A Randomized Double-Blinded Phase 2 Study Evaluating a Proprietary Amino Acid Mixture (Enterade®) in Patients Receiving High-Dose Melphalan Conditioning Followed by Autologous Stem Cell Transplantation for Multiple Myeloma and Non-Hodgkin Lymphoma
Phase: NA
Conditions: Multiple Myeloma, Non-Hodgkin's Lymphoma
Sponsor: Dana-Farber Cancer Institute

 
 
 
 
STATUS PAGE 
PROTOCOL 16-329 
 
 
 
 
Closed To New Accrual 
 
 
Closure Effective Date: 10/05/2017 
Reason: Study Accrual Goal Met 
 
 
No new subjects may be enrolled in the study- as described above. 
Any questions regarding this closure should be directed to the study’s 
Principal Investigator 

 
 
 
 
 
 
 
Office for Human Research Studies 
 
DANA-FARBER / HARVARD CANCER CENTER 
Version: 09.23.16 
 
 
Protocol Front Sheet 
DFCI Protocol No.: 16-329  
 
1.  PROTOCOL INFORMATION 
 
Title: A Randomized Double-Blinded Phase 2 Study Evaluating a Proprietary Amino Acid Mixture (Enterade®) in Patients Receiving High-Dose 
Melphalan Conditioning Followed by Autologous Stem Cell Transplantation for Multiple Myeloma and Non-Hodgkin Lymphoma     
Phase: Phase 2 
Sponsor Study Number: N/A 
 
2.  DF/HCC STUDY CONTACT INFORMATION 
 
Primary Study Contact: Kelly Masone  
Email:  Kmasone@partners.org 
Phone:  617-632-4167 
 
INVESTIGATORS:  (List only those under DFCI IRB, i.e., from institutions listed in Section 6 below) 
Overall PI: 
Brett Glotzbecker, MD 
Phone: 617-632-5808 
Institution(s): DFCI 
Mgmt group: 
DFCI CTO 
Site Responsible PI: Zachariah Defelipp, MD  
Phone: 617-632-2305 
Institution(s): MGH 
Mgmt group: 
MGH CTO 
 
 
3.  DRUG / DEVICE INFORMATION    N/A: 
  
 
 Drug(s), Biologic(s):        
 Device(s) Name:        
Provided by:       
IND Exempt: 
        ‐or‐ 
IND#:            Holder Type: [pull down]    
IND Holder Name:        
Provided by:      
IDE Exempt: 
        ‐or‐ 
IDE #:            Holder Type: [pull down]    
IDE Holder Name:        
 
4.  PROTOCOL COORDINATION, FUNDING, MODE 
 
Regulatory Sponsor: 
Funding/Support (check all that apply): 
Primary Disease Group:  Multiple Myeloma 
DF/HCC Investigator  Brett Glozabecker, MD  
 Industry: Entrinsic Health  
 
 
 Federal Organization:       
 
CTEP Study: No 
      Grant #:       
 
 
 Internal Funding:       
 
 
 Non-Federal:       
 
 Other:       
 
Protocol Involves (check all that apply as listed in the protocol document, even if not part of the research but is mandated by the protocol document): 
 Chemotherapy 
 Hormone Therapy 
 Medical Record Review 
 Immunotherapy 
 Vaccine 
 Questionnaires/Surveys/Interviews 
 Surgery 
 Engineered Cell Therapy (ECT) 
 Data Repository 
 Radiological Exams 
 Bone Marrow/Stem Cell Transplant 
 Exercise/Physical Therapy 
 Required Biopsy Study 
 Cell Based Therapy 
 Genetic Studies 
 Human Embryonic Stem Cell 
 Gene Transfer (use of recombinant DNA or 
synthetic nucleic acid molecules) 
 Human Material Banking 
 Quality of Life 
 
 Radiation Therapy 
 Human Material Collection 
 Other: Supportive Care  
 
5.  SUBJECT POPULATION (also applies to medical record review and specimen collection studies) 
 
Total Study-Wide Enrollment Goal: 114 
Greater than 25% of the overall study accrual will be at DF/HCC: 
 Yes   
 No 
Total DF/HCC Estimated Enrollment Goal: 114 
Adult Age Range: 18+ 
Pediatric Age Range: N/A 
Will all subjects be recruited from pediatric clinics?    
 Yes    
 No 
If enrolling both adults and pediatric subjects, anticipated percent of pediatric subjects: N/A 
Retrospective Medical Record Reviews only (Please provide date range): from       to       
 
6.  DF/HCC PARTICIPANTS UNDER DFCI IRB (check all that apply) 
 
 Beth Israel Deaconess Medical Center (BIDMC) 
 Beth Israel Deaconess Medical Center – Needham (BIDMC-Needham) 
 Boston Children’s Hospital (BCH) 
 Dana-Farber/New Hampshire Oncology-Hematology (DFCI @ NHOH) 
 Brigham and Women’s Hospital (BWH) 
 Dana-Farber at Steward St. Elizabeth’s Medical Center (DFCI @ SEMC) 
 Dana-Farber Cancer Institute (DFCI) 
 Dana-Farber at Milford Regional Cancer Center (DFCI @ MRCC) 
 Massachusetts General Hospital (MGH) 
 Mass General/North Shore Cancer Center (MGH @ NSCC) 
 
 Mass General at Emerson Hospital – Bethke (MGH @ EH) 
 
 DF/BWCC in Clinical Affiliation with South Shore Hospital (DFCI @ SSH) 
 
 
7.  NON-DF/HCC PARTICIPANTS UNDER DFCI IRB (check all that apply) 
 
 
Cape Cod Healthcare (CCH)  
 
Lowell General Hospital (LGH)  
 
New Hampshire Oncology-Hematology-P.A. (NHOH)  
 
Newton-Wellesley Hospital (NWH) 
 Faulkner Hospital (FH) 
 New England Cancer Specialists (NECS)  
 Broad Institute 
 

Protocol Front Sheet 
 
FS Page: 2 
 
8.  DF/HCC INITIATED STUDIES ONLY  - INSTITUTIONAL PARTICIPANTS UNDER OTHER IRB  (N/A: 
) 
 
 
DF/HCC Multi-Center Protocols:  (list institution/location) 
 
DF/PCC Network Affiliates: (list institution/location) 
      
      
     
      
 

Log Sheet 
Page 1 of 1 
 
Protocol Number: 16-329 
 
Approval Date:  
08/30/2016 
(IRB meeting date when protocol/consent  
 approved or conditionally approved) 
 
Activation Date:  
10/05/2016____ (Date when protocol open to patient entry) 
 
Approval signatures are on file in the Office for Human Research Studies, tel. 617-632-3029. 
 
