Weight Loss in Patients With Advanced Stage Pancreatic Cancer: Role of Serotonin and Effects of Telotristat Ethyl
Phase: PHASE2
Conditions: Locally Advanced Unresectable Pancreatic Adenocarcinoma, Metastatic Pancreatic Adenocarcinoma, Recurrent Pancreatic Adenocarcinoma, Stage III Pancreatic Cancer AJCC v8, Stage IV Pancreatic Cancer AJCC v8
Sponsor: Emory University

Telotristat Ethyl in Pancreatic Cancer
Clinical Study Protocol
Version Date: 12/15/2022
Confidential
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Weight Loss in Patients with Advanced Stage Pancreatic Cancer: Role of Serotonin 
and Effects of Telotristat Ethyl 
Sponsor-Investigator
Olumide Gbolahan, MD
Emory University
Co-Investigators
Olatunji Alese, MD
Statistician
Zhengjia Chen, PhD
Trial Management Provided by 
Winship Cancer Institute
Trial Supported by
Lexicon
IND#: 142183
Initial Protocol Version Date: July 24, 2018
Protocol Amendment Version Date: June 13, 2023
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PROTOCOL SIGNATURE PAGE
Evaluation of Chemotherapy Effect on Serotonin Levels & Effect of Telotristat ethyl 
Treatment for Controlling Weight Loss in Patients with Advanced Stage Pancreatic 
Cancer 
VERSION DATE:  
I confirm I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable guidelines for good clinical practices, or the applicable laws and regulations of 
the country of the study site for which I am responsible, whichever provides the greater 
protection of the individual. I will accept the monitor’s overseeing of the study. I will 
promptly submit the protocol to applicable ethical review board(s).
____________________________________
________________________
Signature of Site Investigator
Date
____________________________________
Site Investigator Name (printed)
____________________________________
Site Investigator Title
____________________________________
 Name of Facility
____________________________________
 Location of Facility (City and State)
____________________________________
Not Submitting to IRB
 Expected IRB Approval Date
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SYNOPSIS
TITLE
Weight Loss in Patients with Advanced Stage Pancreatic Cancer: Role of 
Serotonin and Effects of Telotristat ethyl  
SHORT TITLE
Effect on Serotonin Levels & Effect of Telotristat ethyl Treatment for 
Controlling Weight Loss in Pancreatic Cancer (PDAC)
PHASE 
II
OBJECTIVES
Primary Objective: 
1- Aim # 1 - Group 1 (treatment): Weight stability after 3 months 
of telotristat ethyl treatment in patients who have significant 
weight loss (more than 10% by medical history) prior to the start 
of treatment. This will be documented as % weight change at 3 
months compared to baseline. These patients will be treated with 
Telotristat ethyl and gemcitabine/nab-paclitaxel combination 
chemotherapy 
2- Aim # 2 - Group 2 (correlative): Evaluate the change in serum 
serotonin and 24 hr urine 5-HIAA in patients with advanced 
PDAC (locally. advanced or metastatic) receiving 
chemotherapy. In this aim, we will include 40 patients who 
have stable weight or loss of <10% 
Secondary Objectives:
1- Evaluate the impact of weight stabilization/gain on patients in 
Group 1 on performance status, quality of life (QOL), Mid 
Arm Circumference (MAC) and muscle mass on cross 
sectional imaging. 
2- Evaluate correlations between changes in serotonin/ 
5HIAA levels on radiologic response, weight stability, Mid 
Arm Circumference (MAC), and muscle mass on cross 
sectional imaging
3- Evaluate the relation of baseline serotonin and its metabolite 
5-HIAA on weight loss in patients with advanced pancreatic 
(locally advanced unrespectable/recurrent or metastatic) 
cancer. For this aim, we will include baseline measurement 
from patients in Group 1 (N=40) and Group 2 (N=40)
4- Safety and tolerability of telotristat ethyl with 
gemcitabine/nab-paclitaxel combination chemotherapy.
5- Evaluate response rate (RR) assessed per Response Evaluation 
Criteria In Solid Tumors (RECIST), progression free survival 
and overall survival in patients receiving telotristat ethyl 
(Group 1)
STUDY DESIGN
Phase II, single center, double arm trial evaluating efficacy on weight 
stability of telotristat ethyl in combination with chemotherapy (Group 1) 
and effects of chemotherapy (Group 2) on 5-HIAA levels in a total of 80 
advanced stage PDAC subjects 
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ELIGIBILITY 
CRITERIA 
Each of the criteria in the checklist that follows must be met in order for a 
subject to be considered eligible for this study.
Inclusion Criteria 
 GROUP 1 (Telotristat ethyl treatment group)
1- Written informed consent and HIPAA authorization for release of 
personal health information. NOTE:  HIPAA authorization may be 
included in the informed consent or obtained separately.
2- Weight loss of 10% or more (estimated weight loss by history 
within 3 months of diagnosis)
3- Age ≥ 18 years at the time of consent.
4- ECOG Performance Status of 0-2 within 14 days prior to 
registration.
5- Histologic or cytological diagnosis of recurrent or metastatic PDAC 
who present for first line chemotherapy treatment for metastatic 
disease. 
6- Advanced stage pancreas cancer (locally advanced unresectable, 
recurrent/metastatic) 
7- Measurable disease determined using guidelines of RECIST 1.1. 
Baseline tumor assessment should be performed using high 
resolution CT scans or MRI.
8- Prior systemic therapy (adjuvant or neoadjuvant setting are 
acceptable) if disease progressed or recurred within at least 3 
months after treatment
9- Estimated life expectancy of > 12 weeks, as assessed by the site 
investigator.
10- If sexually active, must be postmenopausal, surgically sterile, or 
using effective contraception (hormonal or barrier methods) due to 
unknown risk of teratogenicity 
11- Demonstrate adequate organ function as defined in Table 1 below; 
all screening labs to be obtained within 7 days prior to registration.
12- Prior radiation is allowed if happened more than 2 weeks prior to 
enrollment
Table 1: Organ Function Requirements
System
Laboratory Value
Hematological
Hemoglobin
≥ 8 g/dL
Absolute Neutrophil Count 
(ANC)
≥ 1,200/mm3
Platelet Count (PLT)
≥ 75,000/mm3
Renal
Creatinine 
≤ 1.5 mg/dL
Albumin
≥ 2 g/dL
Hepatic
Bilirubin
≤ 1.5 mg/dL
Aspartate aminotransferase 
≤ 3 × ULN
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Exclusion Criteria for Group 1 (Telotristat ethyl group)
1. Subjects with histology other than adenocarcinoma; Examples 
include: neuroendocrine tumors, acinar cell cancer, sarcoma or 
lymphoma of the pancreas
2. Ongoing or active infection
3. Symptomatic congestive heart failure, unstable angina pectoris, 
symptomatic or poorly controlled cardiac arrhythmia.  
Symptomatic heart failure (NYHA Class II-IV) 
4. Acute or sub-acute intestinal obstruction
5. Ascites
6. Documented and/or symptomatic or known brain or 
leptomeningeal metastases. 
7. Severely immune-compromised (other than being on steroids) 
including known HIV infection
8. Concurrent active malignancy, other than adequately treated non-
melanoma skin cancer, other noninvasive carcinoma, or in situ 
neoplasm. A subject with previous history of malignancy is 
eligible, provided that he/she has been disease-free for > 3 years.
9. Breast-feeding or pregnant.  Serum pregnancy test for women of 
child-bearing potential must be performed within 7 days prior to 
first dose of study treatment
10. Prior autologous or allogeneic organ or tissue transplantation.
11. Known allergy to any of the treatment components
12. Have any condition that does not permit compliance with the study 
schedule including psychological, geographical, or medical.
13. Not able to swallow inability to take oral medications
14. Patients with chronic constipation
Inclusion Criteria  GROUP 2 (Correlative group- Non-Telotristat 
ethyl)
1- Written informed consent and HIPAA authorization for release of 
personal health information. NOTE:  HIPAA authorization may be 
included in the informed consent or obtained separately.
2- Stable weight or loss of < 10% by history within 3 months of 
diagnosis
3- Age ≥ 18 years at the time of consent.
4- ECOG Performance Status of 0-2 within 14 days prior to 
registration.
(AST)
or <5 xULN in the 
setting of liver 
metastases
Alanine aminotransferase (ALT)
≤ 3 × ULN
or <5 xULN in the 
setting of liver 
metastases
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5- Histologic 
or 
cytological 
diagnosis of locally 
advanced 
unresectable, recurrent/ metastatic pancreas adenocarcinoma 
(PDAC) who present for first line chemotherapy treatment for 
metastatic disease. 
6- Advanced stage pancreas cancer (locally advanced unresectable, 
recurrent/ metastatic) 
7- Prior systemic therapy (adjuvant or neoadjuvant setting are 
acceptable) if disease progressed or recurred within at least 3 
months after treatment
8- Estimated life expectancy of > 12 weeks, as assessed by the site 
investigator.
9- Prior radiation is allowed if happened more than 2 weeks prior to 
enrollment
Exclusion Criteria for Group 2 (Non- Telotristat ethyl group)
1. Subjects with histology other than adenocarcinoma; Examples 
include: neuroendocrine tumors, acinar cell cancer, sarcoma or 
lymphoma of the pancreas
2. Ongoing or active infection
3. Acute or sub-acute intestinal obstruction
STATISTICAL 
CONSIDERATIONS
Primary Endpoint
Aim # 1: Estimated weight loss in PDAC patients is 10 % within 3 
months prior to diagnosis. Weight stability is the primary end point. 
Percentage weight change will be calculated at month 3 relative to 
baseline, and a weight loss < 5% will be considered as clinical meaningful 
weight stability. A sample size of 40 achieves 81% power to detect a non-
inferiority margin of -5% weight change from baseline using a one-sided 
Wilcoxon test. We assume the true weight change is 0% and follows 
normal distribution with standard deviation of 12%. The significance level 
(alpha) of the test is set at 0.05.
Aim # 2- This is a descriptive end point to see if we can detect a 
difference of change in serotonin and 5HIAA levels compared to baseline 
(before chemotherapy treatment) 
A sample size of 40 achieves 80% power to detect a mean of paired 
differences of 0.4 with an estimated standard deviation of differences of 
1.0 and with a significance level (alpha) of 0.05000 using a one-sided 
paired t-test.
Secondary Endpoints 
Aim # 1 and 2: We propose to check serum serotonin albumin and 24- hr 
urine 5HIAA levels at baseline and every month when the patient is on 
chemotherapy and telotristat ethyl treatment for 6 months. We will 
document the MAC and abdominal muscle size. For QOL, we will use the 
QOL questionnaire and correlate this to treatment.
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Aim # 3: We will document adverse effects of the treatment using the 
grading system of the CTCAE version 4
Aim # 4: We will correlate response by checking the standard of care 
scans and evaluating RECIST
TOTAL 
NUMBER OF 
SUBJECTS
N = 80 (40 receiving drug)
ESTIMATED 
ENROLLMENT 
PERIOD
Estimated 12 months enrollment, follow up for 8 months 
ESTIMATED STUDY 
DURATION 
Estimated 20 months
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TABLE OF CONTENTS
SCHEMA.................................................................................................................................8
1.
BACKGROUND AND RATIONALE...........................................................................9
2.
STUDY OBJECTIVES AND ENDPOINTS...............................................................12
3.
ELIGIBILITY CRITERIA ..........................................................................................13
4.
SUBJECT REGISTRATION.......................................................................................14
5.
TREATMENT PLAN ...................................................................................................15
6.
TOXICITY MONITORING AND DOSE MODIFICATIONS................................17
7.
STUDY CALENDAR & EVALUATIONS.................................................................19
8.
CRITERIA FOR DISEASE EVALUATION .............................................................23
9.
DRUG INFORMATION ..............................................................................................27
10. ADVERSE EVENTS.....................................................................................................27
11. STATISTICAL METHODS ........................................................................................30
12. TRIAL MANAGEMENT.............................................................................................32
13. DATA HANDLING AND RECORD KEEPING.......................................................34
14. ETHICS..........................................................................................................................35
15. REFERENCES..............................................................................................................37
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SCHEMA
Weight loss >10%
N=40
Non-weight loss
N=40
Baseline
Mo # 1
Mo # 2
Mo # 3
Mo # 4
Progression
Gemcitabine/nab-paclitaxel WITH Telotristat
Any Chemotherapy WITHOUT Telotristat
5HIAA levels:
Group 1
PDAC
Group 2
PDAC
 
