Clinical trial NCT03790111
Conditions: Biliary Tract Cancer (BTC)
Sponsor: TerSera Therapeutics LLC
Start date: 2019-03-13; Completion date: 2022-01-13
Enrollment: 53 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase 2, multicenter, open-label, 2-stage study to assess the safety, tolerability, and efficacy of XERMELO in combination with first-line (1L) therapy (cisplatin \[cis\] plus gemcitabine \[gem\])

Detailed description:
A Phase 2, multicenter, open-label, 2-stage study to assess the safety, tolerability, and efficacy of XERMELO in combination with first-line (1L) therapy cis plus gem in patients with unresectable, locally advanced, recurrent or metastatic biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer), who are naïve to tumor-directed therapy in the locally advanced or metastatic setting, and for which treatment with 1L therapy (defined as a combination of cis plus gem) is planned.

Arms: arm 1: Xermelo 250 milligram (mg) plus first line therapy for a week, then Xermelo 500mg plus first line therapy for the duration of the study
Interventions: intervention 1: telotristat ethyl
Intervention descriptions: intervention 1: XERMELO (telotristat ethyl) tablets administered as 250 mg (1 x 250-mg tablet) three times a day plus first line therapy for 7 days, then XERMELO (telotristat ethyl) tablets administered as 500 mg (2 x 250-mg tablets) three times a day plus first line therapy for the duration of the study

Protocol documents:
Prot_000.pdf: 
 
Title:   A Phase 2, Multicenter, Open-label, Safety and Efficacy Study of XERMELO® 
(Telotristat Ethyl) plus First-line Chemotherapy in Patients with Locally Advanced, 
Unresectable, Recurrent or Metastatic Biliary Tract Cancer (BTC) 
 
 
NCT Number: 03790111 
 
Protocol Approval Date:   November 23, 2020 
 
Certain information within this protocol has been redacted (ie, Specific content is 
masked irreversibly from view with a black bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
• Named persons or organizations associated with the study. 
 
• Proprietary information, such as scales or coding systems, which are 
considered confidential information under prior agreements with license 
holder. 
 
• Other information as needed to protect confidentiality of TerSera or 
partners, personal information, or to otherwise protect the integrity of the 
clinical study. 
 
The information contained in the following document is the property of TerSera 
Therapeutics LLC and should not be shared or used for any purpose other than for 
which it was provided. 
 
 


15 November 2020 
Page 1 of 117 
CLINICAL STUDY PROTOCOL 
Protocol Number: 
LX1606.1-207-BTC 
LX1606.207 (Abbreviated number) 
Investigational Phase: 
2a 
Protocol Title: 
A Phase 2, Multicenter, Open-label, Safety and Efficacy Study 
of XERMELO® (Telotristat Ethyl) plus First-line 
Chemotherapy in Patients with Locally Advanced, 
Unresectable, Recurrent or Metastatic Biliary Tract Cancer 
(BTC) 
Study Name: 
TELE-ABC (Telotristat Ethyl for Advanced Biliary Tract 
Cancer) 
Amendment 3 Date 
23 November 2020 
Administrative Change 
29 May 2020 
Amendment 2 Date 
08 August 2019 
Amendment 1 Date 
13 December 2018 
Original Version Date: 
24 October 2018 
Sponsor: 
TerSera Therapeutics LLC 
 520 Lake Cook Road, Suite 500 
Deerfield, IL 60015 
Medical Director: 
Co-Coordinating 
Investigators 
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A d va nce d, U nresecta ble, Rec urre nt or Metastatic 
Biliar y Tract Ca ncer ( B T C) 
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PROTOCOL AMENDMENT SUMMARY OF KEY CHANGES 
1. Replaced former Sponsor name (Lexicon) and contact details, including Medical
Director, Medical Monitor and Safety reporting contacts with new Sponsor (TerSera
Therapeutics LLC) and contact details throughout the protocol.
2. Added Amendment 3 date.
3. Clarified in the Synopsis and throughout the protocol that efficacy, based on progression-
free survival rate at Month 6 will also be assessed in the Per Protocol population and by
treatment cycle.
4. Clarified in the Synopsis and within the protocol that Cycle 10 Day 1 is considered the
Month 6 timepoint and Cycle 19 Day 1 is considered the Month 12 timepoint for analysis
purposes.
5. Clarified that enrollment into Stage 2 will continue if greater than or equal to (≥) 60% of
patients in the Safety Population and the Per-Protocol (PP) population survive and remain
progression-free at Month 6.
6. Clarified in the Synopsis and throughout the protocol that certain
7. Updated the synopsis and throughout the protocol which endpoints are exploratory
endpoints.
8. Added new exploratory efficacy endpoint
9. Added new exploratory subgroup analyses
10. Included that patients who prematurely discontinued from Treatment Period or withdrew
consent from Treatment Period prior to Month 6 of the Treatment Period, will be asked to
reconsent to allow for images and or imaging reports, obtained locally, to be submitted to
BICR.
11. Added a formal interim analysis to be conducted on the Stage 1 analysis group, i.e., the
first 20 patients enrolled in the study. The interim analysis results will include safety,
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XERMELO® Protocol No. LX1606.207 
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efficacy (response rates) and pharmacodynamic (biomarker) data. These data will be used 
to help plan for future studies. 
12. Outlined that C1D1 images do not need to be collected and submitted to BICR when
images that were obtained within 6 weeks prior to Day 1 were submitted to BICR.
13. Clarified that Screening images obtained within 6 weeks prior to and including Cycle 1
Day 1 (C1D1), or whichever images were closest in date to C1D1, will be considered
Baseline.
14. Minor grammatical edits have been incorporated throughout the protocol.
15. Added Appendix K detailing each edit within the document, except minor grammatical
changes.
For a detailed summary of all changes, please refer to Appendix K. 