Date 
Posted 
Revised Sections 
Approved 
Date 
Version Date 
(OnCore) 
11/09/16 
Protocol and Eligibility Checklist replaced due to 
Amendment #1 
10/25/16 
N/A 
01/11/17 
Temporary closure due to possible contamination of 
study agent: dark substance in bottle.  Sending to 
infection control for further information; All study 
treatment must stop; Amendment #3 (Effective 
01/09/17) 
01/11/17 
N/A 
04/24/17 
Re-open to enrollment due to Amendment #5 
04/20/2017 
n/a 
05/01/17 
MGH site added: Protocol, Consent Form and Front 
Sheet replaced due to Amendment #2 
12/16/16 
04/27/17 
05/24/17 
Protocol and Consent Form replaced due to 
Amendment #6 
04/26/17 
05/02/17 
08/11/17 
Administrative Update #1: Nursing PES update 
N/a 
N/a 
08/22/17 
Study renewal/ Consent form footer replaced due to 
Continuing Review #1 
08/03/17 
08/21/17 
10/05/17 
Study closure – accrual goal met 
10/04/17 
N/A 
07/02/2018 
Study renewal/Consent Form footer replaced per 
Continuing Review #2 
06/28/2018 
07/02/2018 
05/07/2019 
Study renewal due to Continuing Review #3 (Note 
Consent Form removed due to Data Analysis)  
05/06/2019 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Page 1 
 
DF/HCC Protocol #: 16-329  
 
TITLE: A Randomized Double-Blinded Phase 2 Study Evaluating a Proprietary Amino Acid 
Mixture (Enterade®) in Patients Receiving High-Dose Melphalan Conditioning Followed by 
Autologous Stem Cell Transplantation for Multiple Myeloma and Non-Hodgkin Lymphoma  
 
Coordinating Center: Dana-Farber/Harvard Cancer Center 
 
Principal Investigator: 
 
Brett Glotzbecker, MD 
Dana Farber Cancer Institute 
Brigham and Women’s Hospital  
450 Brookline Avenue, Boston, MA 02115 
617-632-5808 
Brett_Glotzbecker@dfci.harvard.edu  
 
Other Investigators: 
Robert Soiffer, MD 
Dana Farber Cancer Institute 
Brigham and Women’s Hospital  
450 Brookline Avenue, Boston, MA 02115 
617-632-4731 
Robert_Soiffer@dfci.harvard.edu 
 
Mounica Vallurupalli, MD 
Brigham and Women’s Hospital  
75 Francis Street, Boston, MA 02115 
617-632-5808 
mvallurupalli@partners.org 
 
Statistician: 
 
Haesook T. Kim, 
PhD
 
 
Dana Farber Cancer 
Institute
 
 
Haesook_Kim@dfci.harvard.edu  
Study Coordinator:  
Lauren Johnston 
Dana Farber Cancer Institute 
Lauren_Johnston@dfci.harvard.edu 
 
Project Manager: 
Kelly Masone 
Dana-Farber Cancer Institute 
Kelly_Masone@dfci.harvard.edu 
 
Responsible Research 
Nurse:
 
 
Laura Amweg 
Dana Farber Cancer Institute 
Laura_Amweg@dfci.harvard.edu 
 
Kathleen McDermott 
Dana Farber Cancer Institute 
Kathleen_McDermott@dfci.harvard.edu 
 
 
 
 
NCI-Supplied Agent(s):  N/A 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
2 
Other Agent(s):  Enterade® (Entrinsic Health) 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b).   
 
Amendment 3/ / January 3, 2017 
 
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
3 
SCHEMA 
 
 
 
 
 
 
Registration
Stratification
Multiple Myeloma 
Non‐Hodgkin's Lymphoma
Randomize
1 : 1 
Enterade® : Placebo
Arm A
Enterade® BID until 
Day +14 or Discharge if earlier
Standard Supportive Care
Arm B
Placebo BID until 
Day +14 or Discharge if earlier
Standard Supportive Care

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
4 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objectives ...................................................................................................6 
1.3 
Secondary Objectives ...............................................................................................6 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease(s).......................................................................................................7 
2.2 
IND Agent(s) ...........................................................................................................7 
2.3 
Other Agent(s) .........................................................................................................7 
2.4 
Rationale ..................................................................................................................8 
2.5 
Correlative Studies Background ..............................................................................9 
3. 
PARTICIPANT SELECTION ...........................................................................................10 
3.1 
Eligibility Criteria ..................................................................................................10 
3.2 
Exclusion Criteria ..................................................................................................11 
3.3 
Inclusion of Women and Minorities ......................................................................11 
4. 
REGISTRATION PROCEDURES ...................................................................................11 
4.1 
General Guidelines for DF/HCC Institutions ........................................................11 
4.2 
Registration Process for DF/HCC Institutions .......................................................12 
4.3 
Guidelines for Other Investigative Sites ................................................................12 
4.4 
Registration Process for Other Investigative Sites .................................................12 
5. 
TREATMENT AND/OR IMAGING PLAN .....................................................................12 
5.1 
Treatment Regimen ................................................................................................12 
5.2 
Pre-Treatment Criteria ...........................................................................................13 
5.3 
Agent Administration .............................................................................................13 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................14 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................14 
5.6 
Duration of Follow Up ...........................................................................................15 
5.7 
Criteria for Taking a Participant Off Study ...........................................................15 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................15 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................15 
7.1 
Expected Toxicities ................................................................................................16 
7.2 
Adverse Event Characteristics ...............................................................................16 
7.3 
Expedited Adverse Event Reporting ......................................................................16 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) ......................17 
7.5 
Expedited Reporting to Hospital Risk Management .............................................17 
7.6 
Routine Adverse Event Reporting .........................................................................17 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................17 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
5 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................19 
9.1 
Biomarker Studies ..................................................................................................19 
9.2 
Special Studies .......................................................................................................20 
10. 
STUDY CALENDAR .......................................................................................................21 
11. 
MEASUREMENT OF EFFECT........................................................................................22 
11.1 
Other Response Parameters ...................................................................................22 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................22 
12.1 
Data Reporting .......................................................................................................22 
12.2 
Data Safety Monitoring ..........................................................................................23 
12.3 
Collaborative Agreements Language .....................................................................23 
13. 
STATISTICAL CONSIDERATIONS...............................................................................23 
13.1 
Study Design/Endpoints.........................................................................................23 
13.2 
Accrual Rate and Study Duration ..........................................................................24 
13.3 
Randomization/Stratification Factors ....................................................................24 
13.4 
Interim Monitoring Plan ........................................................................................25 
13.5 
Analysis of Primary and Secondary Endpoints .....................................................25 
13.6 
Reporting and Exclusions ......................................................................................26 
14. 
PUBLICATION PLAN .....................................................................................................26 
15. 
REFERENCES ..................................................................................................................27 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................29 
APPENDIX B: FACIT-D ..............................................................................................................30 
APPENDIX C: FAACT .................................................................................................................33 
APPENDIX D: EPIC BOWEL DOMAIN ....................................................................................34 
APPENDIX E: MEDICATION AND DIET HISTORY FORM FOR STOOL COLLECTION ..36 
APPENDIX F: CTCAE CRITERIA ..............................................................................................37 
 
 
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
6 
1. OBJECTIVES 
 
This study involves a prospective, 2-arm randomized, double blinded Phase 2 investigation of the 
effectiveness of an amino acid mixture, Enterade® versus placebo in reducing diarrhea associated 
with melphalan conditioning in patients undergoing autologous stem-cell transplantation for 
Multiple Myeloma or Non-Hodgkin Lymphoma. The hypothesis is that Enterade® when combined 
with standard supportive care will help maintain the small bowel’s ability to absorb fluids and lead 
to a reduction in diarrhea volume, as well as patient reported gastrointestinal symptoms and 
improved quality of life following autologous hematopoietic stem cell transplantation (HSCT) 
with Melphalan conditioning as compared to standard supportive care alone.  
 
1.1 
Study Design 
 
This study will be a single-center, double blinded, 2-arm randomized Phase 2 trial, designed to 
compare the efficacy of Enterade® versus placebo in decreasing gastrointestinal toxicity in patients 
undergoing autologous HSCT with high-dose Melphalan conditioning. This study will enroll 114 
patients with Multiple Myeloma or Non-Hodgkin Lymphoma admitted for autologous HSCT. The 
trial will randomize patients over an approximately 12 month period. Randomization will be 
stratified by diagnosis (Multiple Myeloma vs. Non-Hodgkin Lymphoma). Arm A will receive 
Enterade® (one 8-oz bottle) twice daily from admission and/or the day of conditioning to day +14 
(or discharge if occurs prior to day +14) following transplantation in conjunction with institutional 
standard of supportive care. Arm B will receive a placebo twice daily from admission  and/or the 
day of conditioning to day +14 (or discharge if occurs prior to day +14) in addition standard of 
care per institutional guidelines. 
 
