this final FACIT-D questionnaire within 5 days of cycle 4 day 1), by 
cycle and by stratum 
3.2.8 To determine the quantitative FACIT-D diarrhea subset (DS) score, collected day 
1 of each cycle and at the time of study completion (defined as cycle 4 day 1, but 
patients may complete this final FACIT-D questionnaire within 5 days of cycle 4 
day 1), by cycle and by stratum 
3.2.9 To determine the frequency table for stool consistency, as measured by the 
Bristol Stool scale, by cycle and stratum for each treatment group 
 
 
3.3 
Primary Endpoint 
The primary endpoint is incidence of diarrhea of any grade for two or more consecutive days felt 
to be definitely, probably, or possibly due to THP or TCHP (refer to Section 13.4 Attribution), as 
assessed by NCI CTCAE v4.0, during cycle 1 and cycle 2 of chemotherapy. The CTCAE v4.0 
coding for diarrhea is 10012727. 
 


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23 
3.4 
Secondary Endpoints 
If possible, our secondary endpoints are: 
 
3.4.1 Incidence of diarrhea of any grade, as measured by CTCAE v4.0, by cycle and 
by stratum 
3.4.2 Incidence of diarrhea of grade 3-4, as measured by CTCAE v4.0, by cycle and by 
stratum 
3.4.3 Time to onset of first episode of diarrhea of any grade, defined as the number of 
days from day one of THP or TCHP until the day in which the first episode of 
diarrhea classified as of grade 1 or higher occurs, or is censored at the date of 
the last treatment cycle for patients who do not experience diarrhea, overall and 
by stratum 
3.4.4 Duration (days) of any grade diarrhea, by cycle in which the episode started and 
by stratum 
3.4.5 Duration (days) of grade 3-4 diarrhea, by cycle in which the episode started and 
by stratum 
3.4.6 Use of anti-diarrheal medications (other than study drug), by cycle and grade 
3.4.7 Quantitative FACIT-D total score, collected day 1 of each cycle and at the time of 
study completion (defined as cycle 4 day 1, but patients may complete this final 
FACIT-D questionnaire within 5 days of cycle 4 day 1), by cycle and by stratum 
3.4.8 Quantitative FACIT-D diarrhea subset (DS) score, collected day 1 of each cycle 
and at the time of study completion (defined as cycle 4 day 1, but patients may 
complete this final FACIT-D questionnaire within 5 days of cycle 4 day 1), by 
cycle and by stratum 
3.4.9 Frequency table of stool consistency, as measured by the Bristol Stool scale, by 
cycle stratum between treatment groups 
 
4 
PATIENT ELIGIBILITY 
4.1 
Inclusion Criteria 
4.1.1 Willing and able to provide written informed consent 
4.1.2 
Men and women ≥18 years of age 
4.1.3 
Pathologically confirmed diagnosis of HER2 positive breast cancer of any stage 
(previous treatment is allowed without limits on lines of prior therapy) 
4.1.4 
Scheduled to receive at least 3 consecutive cycles of THP or TCHP 
4.1.5 
Performance status of 0-2 according to the ECOG scale (Appendix B) 
4.1.6 
Negative pregnancy test within 2 weeks prior to starting THP or TCHP treatment 
for women of childbearing potential 
4.1.7 Able to read, understand, follow the study procedure and complete crofelemer, 
rescue medication, and bowel movement diaries 
4.1.8 Patients may enroll simultaneously on this study and other studies 
4.1.9 
Patients with brain metastases are allowed on this study (concurrent treatment 
with steroids is allowed). 
4.1.10 Left Ventricular Ejection Fraction (LVEF) greater or equal to 50% at baseline as 
determined by either ECHO or MUGA    
 


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4.2 
Exclusion Criteria  
4.2.1 Pregnant and/or breastfeeding 
4.2.2 Ongoing irritable bowel syndrome (IBS) or colitis (including but not limited to 
ulcerative colitis, Crohn’s disease, microscopic colitis, etc.) 
4.2.3 Use of investigational drugs within 3 weeks of starting THP or TCHP treatment or 
foreseen use during the study 
4.2.4 Use of chemotherapy, trastuzumab, or pertuzumab within the past 2 (two) weeks 
4.2.5 Use of laxatives within the past 7 days - deleted 
4.2.6 Use of chronic laxatives (≥ 30 consecutive days) - deleted 
4.2.7 Use of anti-diarrheal agents (including but not limited to loperamide, octreotide, 
bismuth, tincture of opium, atropine, probiotics in any form other than food) within 
the past 7 days - deleted 
4.2.8 Use of antibiotics within the past 7 days (up to 2 prophylactic doses of antibiotic 
for procedures, including but not limited to port placement, is permitted) 
4.2.9 Any type of ostomy 
4.2.10 Total colectomy 
4.2.11 Fecal incontinence 
4.2.12 Ongoing radiation induced diarrhea or constipation or planned radiotherapy to 
the abdomen or pelvis while on study 
4.2.13 Active systemic infection requiring ongoing intervention, including but not limited 
to oral and intravenous antibiotics, anti-fungals, anti-parasites, anti-virals 
4.2.14 Abdominal or pelvic surgery without recovery of bowel function  
4.2.15 Inadequate organ function for starting THP or TCHP, which may include the 
following laboratory results within 28 days prior to starting THP or TCHP 
treatment (Please refer to the prescribing label instructions on the use of each 
drug in the setting of abnormal organ function): 
 
Serum creatinine > 2.0 mg/dL or 177 μmol/L 
 
Total bilirubin > upper limit of normal (ULN) (unless the patient has 
documented Gilbert’s syndrome) 
 
Exclusion criteria specific for THP with PACLITAXEL (Taxol®) group: 
o Transaminases greater than 10 times ULN  
 
Exclusion criteria specific for TCHP/THP with DOCETAXEL (Taxotere®) 
group: 
o AST and/or ALT > 2.5x ULN 
o AST and/or ALT > 1.5x ULN with concurrent alkaline phosphatase 
>2.5 x ULN (unless bone metastases are present) 
 
4.3 
Inclusion of Women, Minorities, and Other Underrepresented Populations 
The study will be open to men and women of all racial and ethnic groups.  There are no 
separate accrual targets for men and women.   
 
5 
REGISTRATION PROCEDURES 
5.1 
Study Sites 
This study will be open at multiple sites in the United States. 
 
5.2 
Study Coordinators and Pharmacists 
There will be a multi-site study coordinator overseeing the study.  At each individual study site, 
there will be a designated study coordinator, co-investigator, and pharmacist. 
 
5.3 
Patient Enrollment 
Please refer to the procedures below for patient enrollment: 
1. 
Study site study coordinator or treating physician screens patient for eligibility criteria. 


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25 
a. If patient does not meet eligibility criteria, stop and report screen failure and/or 
reason. 
2. 
If patient meets initial eligibility screening, patient can sign informed consent and 
HIPAA authorization form.  Consent obtained by site study coordinator or treating 
physician. 
3. 
Study coordinator or treating physician at site completes eligibility checklist in 
Appendix F.  Investigators can use Appendix K as an additional form for documentation 
of eligibility or put the contents of Appendix K in the screening clinic note. 
4. 
Study coordinator or treating physician at site sends the full eligibility packet (outlined 
below) and completed Lombardi QAO Patient Registration Form (Appendix L) to the 
following within 1 business day of signing consent: 
a. Via fax to the Lombardi QAO at 202-687-9361 or scanned/emailed to 
lcccqao@georgetown.edu. 
b. To Sandra Swain at sandra.swain@georgetown.edu 
5. 
Lombardi QAO verifies patient eligibility and sends Subject Study ID information to 
the multi-site study coordinator and the designated biostatistician(s) at LCCC 
Biostatistics and Bioinformatics Shared Resource. 
a. If patient’s eligibility is not verified, stop. 
6. 
If patient’s eligibility is verified by Lombardi QAO and a Subject Study ID is assigned, 
then multi-site study coordinator does the following: 
a. Registers the patient on the study and in the database 
b. Calls the pharmacist at the study site to make sure crofelemer is available should 
the patient be randomized to the treatment arm 
c. LCCC QAO Informs the biostatistician(s) at LCCC Biostatistics and 
Bioinformatics Shared Resource whether the patient is on TCHP or THP, and if 
on THP, whether the patient will receive docetaxel or paclitaxel via the Patient 
Randomization Form (Appendix I). 
i. The biostatistician stratifies the patient 
ii. The biostatistician randomizes patient to treatment or control group 
iii. The biostatistician completes Appendix I Patient Randomization Form and 
emails or faxes completed Appendix I to the multi-site study coordinator, 
taking no more than 1 business day to do so (from when the multi-site 
study coordinator contacted the biostatistician) 
iv. QAO scans to patient’s EMR the completed Patient Randomization Form 
(Appendix I), signed by the statistician.  The original Patient 
Randomization Form must be stored in the HALT-D study binder. 
d. Multi-site study coordinator emails patient study number and randomization 
results to study coordinator and treating physician at the study site, the study site 
pharmacist, and Dr. Sandra Swain. 
7. 
Patient registration and enrollment is complete.   
8. 
Site study coordinator or treating physician to inform patient of randomization results 
at their earliest convenient, no later than cycle 1 day 1 of chemotherapy.   
9. 
Patient receives first dose of crofelemer on cycle 1 day 1 of THP or TCHP, ideally 
30-60 min prior to chemotherapy. 
 
The full eligibility packet must contain the following: 
1. 
Signed and dated Eligibility Checklist (Appendix F); filled out completely  
2. 
Signed and dated Lombardi QAO Patient Registration Form (Appendix L) 
3. 
Signed and dated informed consent form 
4. 
Signed and dated HIPAA form 
5. 
All source documents required for verification of eligibility: 
a. 
Pathology report stating diagnosis of breast cancer 
b. 
Pathology report stating diagnosis of HER2+ disease 


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c. 
Current negative beta HCG test report for women of childbearing potential 
d. 
Current Bilirubin levels and normal range at local laboratory 
e. 
Current Creatinine levels and normal range at local laboratory 
f. 
Current AST levels and normal range at local laboratory 
g. 
Current ALT levels and normal range at local laboratory 
h. 
Clinic notes containing information on ECOG PS, previous and current 
treatments, co-morbidities, and information pertaining to eligibility for the trial 
 
The full eligibility packet must be faxed or emailed to Lombardi QAO and the Sponsor at 
sandra.swain@georgetown.edu within 1 business day of the patient signing informed consent.  
Please send these during business hours Monday - Friday between 8am and 4:30pm (EST).  In 
the event that there is a time constraint, please notify the research office to discuss possibility of 
expediting the process. 
 