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1 
SYNOPSIS 
Name of Study Drug 
XERMELO® (telotristat ethyl) 
Protocol Number 
LX1606.1-207-BTC 
LX1606.207 (Abbreviated number) 
Protocol Title 
A Phase 2, Multicenter, Open-label, Safety and Efficacy Study of 
XERMELO® (telotristat ethyl) plus First-line Chemotherapy in 
Patients with Unresectable, Locally Advanced, Recurrent or 
Metastatic Biliary Tract Cancer (BTC)  
Primary Objective 
The primary objective of the study is to assess the safety and 
efficacy (PFS rate at Month 6) in the Safety population receiving the 
combination of XERMELO plus 1L treatment with cis/gem 
combination chemotherapy. Efficacy (PFS rate at Month 6) will also 
be evaluated in the Per Protocol Population (PP) and by treatment 
cycle.   
Secondary Objectives 
To assess the effect of study treatment on the following: 
•
Overall survival (OS)
•
OS rate at Months 6 and 12
•
PFS rate at Month 12 and median PFS at Month 12
•
Disease control rate (DCR); defined as complete response (CR)
+ partial response (PR) + stable disease (SD) at Months 6 and
12 and End of Study (EOS)
•
Objective response rate (ORR) defined as CR + PR at Months 6
and 12 and EOS
•
Local radiologist’s assessment of PFS, ORR, and DCR
•
Change from Baseline in plasma 5-hydroxyindoleacetic acid (5-
HIAA) and serum carbohydrate antigen 19-9 (CA 19-9) at
Months 6 and 12 and EOS
•
Change from Baseline in body weight at Months 6 and 12 and
EOS
•
Change from Baseline in serum albumin at Months 6 and 12
and EOS
Note: Unless otherwise indicated, all radiologic endpoints will be 
based on Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 as determined by blinded independent central review (BICR) 
and compared to published historical data of cisplatin/gemcitabine 
(cis/gem) alone. 
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Exploratory Objectives 
To assess the effect of study treatment on the following: 
•
Changes in health-related quality of life (HRQoL) as
measured by European Organisation for Research and
Treatment of Cancer (EORTC) Quality of Life
Questionnaire Core 30 (QLQ-C30) and Cholangiocarcinoma
and Gallbladder Cancer (QLQ-BIL21) items at Baseline,
Months 6 and 12;
•
Change from Baseline in carcinogenic embryonic antigen
(CEA) fragment at Months 6 and 12 and EOS;
•
Subgroup analyses of PFS, OS, ORR, and DCR using both
BICR and local radiologist’s assessment, based on
categorical group of Baseline and change from Baseline at
Months 6 and 12 and EOS in:
o
body weight
o
serum albumin
o
correlation between Baseline neutrophil:lymphocyte
ratio and OS
•
Subgroup analyses in:
o
Patients with changes in liver function tests
o
Patients with Biliary stents
o
Location of disease (intrahepatic, extrahepatic, or
gallbladder)
o
Extent of disease
o
Demographic groups
•
Efficacy analyses by treatment cycles (such as in patients
who completed 
 with combination
treatment)
Pharmacokinetic (PK) 
Objectives 
To identify intrinsic and extrinsic factors contributing to variability 
in exposure of XERMELO and the active metabolite, LP-778902, 
when dosed as a combination treatment with cisplatin and 
gemcitabine, including but not limited to, age, sex, race, body mass 
index (BMI), as compared to historical data  
Substudy Objectives 
•
To assess the effect of study treatment based on
characterization of tumor tissue by immunohistochemical (IHC)
staining (i.e., serotonin [5-HT] and tryptophan hydroxylase-1
[TPH-1])
•
To determine the population PK profile among patients who
participate in intensive PK sampling
Primary Safety Objectives 
Evaluation of overall safety will be assessed by means of the 
following: 
•
Incidence of treatment-emergent adverse events (TEAEs) and
severity assessment using National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE)
v5.0
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•
Change from Baseline in clinical laboratory results including
frequency of values meeting CTCAE severity Grades >1,
laboratory data toxicities as defined by NCI CTCAE v5.0,
physical examination (PE) findings, vital signs, and
electrocardiogram (ECG) findings
Phase of Development 
Phase 2a 
Methodology 
This study will be conducted as a multicenter, open-label, 2-stage 
study to assess the safety, tolerability, and efficacy of XERMELO in 
combination with first-line (1L) therapy (cisplatin plus gemcitabine) 
in patients with unresectable, locally advanced, recurrent or 
metastatic BTC (intrahepatic or extrahepatic cholangiocarcinoma, 
gallbladder cancer), who are naïve to tumor-directed therapy in the 
locally advanced or metastatic setting, and for which treatment with 
1L therapy (defined as a combination of cis/gem) is planned.  
Note: 1L therapy will not be provided for this study by the Sponsor.  
Note: Efficacy (PFS rate at Month 6) will also be assessed in the Per 
Protocol population and by treatment cycle. 
Note: For statistical purposes and most analyses, Cycle 1 Day 
1 is intended as Baseline, Cycle 10 Day 1 is intended as 
Month 6, and Cycle 19 Day 1 is intended as Month 12.  
Study Overview: 
Stage 1 
Stage 1 enrollment will include a Safety Run-in cohort. Safety and 
tolerability data of the combination treatment from the first 6 
patients who complete at least 21 days of safety follow-up after the 
first dose of combination treatment will be evaluated by the 
Coordinating Investigators, Sponsor, and Medical Monitor in 
accordance with established clinical stopping rules. This review will 
include all safety assessments from all patients obtained prior to the 
second chemotherapy cycle of the 6th patient enrolled. During this 
safety review, Stage 1 enrollment will continue as per the study 
schema outlined below. It is anticipated that a total of 20 patients 
will participate in Stage 1. If there are no clinically significant or 
unresolved Grade 3 or higher toxicities considered related to the 
study drug, and if efficacy in 12 (60%) or more of the 20 patients are 
deemed responders, in the Safety population, enrollment will 
continue to Stage 2. In addition, efficacy will be assessed in the Per-
Protocol (PP) population and by treatment cycle.  
Stage 2 
Stage 2 may initiate enrollment once Stage 1 enrollment has been 
completed, in the absence of significant or unresolved Grade 3 or 
higher toxicities considered related to the study drugs. 
Approximately 33 additional patients are anticipated to participate in 
Stage 2. Study duration and assessments in this stage will be 
identical to Stage 1.  