1.2 
Primary Objectives 
 
The primary objective of the study will be to compare the incidence of NCI-CTCAE 4.03, grade 
3 or higher gastrointestinal toxicity in the fourteen days following autologous HSCT between the 
medical food product, Enterade®, with standard of care versus placebo with standard of care, 
following Melphalan conditioning.  
 
1.3 
Secondary Objectives 
 
- 
To compare average total daily stool volume between patients receiving Enterade® and 
placebo 
- 
To compare average daily stool frequency between the Enterade® and placebo groups  
- 
To compare duration of hospitalization (days) from admission to discharge 
- 
To compare change in weight, as a percent of initial weight, between patients receiving 
Enterade® and placebo from admission and/or the first day of conditioning to day +14 
- 
To compare daily calorie counts from the day of admission, day +7 and day +14 following 
HSCT between patients receiving Enterade® or placebo  
- 
To compare total use of anti-diarrheal medications (number of medications, mean number 
of daily doses) from randomization to discharge from the inpatient setting 
- 
To compare use of antibiotic medications from randomization until discharge from the 
inpatient setting  

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
7 
- 
To compare the incidence of fever and neutropenia between the Enterade® and placebo 
groups.  
- 
To compare duration (days) of neutropenia between the Enterade® and placebo groups.  
- 
To characterize the tolerability of Enterade® as measured by the number of total 8-oz 
Enterade® bottles consumed throughout the trial, and average drinks per day.  
- 
To assess patient reported health-related quality of life in patients receiving melphalan 
conditioning and the intervention Enterade® or placebo using the EPIC Bowel Domain, and 
the FAACT and FACIT-D symptom inventory at day +14 following HSCT. 
- 
To assess stool inflammation with fecal lactoferrin on admission, and day +7 following 
HSCT 
- 
To assess markers of systemic inflammation and nutrition, including CRP and pre-albumin 
on admission, and day +7 and day +14 following HSCT 
- 
To assess plasma endotoxin and cytokine levels of IL-1β, TNF-, in all patients receiving 
Melphalan with serum samples collected at day +7 after transplantation.  
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
The alkylating agent, Melphalan, remains the mainstay of conditioning for autologous HSCT in 
multiple myeloma and non-Hodgkin lymphoma patients.1,2 Gastrointestinal symptoms represent 
the most significant non-hematologic  toxicity following high-dose Melphalan conditioning. 2,3 
These symptoms include mucositis, diarrhea, nausea, vomiting and decreased appetite. High dose 
chemotherapy also induces protein catabolism, disruption of the gastrointestinal mucosa, and 
oxidative stress.4-7 Increased intestinal permeability facilitates translocation of microorganisms 
and endotoxins into the bloodstream; which can lead to neutropenic fevers and even sepsis. 8-10   
 
As such, Melphalan functions as a radiomimetic agent in its impact on the integrity of the 
gastrointestinal tract. The mucosal sequelae of Melphalan and the subsequent enteritis are similar 
to those induced by total body irradiation, with approximately 40% of patients experiencing 
CTCAE grade 2 or higher diarrhea following conditioning regimens containing Melphalan.11  
 
For the purposes of this study, participants could have received the original formulation of 
Melphalan or the newer formula called Evomela depending on the availability in the pharmacy.   
 
2.2 
IND Agent(s) 
 
2.2.1 IND Agent #1: N/A 
 
2.3 
Other Agent(s) 
 
Enterade® is a proprietary blend of electrolytes and amino acids in concentrations within the daily 
dose range recommended by the World Health Organization (WHO). All components are GRAS 
(Generally Recognized as Safe), approved and without toxicity. Enterade® is a bottled drink that 
is administered orally in 8 oz. commercially available bottles. Patients will be instructed to drink 
two bottles of Enterade® or placebo each day, at least thirty minutes before meals or one hour after 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
8 
meals but do not need to finish an entire bottle during a single ingestion. No other restrictions on 
diet or dose time will be required. 
 
Please see Section 8.1 for a detailed description of Enterade® and its ingredients.  
 
The placebo will consist of water with natural flavoring agents and stevia, in the same composition 
as used in Enterade®.  
 
2.4 
Rationale 
 
To date, the efficacy of enteral nutrition therapy to support HSCT patients, particularly for those 
experiencing enteritis from radiation or melphalan conditioning, has been unclear. Despite the high 
prevalence of severe diarrhea in this population, there is limited evidence base for its treatment. 
Standard of care represents exclusion of acute infection with Clostridium difficile followed by the 
use of anti-diarrheal agents, and in particular, anti-motility agents to prevent fluid loss, as well as 
opioids to relieve abdominal discomfort and reduce motility.  
 
Enteral nutrition can play a role in the treatment of acute enteritis. While intestinal damage from 
radiation and chemotherapy results in impaired absorption and enzyme production, there may be 
benefit in the use of elemental diets.12,13 The amino acid most studied in HSCT is glutamine. 
Glutamine is a classic nonessential amino acid used as a major fuel by intestinal mucosal cells and 
by lymphocytes and other immune cells. In prospective, randomized, double blind trials, intake of 
oral glutamine was not associated with significant differences between study groups in hospital 
length of stay, days on parenteral nutrition, neutrophil recovery, incidence of positive blood 
cultures and sepsis, diarrhea severity or incidence, or severity of mucositis.14,15 
 
Enterade® is a medical food composed of an amino acid mixture delivered as a beverage. Enterade® 
contains only nutrients, flavoring and sweeteners, listed as GRAS (generally recognized as safe). It is 
created by using 7 of the 20 amino acids that make up the body. All other ingredients are natural. It 
consists of a combination of water, amino acids (Valine, Aspartic Acid, Serine, Isoleucine, Threonine, 
Lysine, Glycine, Tyrosine), sodium chloride, natural flavor, sodium citrate, potassium chloride, gum 
acacia, calcium chloride, magnesium chloride, and stevia.  
 
These specific nutrients can facilitate retention of the absorbing capacity of the small intestine. It 
does not contain nutrients that are poorly absorbed, thus eliminating the presence of unabsorbed 
nutrients and electrolytes in the gut lumen, which reduces the risk of osmotic diarrhea. In a study 
of irradiated mice, Enterade® improved survival and improved body weight following irradiation. 
On electron microscopy of the ileum, there was loss of cell-to-cell contact after irradiation, which 
was restored after the introduction of Enterade®. This study also suggested that the irradiated mice 
who received Enterade® had lower levels of plasma endotoxin and IL-1β suggesting less bacterial 
translocation and inflammation as compared to the control population.  
 
 
 
 
Figure 1: Mitigation using Enterade® improved mouse survival and improved body weight 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
9 
following irradiation. 
 
 
(A) Residual weight of irradiated mice that received saline (control), Enterade®, or a mixture of amino acids that had 
reduced absorption and no beneficial effect on the mucosal barrier following irradiation (other AA).  Mice treated with 
other aa showed > 20% weight loss in less than 10 days, whereas control animals reached > 20% weight loss by the 15th 
day.  Mice treated with the correct amino acid mixture showed steady weight gain beyond 18 days. (B) Mice treated with 
the correct amino acid mixture showed >66% survival beyond 25 days. Mice receiving the poorly absorbed AA died earlier 
than the saline controls. N=25 animals/group. Error bar represents SEM. 
 
This prospective, double-blinded, phase 2 randomized study is to assess the effectiveness of 
Enterade® in reducing diarrhea associated with high dose Melphalan chemotherapy. The 
hypothesis is that Enterade® when combined with standard supportive care will help maintain the 
small bowel’s ability to retain fluids leading to a reduction in diarrhea volume, patient reported 
gastrointestinal symptoms and improved quality of life after autologous HSCT with Melphalan 
conditioning when compared to standard supportive care alone.  
 