The informed consent form should be uploaded to the patient’s electronic medical record 
system, in addition to keeping the physical document signed by the patient and treating 
physician in the study binders, as per standard operating practice. 
 
All participants must be registered and enrolled through the Oncology Research office at 
MedStar Georgetown University Hospital.  
 
5.4 
Informed Consent  
The study coordinator or treating physician at each site will discuss with and obtain written 
informed consent from the patient.  Informed consent must be signed within 28 days of cycle 1 
day 1 of chemotherapy with THP or TCHP.  Patients will be informed that participation is 
voluntary and not necessary for receiving standard of care chemotherapy for their cancer and 
that they can choose to withdraw consent from the study at any time.  This will also be 
documented in writing on the consent form. 
 
The study will not include participants less than 18 years of age.  For adult participants who lack 
decision-making capacity, the legally authorized representative will serve as the proxy.  In the 
event a patient or their proxy does not read, write, or understand English, a trained medical 
interpreter must be present, either in person or via phone or video remote access, to translate.    
 
6 
DRUG FORMULATION AND ADMINISTRATION 
 
6.1 
Crofelemer Acquisition and Storage 
Crofelemer is an FDA approved drug, dispensed in 30-day bottles with 60 pills per bottle.   
 
Crofelemer will be provided without charge to the patients or MedStar by Napo and given to the 
patients on the treatment arm.  Shipment to each study site will be coordinated by a dedicated 
pharmacist at each study site by filling out the Investigational Drug Order Form (Appendix J) 
and stored in the pharmacy until needed, as per standard operating procedures.  The dedicated 
pharmacist at each site will also be responsible for dispensing the drug to the treatment group 
patients, as per standard operating practices.   
 
Crofelemer is to be stored at room temperature of 20-25 degrees Celsius, with a range of 15-35 
degrees Celsius permitted.  There is no placebo control for this study. 
 
 


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6.2 
Drug Accountability 
The dedicated pharmacist at each study site must maintain a careful record of the inventory of 
crofelemer, per standard operating procedures. 
 
Patients are to bring their medication bottles, bowel movement diary (Appendix E), crofelemer 
diary (Appendix C, treatment group only), and rescue medication diary (Appendix D) to the 
study coordinator during each office visit.  The study coordinator will count the remaining pills 
and review the bowel movement and medication diary with the patient.  Remaining/unused pills 
will be counted and documented in the CRF by the study coordinator.  At the end of the 
treatment period, any remaining pills must be returned to the pharmacist at the study site.   
 
6.3 
Trastuzumab, Pertuzumab, Docetaxel, Paclitaxel, and Carboplatin Administration 
Trastuzumab, pertuzumab, docetaxel, paclitaxel, and carboplatin should be administered 
per standard operating procedures at each institution.   
The following are the suggested doses for each drug, although the prescribing physician 
should decide the appropriate dose for each individual patient: 
1. Trastuzumab: administered IV at a loading dose of 8 mg/kg for cycle 1, then 6 
mg/kg for subsequent cycles 
2. Pertuzumab: administered IV at a 840 mg loading dose during cycle 1, then 420 
mg for subsequent cycles 
3. Docetaxel: administered IV at 75 mg/m2 every 3 weeks 
4. Paclitaxel: administered IV at 80 mg/m2 every week 
5. Carboplatin: administered IV with AUC 6 every 3 weeks 
 
7 
EXPECTED TOXICITIES AND DOSING DELAYS AND MODIFICATIONS 
7.1 
Chemotherapy Dose Modifications and Delays 
In the event of a chemotherapy dosing delay or reduction, crofelemer is to be continued at 125 
mg twice a day without dose interruptions or adjustments. 
 
7.2 
Crofelemer Side Effects 
Crofelemer is generally well tolerated with the FDA medical review reporting no adverse events 
(AEs) of special interest identified from clinical trials. 
 
Possible side effects of crofelemer include dyspepsia, flatulence, constipation, nausea, or 
increased alanine aminotransferase (ALT).  All ALT elevations in the phase 3 trial of crofelemer 
in HIV/AIDS patients were grade 1 and felt to be due to the underlying patient population due to 
high prevalence of hepatitis B and C infection, alcohol and/or drug abuse, or anti-retroviral 
medication-related hepatotoxicity.  
 
While there have been no studies looking at crofelemer concurrently with chemotherapy, studies 
have shown that crofelemer is not systemically absorbed due to its size and polarity.  This is 
confirmed by the FDA Medical Review Document where they note the following: [59] 
a. At therapeutic dose level, its systemic absorption is minimal. Thus, 
pharmacodynamics studies are not applicable 
b. The absorption of Crofelemer (enteric-coated tablets or beads) was minimal following 
oral dosing in healthy adults or in human immunodeficiency virus- positive (HIV+) 
subjects, in either the fasted or fed state. Across all the PK studies, less than 5% of 
healthy and HIV-associated diarrhea subjects had detectable plasma concentrations 
of Crofelemer following oral dosing. Crofelemer was detected in plasma samples in 3 
of the 6 trials; however, the plasma Crofelemer concentrations were low, sporadic, 
discontinuous, and not sufficient for calculation of pharmacokinetic parameters. The 
high degree of human plasma protein binding (approximately 97%) further limits 


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systemic exposure to Crofelemer. At the therapeutic Crofelemer dose of 125 mg 
twice daily in ADVENT, less than 1% of plasma samples had Crofelemer 
concentrations above the limit of quantification (LOQ). 
c. In vitro data indicate, at clinical concentrations, no cytochrome P450 (CYP)-mediated 
metabolism or gastrointestinal (GI) absorption-based interactions with other drugs.  
Given this information from the FDA, we have low concern for systemic absorption of crofelemer 
and believe it will not interfere with chemotherapy and therefore a phase 1 study of safety is not 
needed. 
 
7.3 
Crofelemer Dose Modifications  
There are no dose modifications for crofelemer, given there were very few anticipated side 
effects based on the FDA review and phase 3 study. [56] 
 
If a patient develops a CTCAE grade 1 or 2 side effects attributable to crofelemer, provided they 
have no underlying disease or are taking any medication that predisposes them to these 
conditions, or are not related to their metastatic breast cancer (if present), the treating physician 
has the option to hold crofelemer one time for up to 3 consecutive days (6 consecutive doses) 
and must document the reason for holding and how many doses crofelemer was held for.  The 
treating physician must also document if any diarrhea develops during this period of time off 
crofelemer 
 
If a patient develops a CTCAE grade ≥3 side effects attributable to crofelemer, provided they 
have no underlying disease or are taking any medication that predisposes them to these 
conditions, or are not related to their metastatic breast cancer (if present), they will be withdrawn 
from the study. 
 
8 
TREATMENT PLAN 
Treatment will be administered on an outpatient basis.  No investigational or commercial agents 
or therapies other than THP or TCHP may be administered with the intent to treat the patient’s 
breast cancer.   
 
The average baseline number of stools must be collected at baseline and detailed in the 
Bowel Movement Endpoint Form (Appendix M) by the research team, preferably the 
study coordinator.  During each cycle and at the end of treatment, detailed diarrhea 
information, including but not limited to duration, onset, grading, FACIT score, rescue 
medication usage etc., must be collected for ALL patients and documented in the Bowel 
Movement Endpoint Form (Appendix M).  Appendix M must be fully completed by the 
research team, preferably the study coordinator, for each patient at each cycle and end 
of treatment visit and scanned into the patient’s electronic medical record.   
 
8.1 
Crofelemer Arm 
Patients on the treatment arm will take one tablet of crofelemer twice a day (each tablet is 125 
mg), to be swallowed whole without chewing or crushing, during cycles 1-2 of chemotherapy 
with THP or TCHP.  Each chemotherapy cycle is 21 days (3 weeks).  If, for any reason, 
chemotherapy is delayed, the patient should continue to take crofelemer daily without dose 
interruptions until the end of cycle 2 of chemotherapy.  There are no dosage adjustments for 
crofelemer, even if there is a chemotherapy dose reduction.       
 
Patients on the treatment arm will be on study for a total of 3 full cycles of THP or TCHP.  
Crofelemer will be dispensed in 30 day commercially available containers.  Patients will be 
instructed to take one tablet twice a day, to not take any additional tablets, and to bring the pill 
container with them to each clinic visit.  Pills will be counted at each clinic visit.  On cycle 2 day 


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1 of THP or TCHP, the study coordinator will count the remaining pills from cycle 1 and 
dispense a new 30-day supply of crofelemer for cycle 2.  The remainders of the pills from cycle 
1 and 2 should be returned to the study site pharmacist.  All remaining pills and bottles should 
be sent back to the MedStar Georgetown University Hospital pharmacy, where unused pills will 
be destroyed, or be destroyed at the local pharmacy site per SOP. 
 
On day 1 of cycle 1, the morning dose of crofelemer should be administered prior to initiating 
chemotherapy, ideally 30-60 minutes prior.  The date and time (hour and minute) of this dose 
should be documented in Appendix H Crofelemer Flowsheet for C1D1.  Thereafter patients 
should take crofelemer twice a day with no dose interruptions or delays until the end of cycle 2.  
The Crofelemer Flowsheet for C1D1 should be filled out by the nurse administering crofelemer 
to the patient and after completion should be scanned into the patient’s EMR.  The original form 
should be placed in the HALT-D Study Binder. 
 
Should a patient develop diarrhea while on crofelemer, rescue medications, including but not 
limited to loperamide, octreotide, and opiates, should be administered as per the current 
standard of care for chemotherapy induced diarrhea (see Section 8.4 General Concomitant 
Medication and Supportive Care Guidelines below).  Patients should record each instance they 
use the rescue medication in the Rescue Medication Diary and bring this diary with them to 
each office visit.   
 
If a patient who is taking crofelemer experiences severe persistent diarrhea that does not 
respond to standard of care anti-diarrhea treatment, patients will be evaluated for an infectious 
diarrhea etiology with tests such as stool ova and parasites, stool culture, and Clostridium 
difficile.  The patient should stop crofelemer and NOT resume crofelemer.  They should still be 
followed until cycle 4 day 1. 
 