From a total of 53 accrued patients from Stage 1 + Stage 2, if 34 
(>60%) or more responses are observed (i.e., patients are alive and 
progression-free at Month 6) in the Safety population, the study will 
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be declared successful. Efficacy will also be assessed in the PP 
population and by treatment cycle. 
Study Treatment (Stage 1 and Stage 2) 
On Day 1 (D1), eligible patients are to initiate Cycle 1 (C1), a 21-
day cycle of XERMELO plus 1L therapy (herein referred to as 
“combination treatment”) as follows:  
o
XERMELO 250 mg (1 x 250-mg tablet) given as an oral
dose 3 times daily (tid) for 7 days, plus
o
Cisplatin 25 mg/m2 administered intravenously (iv) over 60
to 90 minutes, followed by
o
Gemcitabine 1000 mg/m2 administered iv over 30 minutes
On Day 8, patients will receive combination treatment as follows: 
o
XERMELO 500 mg (2 x 250-mg tablets) tid for 14 days,
plus
o
Cis/Gem as described above
Every 21 days thereafter, patients will initiate a new 21-day cycle 
(eg, Cycle 2 [C2], Cycle 3 [C3]) and will receive combination 
treatment, administered as  
o
XERMELO 500 mg tid, plus
o
Cis/Gem regimen as described above on Day 1 and Day 8 of
each cycle
Dose modification(s) and/or delay in treatment may be permitted as 
described in the sections described below. During the Treatment 
Period, patients may discontinue cisplatin and continue treatment 
with XERMELO plus gemcitabine alone at the Investigator’s 
discretion. Gemcitabine should be administered on the same 
schedule as described above. 
Active symptom control will be permitted during the study as 
clinically indicated.  
Radiological assessment of the tumor by computed tomography (CT) 
or magnetic resonance imaging (MRI) will be conducted prior to 
initiating treatment on Cycle 1 Day 1 (C1D1), then every 9 weeks (3 
cycles) for the remaining duration of the Treatment Period. Note: If 
a radiological assessment has performed within 6 weeks prior to Day 
1, a Day 1 assessment will not be required. 
All imaging will be evaluated by the local radiologist (or designee) 
for clinical management. If a change in response is noted by the local 
radiologist or Investigator at any time during the study a second 
radiological assessment should be performed within 4-6 weeks to 
confirm.    
All images will be sent to a central review facility for 
blinded, independent-parallel reading (i.e., BICR) for assessments of 
study endpoints. No information regarding results of progressive 
disease (PD) determination will be shared between central radiologic 
review and the local radiologist/Principal Investigator at any time 
during the study. 
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Note: Management of biliary obstruction and/or ascending 
cholangitis will not be considered as PD in the absence of 
radiologically confirmed PD. 
Patients may continue to receive combination treatment as described 
above for as many cycles as possible until PD as determined by local 
review, unacceptable toxicity, or the patient withdraws from 
treatment. At this time, chemotherapy will be discontinued, the End-
of-Treatment (EOT) assessments should occur, and the patient 
should enter the Follow-up Period. Visit dates for the Follow-up 
period are based off the EOT date.  
Follow-up Periods: 
All patients are expected to be followed for a total duration of 24 
months after the Treatment Period unless they prematurely 
discontinue or voluntarily withdraw consent from future study visits 
or assessments. This 24-month phase is divided into 2 periods; the 
Post-treatment Follow-up Period (PTFP) where onsite visits occur 
every 3 months, and the Survival Follow-up Period, where survival 
status will be collected by phone and no onsite visits are required. 
Post-treatment Follow-up 
All patients are expected to enter a Post-treatment Follow-up Period 
(PTFP) at the time PD is confirmed locally or the patient experiences 
unacceptable toxicity, or the patient withdraws from chemotherapy 
in the absence of PD. During the Post-treatment Follow-up Period, 
patients may continue treatment with XERMELO at the discretion of 
the treating physician. 
Patients will complete scheduled study visits every 3 months for a 
total of 24 months or until the patient begins a new tumor-directed 
therapy, prematurely discontinues, declines further treatment after 
progression, or withdraws consent from future study visits or 
assessments. At this time, the End of Study (EOS) procedures should 
be performed and the patient should enter the Survival Follow-up 
(unless 24 months of follow-up after the last dose of chemotherapy 
has already occurred). 
Note: For those patients who enter the PTFP prior to PD confirmed 
locally (i.e., those who experience an unacceptable toxicity or 
withdraw from chemotherapy), routine imaging assessments will 
continue to be performed every 3 months until PD is confirmed by 
local review. 
Note: For those patients who enter PTFP prior to having their 6-
month imaging assessment in the Treatment Period, will be asked to 
consent to provide their local scans and/or local scan report closest to 
the Treatment Period 6-month timepoint. This includes the possible 
reconsenting of patients previously prematurely discontinued or 
withdrew consent from the Treatment Period of the study. 
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Survival Follow-up 
Once a new tumor-directed therapy begins, or a patient declines 
further treatment after progression, patients will enter the Survival 
Follow-up Period. All patients will be monitored until death, 
withdrawal of consent, loss to follow-up, or for a period of 24 
months following the last dose of chemotherapy, whichever comes 
first.   
Note: Patients who enter SFP without entering or completing PTFP 
and who entered SFP prior to having their 6-month imaging 
assessment in the Treatment Period, will be asked to consent to 
provide their local scans and/or local scan report closest to the 
Treatment Period 6-month timepoint. This includes the possible 
reconsenting of patients previously prematurely discontinued or 
withdrew consent from the Treatment Period of the study. 
The study scheme is as follows: 
Enroll Safety 
Cohort n=6
TE
1 + 1L
1 Cycle (21 days)
Enroll additional 
cohort n=6
TE
1 + 1L Reduced 
Dose
1 Cycle (21 Days)
Enroll remaining 
Stage 1 n=20
TE
1 + 1L
Terminate Study
Enroll remaining 
Stage 1 n=20
TE
1 + 1L Reduced 
Dose
If Clinically Significant AE*
 seen in ≥2 Patients
Treatment Period
Post Treatment 
Follow-up Period
Survival Follow-up 
Period
LX1606.207 
TE
1 + 1L in 
Patients with BTC 
N= 53
Enroll Stage 2 n=33
TE
1 + 1L Reduced 
Dose
If Clinically Significant AE* 
seen in ≤1 Patient
Enroll Stage 2 
n=33
TE
1 + 1L
If Clinically Significant AE*
 seen in ≤1 patient
If Clinically Significant AE*
 seen in ≥2 Patients
*Clinically Significant AE defined as unresolved, ≥Grade 3 non 
hematological toxicity related to study drug (See Exclusions in 
Protocol).