2.5 
Correlative Studies Background 
 
One of the secondary endpoints in this study will involve evaluation of plasma endotoxin and 
circulating cytokine levels in peripheral blood samples. Radiation and chemotherapy associated 
enteritis results in loss of mucosal integrity and increased paracellular permeability across the 
intestinal mucosa. This leads to increased bacterial translocation as well as increased systemic 
inflammation.  
 
To assess systemic inflammation, blood samples for cytokine analysis will be collected at day +7 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
10 
following autologous HSCT in a 5 mL EDTA tube and stored in the clinical facility until they are 
ready to be tested. Commercially available ELISA assays will be used to assess pro-inflammatory 
cytokines such as IL-1, and TNFα. Gut inflammation will be assessed 
 through the analysis of fecal lactoferrin, with stool specimens collected on admission, and day +7 
following autologous transplantation.  
 
Additionally, stool samples will also be collected from participants on or before admission, and on 
a weekly basis for gut microbiome analysis until day +14 or discharge if it occurs prior to day +14. 
Chemotherapy and radiation result in a decrease in the number and diversity of intestinal 
microbiota and result in enteritis from disruption of the mucosal epithelium. However, it is unclear 
what role commensal flora may play in minimizing gut inflammation, and maintaining gut barrier 
function.16   
 
These correlative studies will characterize the response of the gut microbiome to chemotherapeutic 
conditioning for autologous transplantation and may also help identify characteristic microbial 
signatures that minimize inflammation and gut barrier function in some patients, as well as whether 
elemental supplementation with amino acids influences the type and diversity of gut microbes that 
reconstitute the intestinal mucosa following engraftment.  
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Participants must have histologically or cytologically confirmed Multiple Myeloma, or 
Non-Hodgkin Lymphoma and must be undergoing Melphalan conditioning for autologous 
HSCT.  
 
3.1.2 Age equal or greater than 18 years old. 
 
3.1.3 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) 
 
3.1.4 Participants must have adequate organ and marrow function to proceed to transplant.  
 
3.1.5 Ability to tolerate thin liquids by mouth at the time of admission.  
 
3.1.6 The effects of Enterade® on the developing human fetus are unknown.  For this reason and 
other therapeutic agents used in this trial are known to be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) at the time of study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 4 months after 
completion of the trial. 
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
11 
3.1.7 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participants who have had radiotherapy within 4 weeks prior to entering the study or those 
who have not recovered from GI adverse events due to induction therapy. 
 
3.2.2 Participants who are receiving any other investigational agents. Participants who are 
receiving standard of care induction therapy on a clinical trial may be eligible after 
discussion with the overall principal investigator. 
 
3.2.3 Participants with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
 
3.2.4   Known allergy to Stevia.   
 
3.2.5 Participants receiving any medications or antibiotics to treat Clostridium difficile infection 
prior to the initiation of the study will be ineligible for this study.   
 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
Clostridium difficile infection or history of Clostridium difficile infection. 
 
3.2.7 Participants with evidence of diarrhea as defined by three or more loose or liquid stools per 
day or loose watery stool (greater volume of stool), that occurs more frequently than usual 
and lasting for more than three days prior to admission, history of inflammatory bowel 
disease, irritable bowel syndrome, colectomy or bariatric surgery, Celiac disease. 
 
3.2.8 Participants with psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.9 Pregnant and nursing women are excluded from this study because of teratogenicity and 
toxicity risks associated with the conditioning regimen for patients undergoing autologous 
HSCT.  
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
12 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause treatment 
delays should be discussed with the Overall Principal Investigator (PI). If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
4.3 
Guidelines for Other Investigative Sites 
 
Not Applicable 
 
4.4 
Registration Process for Other Investigative Sites 
 
Not Applicable 
 
5. TREATMENT AND/OR IMAGING PLAN 
 
5.1 
Treatment Regimen 
 
Patients found to be eligible for the study will be enrolled and randomized into either the Enterade® 
treatment arm (Arm A) or placebo (Arm B). During the course of their admission, those patients 
randomized to Arm A will be given two 8 oz. bottles daily of Enterade® from admission and/or 
the day of conditioning until day +14 or until discharge if discharged prior to day +14 following 
autologous HSCT, to augment their daily diet. Those randomized to Arm B will be given two 8 
oz. bottles of placebo from admission and/or the day of conditioning until day +14 or until 
discharge if discharged prior to day +14 following autologous HSCT, to augment their daily diet. 
The average length of inpatient stay for the 159 patients undergoing transplantation for Multiple 
myeloma was 17 days with a range of 14-26 days in the year 2014. Amongst the 81 patients 
undergoing transplantation for NHL, the average length of stay in 2014 was 22 days with a range 
of 17 to 58 days.  
 
Enterade® and placebo administration will begin on the day prior  or the day of initiation of 
conditioning. Enterade® or placebo will be administered on an inpatient basis only. Their daily 
consumption of Enterade® or placebo will be recorded as a fraction of each bottle consumed. 
Timing of Enterade® or placebo administration will be at least thirty minutes prior to meals or at 
least one hour after meals but patients need not consume each bottle in one sitting and can continue 
to consume the drink in sips throughout the day.  
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
13 
Randomization will be completed by the Office of Data Quality.  
 
Table 1: Arm A Enterade® and Standard Supportive Care   
Agent 
Pre-medications/ 
Precautions 
Dose 
Route 
Schedule 
Enterade® 
None 
8 oz. 
Oral 
BID 
Standard 
Supportive 
Care Regimen 
At Investigator’s 
Discretion 
At Investigator’s 
Discretion 
At Investigator’s 
Discretion 
At Investigator’s 
Discretion 
 
Table 2: Arm B Placebo and Standard Supportive Care   
Agent 
Pre-medications/ 
Precautions 
Dose 
Route 
Schedule 
Placebo 
None 
8 oz. 
Oral 
BID 
Standard 
Supportive 
Care Regimen 
At Investigator’s 
Discretion 
At Investigator’s 
Discretion 
At Investigator’s 
Discretion 
At Investigator’s 
Discretion 
 
Reported adverse events and potential risks are outlined in Section 7. Appropriate dose 
modifications are described in Section 6. No other investigational agents will be used to treat the 
participant’s diarrhea during this trial. Institutional standard of care for the treatment of diarrhea, 
including loperamide, lomotil or other similar agents will be allowed in both arms of the study. 
 
5.1.2    Blinding  
 
The only difference between Enterade® and  the placebo will be the color of the cap.  Participants, 
physicians and nursing staff will not be made aware of which bottle cap represents either Enterade® 
or placebo.  The only people with access to which arm each participant is on will be ODQ and the 
research pharmacy staff.   To maintain the blindness for the study team, pharmacy will put the 
Enterade or placebo into a secondary container. Blindness will be kept to both participants and the 
study team until all data have been recorded.   
 
 
5.2 
Pre-Treatment Criteria 
 
There are no specific pre-treatment criteria prior to initiation of trial therapy.  
 
 
 
5.3 
Agent Administration 
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
14 
5.3.1 Enterade® 
 
Two 8 oz. bottles of Enterade® or placebo will be provided to participants for oral consumption on 
a daily basis for from admission and/or the day of conditioning until day +14, or until discharge if 
discharged prior to day +14, following autologous HSCT. Enterade® is a bottled drink and is 
packaged in 8 oz. bottles that are commercially available. The placebo will consist of water, stevia 
and natural flavors and will be packaged in the same way as Enterade®.  
 
Participants will be instructed to drink two bottles of Enterade® or placebo per day. The 
recommended timing of Enterade® or placebo administration will be at least 30 minutes before 
meals or at least one hour after meals. Patients can continue to consume small amounts of 
Enterade® or placebo throughout the day and do not need to consume an entire bottle in one sitting. 
Other types of carbohydrate-based beverages such as Gatorade should be avoided.  
 