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1.
BACKGROUND AND RATIONALE
1.1
Disease Background
The prognosis of pancreas adenocarcinoma (PCA) remains poor with little progress made in 
the last few decades with the exception of FOLFIRINOX (PRODIGE 4/ACCORD 11) 1 and 
gemcitabine/nab-Paclitaxel (MPACT trial) 2 treatments in 2011 and 2013, respectively. 
Current median overall survival (OS) for patients with advanced pancreatic cancer is between 
8.5 and 11.1 months. Despite these advances, there is a continuous need to improve survival 
through the investigation of molecularly targeted agents.
           Pancreas cancer (PDAC) patients have high prevalence of cachexia and anorexia with 
a median weight loss of 14% (10-20%) at the time of diagnosis to a progressive increase in 
weight loss to a median of around 25% in 6 months when on treatment. 3 Weight loss is often 
the presenting symptom of pancreas cancer. Weight loss is a multifactorial phenomenon 
including decreased calorie intake, systemic increase in pro-inflammatory markers, calorie 
loss through diarrhea (whether treatment induced or pancreas insufficiency), and abnormal 
metabolism. Cachexia and anorexia are associated with lower tolerance for chemotherapy, 
limiting the total dose that can be delivered, the number of symptomatic responses and the 
survival advantage associated with treatment. 4,5 Moreover, and added to the quality of life 
and treatment benefit, institution of early palliative care had shown improved survival benefit 
in lung cancer patients with a median survival benefit of 2.7 months 6 highlighting the 
importance of symptom control in the management of cancer.
        In the gastrointestinal (GI) tract 5-HT contributes to motility, secretion, vasodilation, and 
sensation, and it also has both neuroprotective and pro-inflammatory actions in the gut. 7 The 
5-hydroxytryptamine receptor 4 (5-HT4R) is expressed in the colonic epithelium but little is 
known about its functions. Activation of colonic epithelial 5-HT4R protects colons of mice 
from inflammation. 5-HT4R activation maintains motility in healthy colons of mice and 
guinea pigs and reduces inflammation in colons of mice with colitis. 8 5-HT3 and 5-HT4 
receptors initiate one of the key colonic motility patterns, the colonic migrating motor 
complex, in rat by long distance contraction and rhythmic propulsive motor complex. Studies 
demonstrated that 5-HT is released in response to increased intraluminal pressure and that 5-
HT is able to initiate the peristaltic reflex and propulsive motility. 9 5-HT synthesis from L-
tryptophan in enterochromaffin cells of the mucosa is mediated by the rate-limiting enzyme 
tryptophan hydroxylase 1 (TPH1); whereas, neuronal 5-HT synthesis is mediated by the rate-
limiting enzyme tryptophan hydroxylase 2 (TPH2). Serotonin-containing neurons, although 
small in number (about 2% of all myenteric neurons) have broad, diverse projections which 
suggest a role in initiating and/or modulating gut motility. 10 Serotonin, regardless of its 
source, interacts with a variety of receptors present in the gut. Antagonists of the 5-HT3 
receptor have been used to treat diarrhea and abdominal pain, presumably through actions at 
5-HT3 receptors on intrinsic neurons that stimulate propulsive motility and extrinsic sensory 
neurons that signal pain and discomfort. 11 
            Mice deficient in TPH1 (knocked down), the rate-limiting enzyme of serotonin 
synthesis in the GI tract, were healthy, despite a dramatic reduction in intestinal and blood 
serotonin [6]. Their serotonin deficiency was well tolerated in terms of GI function. In normal 
mice, telotristat ethyl was found to reduce serotonin levels throughout the GI tract. 12 The 
maximal effects observed with doses of telotristat ethyl was 150 mg/kg. No significant change 
in brain serotonin or 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite) was 
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observed. Telotristat ethyl is a novel, oral, small-molecule TPH inhibitor that has a high 
molecular weight and acidic moieties, which inhibit it from crossing the blood-brain barrier. 
Two early studies in patients with carcinoid syndrome suggested that telotristat ethyl reduced 
bowel movement frequency and decreased 5-HIAA without overt CNS adverse effects. 13,14 
          Serotonin signaling has a role in carcinogenesis. Serotonin receptors are overexpressed 
on breast 15, prostate 16 and PDAC cell lines. 17 In preclinical trials, 5HT receptors were 
identified to play a role in carcinogenesis. The down-regulation of 5-HT1B and 5-HT1D 
receptors inhibits proliferation, clonogenicity and invasion of human PDAC cells through 
suppression of the -1 integrin that decrease extracellular matrix proteins. In addition, the 
down-regulation of 5-HT1B and 5-HT1D increases claudin 1 which decreases the 
transcriptional repressors needed for EMT resulting in the inhibition of invasion, migration 
and proliferation of the PDAC cells. 17 In a xenograft model, the increased serotonin signaling 
through the 5-HT2B which contributes to the Warburg effect in pancreatic cancer cells and 
promotes growth of pancreatic tumors in mice. The knockdown of the 5-HT2B receptor 
decreased the growth of the xenografted tumors. Following stimulation of the receptor, there 
was an increase activation of the PI3K- AKT-mTOR pathway leading to increased MYC and 
HIF1 expression. 18 This is suggesting an antitumor activity of Telotristat ethyl in PDAC.
1.2
Telotristat ethyl Clinical Experience
             Telotristat ethyl (brand name Xermelo®) is a prodrug of telotristat ethyl, which is an 
inhibitor of tryptophan hydroxylase. The U.S. Food and Drug Administration approved 
Xermelo in combination with somatostatin analog (SSA) therapy for the treatment of adults 
with diarrhea associated with carcinoid syndrome that SSA therapy alone has inadequately 
controlled. 13 In a prospective, randomized study, patients with carcinoid tumor with 
symptoms of ≥4 bowel movements (BMs)/day despite stable-dose octreotide LAR depot 
therapy were enrolled in sequential, escalating, cohorts of four patients per cohort. In each 
cohort, one patient was randomly assigned to placebo and three patients to telotristat ethyl, at 
150, 250, 350, or 500 mg three times a day (tid). In a subsequent cohort, one patient was 
assigned to placebo and six patients to telotristat ethyl 500 mg tid. Patients were assessed for 
safety, BM frequency (daily diary), 24 h urinary 5-hydroxyindoleacetic acid (u5-HIAA), and 
adequate relief of carcinoid gastrointestinal symptoms (using a weekly questionnaire). 
Twenty-three patients treated: 18 received telotristat ethyl and five received placebo. Adverse 
events were mild. Among evaluable telotristat ethyl-treated patients, 5/18 (28%) experienced 
a ≥30% reduction in BM frequency for ≥2 weeks, 9/16 (56%) experienced biochemical 
response (≥50% reduction or normalization in 24-h u5-HIAA) at week 2 or 4, and 10/18 (56%) 
reported adequate relief during at least 1 of the first 4 weeks of treatment. Similar activity was 
not observed in placebo-treated patients. Telotristat ethyl was well tolerated. Our observations 
suggest that telotristat ethyl has activity in controlling diarrhea associated with carcinoid 
syndrome. 
              In the phase III, international TELESTAR trial, 135 patients were randomized 1:1:1 
to receive oral telotristat ethyl at 250 mg (n = 45) or 500 mg (n = 45) or placebo (n = 45) 3 
times daily during a 12-week double-blind treatment period. Patients had well-differentiated 
metastatic neuroendocrine tumors and a documented history of carcinoid syndrome, were 
experiencing an average of at least 4 bowel movements per day and were receiving stable-
dose somatostatin analog treatment for at least 3 months prior to enrollment. Patients remained 
on baseline stable-dose somatostatin analog therapy for the 12-week period. The primary 
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endpoint was change from baseline in the frequency of bowel movements.
          Overall, 44% of patients were receiving above-label doses of stable-dose somatostatin 
analogs, and approximately 57% had urinary 5-HIAA levels above the upper limit of normal. 
Across treatment groups, the mean daily frequency of bowel movements ranged from 5.2 to 
6.1 per day and mean urinary 5-HIAA levels ranged from 81.0 to 92.6 mg/24 h. At week 12, 
reductions in the mean frequency of bowel movements per day were –0.9 with placebo, –1.7 
with telotristat ethyl at 250 mg, and –2.1 with telotristat ethyl at 500 mg. Compared with 
placebo, the estimated difference in bowel movement frequency averaged over 12 weeks was 
–0.81 per day with telotristat ethyl at 250 mg (P < .001) and –0.69 per day with telotristat 
ethyl at 500 mg (P < .001). Response—defined as a reduction in the frequency of bowel 
movements ≥ 30% from baseline for ≥ 50% of the 12-week period—was observed in 20% of 
the placebo group, 44% of the 250-mg telotristat ethyl group (odds ratio = 3.49, 95% 
confidence interval [CI] = 1.33–9.16), and 42% of the 500-mg telotristat ethyl group (odds 
ratio = 3.11, 95% CI = 1.20–8.10). Mean urinary 5-HIAA levels decreased by 40.1 mg/24 h 
(P < .001) and 57.7 mg/24 hours (P < .001) in the 250-mg and 500-mg telotristat ethyl groups 
vs a mean increase of 11.5 mg/24 h in the placebo group. In a post hoc analysis, a ≥ 30% 
reduction occurred in 78% and 87% vs 10% of patients, respectively. Nausea occurred in 
31.1% of the 500-mg telotristat ethyl group, 13.3% of the 250-mg group, and 11.1% of the 
placebo group. Abdominal pain occurred in 22.2%, 11.1%, and 17.8%, respectively. Gamma-
glutamyl transferase levels were elevated in 8.9%, 8.9%, and 0%, and alanine transaminase 
levels increased in 6.7%, 2.2%, and 0%. Depression-related adverse events occurred in 15.6%, 
6.7%, and 6.7%. Treatment was discontinued due to adverse events in 6.7%, 6.7%, and 13.3%. 
The average diarrhea subscale scores on the European Organization for Research and 
Treatment of Cancer (EORTC) Quality-of-Life Questionnaire–Core 30 (QLQ-C30) improved 
by 19.2 points (P = .039) and 21.6 points (P = .051) on a 0-to-100 scale in the 250-mg and 
500-mg telotristat ethyl groups vs 8.5 points in the placebo group. No significant differences 
among groups were observed in the nausea and vomiting subscale or in the global health status 
subscale. Some evidence of improved overall quality of life in responders vs. non-responders 
was reported in all groups.
In an open-label extension, 115 patients received telotristat ethyl at 500 mg. Mean 
treatment exposure was 26.7 weeks. Reduction in the frequency of bowel movements was 
consistent with that in the double-blind treatment period, and no new safety signals were 
observed. 19  The pre-specified subgroup analysis of the TELESTAR trial showed that the 
incidence of weight gain for patients on telotristat ethyl was dose related and greater than that 
on placebo. It was possibly related to reduce diarrhea severity and may be a relevant aspect of 
Telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors.
1.3
Rationale:
1. Serotonin may contribute to weight loss in pancreatic cancer patients. 21 Patients with 
clinically significant weight loss do not tolerate the chemotherapy treatment and have 
worse outcome. We hypothesize that stabilizing the weight by blocking serotonin 
synthesis will improve the overall performance status and enable these patients to 
tolerance of chemotherapy.
2. Serotonin affects GI motility, food absorption, and maybe related to tumor burden. We 
hypothesize that elevated baseline serotonin and its metabolite 5-HIAA will be 
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associated with weight loss in newly diagnosed patients with advanced 
pancreatic cancer (locally advanced unresectable, recurrent, and metastatic).
3. Serotonin as a ligand can promote PDAC cell growth and invasion and may 
contribute to resistance to therapy. We hypothesize that elevated levels of 
serotonin during treatment may contribute to resistance to therapy as well as 
ongoing weight loss. 
4.
Telotristat ethyl, a TPH inhibitor, has been shown in clinical trials of NET to inhibit 
serotonin production and impact bowel motility. 
To test these hypotheses, we propose evaluating two cohorts of patients:
a.
patients with weight loss at baseline – adding telotristat ethyl to chemotherapy will 
result in weight stabilization
b. Patients with no weight loss at baseline would have an increase in the 5-HIAA 
levels as they receive treatment leading to poor outcome. 
2.
STUDY OBJECTIVES AND ENDPOINTS 
2.1.
Objectives
2.1.1. Primary Objective: 
Aim # 1 - Group 1: Weight stability after 3 and 6 months of Telotristat ethyl treatment in 
patients who have significant weight loss (Documented to be more than or equal to 10%) prior 
to the start of treatment. This will be documented as % weight change at 3 and 6 months 
compared to baseline. These patients will be treated with gemcitabine/nab-paclitaxel 
combination chemotherapy.
Aim # 2 - Group 2: Evaluate the change in serum serotonin and 24-hr urine 5-HIAA in 
patients with locally advanced unresectable, recurrent or metastatic PDAC receiving 
chemotherapy. In this aim, we will include 40 patients who have stable weight or loss of 
<10%. These patients will be treated with chemotherapy (at the discretion of the investigator) 
and supportive care.
 