1 TE = Telotristat Ethyl
Number of Patients 
A total of 20 patients are anticipated to be enrolled in Stage 1 and 33 
patients in Stage 2, for a total of 53 patients enrolled in the study.  
Patients 
Eligible patients are defined as, adults of either sex (≥18 years of 
age) with unresectable, locally advanced, recurrent, or metastatic 
BTC (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder 
cancer) naïve to tumor-directed therapy in the locally advanced or 
metastatic setting and are candidates to receive 1L therapy. 
Number of Study Sites 
Approximately 15 sites in the United States 
Study Treatments 
XERMELO (telotristat ethyl) tablets administered as 250 mg (1 x 
250-mg tablet) tid for the first 7 days, then 500 mg (2 x 250-mg
tablets) tid plus 1L therapy for the duration of the study
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Route of Administration 
XERMELO is administered orally, cisplatin and gemcitabine are 
administered intravenously. 
Duration of Treatment 
Approximately 6 months of combination treatment (XERMELO plus 
1L therapy).  
Note: Patients may continue to receive treatment for as many cycles 
possible, until progressive disease (PD) (up to 19 cycles during the 
Treatment Period), and during the Post Treatment Follow-up Period 
(up to an additional 24 months) at the discretion of the Investigator. 
Inclusion Criteria 
Patients must meet all of the following criteria at Screening, or as 
otherwise indicated, to be considered eligible to participate in the 
study: 
1.
Adults of either sex, ≥18 years of age. Patients of
childbearing potential must agree to use an adequate method
of contraception during the study and for 30 days after the
last dose of XERMELO.
a.
Childbearing potential is defined as those who have
not undergone surgical sterilization (eg, documented
hysterectomy, tubal ligation, or bilateral salpingo-
oophorectomy) or those who are not considered
postmenopausal (defined as 12 months of
spontaneous amenorrhea). If necessary, follicular-
stimulating hormone (FSH) results >35 IU/L at
Screening are confirmatory in the absence of a clear
postmenopausal history.
b.
Adequate methods of contraception, defined as
having a failure rate of <1% per year, for patients or
their partner include the following: condom with
spermicidal gel, diaphragm with spermicidal gel,
intrauterine device, surgical sterilization, vasectomy,
oral contraceptive pill, depo-progesterone injections,
progesterone implant (i.e., Implanon®), patch
(Ortho Evra®), NuvaRing®, and abstinence. If a
patient is not sexually active but becomes active,
they or their partner should use medically accepted
forms of contraception.
2.
Histopathologically or cytologically-confirmed,
unresectable, locally advanced, recurrent, or metastatic BTC
(intrahepatic or extrahepatic cholangiocarcinoma,
gallbladder cancer)
3.
Naïve to tumor-directed therapy in locally advanced,
unresectable, or metastatic setting. Note: Previous treatment
with chemotherapy in the adjuvant setting (including
previous exposure to 1L therapy) will be permitted if PD is
confirmed >6 months following treatment.
4.
Measurable disease, defined as the presence of at least 1
measurable lesion as determined by RECIST v1.1 using
conventional imaging with CT or MRI
5.
Eastern Cooperative Oncology Group (ECOG) performance
status 0-1
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6.
Plans to initiate treatment with 1L therapy; defined as
cis/gem: cisplatin 25 mg/m2 administered iv over 60 to 90
minutes followed by gemcitabine1000 mg/m2 administered
iv over 30 minutes as standard of care
7.
Ability to provide written informed consent prior to
participation in any study-related procedure
Exclusion Criteria 
Patients who meet any of the following criteria at Screening, or as 
otherwise indicated, will be excluded from participating in the study:  
1.
Prior exposure to XERMELO, telotristat ethyl, telotristat
etiprate, LX1032, or LX1606
2.
Primary tumor site in the ampulla of Vater
3.
Treatment with photodynamic therapy for localized disease
or to relieve biliary obstruction in the presence of metastatic
disease within the past 30 days
4.
Hematology laboratory values of:
a.
Absolute neutrophil count (ANC) ≤1,500 cells/mm3;
or
b.
Platelets ≤100,000 cells/mm3; or
c.
Hemoglobin (Hgb) ≤9 g/dL; or
d.
White blood count (WBC) ≤3,000 cells/mm3
5.
Hepatic laboratory values of aspartate transaminase (AST)
or alanine aminotransferase (ALT):
a.
>5 x upper limit of normal (ULN) if patient has
documented history of hepatic metastases; or
b.
>2.5 x ULN if no liver metastases are present
6.
Serum albumin <2.8 g/dL
7.
Total bilirubin >1.5 x ULN or >1.5 mg/dL
8.
Prothrombin time (PT) or international normalized ratio
(INR) >1.5 x ULN. Note: Patients receiving therapeutic
doses of anticoagulant therapy may be considered eligible if
PT and INR are within the acceptable therapeutic limits for
the institution.
9.
Serum creatinine or serum urea >1.5 x ULN
10. Estimated glomerular filtration rate (eGFR) <50 mL/min
11. Positive pregnancy test, pregnant, or breastfeeding (female
patients only)
12. Any other clinically significant laboratory abnormality that
would compromise patient safety or the outcome of the
study
13. Any clinically significant and/or uncontrolled cardiac-related
abnormality that would compromise patient safety or the
outcome of the study including, but not limited to:
a.
Arrhythmia
b.
Bradycardia
c.
Tachycardia
d.
Symptomatic valvular disease
e.
Symptomatic congestive heart failure classified by
New York Heart Association (NYHA) as Class III
or IV
f.
Evidence of ischemia on ECG
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g.