Caregivers do not need to apply any particular precautions in the handling of Enterade® or placebo.  
 
For further information regarding dosing, and handling please refer to Section 8.1. 
 
5.3.2 Other Modality(ies) or Procedures 
 
Not Applicable 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Concomitant supportive care can include institutional standard of care for the management of 
diarrhea and enteritis, including anti-diarrheal agents such as loperamide, lomotil, diluted tincture 
of opium, intravenous fluids, and other similar agents. There is no anticipated or known potential 
for interaction of Enterade® with concomitantly administered drugs of the cytochrome P450 
system.  
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of Enterade® administration will be from admission and/or the day of conditioning until 
day+14 following HSCT or the day of discharge if it occurs prior to day +14. In the absence of 
treatment delays due to adverse event(s), treatment may continue until day +14 following HSCT 
or until one of the following criteria applies: 
 
 
Unacceptable adverse event(s) 
 
 
Participant decides to withdraw from the protocol therapy 
 
 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
 
The patient is discharged from the hospital 
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
15 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
A Treatment Ended/Off Study Form will be filled out when a participant is removed from protocol 
therapy. This form can be found on the ODQ website or obtained from the Research Project 
Manager. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Dr. Brett Glotzbecker at 617-632-5808. Pager #43273.  
 
5.6 
Duration of Follow Up 
 
Participants will be followed until discharge or until day +14, whichever occurs first.  Participants 
removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution 
or stabilization of the adverse event. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
 Lost to follow-up 
 Withdrawal of consent for data submission 
 Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
A Treatment Ended/Off Study Form will be filled out when a participant comes off study. This 
form can be found on the ODQ website or obtained from the Research Project Manager. 
 
5.8 
Unblinding 
 
There are no plans for unblinding during this study.  Should an event occur where unblinding is 
believed to be necessary for the care of the patient, the case will be discussed with the study PI.    
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
There will be no dose modifications of enterade. The amount tolerated will be recorded. If the 
patient is unable to drink thin liquids as a result of a transplant related complication, the Enterade® 
will be stopped and the reason for stopping will be recorded. They will restart the Enterade® when 
able to tolerate thin liquids again. Enterade®   can be restarted at any point and will go back to the 
twice daily schedule as tolerated. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
16 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE 
(Section 7.2) will determine whether the event requires expedited reporting in addition to routine 
reporting. 
 
7.1 
Expected Toxicities 
 
7.1.1 Adverse Events List(s) 
 
7.1.1.1 
Adverse Event List(s) for Enterade® 
 
The formulation of Enterade® consists of generally recognized as safe constituents including 
electrolytes, stevia, and amino acids, within WHO recommended required daily doses. We do not 
anticipate any toxicity or potential risks. Patients may experience mild discomfort associated with 
the drink, including off-putting taste, smell, nausea, abdominal discomfort, or constipation.   
 
7.2 
Adverse Event Characteristics 
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.03.  A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP web site: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 For expedited reporting purposes only:   
- 
AEs for the protocol that do not require expedited reporting are outlined in the next 
section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting  
 
7.3.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last dose 
of treatment on the local institutional SAE form.  
 
7.3.2 DF/HCC Expedited Reporting Guidelines 
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
17 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
Table 3: DF/HCC Reportable AEs 
Attribution 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE 
Expected* 
Gr. 4 AE 
Unexpected* 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
10 Business 
Days 
10 Business 
Days 
10 Business Days 
Possible 
Probable 
Definite 
Not required 
10 Business 
Days 
10 Business 
Days 
10 Business 
Days 
10 Business Days 
* If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
 
 
7.3.3 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to the 
Overall PI or the DFCI IRB.  However, they still must be reported through the routine reporting 
mechanism (i.e. case report form). 
 
Grade 4 expected events related to stem cell transplantation, including neutropenia, neutropenic 
fever, thrombocytopenia, minor bleeding (epistaxis), bruising, electrolyte abnormalities, rashes, 
and infections (pneumonia, line sepsis, cellulitis), nausea, diarrhea, mucositis, vomiting, and veno-
occlusive disease, will not require reporting as SAEs, as these are expected events in the course of 
transplantation.  
 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
Not Applicable  
 
7.5 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.6 
 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
18 
8.1.1 Description 
 
Enterade® consists of a combination of amino acids and electrolytes, flavorings and stabilizers:  
 
Amino Acids 
Electrolytes and Other Ingredients 
Valine 
Sodium Chloride 
Aspartic 
Natural Flavor 
Serine 
Sodium Citrate 
Isoleucine 
Potassium Chloride 
Threonine 
Gum Acacia 
Lysine 
Calcium Chloride 
Glycine 
Magnesium Chloride 
Tyrosine 
Stevia 
 
The placebo was formulated to match the flavor and consistency of Enterade®. It is 
composed of water with natural flavoring agents and stevia.  
 
8.1.2 Form 
 
Enterade®, which is delivered as a beverage, was formulated with specific nutrients that 
can retain the absorbing capacity of the small intestine after irradiation. The placebo will 
consist of water with natural flavoring agents and stevia, in the same composition as used 
in Enterade®. 
Enterade® and placebo will be supplied in the same packaging, as prepared by Entrinsic 
Health, with the exception of the bottle cap, which will be different colors based on whether 
it is the medical food or the placebo.  
 
8.1.3 Storage and Stability 
 
Enterade® or placebo is stable at room temperature and can also be refrigerated.  
 
8.1.4 Compatibility 
 
Enterade® or placebo should not be reconstituted or mixed with other agents.  
 
8.1.5 Handling 
 
Enterade®  or placebo can be handled without any precautions or special equipment.  
 
8.1.6 Availability 
 
Enterade® and placebo will be supplied through Entrinsic Health with distribution done 
through Seaboard International (Tampa, FL). For the trial, Entrinsic Health will stock 12-
24 bottle cases at the BWH and MGH Pharmacy. Patients will be supplied with two 8 oz. 
bottles daily free of charge from admission until day +14 following HSCT, or until 
discharge, if discharged prior to day +14. Two 8 oz. bottles of Enterade® or placebo will 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
19 
be given to the patient by his/her clinical nurse twice a day. It can be refrigerated if not 
completely ingested at one time. It can also be stored at room temperature if this is preferred 
by the patient. 
 
8.1.7 Preparation 
 
Participants will receive two 8 oz. bottles of Enterade® or placebo daily. No further dilution 
or preparation will be necessary.  
 
8.1.8 Administration 
 
Patients will be instructed to drink two 8 oz. bottles of Enterade® or placebo per day. The 
timing of Enterade® or placebo administration will be at least 30 min before meals or at 
least one hour after meals. Patients do not need to finish a bottle during a single ingestion. 
For example, sipping during the day is allowed. No other restrictions on diet or dose timing 
will be required. Enterade® or placebo administration will begin on the day of admission 
and will be administered until day +14 following transplantation. There is no need to drink 
another bottle of Enterade or placebo if the liquid is vomited. It can be mixed with water if 
desired. 
 
8.1.9 Ordering 
 
Enterade®  or placebo stock will be replenished by Entrinsic Health. They will stock full 
12-24 bottle cases distributed through Seaboard International.  
 
8.1.10  Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
 
8.1.11  Destruction and Return 
 
Unused or expired supplies of Enterade® or placebo will be returned to the supplier, 
Entrinsic Health throughout the duration of the study or be disposed of as non-toxic waste 
per institutional standard operating procedure.  
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
 
9.1.1  
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
20 
For the cytokine assays, the CRC will drop off tubes and labels to the inpatient floor by day +6. 
Peripheral blood samples will be collected by the RN from the patient’s central venous catheter 
in  six 10 mL EDTA vials on day +7 following HSCT. The samples will be picked up by the 
CRC and brought to the Pasquarello Tissue Laboratory at DFCI. Samples will be refrigerated, 
processed, and evaluated at DFCI, using commercially available ELISA based assays to measure 
IL-1, and TNFα. 
 