If a patient comes off study prior to cycle 4 day 1 for toxicity not related to crofelemer 
(such as but not limited to infusion reaction to monoclonal antibodies), that patient will 
be replaced. 
 
8.2 
Control Arm 
Patients on the control arm will be on the study for cycles 1-3 of THP or TCHP.  Patients on the 
control arm will not receive crofelemer at any time on this study.   
 
Should a patient develop diarrhea while on the control arm, rescue medications, including but 
not limited to loperamide, octreotide, and opiates, should be administered as per the current 
standard of care for chemotherapy induced diarrhea (see Section 8.4 General Concomitant 
Medication and Supportive Care Guidelines below).  Patients should record each instance they 
use the rescue medication in the Rescue Medication Diary and bring this diary with them to 
each office visit.   
 
If a patient experiences severe persistent diarrhea that does not respond to standard of care 
anti-diarrhea treatment, patients will be evaluated for an infectious diarrhea etiology with tests 
such as stool ova and parasites, stool culture, and Clostridium difficile. 
8.3 
Diarrhea Grading 
All patients will maintain a daily bowel diary which will be reviewed by the study coordinator or 
treating physician at each office visit.  Grading of diarrhea will be according to NCI CTCAE V4.0 
and is defined as follows: 
 
Grade 1: increase of < 4 stools per day over baseline; 
 
Grade 2: increase of 4-6 stools per day over baseline; 


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30 
 
Grade 3: increase of ≥ 7 stools per day over baseline, incontinence, hospitalization 
indicated, limiting self care activities of daily living (ADLs); 
 
Grade 4: life threatening consequences, urgent intervention indicated. 
 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
8.4 
General Concomitant Medication and Supportive Care Guidelines 
Because crofelemer is not systemically absorbed, it is unlikely to interact systemically with other 
concomitantly administered drugs.  If anti-diarrheal rescue medications are used, patients on 
the treatment arm should continue crofelemer. 
 
Anti-diarrheal agents are to be used as rescue medications for diarrhea that develops during 
treatment with THP or TCHP is allowed.  Rescue medication must only be used to treat diarrhea 
symptoms on an as-needed basis.  Rescue medication is not to be taken to prevent diarrhea or 
to increase the expected anti-diarrheal effect of the study medication.  Administration of rescue 
medication should follow the current treatment guidelines for CID, which includes, but is not 
limited to the following: 
 
Loperamide at a 4 mg by mouth loading dose followed by 2 mg every 4 hours or after 
every unformed stool, up to 16 mg daily 
 
Lomotil 5 mg 3-4 times a day until control of diarrhea is achieved (maximum 20 mg/day) 
may be used at the discretion of the treating physician if deemed medically appropriate.  
Maintenance doses may be as low as 25% of the initial daily dose required to control the 
diarrhea.  Dose reductions are also at the discretion of the treating physician. 
 
In case of need, add: 
 
Tincture of opium 6 mg PO 4 times a day may be used at the discretion of the treating 
physician, if deemed medically appropriate. 
 
For all patients with diarrhea: 
 
Any patient with diarrhea should be reminded to increase non-alcoholic PO fluid intake 
 
Any patient who needs intravenous fluids on a regular basis due to side effects of 
diarrhea may need to be evaluated for an infectious cause of diarrhea, with stool studies 
that may include stool ova and parasites, stool culture, and Clostridium difficile. 
 
For severe diarrhea (grade 3-4 diarrhea): 
 
Octreotide at a dose of 100-150 micrograms subcutaneously three times a day is 
recommended as first line therapy 
 
Patients may continue to take loperamide if felt appropriate by the treating physician. 
 
The rescue medication agent and dose and date should be documented in the Rescue 
Medication Diary (Appendix D).  If a patient is using loperamide, each pill taken on any given 
day should be documented in the Rescue Medication Diary.  The Rescue Medication Diary 
should be brought to each office visit and scanned into the patient’s EMR at the end of each 
cycle. 
 
Patients are allowed to take anti-nausea medications, including but not limited to ondansetron, 
while on study.  Treating physicians should document frequency, duration, and amount of anti-
nausea medication used in each office visit note. 
 


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9 
FOLLOW-UP PLAN 
9.1 
Duration of Follow Up 
All patients will be followed until cycle 4 day 1 while on THP or TCHP, or until 30 days have 
elapsed since their last dose of crofelemer, whichever occurs later.   
 
9.2 
Criteria for Removal from Study 
Treatment with crofelemer may continue for 2 cycles or until one of the following criteria applies: 
 
Patient voluntarily withdraws from treatment (follow-up permitted); 
 
Patient withdraws consent (termination of treatment and follow-up); 
 
Patient is unable to comply with protocol requirements; 
 
Treating physician judges continuation on the study would not be in the patient’s best 
interest; 
 
Lost to follow-up; 
 
Change in chemotherapy regimen; 
 
If a patient develops a CTCAE grade ≥3 side effect attributable to crofelemer, they will 
be withdrawn from the study. 
 
9.3 
Criteria to Terminate the Study 
 
If ≥4 patients develop the same CTCAE grade 3 side effect attributable to crofelemer, 
the study will be terminated; 
 
If ≥1 patient develops a CTCAE grade 4 or 5 side effect attributable to crofelemer, the 
study will be terminated. 
 
10 STUDY CALENDAR 
 
 
Pre-
Study 
C1D1 
C2D1 
C3D1 
End of 
Studya  
Research 
Crofelemer 
 
X------------------------X 
 
 
 
 
  
 
 
 
Crofelemer Diary 
(Appendix C) 
 
X------------------------X 
 
 
Rescue Medication 
Diary (Appendix D) 
 
X---------------------------------------------------------X 
 
Bowel Movement Diary 
(Appendix E) 
 
X---------------------------------------------------------X 
 
 
 
 
 
 
 
FACIT-D (Appendix A) 
 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
Adverse Eventsb 
 
X---------------------------------------------------------X 
Standard Treatmentd 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Concurrent Medications 
X 
X-------------------------------------------------------X 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
Breast Cancer 
Diagnosis 
X 
 
 
 
 


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32 
HER2 Positive Status 
X 
 
 
 
 
Organ function 
confirmation (bilirubin, 
creatinine, AST, ALT) 
X 
 
 
 
 
Performance Status 
(ECOG) 
X 
X 
X 
X 
X 
Beta-HCGc  
X 
 
 
 
 
Clinic Visitd 
X 
X 
X 
X 
X 
ECHO or MUGA 
X 
 
 
 
Xe 
a within 5 days of cycle 4 day 1 
b all adverse events will be captured from signing consent to 30 days after completing study or 
30 days after last dose of crofelemer, whichever occurs later 
c women of childbearing potential only 
d date of clinic visit each cycle to be determined by treating physician and does not have to be 
on day 1 of each cycle 
e this may occur at cycle 4 day 1 +/- 2 weeks (if LVEF measured every 3 cycles); or at cycle 5 
day 1 +/- 2 weeks (if LVEF measured every 12 weeks) 
 
11 QUALITY OF LIFE ASSESSMENT 
The Functional Assessment of Chronic Illness Therapy (FACIT) is a health-related quality of life 
questionnaire started in 1987 that looks at four primary quality of life domains: physical, social, 
emotional, and functional well-being.  FACIT has been validated in all cancers and there is a 
specific FACIT that focuses on diarrhea symptoms, called FACIT-D.   
 
For each quality of life domain, there are 6-7 questions asking specific questions that reflect 
how the patients are doing in that domain.  Results are scored from 0-4, with 0 reflecting “Not at 
all” and 4 reflecting “Very much”.  There are an additional 11 questions asking patients about 
their bowel function and how diarrhea impacts their quality of life, also scored from 0-4.   
 
FACIT-D scoring will be performed according to FACIT-D Scoring Guidelines (Version 4).  
Comparisons will be made between the treatment and control groups of the total FACIT-D 
score, as well as the diarrhea subscale (DS) score alone.   
 
All patients will be asked to complete the FACIT-D on day 1 of cycles 1-3 and within 5 days of 
cycle 4 day 1 (depending on when their clinic visit is scheduled) of THP or TCHP. 
 
The FACIT questionnaire and scoring guidelines are found in Appendix A. 
 
12 STATISTICAL CONSIDERATIONS 
This is a randomized, 1:1, stratified, open-label phase II study in patients with HER2 positive 
breast cancer receiving THP or TCHP in the neoadjuvant, adjuvant, or metastatic setting.  
Randomization will be stratified according to docetaxel versus paclitaxel. 
 
Patients randomized to the treatment group will receive oral crofelemer 125 mg twice daily 
during cycles 1-2 of THP or TCHP chemotherapy.  The primary endpoint is number of patients 
with all grade diarrhea felt to be definitely, probably, or possibly due to THP or TCHP during 
cycles 1 and 2.  All patients will keep a daily diary of bowel movement number and consistency 
based on the Bristol Stool Scale.   
 


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33 
Should a subject decide to withdraw or drop out before study completion, data will still be 
collected and analyzed if they completed at least 2 cycles of THP or TCHP.  Patients who 
completed fewer than 2 cycles of THP or TCHP will not be included in the analysis population. 
 
12.1 Sample Size/Accrual Rate 
With a sample size of 46 patients (23 per treatment group), the study has 81% power to detect a 
40% absolute decrease (from 60% to 20%) in incidence of all grade diarrhea for two or more 
consecutive days that is definitely, probably, or possibly due to THP or TCHP during cycles 1 
and 2 of chemotherapy, with a two sided significance level of 0.10 based on Fisher’s exact test.  
Anticipating a 10% withdrawal rate, we will accrue 52 patients.   
12.2 Futility 
The futility monitoring of the trial is based on a stochastic curtailing approach based on the trial 
design described above [60]. The statistician will start to calculate information time as soon as 
23 patients have completed two cycles of chemotherapy. Once the information time reaches 
50%, a planned interim analysis for futility will be performed. The test statistic at this time point 
is the proportion of patients with no diarrhea from the treatment group minus the proportion of 
patients with no diarrhea from the control group divided by its standard deviation. It will be 
converted to Brownian motion scale for trial monitoring accounting for unequal incidences of 
diarrhea from the two groups. We will examine conditional powers relative to several expected 
rates of diarrhea and also discordance probabilities of a trend reversal based on the primary 
endpoint (all grade diarrhea) and the main secondary endpoint (high grade diarrhea).  If 
predictive powers over uniform prior are all less than 20%, the trial may be considered futile. 
The overall clinical benefit based on both endpoints will be examined in the report to the 
Medstar-Georgetown LCCC DSMC. The protocol may be amended based on the 
recommendations of this DSMC. 
12.3 Randomization and Stratification Factors 
Stratified randomization will be used to assign patients into the two arms. There will be three 
strata: THP with docetaxel, THP with paclitaxel, and TCHP with docetaxel. Within each stratum, 
blocked randomization with randomly selected block sizes will be used. The stratified 
randomization procedure will be carried out by the biostatistician(s) at the LCCC Biostatistics 
and Bioinformatics Shared Resource. They will implement the randomization, such as generate 
the randomization table and hold the randomization key.  
12.4 Patient Accrual 
We anticipate recruiting 2-3 patients per month across the study sites combined, for an accrual 
duration of approximately 17-26 months.  Currently at each of the study sites, about 5 patients 
are newly treated with THP or TCHP each month.    
 