2.1.2. Secondary Objectives:
Evaluate the impact of weight stabilization/gain on patients in Group 1 on performance 
status, quality of life (QOL), Mid Arm Circumference (MAC) and muscle mass on 
cross sectional imaging. 
Evaluate correlations between changes in serotonin/ 5HIAA levels on radiologic 
response, weight stability, Mid Arm Circumference (MAC), and muscle mass on cross 
sectional imaging
Evaluate the relation of baseline serum serotonin and 24-hr urine 5-HIAA on weight 
loss in patients with advanced PDAC. For this aim, we will include baseline 
measurement from patients in Group 1 (N=40) and Group 2 (N=40)
Safety and tolerability of telotristat ethyl with gemcitabine/nab-paclitaxel combination 
chemotherapy
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Evaluate response rate (RR) assessed per Response Evaluation Criteria In Solid 
Tumors (RECIST), progression free survival and overall survival  in patients receiving 
telotristat ethyl (Group 1)
2.2.
Endpoints
2.2.1. Primary Endpoint

Weight stability will be documented as % weight change at 3 and 6 months or at 
time of progression compared to baseline. These patients will be treated with 
gemcitabine/nab-paclitaxel combination chemotherapy.

Correlative descriptive markers of serum serotonin and 24-hr urine 5HIAA levels 
and chemotherapy effect on these levels
2.2.2. Secondary Endpoints
Sarcopenia refers to the age-associated decreased in muscle mass and function. A 
single dimensional definition of sarcopenia using CT images that includes only 
assessment of the abdominal muscle mass as a measure of sarcopenia
Mid Arm Circumference (MAC) will be measured in inches 
Quality of life testing through QOL questionnaire 
Blood serotonin levels will be compared in the 2 groups
Toxicity evaluation will be assessed per CTCAE v4
Response rate (RR) will be evaluated per RECIST 1.1
Median overall survival (mos.) measured using the Kaplan-Meier method.
Duration of response will be estimated from time of documentation of response to time 
of progression
3.
ELIGIBILITY CRITERIA
Each of the criteria in the checklist that follows must be met in order for a subject to be 
considered eligible for this study. 
Inclusion Criteria 
 GROUP 1 (Telotristat ethyl treatment group)
1- Written informed consent and HIPAA authorization for release of personal health 
information. NOTE:  HIPAA authorization may be included in the informed consent 
or obtained separately.
2- Weight loss of 10% or more 
3- Age ≥ 18 years at the time of consent.
4- ECOG Performance Status of 0-2 within 14 days prior to registration.
5- Histologic or cytological diagnosis of recurrent or metastatic pancreas 
adenocarcinoma (PDAC) who present for first line chemotherapy treatment for 
metastatic disease. 
6- Advanced stage pancreas cancer (recurrent/metastatic) 
7- Measurable disease determined using guidelines of RECIST 1.1. Baseline tumor 
assessment should be performed using high resolution CT scans or MRI.
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8- Prior systemic therapy (adjuvant or neoadjuvant setting are acceptable) if disease 
progressed or recurred within at least 3 months after treatment
9- Estimated life expectancy of > 12 weeks, as assessed by the site investigator.
10- If sexually active, must be postmenopausal, surgically sterile, or using effective 
contraception (hormonal or barrier methods) due to unknown risk of teratogenicity 
11- Demonstrate adequate organ function as defined in Table 1 below; all screening labs 
to be obtained within 7 days prior to registration.
12- Prior radiation is allowed if happened more than 2 weeks of enrollment
Table 1: Organ Function Requirements
Table 1: Organ Function Requirements
Exclusion Criteria for Group 1 (Telotristat ethyl group)
1. Subjects with histology other than adenocarcinoma; Examples include: 
neuroendocrine tumors, acinar cell cancer, sarcoma or lymphoma of the pancreas
2. Ongoing or active infection
3. Symptomatic congestive heart failure, unstable angina pectoris, symptomatic or 
poorly controlled cardiac arrhythmia.  Symptomatic heart failure (NYHA Class II-
IV) 
4. Acute or sub-acute intestinal obstruction
5. Ascites
6. Documented and/or symptomatic or known brain or leptomeningeal metastases. 
7. Severely immune-compromised (other than being on steroids) including known HIV 
infection
8. Concurrent active malignancy, other than adequately treated non-melanoma skin 
cancer, other noninvasive carcinoma, or in situ neoplasm. A subject with previous 
history of malignancy is eligible if he/she has been disease-free for > 3 years.
System
Laboratory Value
Hematological
Hemoglobin
≥ 8 g/dL
Absolute Neutrophil Count 
(ANC)
≥ 1,500/mm3
Platelet Count (PLT)
≥ 100,000/mm3
Renal
Creatinine 
≤ 1.5 mg/dL
Albumin
≥ 2 g/dL
Hepatic
Bilirubin
≤ 1.5 mg/dL
Aspartate aminotransferase 
(AST)
≤ 3 × ULN
or < 5 xULN in the 
setting of liver 
metastases
Alanine aminotransferase (ALT)
≤ 3 × ULN
or < 5 xULN in the 
setting of liver 
metastases
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9. Breast-feeding or pregnant.  Serum pregnancy test for women of child-bearing 
potential must be performed within 7 days prior to first dose of study treatment
10. Prior autologous or allogeneic organ or tissue transplantation.
11. Known allergy to any of the treatment components
12. Have any condition that does not permit compliance with the study schedule 
including psychological, geographical, or medical.
13. Not able to swallow. inability to take oral medications
14. Patients with chronic constipation
Inclusion Criteria-GROUP 2 (Correlative group- Non-Telotristat ethyl)
1- Written informed consent and HIPAA authorization for release of personal health 
information. NOTE:  HIPAA authorization may be included in the informed consent 
or obtained separately.
2- Stable weight or loss of < 10% by history
3- Age ≥ 18 years at the time of consent.
4- ECOG Performance Status of 0-2 within 14 days prior to registration.
5- Histologic 
or 
cytological 
diagnosis 
of 
locally 
advanced 
unresectable, 
recurrent/metastatic PDAC who present for first line chemotherapy treatment for 
metastatic disease. 
6- Advanced stage PDAC (locally advanced unresectable/recurrent/metastatic) 
7- Prior systemic therapy (adjuvant or neoadjuvant setting are acceptable) if disease 
progressed or recurred within at least 3 months after treatment
8- Estimated life expectancy of > 12 weeks, as assessed by the site investigator.
9- Prior radiation is allowed if happened more than 2 weeks of enrollment
Exclusion Criteria for Group 2 (Non-Telotristat ethyl group)
1. Subjects 
with 
histology 
other 
than 
adenocarcinoma; 
Examples 
include: 
neuroendocrine tumors, acinar cell cancer, sarcoma or lymphoma of the pancreas
2. Ongoing or active infection
3. Symptomatic congestive heart failure, unstable angina or arrhythmia.  Symptomatic 
heart failure (NYHA Class II-IV) 
4. Acute or sub-acute intestinal obstruction
5. Severely immune-compromised (other than being on steroids) including known HIV 
infection
4.
SUBJECT REGISTRATION
All subjects must be registered through electronic data capture (EDC) system in Emory 
Oncore. A subject is considered registered when an “On Study” date is entered into the EDC 