Unstable angina pectoris
14. Myocardial infarction within the past 6 months
15. Active bleeding diathesis
16. Life expectancy ≤3 months
17. Current complaints of persistent constipation or history of
chronic constipation, bowel obstruction or fecaloma within
the past 6 months
18. Receiving chronic treatment with corticosteroids, ≥5 mg/day
of prednisone (or equivalent), or other immunosuppressive
agent(s)
19. Known history and/or uncontrolled hepatitis B surface
antigen (HBsAg), hepatitis C antibody (HCV Ab), or human
immunodeficiency virus (HIV)-1 or HIV-2
Note:  Because of the possibility of spontaneous resolution
of and success of treatment for hepatitis C, a clarification is
being provided. Patients who have a history of hepatitis C
will be allowed if their HCV RNA load is below the range
that reflects infection with the virus at a time point that is at
least 12 weeks after a spontaneous remission or 24 weeks
after the end of treatment for hepatitis C.
Hepatitis B patients will continue to be excluded based on having 
history of the disease. 
20. History of substance or alcohol abuse (Diagnostic and
Statistical Manual of Mental Disorders 5th edition [DSM-V]
Criteria for Substance-Related Disorders) within the past 2
years
21. History of galactose intolerance, deficiency of Lapp lactase,
or glucose-galactose malabsorption
22. History of malignancy or active treatment for malignancy
(i.e., radiation or chemotherapy, including monoclonal
antibodies) within 5 years. Note: Patients with squamous or
basal cell carcinomas of the skin, carcinomas in situ of the
cervix or uterus, ductal breast cancer in situ, resected low-
grade prostate cancer, or other malignancies that in the
opinion of the Investigator and the Medical Monitor are
considered cured, may participate.
23. Receipt of live, attenuated vaccine (eg, intranasal influenza,
measles, mumps, rubella, varicella) or close contact with
someone who has received a live, attenuated vaccine within
the past 1 month. Note: Influenza vaccine will be allowed if
administered >21 days prior to planned Day 1.
24. Receipt of any investigational agent or study treatment (i.e.,
any treatment or therapy not approved by the FDA for the
treatment of BTC) within the past 30 days
25. Receipt of any protein or antibody-based therapeutic agents
(eg, growth hormones or monoclonal antibodies) within the
past 3 months
26. Treatment with any tumor-directed therapy including, but
not limited to, chemotherapy or radiotherapy within the past
6 months with curative intent. Note: Treatment (i.e.,
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radiation, chemoembolization, radioembolization, or other 
local ablative therapies, or hepatic resection) is permitted if 
received ≥4 weeks from Screening and the patient has 
recovered to severity ≤Grade 1 toxicities as defined by NCI 
CTCAE v5.0. 
27. Existence of any surgical or medical condition that, in the
judgment of the Investigator, might compromise patient
safety or the outcome of the study
28. Presence of any clinically significant findings (relative to the
patient population) during review of medical history or upon
PE that, in the Investigator’s or Medical Monitor’s opinion,
would compromise patient safety or the outcome of the
study (e.g., psychiatric illness/social situations that would
limit compliance with study requirements)
29. Evidence of brain metastases
30. Unable or unwilling to communicate or cooperate with the
Investigator for any reason
31. Employee of Sponsor or clinical site, or relative of any
member of a clinical site’s staff
Interim Analysis 
A formal statistical interim analysis will be performed on patients 
included in the Stage 1 analysis. The interim analysis results will 
include safety, efficacy (PF responder rates), and pharmacodynamic 
(biomarker) data. These data will be used to help plan for future 
studies. 
Interim Analysis will be conducted: 
•
In addition to (Stage 1 + Stage 2) analysis, after all 53 patients
complete Month 6
•
In addition to (Stage 1 + Stage 2) analysis after, all 53 patients
complete Month 12
Statistical Methods 
Three patient populations will be used for analyses. A Per-protocol 
(PP) population will consist of those patients that 
and who have no major protocol 
violation(s) that would interfere with the collection or interpretation 
of the efficacy data. A Safety population will consist of all patients 
receiving any fraction of a dose of study drug. A PK population will 
be made up of all patients treated with at least 1 dose of study drug 
and who have adequate samples taken to reliably estimate the 
parameters of interest. 
The primary and secondary efficacy endpoints will be analyzed 
based on the Safety population. Additional analyses for the primary 
and secondary efficacy endpoints will be performed using the PP 
population.  
A Simon’s 2-stage design algorithm will be used to assess whether 
the study is successful at each stage of the analysis. In the Stage 1 
Safety population, if there are no clinically significant or unresolved 
Grade 3 or higher toxicities considered related to the study drug and 
if 12 or more (≥60%) of the 20 patients enrolled are deemed 
responders per the definition below after the 20th patient is censored, 
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is alive and progression-free at the Month 6 assessment, or has 
discontinued for any reason, the first stage of the study will be 
declared successful and enrollment will continue in Stage 2. Efficacy 
will also be assessed in the PP populations and by treatment cycle. 
Note: Patients are considered responders if they are alive and 
progression-free at the Month 6 assessment; otherwise, they are 
considered non-responders. 
In Stage 2, an additional 33 patients will be enrolled. If 34 (>60%) or 
more of the 53 patients enrolled (Stage 1 + Stage 2) are deemed 
responders, the study will be considered successful. Efficacy will 
also be assessed in the PP populations and by treatment cycle. 
For the primary endpoint, the distribution of PFS will be estimated 
using the Kaplan-Meier (KM) approach. The distribution of PFS 
from KM will be used to estimate the PFS rates and corresponding 
95% confidence intervals (CI) at Month 6. In addition, the PFS rate 
at Month 12 and EOS visit along with their corresponding 95% CI 
will be presented. The median PFS value computed from this study 
will be compared with the historical/published median PFS time of 
cis/gem alone. Patients without PD or death will be censored at the 
last centrally confirmed radiographic assessment prior to study 
completion. In addition, patients who are lost to follow-up or 
discontinued from the study after receiving study treatment will be 
censored at the last date of contact prior to lost to follow-up or date 
of discontinuation, respectively. The same model will be applied to 
analyze the median OS and the OS rate at Months 6 and 12. 
Subgroup analyses may be performed based on the primary tumor 
site, prior therapy(ies), performance status, major demographic and 
prognostic subgroups, extent of disease, and Baseline biomarker 
levels. 