12.5 Analytic Plan for Primary Objective 
The number and percent of patients who experience diarrhea of any grade during cycle 1 or 2 
for two or more consecutive days and that is felt to be definitely, probably, or possibly due to 
THP or TCHP will be summarized with two-sided 90% confidence interval overall and by 
treatment assignment, and compared between treatment arms using a Fisher’s exact test.  The 
analysis population is defined as all randomized patients who complete 2 cycles of THP or 
TCHP chemotherapy.  
 
12.6 Analytic Plan for Secondary Objectives 
We plan on using the following analytic plans for the secondary objectives, if possible. 
 
According to treatment group, for each of the cycles and stratum, we will summarize: 1) the 
number and percent of patients (and 95% CI) who experience diarrhea of any grade; 2) the 


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34 
number and percent of patients (and 95% CI) who experience diarrhea of grade 3-4; 3) the 
median, range, and interquartile range of the duration of the episodes; and 4) the number (%) of 
patients requiring anti-diarrheal rescue medication. 
 
The time to onset of first episode of diarrhea will be summarized using the Kaplan-Meier 
method, and compared between treatment groups and stratum using log-rank test. 
 
The FACIT-D and FACIT-D DS scores will be summarized descriptively and graphically by 
cycle, treatment assignment, and stratum. The change in FACIT-D and FACIT-D DS scores 
between day 1 of cycles 1-3 and end of study (within 5 days of cycle 4 day 1) will be compared 
at each time point between treatment groups using a Wilcoxon rank sum-test. 
 
The stool consistency, as measured by the Bristol Stool scale, will be summarized in frequency 
tables by cycle and stratum and compared between treatment groups using a Wilcoxon rank 
sum-test. 
 
Adverse events will be summarized by type, grade, and stratum, according to treatment arm. 
 
If the primary endpoint is not met statistically, the previously stated secondary endpoints and 
overall incidence of all grade diarrhea in both arms will still be evaluated for clinical benefit. 
 
13 SAFETY REPORTING OF ADVERSE EVENTS 
Safety assessments will consist of monitoring and recording adverse events (AEs) and serious 
adverse events (SAEs) during cycles 1-3 of treatment with THP or TCHP.  The Sponsors or 
their designee are responsible for reporting relevant SAEs to the FDA, DSMC, Genentech, and 
Napo.   
 
Please refer to the FDA-approved package insert for a comprehensive listing of adverse events 
related to crofelemer.  The FDA medical review reported no adverse events (AEs) of special 
interest identified from clinical trials. 
 
13.1 Assessment of Safety 
 
13.1.1 Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol.  This includes all events of death, and any study specific 
issue of concern. 
 
13.1.2 Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution. 
 
This includes the following: 
 
AEs not previously observed in the subjects that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with [insert condition being 
studied] that were not present prior to the AE reporting period. 
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 


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35 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period.  
 
13.1.3 Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
 
It results in death (i.e., the AE actually causes or leads to death). 
 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.). 
 
It requires or prolongs inpatient hospitalization. 
 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical intervention 
to prevent one of the outcomes listed above). 
 
 
13.2 Methods and Timing for Assessing AND Recording Safety variables 
The Sponsor is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to the FDA, appropriate IRB(s), Napo, and 
Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports).  
 
13.2.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier. After 
this period, investigators should only report SAEs that are attributed to prior study treatment. 
 
13.2.2 Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to crofelemer, 
trastuzumab, and pertuzumab and actions taken.  
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guidelines: 
 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of 
crofelemer, trastuzumab, or pertuzumab and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a 
known pattern of response to crofelemer, trastuzumab, and pertuzumab; and/or the AE abates 
or resolves upon discontinuation of crofelemer, trastuzumab, or pertuzumab or dose reduction 
and, if applicable, reappears upon re-challenge. 
 
No 
Evidence exists that the AE has an etiology other than crofelemer, trastuzumab, or pertuzumab 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant 


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36 
medication); and/or the AE has no plausible temporal relationship to crofelemer, trastuzumab, or 
pertuzumabadministration (e.g., cancer diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert (P.I.) or Investigational Brochure (I.B.) 
 
Unexpected adverse events are those not listed in the P.I., or I.B., or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the description 
in the P.I. or I.B.  For example, under this definition, hepatic necrosis would be unexpected if the 
P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
Please refer to Section 7.2 Crofelemer Side Effects for a list of expected side effects associated 
with crofelemer. 
 
13.3 Procedures for Eliciting, Recording, and Reporting Adverse Events 
Adverse events can be “Expected” or “Unexpected”.  Expected adverse events are those that 
have been previously identified as resulting from administration of the agent. For the purposes 
of this study, an adverse event is considered expected when it appears in the current adverse 
event list, the Investigator’s Brochure, the package insert or is included in the informed consent 
document as a potential risk.  For the purposes of this study, an adverse event is considered 
unexpected when it varies in nature, intensity or frequency from information provided in the 
current adverse event list, the Investigator’s Brochure, the package insert or when it is not 
included in the informed consent document as a potential risk.  
 
When faxing reports to Genentech, please use the cover sheet found in Appendix G. 
 
13.3.1 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted. Examples of non-directive questions include:  
 
“How have you felt since your last clinical visit?” 
 
“Have you had any new or changed health problems since you were last here?”  
 
13.3.2 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations.  
 
13.3.2.1 Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to 
report the information that is currently available. If a diagnosis is subsequently established, it 
should be reported as follow-up information. 
 
13.3.2.2 Deaths 
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death”. 
 


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13.3.2.3 Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be 
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
 
13.3.2.4 Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions 
 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study or 
 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease 
of the study. 
 
13.3.2.5 Pregnancy 
If a female subject becomes pregnant while receiving the study drug or within 30 days after the 
last dose of crofelemer, trastuzumab, or pertuzumab a report should be completed and 
expeditiously submitted to Genentech and Napo. Follow-up to obtain the outcome of the 
pregnancy should also occur. Abortion, whether accidental, therapeutic, or spontaneous, should 
always be classified as serious, and expeditiously reported as an SAE. Similarly, any congenital 
anomaly/birth defect in a child born to a female subject exposed to crofelemer, trastuzumab, or 
pertuzumab should be reported as an SAE. 
 
Additional information on any crofelemer, trastuzumab, or pertuzumab -
exposed pregnancy and infant will be requested by Genentech Drug Safety at specific 
time points (i.e. after having received the initial report, at the end of the second 
trimester, 2 weeks after the expected date of delivery, and at 3, 6, and 12 months of 
the infant’s life). 
 
13.3.2.6 Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior crofelemer, trastuzumab, or pertuzumab 
exposure. If the investigator should become aware of the development of cancer or a congenital 
anomaly in a subsequently conceived offspring of a female subject who participated in the 
study, this should be reported as an SAE.  
 
13.3.2.7 Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor will 
agree to the reconciliation periodicity and format, but agree at minimum to exchange quarterly 
line listings of cases received by the other party.  
 
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-


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38 
case basis until satisfactory resolution.  The Sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’. 
 
13.3.2.8 AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product  
  
Please refer to Section 7.2 Crofelemer Side Effects for a list of expected side effects associated 
with crofelemer. 
 
Trastuzumab AESI: 
Congestive heart failure 
 
Pertuzumab AESI: 
Asymptomatic decline in LVEF requiring treatment or leading to discontinuation of monoclonal 
antibodies 
 
Patients will have Left Ventricular Ejection Fraction (LVEF) evaluated at enrollment to fulfill 
eligibility criteria. A second standard of care measurement of LVEF will be done at end of study. 
This may occur within 5 days of cycle 4 day 1 (if LVEF measured every 3 cycles); or within 5 
days of cycle 5 day 1 (if LVEF measured every 12 weeks). 
 
13.3.2.9 Adverse Event Reporting 
All AEs and SAEs will be captured for the full study duration.  Investigators must report all SAEs 
to Genentech and Napo within the timelines described below. The completed MedWatch/case 
report should be faxed immediately upon completion to Genentech Drug Safety at: (650) 238-
6067   and to Napo at (415) 371-8311. 
 
Serious adverse events (SAEs), pregnancy reports and AEs of special interest (AESIs), where 
the patient has been exposed to the Product, will be sent on a MedWatch or CIOMS I form to 
Genentech and Napo. Transmission of these reports (initial and follow-up) will be either 
electronically or by fax and within the timelines specified below: 
 
 
SAEs 
Serious AE reports that are related to the Product shall be transmitted to Genentech and 
Napo within fifteen (15) calendar days of the awareness date.   
 
The Sponsor or their designee will notify the IRB and DSMC of relevant SAEs (i.e., death, a 
life-threatening experience, inpatient hospitalization, prolonged hospitalization or significant 
disability/incapacity) to the by a written safety report within 1 business day of learning of the 
SAE.  


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39 
 
 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech and 
Napo within thirty (30) calendar days of the awareness date. 
 
 
Pregnancy reports 
While such reports are not serious AEs or ADRs per se, as defined herein, any reports of 
pregnancy, where the fetus may have been exposed to the Product, shall be transmitted to 
Genentech and Napo within thirty (30) calendar days of the awareness date. Pregnancies 
will be followed up until the outcome of the pregnancy is known, whenever possible, based 
upon due diligence taken to obtain the follow-up information. 
 
 
AESIs  
AESIs requiring expedited reporting shall be forwarded to Genentech and Napo within 
fifteen (15) calendar days of the awareness date. Others shall be sent within thirty (30) 
calendar days.  
 