system.
Subjects must be registered prior to starting protocol therapy.
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5.
TREATMENT PLAN
5.1.
Treatment Regimen

Telotristat ethyl Treatment group: Group 1 will receive gemcitabine/nab-paclitaxel 
combination therapy with Telotristat ethyl at a dose of 250 mg po TID and supportive 
care with a run-in phase trial design.
A total of 40 patients will be enrolled with the aim to control weight loss by adding 
Telotristat ethyl.
One cycle will be equal to 28 days. 

Group 2: Patients will receive chemotherapy (at the discretion of the investigator) and 
supportive care. This is the group that has no Telotristat ethyl drug intervention. We 
intend to collect serum serotonin and the 24 hr-urine for the 5HIAA at baseline and 
every cycle for the first 4 cycles to evaluate the effect of chemotherapy on the 5HIAA 
serum serotonin and urine levels and correlate the levels to response. We will correlate 
baseline levels to response/outcome and the change of levels while on treatment with 
response/outcome.
5.2.
Pre-medications and Home Medications
Premedication will be given according to the institution standard prior to chemotherapy. No 
premedication needed for Telotristat ethyl.
5.3.
Home Medications
At the discretion of the investigator. No specific medication will be given as a support to 
Telotristat ethyl
5.4.
Drug Administration
Table 2. Drug Administration
Telotristat 
ethyl
Dose
Frequency of 
administration
Route of administration
250 mg
Three times 
daily
po
DL-1 
250 mg
Twice daily
po
DL-2
250 mg
Once daily
po
Telotristat ethyl of the 250 mg po tid will be held for Grade ≥ 3 (constipation (obstipation, 
constipation affecting activities of daily living, need of impaction) or for development of 
severe, persistent or worsening abdominal pain study drug related adverse events until 
recovery to Grade ≤ 1 and then resume at dose reduction of 250 mg po bid if the investigator 
evaluation relates toxicity to Telotristat ethyl. If a second Grade ≥ 3 related adverse events 
does not resolve within 2 weeks of the dose reduction, another dose reduction will be planned 
for 250 po once daily. If a third Grade ≥ 3 related adverse events does not resolve within 2 
weeks of the dose reduction, the subject will be taken off the trial. 
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In case of grade 2 toxicity, continuation of the medication with a planned dose reduction to 
the lower dose level will be planned. In case toxicity remains at grade 2 as DL-1, then a plan 
to a DL-2 without interruption of treatment. The addition of stool softners and laxatives should 
be instituted from the first occurrence of any constipation grade.
Guidance for Constipation treatment:
Patients with a fecal impaction (a solid immobile bulk of stool in the rectum) should initially 
be disimpacted starting with manual fragmentation if necessary. After this is accomplished, 
an enema with mineral oil will help to soften the stool and provide lubrication.
If disimpaction is unsuccessful or only partially successful, a water-soluble soap enema will 
be advised. We suggest that sodium phosphate enemas be avoided in older adults.
Lactulose may be given after bowel cleansing to produce one stool at least every other day. 
The patient is instructed to use the bathroom after meals to take advantage of meal-stimulated 
increases in colonic motility. Bisacodyl or glycerine suppository is administered if there is no 
defecation after two days to prevent recurrence of fecal impaction. Alternatively, enemas may 
be administered. 
Patient will be advised to drink lots of fluids, eat high fiber diet, and be active as possible. 
Bulk-forming laxatives include psyllium seed (eg, Metamucil), methylcellulose (eg, 
Citrucel), calcium polycarbophil (eg, FiberCon), and wheat dextrin (eg, Benefiber) is advised 
for all patients with any grade of constipation.
5.5.
Missed Doses
All medications are given on Day 1. A missed dose implies delay of that cycle. Infusions may 
be given within 3 days for reasons such as observed holidays, inclement weather, scheduling 
conflicts, etc. It should be clearly documented in subject’s chart and case report forms. 
Telotristat ethyl should continue irrespective of the chemotherapy standard of care infusions. 
A missed dose of the Telotristat ethyl will not need to be made for the next day or double the 
dose. Patient should continue same daily dosing.
5.6.
Supportive Care
Subjects should receive full supportive care in accordance with ASCO or equivalent 
guidelines on supportive care for solid tumors, if necessary. Supportive care measures may 
include but are not limited to anti-diarrheal agents, anti-emetic agents, opiate and non-opiate 
analgesic agents, appetite stimulants, and granulocyte and erythroid growth factors. Subjects 
will receive supportive care as judged by their treating physician. If it is unclear whether a 
therapy should be regarded as supportive care, the investigator should consult with the 
principle investigator. Use of any supportive care therapy should be reported on the eCRFs. 
5.6.1. Analgesic agents
The use of analgesic agents during the study is permitted at the discretion of the site 
investigator.  
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5.6.2. Antiemetic therapy
The use of antiemetic agents is permitted during this study and at the discretion of the 
investigator. However, it is recommended to follow the guidelines of the Multinational 
Association of Supportive Care in Cancer (MASCC) and ASCO. 
5.6.3. Appetite Stimulants
The use of appetite stimulants is permitted at the discretion of the site investigator in Group 2 
and will not be used in Group 1.
5.6.4. Blood Product Transfusions
Transfusions of red blood cells, platelets or other blood products are permitted at the site 
investigators discretion during the conduct of the study.
5.6.5. Contraception
Telotristat ethyl and chemotherapy may have adverse effects on a fetus in utero. Furthermore, 
it is not known if Telotristat ethyl has transient adverse effects on the composition of sperm. 
Subjects of childbearing potential should start using birth control from time of consent 
throughout the study period up to 90 days after the last dose of study therapy.
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestin agent (including oral, subcutaneous, intrauterine, or intramuscular 
agents).
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study, they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section If there is any question 
that a subject will not reliably comply with the requirements for contraception, that subject 
should not be entered into the study.
5.7.
Treatment Compliance
Standard of care chemotherapy will be administered only at Emory sites approved for 
enrolling patients by the authorized study personnel. As a result, treatment compliance is 
ensured.
5.8.
Concurrent Therapy
Additional concurrent chemotherapy or radiation therapy, biologic response modifiers, or 
other investigational agents may not be administered to subjects on this study. However, 
palliative radiation during the study is allowed if clinically indicated.
5.9.
Concomitant Medications
Medications allowed: 