The CBC with differential, pre-albumin, and CRP will be drawn by the RN from the patient’s 
central venous catheter as per current standard of care in the post-HSCT setting. Labs are sent to 
and processed at the BWH or MGH clinical laboratory. 
 
9.2 
Special Studies 
 
9.2.1 Evaluation of the gut microbiome in the autologous HSCT population receiving 
Enterade® or placebo 
 
 Outcome Measure Stool bacterial composition and diversity 
 
 Method of Assessment Stool samples will be banked for 16S ribosomal RNA 
gene sequencing to profile stool bacterial composition. This will allow for 
evaluation of stool diversity and variability of bacterial species.  
 
 Timing of Assessment Stool samples will be collected on admission, and on a 
weekly basis during the course of inpatient admission.  
 
Stool samples will be collected while patients are inpatient in sterile specimen containers. The 
samples will be picked up by the CRC and will be transported in biohazard bags to the BWH 
clinical laboratory. Once collected, stool specimens will be placed immediately at 4C. Within 24 
hours of collection, the stool samples will be picked up by the CRC and transported to the 
Crimson Core Specimen Bank at Brigham and Women’s Hospital where they will be frozen in a 
-80C freezer for storage.  
 
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
21 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted in accordance with FACT guidelines for HSCT and 
may be within 45 days of starting therapy. Baseline assessments must be performed prior to 
administration of any study agent. Study assessments and agents should be administered within + 
3 days of the protocol-specified date, unless otherwise noted. 
 
Arm A: Enterade® and Standard Supportive Care   
 
Screening 
Admission* 
D0 of HSCT 
D+7 of HSCT 
D+14 of HSCT 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Performance Status 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Concurrent Meds 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Stool Frequency 
 
X 
X 
X 
X 
Stool Volume  
 
X 
X 
X 
X 
Stool Collection 
 
X3 
X 
X 
X 
Physical exam 
 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
Weight 
 
X 
 
X 
X 
Calorie Counts 
 
X 
 
X 
X 
Adverse Event Evaluation 
 
X 
X 
X 
X 
Medication and Diet History  
 
X 
X 
X 
X 
Quality of Life  
 
 
 
 
X 
CTCAE 
 
X 
X 
X 
X 
EPIC 
 
 
 
 
X 
Fecal Lactoferrin 
 
X 
 
X 
 
Cytokine blood draw 
 
 
 
X 
 
Pre-albumin 
 
X 
 
X 
X 
CRP 
 
X 
 
X 
X 
CBC w/ diff1 
 
X 
X 
X 
X 
Chemistry Panel2 
 
X 
X 
X 
X 
Enterade® 
 
X 
X 
X 
X 
Amount of Enterade® Consumed 
 
X 
X 
X 
X 
* For NHL patients t≈0 is D-7 of HSCT, For MM patients t≈0 is D-3 of HSCT
 
1. CBC w/diff includes White Blood Cell count (WBC), Hematocrit (HCT), Platelet count, and Absolute Neutrophil Count 
(ANC). 
2. Chemistry Panel includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, albumin, AST/SGOT, 
ALT/SGPT, alkaline phosphatase, total bilirubin, magnesium, phosphorous 
3. The admission stool sample may be collected at any point between screening and admission. 
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
22 
 
Arm B: Placebo and Standard Supportive Care   
 
Screening 
Admission* 
D0 of HSCT 
D+7 of HSCT 
D+14 of HSCT 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Performance Status 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Concurrent Meds 
X 
X 
X 
X 
X 
Stool Diary 
 
X 
X 
X 
X 
Stool Frequency 
 
X 
X 
X 
X 
Stool Volume  
 
X 
X 
X 
X 
Stool Collection 
 
X3 
X 
X 
X 
Physical exam 
 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
Weight 
 
X 
 
X 
X 
Calorie Counts 
 
X 
 
X 
X 
Adverse Event Evaluation 
 
X 
X 
X 
X 
Medication and Diet History  
 
X 
X 
X 
X 
Quality of Life  
 
 
 
 
X 
CTCAE 
 
X 
X 
X 
X 
EPIC 
 
 
X 
 
X 
Fecal Lactoferrin 
 
X 
 
X 
 
Cytokine blood draw 
 
 
 
X 
 
Pre-albumin 
 
X 
 
X 
X 
CRP 
 
X 
 
X 
X 
CBC w/ diff1 
 
X 
X 
X 
X 
 Chemistry2 
 
X 
X 
X 
X 
Placebo 
 
X 
X 
X 
X 
Amount of Placebo Consumed 
 
X 
X 
X 
X 
* For NHL patients t≈0 is D-7 of HSCT, For MM patients t≈0 is D-3 of HSCT
 
1. CBC w/diff includes White Blood Cell count (WBC), Hematocrit (HCT), Platelet count, and Absolute Neutrophil Count 
(ANC). 
2. Chemistry Panel includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, albumin, AST/SGOT, 
ALT/SGPT, alkaline phosphatase, total bilirubin, magnesium, phosphorous 
3. The admission stool sample may be collected at any point between screening and admission. 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Other Response Parameters 
 
Not applicable 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
12.1 
Data Reporting 
 
 
 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
23 
12.1.1 Method 
 
The DF/HCC Office of Data Quality will collect, manage, and perform quality checks on the 
data for this study. 
 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the Office of Data Quality (ODQ) according to the schedule set by the ODQ. Data should 
be entered within 14 business days of the corresponding visit.  
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study progress, 
toxicity, safety and other data from this study. The board is chaired by a medical oncologist from 
outside of DF/HCC and has external and internal representation. Information that raises any 
questions about participant safety or protocol performance will be addressed by the Overall PI, 
statistician and study team. Should any major concerns arise, the DSMB will offer 
recommendations regarding whether or not to suspend the study. 
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting information. 
Information to be provided to the DSMB may include: participant accrual; treatment regimen 
information; adverse events and serious adverse events reported by category; summary of any 
deaths on study; audit results; and a summary provided by the study team. Other information (e.g. 
scans, laboratory values) will be provided upon request.  
 
 
12.3 
Collaborative Agreements Language 
 
Not Applicable 
 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a randomized, double-blinded  phase 2 trial of comparing the efficacy of the investigational 
drug, Enterade® versus placebo in conjunction with standard-of-care (SOC) in decreasing diarrhea-
related gastrointestinal (GI) toxicity in patients undergoing autologous hematopoietic stem cell 
transplantation (HSCT) with melphalan conditioning for Multiple Myeloma or non-Hodgkin 
Lymphoma. 
 
13.1 
Study Design/Endpoints 
 
The study is a one stage phase II trial with two arms. The primary endpoint is the incidence of 
NCI-CTCAE 4.0 grade 3 or higher diarrhea GI toxicity in the 14 days following autologous HSCT. 
The primary endpoint will be evaluated at day 14 after autologous HSCT. A total of 114 patients 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
24 
(57 patients per arm) will be randomly assigned in 1:1 ratio to either the investigational drug (Arm 
A) or  placebo  (Arm B) prior to autologous HSCT.  
 
Based on the preliminary data with SOC alone, we hypothesize that the grade 3 or higher diarrhea 
GI toxicity will be 30%  in the placebo arm.  With the investigational drug, we project that the 
grade 3 or diarrhea higher GI toxicity will be 10% . With the sample size 57 per arm, there will be 
80% power to detect a 20% difference in grade 3 or higher diarrhea GI toxicity between two arms. 
This power calculation is based on Fisher’s exact test at one-sided type I error rate of 0.05.   
 