 
 
Special situation reports 
In addition to all AEs, pregnancy reports and AESIs, the following Special Situations Reports 
should be collected and transmitted to Genentech and Napo even in the absence of an 
Adverse Event within thirty (30) calendar days: 
 
Data related to the Product usage during pregnancy or breastfeeding 
Data 
related 
to 
overdose, 
abuse, 
off-label 
use, 
misuse, 
inadvertent/erroneous 
administration, medication error or occupational exposure, with or without association with 
an AE/SAE unless otherwise specified in the protocol 
Data related to a suspected transmission of an infectious agent via a medicinal product 
(STIAMP) 
Lack of therapeutic efficacy 
 
In addition, reasonable attempts should be made to obtain and submit the age or age group 
of the patient, in order to be able to identify potential safety signals specific to a particular 
population 
 
13.3.2.10 
Aggregate Reports (For Non-serious AE) 
The Sponsor will forward a copy of the final study report to Genentech and Napo upon 
completion of the study.  
 
The Sponsor will forward periodically listings of non-serious AEs originating from the study to 
Genentech and Napo.  
 
13.3.3 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description of the MedWatch 
3500A form: 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics 
 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 


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13.3.3.1 Follow-up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
 
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form  
 
Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e. D.O.B. initial, patient number), protocol description and number, if assigned, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted (The patient identifiers are important so that the new information is added to the 
correct initial report). 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom an adverse event was reported. For questions regarding 
SAE reporting, you may contact the Genentech Drug Safety representative noted above or 
Napo or the MSL assigned to the study. Relevant follow-up information should be submitted to 
Genentech Drug Safety and Napo as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
 
13.4 Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech and Napo. This includes all IND annual reports and the Clinical Study Report (final 
study report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech and Napo. Copies of such reports should be mailed to the Oncology Research office 
at Georgetown. 
 
13.4.1.1 Seven Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that 
is unexpected and assessed by the Investigator to be possibly related to the use of crofelemer, 
trastuzumab, or pertuzumab.  An unexpected adverse event is one that is not already described 
in the crofelemer, trastuzumab, or pertuzumab Investigator Brochure. Such reports are to be 
telephoned or faxed to the FDA, Napo, and Genentech within 7 calendar days of first learning of 
the event. 
 
13.4.1.2 Fifteen Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of crofelemer, trastuzumab, or pertuzumab. An unexpected adverse event is 
one that is not already described in the crofelemer, trastuzumab, or pertuzumab investigator 
brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of 
the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, Napo, and all participating investigators within 15 calendar days of first learning of 
the event. The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter). 


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41 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be 
faxed to Genentech Drug Safety at (650) 225-4682 or (650) 225-4630 and to Napo at: (415) 
371-8311 
 
And to the Site IRB: 
MedStar Health Research-Georgetown University Oncology Institutional Review Board 
SW104 Medical Dental Building 
3900 Reservoir Road, NW 
Washington, DC. 20057 
Fax: (202) 687-4847 
Phone: (202) 687-1506 
E-mail: irboard@georgetown.edu  
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
And Napo: (415) 371-8311 
 
13.4.2 IND Annual Reports 
 
13.4.2.1 Copies to Genentech and Napo: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech and Napo. Copies of such reports should be faxed to Genentech Drug Safety at 
(650) 225-4682 or (650) 225-4630; and Napo at (415) 371-8311.  
 
13.5 Reporting to the Sponsor 
All AEs and SAEs will be recorded for the entire study duration and reported to the Sponsor.  All 
serious adverse events that occur after the initial dose of study treatment, during treatment, or 
within 30 days of the last dose of treatment must be reported to the Sponsor. This includes but 
is not limited to the following: 
 
Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are unexpected 
and possibly, probably or definitely related/associated with the intervention.   
 
All Grade 4 (life-threatening or disabling) Events – Unless expected AND specifically 
listed in the protocol as not requiring reporting.  
 
All Grade 5 (fatal) Events – When the participant is enrolled and actively participating in 
the trial OR when the event occurs within 30 days of the last study intervention.  
 
Participating investigators must report each serious adverse event to the Sponsor within 24 
business hours of learning of the occurrence. In the event that the participating investigator 
does not become aware of the serious adverse event immediately (e.g., participant sought 
treatment elsewhere), the participating investigator is to report the event within business hours 
after learning of it and document the time of his or her first awareness of the adverse event. 
Report serious adverse events by telephone, email or facsimile to:  
 
Sandra M. Swain, MD, FACP, FASCO 
4000 Reservoir Road NW 
120 Building D 
Washington, DC 20057 


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42 
Phone: 202-687-4600 
Fax: 202-687-1110 
Email: Sandra.swain@georgetown.edu 
 
Within the following 1-2 business days of awareness, the participating investigator must provide 
follow-up information on the serious adverse event if a full description of events was not 
included with the initial reporting of the event. Follow-up information should describe whether 
the event has resolved or continues, if and how the event was treated, and whether the 
participant will continue or discontinue study participation. This information should be submitted 
to the Sponsor at sandra.swain@georgetown.edu.  All non-serious adverse events will be 
reported to the Sponsor on the adverse events CRFs. 
 
13.6 Compliance With Laws and Regulations  
This study will be conducted in accordance with FDA regulations, the International Conference 
on Harmonization (ICH) E6 Guideline for Good Clinical Practice (GCP), the Declaration of 
Helsinki, and applicable local, state, and federal laws.  
 
13.7 Information Regarding Genentech Product Complaints 
 
WHAT IS A PRODUCT COMPLAINT? 
A product complaint is any written or oral information received from a complainant that alleges 
deficiencies related to identity, quality, safety, strength, purity, reliability, durability, effectiveness 
or performance of a product after it has been released and distributed to the commercial market 
or clinical trial. 
 
HOW DO I FILE A COMPLAINT? 
For all Investigator Initiated Studies (interventional and non-interventional): 
 
Product Complaints with an AE (adverse event) should be reported via email/fax to: 
usds_aereporting-d@gene.com OR 650-238-6067. 
 
Product Complaints without an AE (adverse event) should be reported via email to: 
For Interventional Investigator Initiated Studies: 
kaiseraugst.global_impcomplaint_management@roche.com 
 
For Non-Interventional Investigator Initiated Studies: 
us-acmo-d@gene.com  
 
All complaints must be filed within 1 business day for pre-approved products and 15 calendar 
days for approved products. Complaints can be reported using a Medwatch, CIOMS or any 
Genentech-approved reporting form (same as SAEs, AESI etc.). 
 
14 DATA SAFETY MONITORING COMMITTEE 
The Georgetown Lombardi Comprehensive Cancer Center will be responsible for the data and 
safety monitoring of this trial.  This study is an investigator initiated study utilizing a FDA 
approved drug for the same indication as the FDA approval (diarrhea), though in a different 
patient population (chemotherapy induced as opposed to anti-retroviral therapy induced).  The 
Sponsor has applied for an IND exemption with the FDA.  This drug is not systemically 
absorbed and this is therefore a low risk study, requiring reviews by the LCCC Data and Safety 
Monitoring Committee (DSMC) every six months.   
 
The Sponsor or their designee will review the data including safety monitoring at institution 
based disease group meeting and on any meetings with participating sites. All Severe Adverse 


MHRI GU IRB# 2015-0547: HALT-D PROTOCOL 
 
            
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43 
Events (SAEs) are required to be reported to the IRB.  Based on SAEs, the IRB retains the 
authority to suspend further accrual pending more detailed reporting and/or modifications to 
further reduce risk and maximize the safety of participating patients. 
 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC DSMC every 
six months from the time the first patient is enrolled on the study. Results of the DSMC meetings 
will be forwarded to the IRB with recommendations regarding need for study closure. 
 
DSMC recommendations should be based not only on results for the trial being monitored as 
well as on data available to the DSMC from other studies.  It is the responsibility of the Sponsor 
to ensure that the DSMC is kept apprised of non-confidential results from related studies that 
become available.  It is the responsibility of the DSMC to determine the extent to which this 
information is relevant to its decisions related to the specific trial being monitored. 
 
A written copy of the DSMC recommendations will be given to the Sponsor and the IRB.  If the 
DSMC recommends a study change for patient safety or efficacy reasons the Sponsor must act 
to implement the change as expeditiously as possible.  If a recommendation is made to change 
a trial for reasons other than patient safety or efficacy the DSMC will provide an adequate 
rationale for its decision. If the DSMC recommends that the trial be closed for any reason, the 
recommendation will be reviewed by the Associate Director for Clinical Research at LCCC.  
Authority to close a trial for safety reasons lies with the IRB, with the above described input from 
DSMC and the LCCC Associate Director for Clinical Research.   
 
14.1 Collection of Private Information on Individuals Other than Study Subject 
This research will not involve collection of private information pertaining to individuals other than 
the study subject. 
 
14.2 Subject Compensation 
Subjects will not be compensated in cash or in kind. 
 
14.3 Privacy and Confidentiality of Data Records 
Personal information about the patients, including but not limited to name, date of birth, sex, 
race, ethnicity, previous treatment (including but not limited to pathology reports, imaging 
reports, laboratory reports, surgery, radiation oncology, medical oncology, etc.), office notes, 
physical exam, history, medications, adverse events, etc. will be collected on each study 
patient.  This data is important for evaluating the primary and secondary endpoints of the study 
and will be protected from improper use and disclosure as per MedStar standard operating 
procedures.  This plan will be implemented at the time of signing consent for each patient.   
 
Protected Health Information (PHI) will be accessed in this study.  PHI will be received via a 
CRF and also be recorded in a CRF.  PHI information will be retained until all follow up 
publications and studies stemming from this study have been completed.  This information will 
only be shared within the research team.  Confidentiality will be maintained via standard 
MedStar standard operating procedures.  All electronic transmission of PHI data will be in 
encrypted/secured form.  No names of subjects will be included in the publication.  No digital, 
video, audio, or photographic recordings of the subject will be made public.   
 
14.4 Privacy and Confidentiality of Data Records – Data Security 
All hardcopy and electronic data will be kept in accordance with the MedStar standard operating 
procedures.  Upon completion of all publications related to this study, the data will be destroyed 
in accordance with institutional protocols.  No members other than those on the research team 
will have access to the study data.  Data will not be shared outside of the research team.         
 