Descriptive statistics will be used to summarize the data for the 
response rates and pharmacodynamic endpoints. Continuous 
variables will be summarized by n, mean, standard deviation (SD), 
median, minimum, and maximum values. Categorical variables will 
be summarized by patient counts and percentages.  
All imaging for study endpoints will be assessed by the local 
radiologist and BICR. The BICR will supersede the local 
radiologist’s assessment for the purpose of primary analysis of all 
applicable study objectives. A secondary analysis will be performed 
to further evaluate study objectives using the local radiologist 
assessments.  
For binary endpoints, such as ORR and DCR, the frequency and 
proportion of patients achieving the outcome in association with 
Fishers exact test will be presented at each assessed study time point. 
Other efficacy endpoints will be summarized descriptively by study 
time point. Change from Baseline for plasma 
will be summarized descriptively and 1-sample t-tests 
may be performed to test for significance. In addition, descriptive 
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summaries of these endpoints will also be reported for responder and 
non-responder subgroups with respect to ORR and DCR. 
Efficacy Assessments 
Efficacy assessments include radiological study by CT or MRI and 
measurement of the tumor by RECIST v1.1 for the determination of 
PFS, ORR (CR+PR), and DCR (CR + PR + SD). In addition, 
HRQoL will be evaluated by EORTC QLQ-30 and QLQ-BIL21. 
Safety Assessments 
Safety and tolerability will be evaluated through the collection and 
review of TEAEs, including out-of-range laboratory parameters as 
graded by the CTCAE v5.0, vital signs measurement, 12-lead ECG 
findings, PE findings, and clinical laboratory parameters (chemistry, 
hematology, and urinalysis) including changes from Baseline and 
frequency of values meeting CTCAE Grades >1 for severity. 
Pharmacodynamic and 
Pharmacokinetic 
Assessments 
Pharmacodynamic assessments include the determination of 
Pharmacokinetic (PK) assessments include the determination of 
concentrations of XERMELO and the active metabolite, LP-778902. 
Dose Modification - 
XERMELO 
In general, the following dose modification rules will be used with 
respect to potential toxicity and management of TEAEs believed to 
be related to XERMELO. Toxicity will be assessed according to the 
NCI CTCAE v5.0. 
Grade of 
Event 
Management/Next XERMELO Dose2 
Grade 1 
No change in dose 
Grade 2 
Hold until ≤Grade 1. Resume at same dose level. 
Grade 3 
Hold until ≤Grade 1. Resume at 1 dose level 
lower (250 mg tid).1
Grade 4 
Discontinue treatment. 
1Patients unable to tolerate 250 mg tid should be discontinued from 
XERMELO.
2Rechallenge may be permitted upon consultation with the Medical Monitor.
Recommended management for the following AEs: 
•
Nausea and/or vomiting: treat with antiemetics
•
Diarrhea: treat as indicated for underlying cause
•
Gastrointestinal toxicity:
o
Monitor concomitant medication usage
o
Constipation (Grade 1 and above): initiate treatment as
clinically indicated; examples of therapy(ies) include:
laxatives, enemas, suppositories, psyllium hydration, over-
the-counter (OTC) agents
o
Abdominal pain (Grade 1 and above): initiate treatment as
clinically indicated; examples of therapy(ies) include:
analgesics, anti-gas/bloating agents
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o
Hold XERMELO for Grade 2 constipation or abdominal
pain until ≤Grade 1. Resume at 1 dose level lower (250 mg
tid).
o
Discontinue XERMELO for Grade 3 constipation or
abdominal pain.
•
Suicidal ideation: discontinue XERMELO
Dose Modification- 
Cisplatin/Gemcitabine 
In general, the following dose modification rules will be used with 
respect to potential toxicity and management of any TEAEs believed 
to be related to cisplatin or gemcitabine. Toxicity will be assessed 
according to the NCI CTCAE v5.0. 
ANC 
Platelet Count 
Gemcitabine/Cisplat
in 
≥1,000/mm3
and 
≥100,000/mm3
Treat as scheduled 
<1,000/mm3
or/ 
and 
<100,000/mm3
Defer treatment by 1 
week. Reduce dose 
by 1 level for next 
treatment. 
The following dose modification rules will be used with respect to 
hematologic toxicity on Day 8 of each treatment cycle believed to 
be related to cisplatin or gemcitabine: 
ANC 
Platelet Count 
Gemcitabine/Cisplatin 
≥1,000/mm3
and 
≥75,000/mm3
Treat as scheduled 
<1,000/mm3
or/ 
and 
<75,000/mm3
Defer for 1 week. 
Reduce dose by 1 level 
for next treatment. If 
second deferral is 
needed, treatment will 
be omitted.
Note: Administration of granulocyte-colony stimulating factor (G-
CSF) is allowed, but discontinuation is required at least 2 days prior 
to the next administration of chemotherapy. If symptoms do not 
resolve after 28 days of uninterrupted G-CSF, chemotherapy 
treatment should be stopped. 
The following dose modification rules will be used with respect to 
nonhematologic toxicity on Day 1 of each treatment cycle 
believed to be related to cisplatin or gemcitabine. 
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Nonhematologic 
Toxicity1 
Gemcitabine/Cisplatin 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Defer treatment until resolves to ≤Grade 
1. Reduce dose by 1 level for next
treatment.
1Permissible exceptions to this rule are Grade 3 nausea, vomiting, 
hypertension, diarrhea, constipation, and transient electrolyte 
abnormalities that resolve within 72 hours following institution of 
appropriate supportive care, and alopecia.  
The following dose modification rules will be used with respect to 
nonhematologic toxicity on Day 8 of each treatment cycle 
believed to be related to cisplatin or gemcitabine. 
Nonhematologic 
Toxicity1 
Gemcitabine/Cisplatin 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Defer treatment until resolves to ≤Grade 1. 
Reduce dose by 1 level for next treatment. 
If deferral is needed for more than 1 week, 
treatment will be omitted. 
1Permissible exceptions to this rule are Grade 3 nausea, vomiting, 
hypertension, diarrhea, constipation, and transient electrolyte 
abnormalities that resolve within 72 hours following institution of 
appropriate supportive care, and alopecia. 