13.2 
Accrual Rate and Study Duration 
 
Based on the current practice, we conservatively anticipate that the accrual rate will be 
approximately 12 patients per month and thus the accrual will complete within one year.  The 
projected accrual targets presented below is based on patients at DFCI who underwent autologous 
HSCT for Multiple Myeloma or Non-Hodgkin Lymphoma between 2013 and 2014. In the year 
2013, 274 patients underwent autologous transplantation for Multiple Myeloma (182 patients) or 
Non-Hodgkin’s Lymphoma (92 patients). The following year, 159 patients underwent autologous 
transplantation for Multiple Myeloma and 81 for Non-Hodgkin’s Lymphoma, accounting for a 
total of 240 patients. We anticipate recruitment of approximately sixty percent of eligible patients. 
  
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females
Males
 
Total
Hispanic or Latino 
2 
+
4 
= 
6 
Not Hispanic or Latino 
50 
+
58 
= 
108 
Ethnic Category:  
Total of all subjects 
(52) 
+
(62) 
= 
(114) 
Racial Category 
 
American Indian or Alaskan 
Native 
 
+
1 
= 
1 
Asian 
1 
+
1 
= 
2 
Black or African American 
2 
+
3 
= 
5 
Native Hawaiian or other Pacific 
Islander 
 
+
1 
= 
1 
White 
49 
+
56 
= 
105 
Racial Category:  
Total of all subjects 
(52) 
+
(62) 
= 
(114) 
 
 
13.3 
Randomization/Stratification Factors 
 
After enrollment, patients will be randomized in 1:1 ratio between two arms using 

DF/HCC Protocol #: 16-329 
Protocol Version Date:   3 January 2017 
 
25 
permuted block algorithm within strata. Randomization will be stratified based on diagnosis of 
Non-Hodgkin Lymphoma or Multiple Myeloma prior to transplantation. No additional interim 
monitoring will be performed that is unique to each stratum. Efficacy determination will be the 
same for each stratum as noted in the primary and secondary endpoints outlined in section 1.2 and 
1.3.  
 
13.4 
Interim Monitoring Plan 
 
All adverse events will be monitored closely. Monitoring of key safety endpoints (GI toxicity, 
fever, neutropenia) will be conducted in accordance with the DF/HCC DSMB meeting (see Section 
12.2). The investigational drug is a medical food composed of an amino acid mixture and generally 
recognized as safe constituents. We thus do not anticipate any toxicity or potential risks. However, 
taking the advantage of a randomized trial with a standard treatment arm, we will compare all 
grade 2 or higher treatment related toxicity in accordance with the DSMB meeting.  
If, at any of these looks, this difference is significant at the two-sided level of 0.05, this would 
trigger a consultation with the DF/HCC DSMB for additional review. However, this will not be 
formal stopping rules that would mandate automatic closure of study enrollment. In addition, we 
will assess the feasibility of the trial at the first look. With the anticipated accrual rate, we project 
2-3 looks before the completion of the accrual.  
 
13.5 
Analysis of Primary and Secondary Endpoints 
 
The primary analysis will be the modified intention-to-treat (ITT) analysis for the primary endpoint 
of grade 3 or higher diarrhea GI toxicity occurred within 14 days of autologous HSCT. Although 
it is unlikely to occur, patients who are randomized but do not receive autologous HSCT or do not 
receive any study drug will be replaced and not be included in the primary or secondary analysis.  
The proportion of grade 3 or higher GI toxicity in the 14 days following autologous HSCT will be 
compared using Fisher’s exact test.  
 
Secondary endpoints as listed in Section 1.3 include frequency and duration of fever and 
neutropenia, average total daily stool volume, average daily stool frequency, change in weight, 
calorie consumption, stool microbiome, total use of anti-diarrheal medications, use of antibiotic 
medications, tolerability, patient reported quality of life (QOL), and the length of hospital stay. 
Correlative studies include assessment of cytokine levels, fecal lactoferrin, and markers of 
nutrition and inflammation. For group comparison, Fisher’s exact test or a Chi-square test, as 
appropriate, will be used for categorical variables and Wilcoxon-Rank-Sum or t-test, as 
appropriate, will be used for continuous variables. In addition, correlation analysis between the 
primary and secondary endpoints will be performed and multivariable linear regression and 
logistic regression analysis will be explored to identify factors that are associated with the primary 
outcome and to identify a subset patients who develop grade 3 or higher GI toxicity.  For the 
analysis of pre-to-post treatment change, graphical assessments, McNamer’s test or Wilcoxon-
Signed rank test as appropriate, and regression analysis will be utilized.  
 
As to the assessment of patient reported QOL, we project that 70% of all randomized patients 
will agree to participate in the QOL assessment. This projection is based previous QOL 
assessment in the HSCT setting. In particular, we are interested in the overall Epic bowl 

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domain score whether this score is higher in the Enterade arm compared with the placebo 
arm (the higher score the better). For example, if the effect size of epic bowel domain score 
(i.e., mean difference between two groups divided by its standard deviation) is 0.7, there will 
be 86% power to detect this difference. If the effect size is 0.8, then there will be 94% power 
to detect this difference. This power calculation is based on asymptotic power of the 
Wilcoxon‐Rank‐Sum test at the two sided significance level of 0.05 without adjustment for 
multiple comparisons and assuming the sample size 40 in each arm. As to the missing items 
in each QOL assessment, we will take a standard approach to handling individual missing 
items that are received. That is, if an item is missing, the subscale score will be prorated by 
multiplying the sum of the subscale by the number of items in the subscale and then dividing 
by the number of items actually answered. 
 
Although we hypothesize that Enterade in combination with SOC will help stabilize small bowel 
environment, since there have been no rigorous comparative studies performed, all secondary 
endpoints will be evaluated in an exploratory analysis to characterize the GI response to 
chemotherapeutic conditioning for autologous HSCT and thus will serve hypothesis-generating 
purpose for future clinical/scientific research. For this reason, provision of power statement is 
limited for secondary endpoints.  
 
13.6 
Reporting and Exclusions 
 
13.6.1 Evaluation of Toxicity 
 
All participants who receive any amount of study drug will be evaluable for toxicity from 
the time of their first treatment. 
 
13.6.2 Evaluation of the Primary Efficacy Endpoint 
 
Analyses will be modified intent-to-treat per Section 13.5. All eligible participants who 
receive the study treatment in the study will be assessed for response/outcome to therapy, 
even if there are major protocol therapy deviations.   
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome data 
are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and 
Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial 
release may be an abstract that meets the requirements of the International Committee of Medical 
Journal Editors. A full report of the outcomes should be made public no later than three (3) years 
after the end of the study.  
 
 

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15. REFERENCES 
 
1.   Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood 
stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a 
multicenter sequential randomized clinical trial. Blood 1998;92:3131-6. 
 
2.   Lazarus HM, Phillips GL, Herzig RH, Hurd DD, Wolff SN, Herzig GP. High-dose 
melphalan and the development of hematopoietic stem-cell transplantation: 25 years later. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2008;26:2240-3. 
 
3.   Castellino S, Elion GB, Griffith OW, et al. Development of a model of melphalan-induced 
gastrointestinal toxicity in mice. Cancer chemotherapy and pharmacology 1993;31:376-80. 
 
4.   Blijlevens NM, Donnelly JP, De Pauw BE. Mucosal barrier injury: biology, pathology, 
clinical counterparts and consequences of intensive treatment for haematological 
malignancy: an overview. Bone marrow transplantation 2000;25:1269-78. 
 
5.   Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy of glutamine-
supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-
blind, controlled study. Annals of internal medicine 1992;116:821-8. 
 
6.   Szeluga DJ, Stuart RK, Brookmeyer R, Utermohlen V, Santos GW. Nutritional support of 
bone marrow transplant recipients: a prospective, randomized clinical trial comparing total 
parenteral nutrition to an enteral feeding program. Cancer research 1987;47:3309-16. 
 