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44 
15 STUDY MANAGEMENT 
 
15.1 Conflict of Interest  
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by MHRI or LCCC. All investigators will follow the MHRI and LCCC conflict of interest 
policy.  
 
15.2 Institutional Review Board (IRB) Approval and Consent  
All oncology clinical research protocols must be submitted to the Clinical Research Committee 
(CRC) for scientific review before submission to and final approval by the IRB. The initial review 
includes an assessment of the specific plans for data and safety monitoring, which vary 
depending on the study type, phase, size, and sponsorship.  
 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations. The IRB should approve the consent form and protocol.  In 
obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical 
principles that have their origin in the Declaration of Helsinki.  
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form.  
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion.  
 
15.3 Required Documentation  
Before the study can be initiated at any site, the following documents must be filed at MGUH 
Regulatory (Study Binder):  
• 
Original U.S. FDA Form 1572.   The names of all investigators must appear on this 
form. Investigators must also complete all regulatory documentation as required by local 
and national regulations; 
• 
Sponsor’s and sub-Investigator’s medical licenses, CITI training, Current curriculum 
vitae 
• 
Written documentation of IRB approval of protocol and informed consent document; 
• 
A copy of approved protocol 
• 
A copy of the IRB-approved informed consent document and IRB communications; 
• 
CRC communication 
• 
A signed Clinical Research Agreement 
• 
Delegation of authority log 
• 
Lab CAP/CLIA, Laboratory normals 
• 
Any sponsor communication, including newsletters 
• 
Monitoring visits letters – pre/post 
 
15.4 Adherence to the Protocol  
Except for an emergency situation in which proper care for the protection, safety, and well-being 


MHRI GU IRB# 2015-0547: HALT-D PROTOCOL 
 
            
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45 
of the study patient requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol.  Minor deviations should be summarized and reported to the 
IRB at the time of continuing review. Major deviations should be summarized and reported to 
the Regulatory Affairs Coordinator who will submit to the IRB as soon as possible, but not more 
than 10 calendar days after acquiring information reasonably suggesting that a reportable 
(major) deviation has occurred.  
 
15.5 Amendments to the Protocol  
Should amendments to the protocol be required, the amendments will be originated and 
documented by the PI. It should also be noted that when an amendment to the protocol 
substantially alters the study design or the potential risk to the patient, a revised consent form 
might be required.  The written amendment, and if required the amended consent form, must be 
sent to the IRB for approval prior to implementation.  
 
15.6 Record Retention  
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor or their designee correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient consent 
forms).  
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the study.  
 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the Sponsor.  Study documents should be kept 
on file until after the study is fully completed, including but not limited to publications related to 
the study. 
 
15.7 Obligations of Investigators  
The Sponsor is responsible for the conduct of the clinical trial at the site in accordance with Title 
21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Sponsor must 
assure that all study site personnel, including sub- investigators and other study staff members, 
adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical 
trials both during and after study completion.  
 
A dedicated co-investigator at each study site will be responsible for assuring that all the 
required data will be collected and entered onto the CRFs.  At the completion of the study, all 
CRFs will be reviewed by the Sponsor and will require her final signature to verify the accuracy 
of the data.  
 
15.8 Study Close-Out  
Any study report submitted to the FDA by the Sponsor or their designee should be copied 
to Genentech and Napo. Additionally, any literature articles that are a result of the study 
should be sent to Genentech and Napo.  


MHRI GU IRB# 2015-0547: HALT-D PROTOCOL 
 
            
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46 
16 APPENDICES 
16.1 APPENDIX A: FACIT-D AND SCORING GUIDELINES (Version 4) 
Patient #:__________ 
Cycle #:________ 
 
Study Site________________ 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy .................................................
0 
1 
2 
3 
4 
GP2 
I have nausea ..............................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family ...................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ...................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment ...................
0 
1 
2 
3 
4 
GP6 
I feel ill .........................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ..................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends ..............................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ........................
0 
1 
2 
3 
4 
GS3 
I get support from my friends .......................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ...............................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ...........................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my 
main support) ...............................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer 
it, please mark this box   ☐   and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life .......................................
0 
1 
2 
3 
4 


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47 
Patient #:__________ 
Cycle #:________ 
 
Study Site________________ 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
GE1 
I feel sad ......................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness .....
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness............
0 
1 
2 
3 
4 
GE4 
I feel nervous ...............................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying ......................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse .......................
0 
1 
2 
3 
4 
 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) .....................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ..................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life....................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ...........................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well .........................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun .................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now ..........
0 
1 
2 
3 
4 


MHRI GU IRB# 2015-0547: HALT-D PROTOCOL 
 
            
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48 
 
Patient #:__________ 
Cycle #:________ 
 
Study Site________________ 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
C3 
I have control of my bowels .......................................  
0 
1 
2 
3 
4 
ITF1 
I move my bowels more frequently than usual ..........  
0 
1 
2 
3 
4 
ITU2 
I am afraid to be far from a toilet ...............................  
0 
1 
2 
3 
4 
D1 
I have to limit my social activity because of diarrhea 
(diarrhoea) ................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
D2 
I have to limit my physical activity because of 
diarrhea (diarrhoea) ..................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
D3 
I have to limit my sexual activity because of diarrhea 
(diarrhoea) ................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
D4 
I am embarrassed by having diarrhea (diarrhoea) ....  
0 
1 
2 
3 
4 
D5 
I have abdominal cramps or discomfort due to my 
diarrhea (diarrhoea) ..................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
D6 
My problem with diarrhea (diarrhoea) keeps/wakes 
me up at night ...........................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
ITF3 
I must move my bowels frequently to avoid 
accidents ...................................................................  
0 
1 
2 
3 
4 
ITF5 
I wear pads or protection to prevent soiling my 
underwear .................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
 
 
 
 
 
 
 
 
 


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49 
 
 
Patient #:__________ 
Cycle #:________ 
 
Study Site________________ 
 
FACIT-D SCORING GUIDELINES (VERSION 4)  
 
Instructions:* 1. Record answers in "item response" column. If missing, mark with an X 
    
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, 
then divide by the   
    number of items answered.  This produces the subscale score. 
4. Add subscale scores to derive total scores (TOI, FACT-G & FACIT-D).  
5. The higher the score, the better the QOL 
 
Subscale 
 
  Item Code    Reverse item?       Item response         Item Score  
 
PHYSICAL 
GP1 
 
4 
- 
________ 
 
=________ 
WELL-BEING 
GP2 
 
4 
- 
________ 
 
=________ 
   (PWB) 
GP3 
 
4 
- 
________ 
 
=________ 
       
GP4 
 
4 
- 
________ 
 
=________ 
       
GP5 
 
4 
- 
________ 
 
=________ 
       
GP6 
 
4 
- 
________ 
 
=________ 
       
GP7 
 
4 
- 
________ 
 
=________ 
 
              Sum individual item scores: ________   
 
 
 
                      Multiply by 7: ________ 
             Divide by number of items answered: ________=PWB 
subscale score 
 
SOCIAL/FAMILY 
GS1 
 
0 
+ 
________ 
 
=________ 
WELL-BEING 
GS2 
 
0 
+ 
________ 
 
=________ 
    (SWB) 
GS3 
 
0 
+ 
________ 
 
=________ 
       
GS4 
 
0 
+ 
________ 
 
=________ 
       
GS5 
 
0 
+ 
________ 
 
=________ 
    
GS6 
 
0 
+ 
________ 
 
=________ 
       
GS7 
 
0 
+ 
________ 
 
=________ 
 
             Sum individual item scores: ________   
 
 
 
                     Multiply by 7: ________ 
            Divide by number of items answered: ________=SWB 
subscale score 
 
EMOTIONAL 
GE1 
 
4 
- 
________ 
 
=________ 
WELL-BEING 
GE2 
 
0 
+ 
________ 
 
=________ 
    (EWB) 
GE3 
 
4 
- 
________ 
 
=________ 
       
GE4 
 
4 
- 
________ 
 
=________ 
      
GE5 
 
4 
- 
________ 
 
=________ 
 
 
 
 
GE6 
 
4 
- 
________ 
 
=________ 
 
             Sum individual item scores: ________   
 
 
 
                     Multiply by 6: ________ 
            Divide by number of items answered: ________=EWB 
subscale score 
 
 
 
Score range: 0-28 
Score range: 0-28 
Score range: 0-24 


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50 
 
Patient #:__________ 
Cycle #:________ 
 
Study Site________________ 
 
FUNCTIONAL   
GF1 
 
0 
+ 
________ 
 
=________ 
WELL-BEING  
GF2 
 
0 
+ 
________ 
 
=________ 
     (FWB) 
GF3 
 
0 
+ 
________ 
 
=________ 
       
GF4 
 
0 
+ 
________ 
 
=________ 
       
GF5 
 
0 
+ 
________ 
 
=________ 
       
GF6 
 
0 
+ 
________ 
 
=________ 
       
GF7 
 
0 
+ 
________ 
 
=________ 
 
             Sum individual item scores: ________   
 
 
 
                     Multiply by 7: ________ 
            Divide by number of items answered: ________=FWB 
subscale score 
 
 
Subscale 
         Item Code       Reverse item?            Item response          Item Score  
 
DIARRHEA  
 
C3 
 
0 
+ 
________ 
 
=________ 
SUBSCALE 
 
ITF1 
 
4 
- 
________ 
 
=________ 
    (DS)  
 
ITU2 
 
4 
- 
________ 
 
=________ 
       
D1 
 
4 
- 
________ 
 
=________ 
       
D2 
 
4 
- 
________ 
 
=________ 
      
D3 
 
4 
- 
________ 
 
=________ 
      
D4 
 
4 
- 
________ 
 
=________ 
      
D5 
 
4 
- 
________ 
 
=________ 
       
D6 
 
4 
- 
________ 
 
=________ 
       
ITF3 
 
4 
- 
________ 
 
=________ 
       
ITF5 
 
4 
- 
________ 
 
=________ 
 
              Sum individual item scores:________   
 
 
 
                   Multiply by 11: ________ 
            Divide by number of items answered: ________=D 
Subscale score 
 
 
To derive a FACIT-D Trial Outcome Index (TOI): 
 
  __________ + __________ + __________ =________=FACIT-D 
TOI 
  (PWB score)   (FWB score)   (DS score)   
 
To Derive a FACT-G total score: 
 
        __________ + __________ + __________ + __________=________=FACT-G 
Total score 
        (PWB score)    (SWB score)   (EWB score)  (FWB score) 
 
To Derive a FACIT-D total score: 
 
 
              _________ + __________ + __________ + __________ + __________ =________=FACIT-
D Total score 
                            (PWB score)  (SWB score)   (EWB score)   (FWB score)    (DS score) 
 
PLEASE SCAN THIS COMPLETED FORM TO THE PATIENT’S ELECTRONIC MEDICAL 
RECORD
Score range: 0-28 
Score range: 0-100 
Score range: 0-108 
Score range: 0-152 
Score range: 0-44 


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51 
 
16.2 APPENDIX B: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
 
Grade  
ECOG Performance Status*  
   
0  
Fully active, able to carry on all pre-disease performance without restriction  
  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work  
2  
  
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours  
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours  
4  
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair  
5   
Dead  
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.  