Medications required for supportive care during the study (See Section 5.6) 
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
Medications subject requires for treatment of previous comorbidities.
6.
TOXICITY MONITORING AND DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events CTCAE v4 will be used to grade 
adverse events.
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Study 
Calendar & Evaluations.
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation at each study visit for the duration 
of their participation in the study. 
6.1.
Dose Modifications for Telotristat ethyl 
Telotristat ethyl of the 250 mg po tid will be held for Grade ≥ 3 study drug related adverse 
events until recovery to Grade ≤ 1 and then resume at dose reduction of 250 mg po bid if the 
investigator evaluation relates toxicity to Telotristat ethyl. If a second Grade ≥ 3 related 
adverse events does not resolve within 2 weeks of the dose reduction, another dose reduction 
will be planned for 250 po once daily. If a third Grade ≥ 3 related adverse events does not 
resolve within 2 weeks of the dose reduction, the subject will be taken off the trial. 
Table 3. Modified dose of Telotristat ethyl
Dose level
Telotristat ethyl 
Starting dose
250 mg po tid
Level -1 dose reduction
250 mg po bid
Level -2 dose reduction
250 po daily
6.2
Dose Modification for chemotherapy
The dose adjustment of chemotherapy agents will be according to the package inserts of each 
medication and according to what the investigator assessment of which medication to adjust.
We will evaluate all the adverse events on study Group 1 (the Telotristat ethyl intervention 
group). 
6.3
Protocol Therapy Discontinuation
For Group 1:
In addition to discontinuation from therapy related to toxicities, a subject will discontinue 
therapy with Telotristat ethyl and followed up per protocol under the following 
circumstances:
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
The physician thinks a change of therapy would be in the best interest of the subject

The subject requests to discontinue protocol therapy, whether due to unacceptable 
toxicity or for other reasons
o
In case a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if she or he may still be contacted for 
further scheduled study assessments. The outcome of that discussion should be 
documented in both the medical records and in the eCRF.

A female subject becomes pregnant 

If protocol therapy is interrupted for ≥ 30 days. 
For Group 2
The discontinuation of treatment will be left to the discretion of the investigator or the choice 
of the patient to discontinue the chemotherapy.  If the therapy is discontinued, the blood and 
urine tests for 5HIAA will be discontinued.
6.4
Study Withdrawal
If a subject decides to withdraw from the study by revoking, all efforts should be made to 
complete and report study assessments as thoroughly as possible. The investigator should 
contact the subject or a responsible relative by telephone or through a personal visit to 
establish as completely as possible the reason for the study withdrawal. A complete final 
evaluation at the time of the subject’s study withdrawal should be made with an explanation 
of why the subject is withdrawing from the study. If the reason for removal of a subject from 
the study is an adverse event, it will be recorded on the eCRF.
7. Stopping Rules
This is a run-in phase trial (For Group 1 only). Toxicity will be assessed within 28 
days of enrollment on the combination treatment (Telotristat + gemcitabine/nab-
paclitaxel). The dose limiting toxicity proposed as per table below (Cumulative 
Distribution Function (CDF) Calculator for the Binomial Distribution) for grade 
3 constipation or perforation, the combination will be deemed not safe to proceed on 
the treatment and the study will halt accrual. This plan is for 10% of patients 
developing grade 3 constipation or perforation at any time point during accrual. We 
used the cumulative distribution function (CDF) to make sure there is at least 95% 
probability the true DLT rate is above 10% before stopping the trial for over-toxicity. 
Please note that if the trial stops at 10% of patients with DLT, it means that there is 
50% chance that the true DLT rate is below 10%. But we aim to have at least 95% 
chance that the true DLT rate is above 10% before stopping the trial, therefore table 
allow for up to much higher percentage (>10%) of patients to incur a DLT before the 
study is stopped.
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Total number of 
treated patients
Number of DLT to stop 
the trial for toxicity
3
≥1
4
≥2
5
≥2
6
≥2
7
≥2
8
≥2
9
≥3
10
≥3
11
≥3
12
≥3
13
≥3
14
≥3
15
≥4
16
≥4
17
≥4
18
≥4
19
≥4
20
≥4
21
≥5
22
≥5
23
≥5
24
≥5
25
≥5
26
≥5
27
≥5
28
≥6
29
≥6
30
≥6
31
≥6
32
≥6
33
≥6
34
≥6
35
≥7
36
≥7
37
≥7
38
≥7
39
≥7
40
≥7
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9. STUDY CALENDAR & EVALUATIONS
CYCLE = 28 DAYS
Laboratory assessments and clinical procedures performed per SOC in the past 7 days are can be used as screening procedures. 
Patients on arm 2 will follow standard of care visit schedule (as per institutional guidelines)
Screening
Cycle 1-2
Cycle 3–4
Cycle 5+
End of 
Treatmen
t Visit 
(Cycle 6)
Follow 
up
Examination
Within 7 
days of 
registratio
n
Day 1
(±7)
Day , 
1510 (±3)
Day 1
(±3)
Day 1510 
(±3)
Day 1
Day 15
30 days  
(± 7)
after last 
dose of 
study 
drug
REQUIRED ASSESSMENTS
Demographics and Medical 
History/Height
X
Physical Examination
X
X
X
X
X
X
X
X
Vital Signs and ECOG PS1
X
X
X
X
X
X
Comprehensive Metabolic Panel2
X
X
X
X
X
X
CBC with Differential3
X
X
X
X
X
X
Serotonin blood level11
X
X
X
X
X
CA19-94
X
X
X
Pregnancy Test (Serum β-HCG)5
X
Urine 5-HIAAs6
X
X
X
X
X
AEs and Con Meds#
X
X
X
X
X
X
Diagnosis Confirmation7
X
Mid Arm Circumference (MAC) 
measurement
X
X
X
X
X
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Questionnaire QLQ-30
X
X
X
X
DISEASE ASSESSMENT
CT or MRI of Chest, Abdomen and 
Pelvis8
X
X
X
X9
TREATMENT
Telotristat ethyl*
X
X
X
X
X
X
Chemotherapy^
X
X
X
X
X
X
FOLLOW-UP
For progression, start of additional 
cancer treatment, and survival9
X9
1: Vital signs to include blood pressure, weight, height (screen only) and ECOG performance status.
2: CMP to include Sodium, potassium, total bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), blood urea nitrogen (BUN), creatinine, calcium, random glucose, albumin, magnesium and uric acid
3: CBC to include Hemoglobin, hematocrit, erythrocyte count (RBC), mean cell volume, mean cell hemoglobin concentration, 
leukocytes (WBC), neutrophils, lymphocytes, monocytes, basophils, platelets
4: CA19-9 at screening and every 2 cycles
5: Serum pregnancy test for women of child-bearing potential must be performed within 7 days prior to first dose of study treatment
6: 24 hr urine collection for 5-HIAA testing. This will occur at baseline and then monthly for 6 months (6 cycles)
7: Confirmation of diagnosis must be obtained during screening.  A pathology report with staging information will be obtained from the 
institution that performed the diagnosis procedure.
8: Scans to be repeated every 8 weeks (± 7 days) until progression of disease. Pre-treatment scans to be performed within 28 days prior 
to registration. Abdominal muscle mass will be evaluated by a radiologist at every scan evaluation.
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9: For subjects who discontinue study treatment without radiographically documented PD, the investigative sites will continue to 
evaluate tumor response every 8 weeks (± 7 days) by the same method used at baseline and throughout the study until time of disease 
progression, death or until study completion, except when not feasible in the opinion of the site investigator due to subject's clinical 
status.  After the subject has documented PD, radiologic assessments are no longer required and the subject will be followed every 8 
weeks (± 7 days) until the subject's death or study completion, whichever is earlier.
10: Each cycle is 28 days. Assessments will be done every 2 weeks
11: Serotonin blood levels. This will occur at baseline and then monthly for 6 months (6 cycles)
*Telotristat ethyl treatment is only for Group 1 of the study. It should be administered with food. Duration of treatment is until disease 
progression.
^ Treatment with chemotherapy will be gemcitabine/nab-paclitaxel combination for Group 1. 
Group 2 chemotherapy will be decided by the investigator and should be either gemcitabine-based or 5fluropyrimidine-based therapy. 
Treatment schedule will differ depending on the chemotherapy regimen.
# These are not needed for Group 2 of the study.
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a.
Screening
i.
Within 28 Days Prior to Registration for Protocol Therapy:
-
The following should be collected before registration for protocol therapy: 

Prior to the subject being registered to the study, confirmation of diagnosis must be 
obtained via pathology report including staging information.

Medical history and Height

Physical examination

Vitals Signs (including blood pressure), Weight [kg] and ECOG PS

Laboratory Testing:
o
CBC with differential: Hemoglobin, hematocrit, erythrocyte count (RBC), mean 
cell volume, mean cell hemoglobin concentration, leukocytes (WBC), neutrophils, 
lymphocytes, monocytes, basophils, platelets.
o
CMP: Sodium, potassium, total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen 
(BUN), creatinine, calcium, random glucose, albumin 
o
CA 19-9 
o
Serum pregnancy test for women of child-bearing potential must be performed 
within 7 days prior to first dose of study treatment 
o
Documented weight loss of > or = 10% as an estimate* NOT NEEDED FOR 
GROUP 2

Radiological assessment (CT or MRI of chest, abdomen, and pelvis) with tumor 
measurements. Pre-treatment scans to be performed within 28 days prior to 
registration.