Clinical Stopping Rules 
While the combination treatment in this study is assumed safe due to 
minimal overlapping toxicities, untoward side effects may occur. 
Therefore, assessment of the safety and tolerability data of all 
enrolled patients will occur once the 6th patient has completed 21 
days of combination treatment and will include all safety 
assessments for all patients obtained prior to the second 
chemotherapy cycle of the 6th patient enrolled. The subsequent 
approach will be followed: 
•
If ≤1 patient has a clinically significant (CS) adverse event
(AE), the study will continue without a dose adjustment.
•
If ≥2 patients have CS AE, the dose level will be decreased to
the Reduced Dose level in accordance with the table below, and
6 additional patients will be enrolled and treated with the
Reduced Dose for 1 full cycle.
o
If ≤1 of these patients has a CS AE at the Reduced Dose for
the 1st cycle, the Reduced Dose will be used for the study.
o
If ≥2 patients have a CS AE at the Reduced Dose, the study
will be stopped.
Note: A CS AE is considered an unresolved ≥Grade 3 
nonhematological toxicity, which is related to the study drugs, 
excluding: controllable nausea, vomiting, hypertension, diarrhea, 
constipation, transient electrolyte abnormalities and alopecia; Grade 
3 or higher febrile neutropenia.  
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Dose Level 
Gemcitabine 
Cisplatin 
XERMELO 
Starting Dose 
1000 mg/m2
25 mg/m2
500 mg tid 
Reduced Dose 
800 mg/m2
20 mg/m2
250 mg tid 
Note: If any patient experiences a Grade 4 toxicity during the Safety 
Run-in, the Sponsor, in consultation with the Investigator, will 
determine if additional patients should be enrolled at the Reduced 
Dose level. 
Safety Data Analysis 
Safety analysis will involve examination of the descriptive statistics 
and individual patient listings for any effects of XERMELO on 
clinical tolerability and safety. All safety data will be listed by 
patient. 
Summaries will be prepared by CTCAE grade for severity and, as 
needed, by cycle. The TEAE summaries will include the overall 
incidence (by System Organ Class [SOC] and Preferred Term [PT]), 
events by maximum intensity, event by relationship to each study 
drug, TEAEs by study drug exposure time, events leading to 
discontinuation of study drug, and serious adverse events (SAEs). 
Vital signs, ECG findings, PE findings, and laboratory variables 
(hematology, chemistry, and urinalysis) will be summarized 
descriptively at each time point. Actual and change from Baseline 
data will be calculated and summarized. In addition, shift tables will 
be generated for the laboratory variables including changes from 
Baseline and frequency of values meeting CTCAE Grades >1 for 
severity. 
Pharmacokinetic Analysis 
PK data will be summarized by n, arithmetic and geometric mean, 
standard deviation, median, minimum, and maximum values at 
various time points. Regression models may be used to evaluate the 
type and magnitude of associations between trough concentrations 
and clinical outcomes at selected time points. 
Based on intensive PK sampling from a subset of patients and sparse 
PK sampling (eg, trough concentrations) from the study population, 
population PK analyses will explore the effects of covariates 
including, but not limited to, age, sex, race, and body mass index 
(BMI) on the systemic exposure of XERMELO and the active 
metabolite, LP-778902, when dosed as a combination treatment with 
cisplatin and gemcitabine. PK data from this study may be integrated 
with PK data from other clinical trials to further enhance the 
population PK analysis. Details of population PK analysis plan will 
be prepared in a separate document. 
The data analysis plan and results from the population (cumulative) 
PK analysis will be documented in a separate report. 
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TABLE OF CONTENTS 
1 
SYNOPSIS ........................................................................................................................ 5 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................. 24 
3 
INTRODUCTION .......................................................................................................... 27 
3.1 Background on XERMELO and Biliary Tract Cancer .......................................... 27 
3.2 XERMELO Pharmacology .................................................................................... 29 
3.3 XERMELO Toxicology ......................................................................................... 29 
3.4 Clinical Trials of XERMELO in Humans .............................................................. 29 
3.5 Rationale for Current Study ................................................................................... 29 
3.6 Rationale for Selection of Dose ............................................................................. 30 
3.7 Rationale for Study Design .................................................................................... 31 
4 
STUDY OBJECTIVES ................................................................................................... 32 
4.1 Primary Objective .................................................................................................. 32 
4.2 Secondary Objectives ............................................................................................. 32 
4.3 Exploratory Objectives .......................................................................................... 32 
4.4 Pharmacokinetic (PK) Objective ........................................................................... 33 
4.5 Substudy Objectives............................................................................................... 33 
4.6 Safety Objectives ................................................................................................... 33 
5 
INVESTIGATIONAL PLAN ......................................................................................... 34 
5.1 Overall Study Design ............................................................................................. 34 
5.1.1 
Screening .................................................................................................. 34 
5.1.2 
Study Overview ........................................................................................ 34 
6 
STUDY POPULATION .................................................................................................. 39 
6.1 Inclusion Criteria ................................................................................................... 39 
6.2 Exclusion Criteria .................................................................................................. 40 
6.3 Criteria for Stopping Treatment/Study Withdrawal ............................................... 43 
6.3.1 
End-of-Treatment (EOT)/End-of-Study (EOS) Procedures ..................... 43 
6.4 Criteria for Termination of the Study ..................................................................... 45 
6.5 Clinical Stopping Rules ......................................................................................... 45 
6.6 Method of Assigning Patients to Treatment ........................................................... 46 
6.7 Blinding and Unblinding of Study Drug ................................................................ 46 
6.8 Replacement of Patients ......................................................................................... 46 
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6.9 Rescreening of Patients .......................................................................................... 46 
7 
TREATMENT ................................................................................................................. 47 
7.1 XERMELO (telotristat ethyl) ................................................................................ 47 
7.1.1 
Identity ...................................................................................................... 47 
7.1.2 
Packaging, Labeling, and Storage ............................................................ 47 
7.2 Prior and Concomitant Medications ...................................................................... 47 
7.2.1 
Prior Medication ....................................................................................... 47 
7.2.2 
Concomitant Medication .......................................................................... 47 
7.3 Prohibited Medication or Concomitant Therapy ................................................... 48 
7.4 Administration of Study Drug ............................................................................... 48 
7.4.1 
Treatment Compliance ............................................................................. 48 
7.5 Dose Adjustment/Modification .............................................................................. 49 
7.5.1 