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52 
16.3 APPENDIX C: CROFELEMER DIARY 
Patient #:__________ 
Cycle #:________ 
 
Study Site________________ 
 
Cycle start date (mm-dd-yyyy) __________  Cycle end date (mm-dd-yyyy) ____________ 
 
 
In this study your treatment is described in “cycles”.  A cycle for this study is a “21 day” length of time. 
The days of the cycle are numbered 1 through 21; therefore, “Day 1” is the first day of the 21-day cycle. 
The cycle may start on any calendar date, thus a cycle Day does not usually match the calendar date.  
 
Take one tablet of crofelemer 125 mg by mouth with water every 12 hours ±2 hours at approximately 
the same time each day, with or without food. 
 
Take crofelemer tablets whole – do not chew or crush.  
 
If you miss a dose or vomit after dosing, do not retake this medication. Document it in this medication 
diary and report it to your health care provider at your next visit. 
 
On Day 1 of every cycle, you should take the a.m. dose of crofelemer before you start chemotherapy, 
ideally 30-60 minutes prior.  
 
Write the date and time when you took your medication at home in the tables below for all days through 
the last day of every cycle.  
 
Keep crofelemer tablets out of reach of children.  
 
The crofelemer tablets need to be stored in the original package.  Please see product label for 
appropriate storage conditions.  
 
You will receive a new Crofelemer Diary and crofelemer supply at the first day of each cycle. 
 
If, for any reason, you run out of crofelemer tablets, or anticipate running out before your next 
clinic appointment, please contact the research nurse at 202-877-8100 IMMEDIATELY.   
 
While you are taking crofelemer, always bring your medication bottle(s) even if empty and/or 
unused capsules to the clinic to your next visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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53 
Patient #:__________ 
Cycle #:________ 
 
Study Site________________ 
Day  
 
Date 
(mm-dd-yyyy) 
Time 
(write the time you took crofelemer in 
hh:mm format) 
Comments 
1 
 
AM 
 
: 
 
 PM 
 
: 
2 
 
AM 
 
: 
 
 PM 
 
: 
3 
 
AM 
 
: 
 
 PM 
 
: 
4 
 
AM 
 
: 
 
 PM 
 
: 
5 
 
AM 
 
: 
 
 PM 
 
: 
6 
 
AM 
 
: 
 
 PM 
 
: 
7 
 
AM 
 
: 
 
 PM 
 
: 
8 
 
AM 
 
: 
 
 PM 
 
: 
9 
 
AM 
 
: 
 
 PM 
 
: 
10 
 
AM 
 
: 
 
 PM 
 
: 
11 
 
AM 
 
: 
 
 PM 
 
: 


MHRI GU IRB# 2015-0547: HALT-D PROTOCOL 
 
                
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54 
 
PLEASE SCAN THIS COMPLETED FORM TO THE PATIENT’S ELECTRONIC MEDICAL RECORD 
 
Patient #:__________ 
Cycle #:________ 
 
Study Site________________ 
 
12 
 
AM 
 
: 
 
 PM 
 
: 
13 
 
AM 
 
: 
 
 PM 
 
: 
14 
 
AM 
 
: 
 
 
 
 
 PM 
 
: 
15 
 
AM 
 
: 
 
 PM 
 
: 
16 
 
AM 
 
: 
 
 PM 
 
: 
17 
 
AM 
 
: 
 
 PM 
 
: 
18 
 
AM 
 
: 
 
 PM 
 
: 
19 
 
AM 
 
: 
 
 PM 
 
: 
20 
 
AM 
 
: 
 
 PM 
 
: 
21 
 
AM 
 
: 
 
 PM 
 
: 


MHRI GU IRB# 2015-0547: HALT-D PROTOCOL 
 
                
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55 
16.4   APPENDIX D: RESCUE MEDICATION DIARY 
 
Patient #:__________ 
Cycle #:________ 
 
Study Site________________ 
 
We ask you to keep a daily count of how many doses of rescue medication you used, if any.  The “Day” 
column refers to which day in the chemotherapy cycle you are.  Each time you use a rescue medication, 
please check off one of the boxes to document this.  
 
 
 
PLEASE SCAN THIS COMPLETED FORM TO THE PATIENT’S ELECTRONIC MEDICAL RECORD 


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56 
16.5 APPENDIX E: BOWEL MOVEMENT DIARY AND BRISTOL STOOL SCALE 
 
Patient #:__________ 
Cycle #:________ 
 
Study Site: __________________ 
 
After each bowel movement, record in the box under the appropriate day the consistency of the stool.   
 
Please refer to the attached Bristol Stool Chart for stool consistency definitions. 
 
 
Day 
Date 
Bowel Movements 
1 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
 
 
 
PLEASE SCAN THIS COMPLETED FORM TO THE PATIENT’S ELECTRONIC MEDICAL RECORD 
 


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57 
  


MHRI GU IRB# 2015-0547: HALT-D PROTOCOL 
 
                
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58 
16.6 APPENDIX F: ELIGIBILITY CHECKLIST 
Patient #:__________ 
Cycle #:________ 
 
Study Site: __________________ 
# 
Yes 
No 
N/A 
Inclusion Criteria 
I1 
 
 
 
Willing and able to provide written informed consent 
I2 
 
 
 
Men and women ≥18 years of age 
I3 
 
 
 
Pathologically confirmed diagnosis of HER2 positive breast cancer of any stage (previous 
treatment is allowed without limits on lines of prior therapy) 
I4 
 
 
 
Scheduled to receive at least 3 consecutive cycles of THP or TCHP 
I5 
 
 
 
Performance status of 0-2 according to the ECOG scale 
I6 
 
 
 
Negative pregnancy test within 2 weeks prior to starting THP or TCHP treatment for 
women of childbearing potential 
I7 
 
 
 
Able to read, understand, follow the study procedure and complete crofelemer, rescue 
medication, and bowel movement diaries 
I8 
 
 
 
Patients may enroll simultaneously on this study and other studies 
I9 
 
 
 
Patients with brain metastases are allowed on this study (concurrent treatment with 
steroids is allowed).   
I10 
 
 
 
Left Ventricular Ejection Fraction (LVEF) greater or equal to 50% at baseline as 
determined by either ECHO or MUGA 
 
# 
Yes 
No 
N/A 
Exclusion Criteria 
E1 
 
 
 
Pregnant and/or breastfeeding 
E2 
 
 
 
Ongoing irritable bowel syndrome (IBS) or colitis (including but not limited to ulcerative 
colitis, Crohn’s disease, microscopic colitis, etc.) 
E3 
 
 
 
Use of investigational drugs within 3 weeks of starting THP or TCHP treatment or foreseen 
use during the study  
E4 
 
 
 
Use of chemotherapy, trastuzumab, or pertuzumab within the past 2 (two) weeks  
E5 
 
 
 
Use of laxatives within the past 7 days - deleted 
E6 
 
 
 
Use of chronic laxatives (≥ 30 consecutive days) - deleted 
E7 
 
 
 
Use of anti-diarrheal agents (including but not limited to loperamide, octreotide, bismuth, 
tincture of opium, atropine, probiotics in any form other than food) within the past 7 days - 
deleted 
E8 
 
 
 
Use of antibiotics within the past 7 days (up to 2 prophylactic doses of antibiotic for 
procedures, including but not limited to port placement, is permitted) 
E9 
 
 
 
Any type of ostomy 
E10 
 
 
 
Total colectomy 
E11 
 
 
 
Fecal incontinence 
E12 
 
 
 
Ongoing radiation induced diarrhea or constipation or planned radiotherapy to the abdomen 
or pelvis while on study 
E13 
 
 
 
Active systemic infection requiring ongoing intervention, including but not limited to oral and 
intravenous antibiotics, anti-fungals, anti-parasites, anti-virals 
E14 
 
 
 
Abdominal or pelvic surgery without recovery of bowel function  
E15 
 
 
 
Inadequate organ function for starting THP or TCHP, which may include the following 
laboratory results within 28 days prior to starting THP or TCHP treatment (Please refer to the 
prescribing label instructions on the use of each drug in the setting of abnormal organ 
function): 
 
Serum creatinine > 2.0 mg/dL or 177 μmol/L 
 
Total bilirubin > upper limit of normal (ULN) (unless the patient has documented Gilbert’s 
syndrome) 
 
Exclusion criteria specific for THP with PACLITAXEL (Taxol®) group: 
o Transaminases greater than 10 times ULN  
 
Exclusion criteria specific for TCHP/THP with DOCETAXEL (Taxotere®) group: 
o AST and/or ALT > 2.5x ULN 
o AST and/or ALT > 1.5x ULN with concurrent alkaline phosphatase >2.5 x ULN 
(unless bone metastases are present) 


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Enrolling Physician Signature 
 
 
 
 
 
 
Date 
 
PLEASE SCAN THIS COMPLETED FORM TO THE PATIENT’S ELECTRONIC MEDICAL RECORD


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16.7 APPENDIX G: SAFETY REPORTING FAX COVER SHEET 
 


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16.8 APPENDIX H: CROFELEMER FLOWSHEET FOR C1D1 
 
 
 
 
 
 
Crofelemer Flowsheet for C1D1 
 
HALT-D Study: LCCC #2015-0547 
 
Coordinator   
____________________________ 
 
Pager (if available) ____________________________ 
 
 
 
Patient Name 
  
IRB Number 
2015-0547 
DOB 
  
Patient ID 
  
MRN 
  
Physician 
  
Today's Date 
  
Cycle 
C1D1 
CROFELEMER 
Time administered 
  
RN Initials 
  
INFUSION(S) 
Time 1st infusion started   
RN Initials 
  
 
 
 
 
NOTE: Crofelemer must be given BEFORE any infusion is started, ideally 30-60 minutes prior.  
After the document is fully filled out, please scan it into the electronic medical record immediately. 
 