Mid Arm Circumference (MAC)
ii.
On Treatment; Day 1 of each cycle
Note: Day 1 lab testing need not be repeated if completed within 7 days of starting protocol 
therapy.

Physical examination

Vitals Signs (including blood pressure), Weight [kg] and ECOG PS

Laboratory Testing:
o
CBC with differential: Hemoglobin, hematocrit, erythrocyte count (RBC), mean 
cell volume, mean cell hemoglobin concentration, leukocytes (WBC), neutrophils, 
lymphocytes, monocytes, basophils, platelets.
o
CMP: Sodium, potassium, total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen 
(BUN), creatinine, calcium, random glucose, albumin 
o
CA 19-9 every 2 cycles
o
24 hr- Urine for the 5HIAA levels
o
Questionnaire

CT or MRI of chest, abdomen/pelvis after every 2 cycles of treatment
Chemotherapy either gemcitabine/nab-paclitaxel combination chemotherapy or 
5fluoropyrimidine-based depending on which group the patient is assigned to.
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iii.
On Treatment; Day 15 of each cycle

Physical examination

Vitals Signs (including blood pressure), Weight [kg] and ECOG PS

Laboratory Testing:
o
CBC with differential: Hemoglobin, hematocrit, erythrocyte count (RBC), mean 
cell volume, mean cell hemoglobin concentration, leukocytes (WBC), neutrophils, 
lymphocytes, monocytes, basophils, platelets.
o
CMP: Sodium, potassium, total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen 
(BUN), creatinine, calcium, random glucose, albumin 

Chemotherapy either gemcitabine/nab-paclitaxel combination chemotherapy or 
5fluoropyrimidine-based depending on which group the patient is assigned to.

Patients will be evaluated every 2 weeks
iv.
Protocol therapy discontinuation:
A subject will be discontinued from the protocol therapy under the following circumstances:

Evidence of disease progression (per RECIST 1.1)

Site physician determines a change of therapy would be in the best interest of the 
subject

Subject requests to discontinue protocol therapy

Subject exhibits unacceptable toxicity

Female subject becomes pregnant 

Protocol therapy is interrupted for ≥ 30 days. 
v.
Safety follow up visit 30 days (±7 days) after last dose of study treatment for 
cohort 1
Subjects will be evaluated 30 days (± 7) after the last dose of study drug. Suggested testing 
includes:

Physical examination

Vitals Signs (including blood pressure), Weight [kg] and ECOG PS

Laboratory Testing:
o
CBC with differential: Hemoglobin, hematocrit, erythrocyte count (RBC), mean 
cell volume, mean cell hemoglobin concentration, leukocytes (WBC), neutrophils, 
lymphocytes, monocytes, basophils, platelets.
o
CMP: Sodium, potassium, total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen 
(BUN), creatinine, calcium, random glucose, albumin 
o
Mid Arm Circumference (MAC)* NOT NEEDED FOR GROUP 2
o
Serotonin blood levels and 24 hr urine 5HIAA levels
o
Questionnaire
vi.
Follow-up
For subjects who discontinue study treatment without radiographically documented PD, the 
investigator will continue to evaluate tumor response every 8 weeks by the same method used 
at baseline and throughout the study until time of disease progression, death or until study 
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completion, except when not feasible in the opinion of the site investigator due to subject's 
clinical status. 
After the subject has documented PD, radiologic assessments are no longer required and the 
subject will be followed up every 8 weeks (+/- 7 days) until the subject's death or study 
completion, whichever is earlier.
10.
CRITERIA FOR DISEASE EVALUATION
a.
Definitions Associated with Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 20
i.
Measurable disease 
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
ii.
Measurable lesions 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).
iii.
Non-measurable lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions.
iv.
Malignant lymph nodes
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.
v.
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
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the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion, which can be measured reproducibly, should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then only the short axis is added into the sum. The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
vi.
Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up.
b.
Response Criteria
i.
Evaluation of target lesions
Complete Response (CR)
Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to 
<10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference 
the baseline sum diameters
Progressive Disease (PD)
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference 
the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at 
least 5 mm. (Note:  the appearance of one or 
more new lesions is also considered 
progressions).
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while 
on study
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ii.
Evaluation of non-target lesions
Complete Response (CR)
Disappearance of all non-target lesions and 
normalization of tumor marker level. All 
lymph nodes must be non-pathological in size 
(<10 mm short axis)
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
subject to be considered in complete clinical 
response.
Non-CR/ Non-PD
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level 
above the normal limits
Progressive Disease (PD)
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, 
not a single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor-investigator.
iii.
Evaluation of best overall response
Target Lesions
Non-Target Lesions
New Lesions
Overall 
Response
CR
CR
No
CR
CR
Non-CR/ Non-PD
No
PR
Not evaluated
No
PR
PR
Non-CR/ Non-PD/ not 
evaluated
No
PR
SD
Non-CR/ Non-PD/ not 
evaluated
No
SD
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
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Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status.
c.
Definitions for Response Evaluation – RECIST version 1.1
i.
First Documentation of Response
The time between initiation of therapy and first documentation of PR or CR.
ii.
Confirmation of Response
To be assigned a status of complete or partial response, changes in tumor measurements must 
be confirmed by repeat assessments performed no less than four weeks after the criteria for 
response are first met.
iii.
Duration of Response
Duration of overall response—the period measured from the time that measurement criteria 
are met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started).
iv.
Duration of Overall Complete Response
The period measured from the time that measurement criteria are met for complete response 
until the first date that recurrent disease is objectively documented.
v.
Objective response rate 
The objective response rate is the proportion of all subjects with confirmed PR or CR 
according to RECIST v1.1, from the start of treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest measurements recorded since the start 
of treatment).
vi.
Disease Control Rate:
The disease control rate is the proportion of all subjects with stable disease (SD) for 8 weeks, 
or partial response (PR), or complete response (CR) according to RECIST v1.1, from the start 
of treatment until disease progression/recurrence (taking as reference for progressive disease 
the smallest measurements recorded since the start of treatment).
vii.
Time to Progression:
A measurement from the date of randomization until the criteria for disease progression is met 
as defined by RECIST 1.1. Subjects who have not progressed or have died due to any cause 
will be right-censored at the date of the last disease evaluation or date of death.
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viii.
Progression Free Survival
A measurement from the date of randomization until the criteria for disease progression is met 
as defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be right-
censored at the date of the last disease evaluation.
ix.
Overall Survival
Overall survival is defined by the date of randomization to date of death from any cause.
x.
Duration of response
Duration of response is defined by the date of first response to date of progression of the 
disease
11.
DRUG INFORMATION
a.
Telotristat ethyl (Xermelo)
i.
Formulation and Storage: 
Telotristat ethyl is a 250mg tablet: white to Off-white coated tablet with “T– E” debossed on 
one side and 250 debossed on the other side.
Telotristat ethyl dispensed in a monthly case for a total of 28 days of therapy. Each monthly 
case contains four weekly boxes. Each weekly box contains seven daily dose packs.
Telotristat ethyl is administered with food.
Duration of therapy is until disease progression.
ii.
Storage
Stored at 25°C [77°F]; excursions limited to 15° C [59°F to 89°F). 
b.
Patient counseling information
Advise patient:
1. If the severe constipation or severe or persistent or worsening abdominal pain to 
discontinue Telotristat ethyl and contact healthcare provider
2. To take did not restart with food
3. If a dose is missed, take the next dose at the regular time. Do not take 2 doses at 
the same time to make up for the missed dose.
12.
ADVERSE EVENTS
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) v4 will be utilized for AE reporting. A copy of the CTCAE v4 
can be downloaded from the CTEP website at http://ctep.cancer.gov
a.
Definitions 
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i.
Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence whether or not considered related 
to the study drug that appears to change in intensity during the course of the study. The 
following are examples of AEs: 

Unintended or unfavorable sign or symptom

A disease temporally associated with participation in the protocol

An intercurrent illness or injury that impairs the well-being of the subject
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce 
clinical signs or symptoms or require treatment or further diagnostic tests  
Hospitalization for elective surgery or routine clinical procedures that are not the result of an 
AE (e.g., surgical insertion of central line) should not be recorded as an AE. 
Disease progression should not be recorded as an AE unless it is attributable to the study 
regimen by the site investigator.
ii.
Serious Adverse Event
A serious adverse event (SAE) is any untoward medical occurrence resulting in one or more 
of the following:

Death- Death due to progression is not considered a SAE unless the site investigator 
feels the study drug contributed to disease progression.

Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly or birth defect

Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above). Examples of such events include, but are not 
limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; or the 
development of drug dependency or drug abuse.
iii.
Unexpected Adverse Event
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included 
in the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug but are not specifically mentioned as occurring with 
the particular drug under investigation.  
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iv.
Relatedness
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms: 
Unrelated
Adverse Event is not related to the study drug(s) 
Unlikely
Adverse Event is doubtfully related to the study drug(s) 
Possible
Adverse Event may be related to the study drug(s) 
Probable
Adverse Event is likely related to the study drug(s) 
Definite
Adverse Event is clearly related to the study drug(s)
b.
Reporting adverse events
i.
Adverse Event (AE)

AEs will be recorded from start of treatment until 30 days after discontinuation of 
study drug(s). 

AEs will be recorded regardless of whether or not they are considered related to the 
study drug(s).  