7.   Jonas CR, Puckett AB, Jones DP, et al. Plasma antioxidant status after high-dose 
chemotherapy: a randomized trial of parenteral nutrition in bone marrow transplantation 
patients. The American journal of clinical nutrition 2000;72:181-9. 
 
8.   Johansson JE, Ekman T. Gastro-intestinal toxicity related to bone marrow transplantation: 
disruption of the intestinal barrier precedes clinical findings. Bone marrow transplantation 
1997;19:921-5. 
 
9.   Berg RD. Bacterial translocation from the intestines. Jikken dobutsu Experimental animals 
1985;34:1-16. 
 
10. Wong M, Barqasho B, Ohrmalm L, Tolfvenstam T, Nowak P. Microbial translocation   
contribute to febrile episodes in adults with chemotherapy-induced neutropenia. PloS one 
2013;8:e68056. 
 
11. Kim JE, Lee DH, Yoo C, Kim S, Kim S-W, Lee J-S, Park CJ, Huh J, Suh C. BEAM or 
BuCyE high-dose chemotherapy followed by autologous stem cell transplantation in non-
Hodgkin’s lymphoma patients: A single center comparative analysis of efficacy and toxicity. 
Leukemia Research 2011:35: 183-187. 
 

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12. Beer WH, Fan A, Halsted CH. Clinical and nutritional implications of radiation enteritis. Am 
J Clin Nutr 1985:41: 85-91.  
 
13. Voitk AJ, Brown RA, McArdle AH, Hinchey EJ, Gurd FN. Clinical uses of an elemental 
diet: preliminary studies. Can Med Assoc J 1972: 107:123-129.  
 
14. Ziegler TR. Glutamine supplementation in bone marrow transplantation. The British journal 
of nutrition 2002;87 Suppl 1:S9-15. 
 
15. da Gama Torres HO, Vilela EG, da Cunha AS, et al. Efficacy of glutamine-supplemented 
parenteral nutrition on short-term survival following allo-SCT: a randomized study. Bone 
marrow transplantation 2008;41:1021-7. 
 
16. van Vliet MJ, Harmsen HJM, de Bont ESJM, Tissing WJE. The role of intestinal microbiota 
in the development and severity of chemotherapy-induced mucositis.  PLoS Pathogens 2010; 
6:e1000879.  
 
 

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APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work.
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX B: FACIT-D 
 

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APPENDIX C: FAACT 

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APPENDIX D: EPIC BOWEL DOMAIN 
 

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APPENDIX E: MEDICATION AND DIET HISTORY FORM FOR STOOL 
COLLECTION 
 
Participant Name:  
Participant MRN:  
Stool sample collection date:  
Day of transplant:  
 
Antimicrobials: Please list all oral and IV antibiotics, antifungals, or anti-viral therapies given 
to the participant at the time of the stool sample collection.  
 
1.  
2. 
3. 
4. 
5. 
6.  
7. 
8. 
 
Gastrointestinal (GI) prophylaxis: Please list the names of all GI prophylaxis medications (eg. 
Omeprazole, TUMS, Maalox, Carafate), being given to the participant at the time of the stool 
sample collection.  
 
1.  
2. 
3. 
4. 
5. 
6.  
 
Diet: please note the type of nutrition that the participant is receiving at the time of the stool 
sample collection.  
 
[ ] Regular diet 
[ ] Formula via nasogastric or gastric tube 
[ ] Total parenteral nutrition 
[ ] Other diet ______________________ 
 
 
 
 
 
 

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APPENDIX F: CTCAE CRITERIA 
 
This study will utilize the NCI-CTCAE v4.03 for toxicity and Serious Adverse Event (SAE) 
reporting. A copy of the CTCAE v4.03 can be downloaded from the website: 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.  
 
All appropriate treatment areas should have access to a copy of the CTCAE v4.03. 
 
 
 
 
 

Protocol #16329:  (10.3.16)(KMcD) /Approved; revised 8/10/17 (HD/KC) 
 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
16329 
Protocol Name: 
A Randomized Double-Blinded Phase 2 Study Evaluating a Proprietary Amino Acid Mixture (Enterade®) in Patients Receiving 
High-Dose Melphalan Conditioning Followed by Autologous Stem Cell Transplantation for Multiple Myeloma and Non-Hodgkin 
Lymphoma 
DFCI Site PI: 
Brett Glotzbecker, MD 
DFCI Research Nurse: 
Kristen Cummings and Heidi DiPietro/ Kathleen McDermott        
DFCI/BWH CRC: 
Lauren Johnston #40515 
 
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol. 
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
*** Remember to check the ALERT PAGE*** 
 
SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study 
Design 
 
 
 
Description of the study agent ( Enterade) : Section 2.3; 8.1  
 
The Study Design is in Section: 1.1 
 
The Study Rationale is in Section. 2.4 
 
Definition of cycle :  N/A 
Dose 
Calc. 
 
N/A 
Study Drug  
Administration 
Agent Administration Guidelines :  Section 5.1; 5.3; 8.1.6; 8.1.8 
 
 Randomized Enterade  treatment (Arm A)  or Placebo ( Arm B) 
 
Two 8 oz bottles daily (Enterade or Placebo) from admission to Day +14 or until discharge 
 
Dosing ordered for twice a day at 7:30 and 16:30: Timing at least 30 minutes prior to meal or 1 hour after but patients need not consume in 
one sitting may  consume in sips throughout the day. Dosing ordered for twice a day at 7:30 and 16:30 
 
Admission day – Supplement is ordered x 1. Can be given at any point – no requirements about timing premeals. 
 
If supplement not completed at time of next dose then discard rest of dose ( see charting tips) 
 
Dose  
Mods & 
Toxicity 
 
Dose Modifications/Dosing Delay: 
 
No dose modifications   see:  Section 6.0 
 
NCI CTCAE criteria, version  4.03  ( section 7.2                                                                                                                                               
 
 
Con 
Meds 
 
Concomitant Therapy Guidelines/Recommendations are in Section 6.4 
 
Supportive measures: 
 
Calorie Counts:  Around admission, day +7 and day +14 (or day of discharge if prior to Day +14) by Nutrition staff 
 
FACT QOL and Epic Domain questionnaires  by medical team 
 
Required  
Data  
Study Calendar and Assessment Required data are outlined: Section 10      
 
Daily labs: CRP/prealbumin :  Admission, Day 7, Day 14 (or day of discharge if prior to Day +14).         
 
Special Studies   Stool Samples: Section 9.1   
 
Admission, Day 0, Day +7, Day +14 (or day of discharge if prior to Day +14) 
 
 
 
Biomarkers: The time points are in Section 9.1 
 
Cytokines  Day +7 ( Blood tubes provided and after drawn  place in dedicated bin on unit for CRC to collect) 
 
Charting Tips 
 
Intake: All study agents require documentation of  administration time as well as the amount tolerated  
 
Amount drank should be documented in the Intake-> Other section of the Intake/Output Flowsheet.  
 
At time of discarding the bottle, document how much was drank in mL in the flow sheet. 
 
Flow sheet documentation can occur at any point after supplement given but before or at the time of next supplement.  
Output: 
 
Strict I/Os should be kept daily.  
 
Stool output needs to be documented daily in the Output  -> Stool assessment section of the Intake/Output Flowsheet. 
 
Incontinence, Stool Appearance and Stool amount should be documented. If the stool is formed then a x1 as currently documented is fine. If 
there is mixed urine/stool – this should be documented in a separate row with the volume of the output.  
Weights: 
o 
Weights should be documented in EPIC on Admission, Day +7 and Day +14 (or day of discharge if prior to Day +14). 
 
 
 
 
 

Protocol #16329:  (10.3.16)(KMcD) /Approved; revised 8/10/17 (HD/KC)