 
PLEASE SCAN THIS COMPLETED FORM TO THE PATIENT’S ELECTRONIC MEDICAL RECORD 


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16.9 APPENDIX I: PATIENT 
RANDOMIZATION FORM 
 
 
Patient Randomization Form: HALT-D (IRB 2015-0547) 
Site and Patient Information 
Site Name 
 
Site ID 
 
Patient Initials 
 
Patient DOB 
 
Patient  # 
 
 
Action 
Staff Name 
Staff Role 
Date 
Screening Date 
 
 
 
Screened By 
 
 
 
Eligibility Confirmed by 
 
 
 
 
Randomization 
Arm 
Group 
Treatment 
Assigned    
(check one) 
Description 
CROFELEMER 
A 
TCHP Crofelemer 
  
Taxotere®, Carboplatin, 
Trastuzumab, Pertuzumab + 
CROFELEMER 
Control 
B 
TCHP Control 
  
Taxotere®, Carboplatin 
Trastuzumab, Pertuzumab 
CROFELEMER 
C 
THP Docetaxel 
Crofelemer 
  
Taxotere®, Trastuzumab, 
Pertuzumab + CROFELEMER 
Control 
D 
THP Docetaxel Control   
Taxotere®, Trastuzumab, 
Pertuzumab 
CROFELEMER 
E 
THP Paclitaxel 
Crofelemer 
  
Taxol®, Trastuzumab, 
Pertuzumab + CROFELEMER 
Control 
F 
THP Paclitaxel Control 
  
Taxol®, Trastuzumab, 
Pertuzumab 
Taxotere = docetaxel, Taxol = paclitaxel 
 
Biostatistician Signature ______________________ 
Date ________________ 
 
Biostatistician Print Name _____________________ 
 
PLEASE RETURN COMPLETED FORM TO MULTI-SITE COORDINATOR WITHIN 1 
BUSINESS DAY OF RECEIPT AND SCAN INTO PATIENT’S ELECTRONIC MEDICAL 
RECORD.


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16.10  APPENDIX J: INVESTIGATIONAL DRUG ORDER FORM 
 


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16.11  APPENDIX K: ADDITIONAL ELIGIBILITY INFORMATION 
 
HALT-D: Additional Clinic Note Information (Optional for Documentation) 
PATIENT:   ___________________________ 
MRN:         ___________________________ 
DOB:          ___________________________ 
 
 
 
The patient will start systemic chemotherapy with one of the regimens listed below: 
□ TCHP – Docetaxel (Taxotere), carboplatin, trastuzumab and pertuzumab 
□ THP – Docetaxel (Taxotere), trastuzumab and pertuzumab 
□ THP – Paclitaxel (Taxol), trastuzumab and pertuzumab 
PS:  0 – 1 – 2  
□ Currently the patient is not pregnant and not breast feeding.  
If unknown, beta HCG test will be done on ____ / ____ / __________ 
□ The patient denies any history or diagnosis of irritable bowel syndrome (IBS) or colitis (UC, 
Crohn’s, microscopic colitis). 
□ The patient is not receiving investigational drugs and has not received chemotherapy 
within the past 2 weeks 
□ The patient did not use antibiotics in the past 7 days (up to 2 prophylactic doses of 
antibiotic for procedures, including but not limited to port placement, is permitted) 
□ The patient denies history of total colectomy, ostomy, fecal incontinence, current infection 
or abdominal or pelvic surgery without recovery of bowel function. 
□ There is no plan for radiation involving abdomen or pelvis while on study. 
□ I reviewed the treatment plan, diarrhea treatment and bowel movement diaries. Patient 
manifested understanding of all instructions.  
 
PROVIDER NAME (PRINT):    
__________________________________ 
 
PROVIDER SIGNATURE:   
__________________________________ 
 
DATE: 
 
 
__________________________________ 
 
PLEASE SCAN THIS COMPLETED FORM TO THE PATIENT’S ELECTRONIC MEDICAL 
RECORD 


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16.12  APPENDIX L: QAO PATIENT REGISTRATION FORM 
 
Patient Registration Form    Patient Initials: _______  
 
Study ID (IRB#): 
_______________________ 
 
Enrolling site: 
 MedStar Georgetown University Medical Center 
 MedStar Union Memorial Hospital 
MedStar Good 
Samaritan Hospital 
 Hackensack University Medical Center 
 MedStar Franklin Square Medical Center 
 
MedStar Montgomery Medical Center 
 Other: ___________________________________________ 
1. Site PI: _________________________________________ 
2. Enrolling MD: ____________________________________ 
3. Date Informed Consent signed: ___/___/______ 
4. Date HIPAA authorization signed: ___/___/_____ 
5. Proposed Start date for Treatment: ___/____/______ 
6. Treatment Location: ___________________________________ 
7. Date of last chemotherapy: ___/____/_____ 
8. Prior antineoplastic therapy- ie. Cytotoxic, Cytokine base immunotherapy, 
immunoregulatory antibody therapy, radiation (Date/Type): 
________________________________________________________________________
________________________________________________________________________
______________________________ 
9. Please fax documentation supporting eligibility per protocol (Check those included): 
  
 Eligibility Checklist 
 Pathology Report 
 Physicians Note  
 CT showing RECIST 
 Laboratory Results (per protocol)  
 Past Medical History 
 EKG 
 ECOG score 
 Genetic Test Summary (if 
applicable) 
 Tumor tissue block. (per 
protocol) 
 Other _____________________ 
Instructions: This form and all supporting documentation should be completed by the research 
staff and faxed to the Lombardi QAO at 202-687-9361 or scanned/emailed to 
lcccqao@georgetown.edu .  
Patient may not start treatment until eligibility is verified and Subject Study ID is assigned 
by LCCC QAO. 


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ON-STUDY CARD 
MRN: _______________________ 
DOB: ____/____/____ 
Zip Code: ___________ 
 
Race      
 African American  
 Asian 
 Caucasian 
 Hispanic 
Native American 
 Pacific Islander 
 Other 
 Unknown  
 
Gender: 
 Male 
 Female
 Unknown 
Treating Physician ____________________ RN_________________________________ 
 
Ethnicity:   
Hispanic or Latino 
    
Not Hispanic or Latino 
    
 Unknown 
Consent Approval Date: ___/___/___ 
Screen Failure 
 Yes 
 No 
Baseline Start Date: ___/____/____ 
On Study Date ____/____/____ 
 
Protocol Waiver: 
 Yes  
 No  
 
Reason _________________ 
Registration Site: ___________________ 
First Scheduled Date: ____/_____/_____ 
Primary Site: _____________________ 
 
 
FOR QAO USE ONLY: 
 
Subject Study ID: _________________________________ 
 
Comments: 
 
 
PLEASE SCAN THIS COMPLETED FORM TO THE PATIENT’S ELECTRONIC MEDICAL 
RECORD 
 


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16.13  APPENDIX M: 
HALT-D BOWEL MOVEMENT 
ENDPOINT FORM 
 
 
 
 
 
HALT-D Bowel Movement Endpoint Form 
Study: IRB #2015-0547 
 
Patient Name ______________ 
Patient DOB _______________ 
Patient Study ID Number __________ 
MRN _____________________ 
Site ID ____________________ 
 
1) Baseline number of stools per day at the time of screening: ________ BM/day 
2) Current treatment cycle number on HALT-D trial: 
 □ 1 
 
□ 2  
 
□ 3  
 
□ End of Treatment 
 
3) Did the patient have diarrhea during this cycle?  
Diarrhea is defined as bowel movements that are increased  in frequency from baseline 
AND are loose or watery. 
 □ Yes    
 
 □No    (primary endpoint) 
4) Regarding diarrhea timeline in days 
a) Date of first diarrhea episode in this cycle: ___ /  ___ / _______ 
b) Date of last diarrhea episode in this cycle: ___ /  ___ / _______ 
c) Total number of days of diarrhea during this cycle: ___________ 
d) Did the patient have 2 or more CONSECUTIVE days of diarrhea during this cycle? 
□ Yes     
 
□No  
 
5) Regarding number and grade of diarrhea episodes 
a) Total number of diarrhea episodes during this cycle: __________ 


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b) Did the patient have diarrhea GRADE ≥3 during this cycle (refer to CTCAE grading below)? 
 
□ Yes    
 
 □No     
 
c) Date of first diarrhea GRADE ≥3  in this cycle : ___ /  ___ / ______ 
d) Date of last diarrhea GRADE ≥3  in this cycle : ___ /  ___ / ______ 
6) Regarding diarrhea breakthrough medication use during this cycle 
a) Did patient use anti-diarrheal medication in this cycle? 
 □ Yes    
 □No     
 
b) What medication did the patient use?  
i) Medication A: Loperamide 2mg (Imodium®) 
(1) Date of first dose in this cycle : ___ /  ___ / _______ 
(2) Total mg amount in this cycle ______________________________ 
ii) Medication B: Lomotil, specify strength:_____ 
(1) Date of first dose in this cycle : ___ /  ___ / _______ 
(2) Total mg amount of medication B in this cycle _________________ 
iii) Medication C: OTHER, specify name and strength:_____ 
(1) Date of first dose in this cycle : ___ /  ___ / _______ 
(2) Total mg amount of medication C in this cycle _________________ 
iv) Medication D: OTHER, specify name and strength:_____ 
(1) Date of first dose in this cycle : ___ /  ___ / _______ 
(2) Total mg amount of medication D in this cycle _________________ 
7) FACIT-D total score in this cycle __________ 
8) FACIT-D diarrhea subset score in this cycle ______________ 
9) Mean Bristol Stool Score in this cycle _______________ 
10) Median Bristol Stool Score in this cycle ______________ 
 
PROVIDER NAME (PRINT):    
__________________________________ 
PROVIDER ROLE:   
 
__________________________________ 


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PROVIDER SIGNATURE:   
__________________________________ 
DATE: 
 
 
__________________________________ 
 
PLEASE SCAN THIS COMPLETED FORM INTO THE PATIENT’S ELECTRONIC MEDICAL 
RECORD 
 


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