All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within OnCore.

AEs considered related to study drug(s) will be followed until resolution to 
Grade ≤ 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer 
treatment starts, whichever occurs first.
ii.
Serious Adverse Event (SAE) 
10.2.2.1
Site Requirements for Reporting SAEs For Group 1 only (Telotristat ethyl 
treatment group)

SAEs will be reported from start of treatment until 30 days after discontinuation of 
study drug(s). 

SAEs will be reported on the SAE Submission Form within 24 hours of discovery of 
the event.  

SAEs include events related and unrelated to the study drug(s). 

All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within OnCore.  

All SAEs regardless of relation to study drug will be followed until resolution to ≤ 
Grade 1 or baseline and/or deemed clinically insignificant and/or until a new anti-
cancer treatment starts, whichever occurs first.
The completed SAE Submission Form must be sent either electronically to coordinators on 
the trial. The site investigator is responsible for informing the IRB and/or the Regulatory 
Authority of the SAE as per local requirements.  The original copy of the SAE Submission 
Form and the email correspondence or fax confirmation sheet must be kept within the Trial 
Master File at the study site.
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Once the SAE has resolved (see resolution guidelines listed in 11.2.2.1), sites must submit a 
follow-up SAE Submission Form within a reasonable timeframe 
No SAE needed to be reported for Group 2 as treatment does not include Telotristat 
ethyl and the intervention is only checking blood and urine samples for serotonin and 
5HIAA levels, respectively.
10.2.2.2
Sponsor-Investigator Responsibilities 
Coordinator will send a SAE summary to the sponsor-investigator within 24 hours of receipt 
of SAE Submission Form.  The sponsor-investigator will promptly review the SAE summary 
and assess for expectedness and relatedness.  
10.2.2.3
Requirements for Reporting to the Food and Drug Administration (FDA)
The PI will hold the IND. Written IND safety reports will be submitted to the FDA by the 
IND sponsor, for serious, unexpected suspected adverse reactions within 15 calendar days of 
learning of its occurrence. If the event is fatal or is deemed to be life threatening, the report 
will be made within 7 calendar days.  The IND sponsor will also make an assessment of 
whether the event constitutes an unanticipated problem posing risks to subjects or others 
(UP). This assessment will be provided to the Emory University IRB, which, in turn will 
make a final determination.  If the Emory IRB determines an event is a UP it will notify the 
appropriate regulatory agencies and institutional officials.
13.
STATISTICAL METHODS
a.
General Considerations
This is a phase II, single institution, randomized, 2-arm trial evaluating the efficacy and safety 
of Telotristat ethyl combination with chemotherapy (Arm A) vs. standard of care 
chemotherapy (Arm B) in 80 subjects with advanced PCA, not amenable to curative treatment. 
b.
Study Design
i.
Sample Size and Statistics
Aim # 1: Estimated weight loss in pancreatic cancer patients is 10 %. Weight stability is the 
primary end point. Percentage weight change will be calculated at month 3 and 6 relative to 
baseline, and a weight loss < 5% will be considered as clinical meaningful weight stability. 
A sample size of 40 achieves 81% power to detect a non-inferiority margin of -5% weight 
change from baseline using a one-sided Wilcoxon test. We assume the true weight change is 
0% and follows normal distribution with standard deviation of 12%. The significance level 
(alpha) of the test is set at 0.05
Aim # 2: This is a descriptive end point to see if we can detect a difference of change in 
serotonin and 5HIAA levels compared to baseline (before chemotherapy treatment) 
A sample size of 40 achieves 80% power to detect a mean of paired differences of 0.4 with 
an estimated standard deviation of differences of 1.0 and with a significance level (alpha) of 
0.05000 using a one-sided paired t-test.
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ii.
Correlative markers 
Aim # 1 and 2: We propose to check serum serotonin, albumin and 24-hr urine 5HIAA levels 
at baseline and every month when the patient is on chemotherapy and Telotristat ethyl 
treatment until disease progression.
Aim # 3: Evaluate QOLeffect on MAC and abdominal muscle
Aim # 4: Evaluate safety of the combination of Telotristat ethyl with gemcitabine/nab-
paclitaxel combination treatment for Group 1.
Aim #5: Evaluate median progression free survival and overall survival in both groups
Aim # 6: Evaluate the response rates for patients on Group 1 and Group 2
c.
Definition of Primary Endpoint
Weight stability over a period of 3 months while on trial.
d.
Definitions of Secondary Endpoints
Performance status will be assessed clinically
Quality of life (QOL) will be assessed by the EORTC QLQ-30  
Mid Arm Circumference (MAC) and muscle mass on cross sectional imaging. This 
will be assessed with imaging guided measurements of the psoas and rectus abdominus 
muscle
Evaluate correlations between changes in 5HIAA levels on radiologic response, 
weight stability, Mid Arm Circumference (MAC), and muscle mass on cross sectional 
imaging
Evaluate the relation of baseline serum serotonin and 24-hr urine 5-HIAA on weight 
loss in patients with locally advanced unresectable, recurrent, metastatic PDAC. For 
this aim, we will include baseline measurement from patients in Group 1 (N=40) and 
Group 2 (N=40)
Safety and tolerability of telotristat ethyl with gemcitabine/nab-paclitaxel combination 
chemotherapy assessed by the CTCAE v 4 to grade toxicities
PFS is based upon the time of enrollment until progression or death. Disease is 
evaluated by CT/MRI scans of the organ(s) with the target lesion(s) based on 
RECIST 1.1 criteria.
Overall survival is defined as the time of enrollment to time of death. Response is 
defined as a complete or partial response according to CT/MRI evaluations based on 
RECIST criteria. 
Duration of Response: Time from first response to time of progression evaluated by 
CT/MRI scans of the organ(s) with the target lesion(s) based on RECIST criteria.
e.
Analysis Plan for Primary Objective
For the Aim # 1 of proving weight stability in the treatment arm, the patients in Group 1 will 
be treated with Telotristat ethyl and gemcitabine/nab-paclitaxel combination chemotherapy. 
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Their weight will be measured at baseline and after 3 and 6 months of telotristat ethyl 
treatment or at time of progression. The absolute weight change will be calculated by the 
weight after 3 months minus the baseline and the % weight will be the weight change at 3 and 
6 months or time of disease progression compared to baseline. Weight stability is defined as 
weight change of less or equal to 5%. One sided Wilcoxon signed rank test will be used to test 
whether there is significant weight loss at 3 months after treatment compared to baseline, 
given a non-inferiority margin of -5%.  
For the Aim # 2 of evaluating the change in serum serotonin and 24 hr urine 5-HIAA in the 
group 2 patients with locally advanced unresectable, recurrent, metastatic PDAC receiving 
chemotherapy, the change will be summarized as mean and standard deviation. Then one-
sided paired t-test will be employed to test whether there is a significant change in serotonin 
and 5HIAA levels compared to baseline (before chemotherapy treatment). Finally, General 
linear model (GLM) will be used in the multivariate analysis to test whether the adjusted 
change is still significant after adjusting for other factors.  
f.
Analysis Plan for Secondary Objectives
Descriptive statistics will be first used to summarize weight stabilization/gain on patients, 
performance status, quality of life (QOL), Mid Arm Circumference (MAC) and muscle mass 
on cross sectional imaging. For categorical variables, the number and percent of each 
category within a parameter will be calculated. For continuous variables, the sample size (n), 
mean, median, standard deviation, and coefficient of variation, as well as the minimum and 
maximum values, will be presented. Missing data will not be imputed unless otherwise 
stated. T-test, Chi-square test, General linear model will be further employed to test the 
impact of weight stabilization/gain on performance status, quality of life (QOL), Mid Arm 
Circumference (MAC) and muscle mass on cross sectional imaging. 
Similarly, T-test, Chi-square test, General linear model will be further employed to evaluate 
correlations between changes in serotonin/ 5HIAA levels on radiologic response, weight 
stability, Mid Arm Circumference (MAC), and muscle mass on cross sectional imaging.
To evaluate the relation of baseline serotonin and its metabolite 5-HIAA on weight loss in 
patients with locally advanced unresectable, recurrent, and metastatic) pancreatic cancer, 
Pearson or Spearman correlation coefficient will be first used to measure their correlation. 
General linear model will be further used to estimate their adjusted relationship after 
adjusting for other factors. 
RR will be estimated for each arm and reported along with exact 95% confidence intervals. 
A Fisher’s exact test will be used to compare RR between the two arms. Toxicities will be 
described for each arm using frequency tables. Fisher’s exact tests will be used compare 
toxicities between arms. The ITT populations will be used for secondary analyses related to 
OS and RR. The safety analysis dataset will be used for analyses related to toxicities.
For progression free survival, progression or death from any cause will be defined as the 
event. Patients will be censored at time of last follow-up. For overall survival, death from 
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any cause will be defined as the event. Patients will be censored at time of last follow-up. 
Overall survival (OS) and progression free survival (PFS) rates of two patient groups will be 
estimated with the Kaplan-Meier method and compared between different groups using the 
log-rank test, respectively. The PFS and OS of each patient group at specific time points, 
such as 6 moths, 1 year, 3 year, and 5 year, etc. will be also estimated alone with 95% CI. 
Cox proportional hazards models will be further used in the multivariable analyses to assess 
adjusted effect of treatment on the patients’ OS and PFS after adjusting for other factors. 
Interaction terms between these factors will also be tested for statistical significance. The 
proportional hazards assumption will be evaluated graphically and analytically with 
regression diagnostics. Violations of the proportional hazards assumptions will be addressed 
by use of time-dependent covariates or extended Cox regression models. 
g.
Analysis Population
The intention-to-treat (ITT) population includes all subjects who meet the eligibility criteria 
and are registered onto the study irrespective of their compliance to the planned course of 
treatment. The intention-to-treat principle asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a subject (i.e. the planned 
treatment regimen) rather than the actual treatment given. It has the consequence that subjects 
allocated to a treatment group should be followed up, assessed and analyzed as members of 
that group irrespective of their compliance to the planned course of treatment.
The safety analysis dataset includes all subjects who are enrolled and receives a fraction of 
Telotristat ethyl (on either arm). Subjects will be analyzed for safety according to the treatment 
actually received.
h.
Sample Size/Accrual/Study Duration 
Estimated weight loss in PDAC patients is 10 % within 3 months prior to diagnosis. 
Weight stability is the primary end point. Percentage weight change will be 
calculated at month 3 and 6 or time of progression relative to baseline, and a weight 
loss < 5% will be considered as clinical meaningful weight stability. A sample size 
of 40 achieves 81% power to detect a non-inferiority margin of -5% weight change 
from baseline using a one-sided Wilcoxon test. We assume the true weight change is 
0% and follows normal distribution with standard deviation of 12%. The significance 
level (alpha) of the test is set at 0.05
Aim # 2- This is a descriptive end point to see if we can detect a difference of 
change in serotonin and 5HIAA levels compared to baseline (before chemotherapy 
treatment) 
A sample size of 40 achieves 80% power to detect a mean of paired differences of 
0.4 with an estimated standard deviation of differences of 1.0 and with a significance 
level (alpha) of 0.05 using a one-sided paired t-test.
The estimated enrollment period for this study is 12 months and the estimated study duration 
is 20 months.
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i.
Subject Characteristics 
Baseline, demographic, and medical history information will be summarized for each arm. 
Demographic and baseline data will also be provided in by-subject data listings.  
j.
Concomitant Medications
Concomitant medication use will be summarized for each arm and will be included in by-
subject data listings.
k.
Disposition
A tabulation of subject disposition will be presented, including the number in each analysis 
population, the number who withdrew from treatment and the reasons for withdrawal, and the 
number who withdrew during the follow-up phase and the reasons for withdrawal. 
14.
TRIAL MANAGEMENT
a.
Data and Safety Monitoring Plan
The study will be conducted in accord with the Winship Cancer Institute of Emory 
University’s Data and Safety Monitoring Plan (DSMP). 
In addition, data and safety activities include:

Review all adverse events requiring expedited reporting as defined in the protocol

Provide data summary reports to the sponsor-investigator on a monthly basis

Submit data summary reports to the lead institution Data Safety Monitoring 
Committee for review as per their guidelines.
b.
Winship Cancer Institute Data Safety Monitoring Committee
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study which has been deemed Moderate Risk.  The 
DSMC functions independently within Winship Cancer Institute to conduct internal 
monitoring functions to ensure that research being conducted produces high-quality scientific 
data in a manner consistent with good clinical practice (GCP) and appropriate regulations that 
govern clinical research.  Since this study is Moderate Risk, initial study monitoring will occur 
within 1 year from the date of the first subject accrued, with 2 of the first 5 subjects being 
reviewed.  Subsequent monitoring will occur in routine intervals per the Winship Data and 
Safety Monitoring Plan (DSMP). 
The DSMC will review the following:

Adverse event summary report

Monitoring and/or audit results if applicable

Summary of enrollment including number of subjects consented, enrolled, treated and 
active and discontinued 

Any regulatory compliance findings from all active sites

Summary of investigational product accountability, handling, and dose delivery

Summary of protocol compliance relative to tumor response evaluation

Summary of data accuracy and timeliness of reporting
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
Any site-specific concerns with elements above, with recommendation/documentation 
or corrective actions and re-monitoring as needed
The Winship Cancer Institute DSMC will review aggregate AE data on an annual basis.  
Documentation of DSMC reviews will be provided to sponsor-investigator.  Issues of 
immediate concern by the DSMC will be brought to the attention of the sponsor-investigator 
and other regulatory bodies as appropriate.  The sponsor-investigator will work to address the 
DSMC’s concerns.  
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Following the monitoring review, monitors 
will provide a preliminary report of monitoring findings to the PI and other pertinent 
individuals involved in the conduct of the study.  The PI is required to address and respond to 
all the deficiencies noted in the preliminary report.  Prior to the completion of the final 
summary report, monitors will discuss the preliminary report responses with the PI and other 
team members (when appropriate).  A final monitoring summary report will then be prepared 
by the monitor.  Final DSMC review will include the final monitoring summary report with 
corresponding PI response, submitted CAPA (when applicable), PI Summary statement, and 
available aggregate toxicity and safety data.  
The DSMC will render a recommendation and rating based on the overall trial conduct.  The 
PI is responsible for ensuring that instances of egregious data insufficiencies are reported to 
the IRB.  Continuing Review submissions will include the DSMC recommendation letter.  
Should any revisions be made to the protocol-specific monitoring plan after initial DSMC 
approval, the PI will be responsible for notifying the DSMC of such changes.  The Committee 
reserves the right to conduct additional audits if necessary. 
c.
Data Quality Oversight Activities
Remote validation of OnCore data will be completed on a continual basis throughout the life 
cycle of the study by study coordinators.  A summary report (QC Report) of these checks 
together with any queries resulting from manual review of the eCRFs will be generated. 
Corrections will be made by the study site personnel. 
Additional for-cause visits may occur as necessary. Source documents will be reviewed for 
verification of agreement with data entered into OnCore. It is important for the site 
investigator and their relevant personnel to be available for a sufficient amount of time during 
the monitoring visits or audit, if applicable. The site investigator and institution guarantee 
access to source documents. 
The trial site may also be subject to quality assurance audit by Lexicon. or its designee as well 
as inspection by appropriate regulatory agencies.
d.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
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requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. 
All results of primary and secondary objectives must be posted to CT.gov within a year of 
completion. 
15.
DATA HANDLING AND RECORD KEEPING
a.
Case Report Forms and Submission
This study will utilize electronic case report forms (eCRFs) in an electronic data capture 
system OnCore. OnCore will be compliant with Good Clinical Practices . 
Generally, clinical data will be electronically captured in OnCore. If procedures on the study 
calendar are performed for standard of care, at minimum, that data will be captured in the 
source document. Select standard of care data will also be captured in OnCore, according to 
study-specific objectives. 
The completed dataset is the sole property of Emory University and will not be exported to 
third parties, except for authorized representatives of appropriate Health/Regulatory 
Authorities, without written permission from the sponsor-investigator.
b.
Record Retention
To enable evaluations and/or audits from Health Authorities, the site investigator agrees to 
keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, 
and detailed records of drug disposition. All source documents are to remain in the subject’s 
clinic file. To comply with international regulations, the records should be retained by the site 
investigator in compliance with regulations.
During data entry, range and missing data checks will be performed on-line. The checks to be 
performed will be documented in the Data Monitoring Plan for the study. A summary report 
(QC Report) of these checks together with any queries resulting from manual review of the 
eCRFs will be generated for each site and transmitted to the site and the site monitor. 
Corrections will be made by the study site personnel. This will be done on an ongoing basis.
c.
Confidentiality
There is a slight risk of loss of confidentiality of subject information. All records identifying 
the subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. 
Information collected will be maintained on secure, password protected electronic systems. 
Paper files that contain personal information will be kept in locked and secure locations only 
accessible to the study team. Samples that are collected will be identified by a subject’s study 
number assigned at the time of registration to the trial. Any material issued to collaborating 
researchers will be anonymized and only identified by the subject’s study number.
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Subjects will be informed in writing that some organizations, including the sponsor-
investigator and his/her research associates, Emory University, Lexicon, IRB, or government 
agencies, like the FDA, may inspect their medical records to verify the information collected, 
and that all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection laws.
If the results of the study are published, the subjects’ identity will remain confidential.
d.
Changes to the Protocol and Informed Consent
Study procedures will not be changed without the mutual agreement of the sponsor-
investigator, Emory University IRB and Lexicon.
If it is necessary for the study protocol to be amended, the amendment or a new version of the 
study protocol (amended protocol) will be generated by the sponsor investigator and must be 
approved by Lexicon in addition to each site’s IRB. Local requirements must be followed.
If a protocol amendment requires a change to the informed consent form, then the IRB must 
be notified. Approval of the revised informed consent form by the IRB is required before the 
revised form is used. 
The site investigator is responsible for the distribution of these documents to his or her IRB, 
and to the staff at his or her center. 
Lexicon’s willingness to supply study drug is predicated upon the review of the protocol. 
Sponsor-Investigator agrees to provide written notice Lexicon of any modifications to the 
protocol or informed consent.
Complion Document ID: 6365537

Clinical Study Protocol
Version Date: 6/13/2023
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16.
ETHICS
a.
Ethics Review
Each site must obtain approval of the final study protocol, including the final version of the 
informed consent form, from its IRB. 
The site investigator must inform the IRB of any amendment to the protocol in accordance 
with local requirements. In addition, the IRB must approve all advertising used to recruit 
subjects for the study. The protocol must be re-approved by the IRB annually, as local 
regulations require. 
Sites will provide progress reports and notifications of serious unexpected adverse drug 
reactions will be provided to the IRB as required by local regulations and guidelines.
b.
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles which are consistent with 
ICH/Good Clinical Practice E6 as adopted by the FDA, and applicable regulatory 
requirements.
c.
Informed Consent Process
The site investigator will ensure the subjects is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided.
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.
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Clinical Study Protocol
Version Date: 6/13/2023
Confidential
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17.
REFERENCES
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Clinical Study Protocol
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Complion Document ID: 6365537