XERMELO (telotristat ethyl) ................................................................... 49 
7.5.2 
Cisplatin/Gemcitabine .............................................................................. 51 
8 
STUDY PROCEDURES ................................................................................................ 53 
8.1 Restrictions during Study ....................................................................................... 53 
8.2 Description of Study Assessments ......................................................................... 53 
8.2.1 
Efficacy Assessments ............................................................................... 53 
8.2.2 
Clinical Laboratory Assessments ............................................................. 54 
8.2.3 
Pharmacodynamic and Pharmacokinetic Assessments ............................ 55 
8.2.4 
Safety Assessments ................................................................................... 55 
8.3 Other Assessments ................................................................................................. 57 
8.3.1 
Performance Status Based on Eastern Cooperative Oncology Group 
(ECOG) .................................................................................................... 57 
8.3.2 
Health-related Quality of Life (HRQoL) .................................................. 58 
8.3.3 
Characterization of the Tumor - Substudy ............................................... 58 
8.4 Appropriateness of Assessments ............................................................................ 58 
9 
SAFETY REPORTING .................................................................................................. 59 
9.1 Definitions and Special Considerations ................................................................. 59 
9.1.1 
Adverse Events ......................................................................................... 59 
9.1.2 
Serious Adverse Events ............................................................................ 60 
9.1.3 
Unexpected Adverse Events ..................................................................... 61 
9.2 Assessment of Adverse Events .............................................................................. 61 
9.2.1 
Severity ..................................................................................................... 61 
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9.2.2 
Causality ................................................................................................... 61 
9.3 Special Situations ................................................................................................... 62 
9.3.1 
Pregnancy ................................................................................................. 62 
9.3.2 
Adverse Events of Special Interest (AESIs) ............................................. 63 
9.4 Reporting of Serious Adverse Events and Pregnancies ......................................... 64 
9.5 Follow-up of Adverse Events ................................................................................. 65 
9.6 Safety Oversight..................................................................................................... 65 
10 
STATISTICAL METHODOLOGY ................................................................................ 66 
10.1 Determination of Sample Size ............................................................................... 66 
10.2 Analysis Populations .............................................................................................. 66 
10.3 Study Endpoints ..................................................................................................... 67 
10.3.1 Efficacy Endpoints ................................................................................... 67 
10.3.2 Safety Endpoints ....................................................................................... 68 
10.3.3 Pharmacokinetic Endpoints ...................................................................... 68 
10.3.4 Characterization of Tumor Substudy Endpoint ........................................ 69 
10.4 Statistical Methods ................................................................................................. 69 
10.4.1 Efficacy Analyses ..................................................................................... 69 
10.4.2 Safety Analyses ........................................................................................ 71 
10.4.3 Pharmacodynamic Analyses ..................................................................... 72 
10.4.4 Pharmacokinetic Analyses ........................................................................ 72 
10.4.5 Analysis of Health-related Quality of Life (HRQoL) .............................. 73 
10.4.6 Baseline Characteristics and Other Summaries ........................................ 73 
10.4.7 Interim Analysis ....................................................................................... 73 
10.4.8 Protocol Deviations .................................................................................. 74 
11 
STUDY MANAGEMENT ............................................................................................. 75 
11.1 Monitoring ............................................................................................................. 75 
11.2 Protocol Deviations ................................................................................................ 76 
11.3 Audits and Inspections ........................................................................................... 76 
11.4 Amendments .......................................................................................................... 76 
11.5 Record Keeping ..................................................................................................... 77 
11.5.1 Drug Accountability ................................................................................. 77 
11.5.2 Health Insurance Portability Accountability Act of 1996 and Subsequent 
Updates ..................................................................................................... 77 
11.5.3 Financial Disclosure ................................................................................. 77 
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11.5.4 Access to Original Records ...................................................................... 78 
11.5.5 Retention of Study Documents ................................................................. 78 
12 
ADMINISTRATIVE STRUCTURE OF THE STUDY ................................................. 79 
13 
APPENDIX A – SCHEDULE OF EVENTS: ................................................................. 80 
14 
APPENDIX B – INTENSIVE PK SUBSTUDY SCHEDULE ...................................... 85 
15 
APPENDIX C – ESTIMATED AMOUNT OF BLOOD TO BE COLLECTED FROM 
EACH PATIENT ............................................................................................................. 86 
16 
APPENDIX D – ETHICAL STANDARDS ................................................................... 87 
17 
APPENDIX E – INVESTIGATOR OBLIGATIONS ..................................................... 89 
18 
APPENDIX F – CALCULATIONS ............................................................................... 94 
19 
APPENDIX G – ECOG AND KARNOFSKY PERFORMANCE SCALE 
CONVERSION TABLE ................................................................................................. 95 
20 
APPENDIX H – NATIONAL CANCER INSTITUTE (NCI) COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) V5.0 .................. 96 
21 
APPENDIX I – EORTC QUALITY OF LIFE QUESTIONNAIRE CORE 30 (QLQ-
C30) AND CHOLANGIOCARCINOMA AND GALLBLADDER CANCER (QLQ-
BIL21) MODULE ........................................................................................................... 97 
22 
APPENDIX J – RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) ...................................................................................................................... 100 
23 
APPENDIX K - DETAILED SUMMARY OF PROTOCOL CHANGES ................... 101 
24 
REFERENCES ............................................................................................................. 114 
List of Tables 
Table 6-1 Safety Run-In Dose Reduction .............................................................................. 46 
Table 7-1  Xermelo Dose Modifications ................................................................................. 49 
Table 7-2 Dose Reduction ...................................................................................................... 51 
Table 7-3 Dose Reduction For Hematologic Toxicity On Day 1 ........................................... 51 
Table 7-4 Dose Reduction For Hematologic Toxicity On Day 8 ........................................... 51 
Table 7-5 Dose Reduction For Nonhematologic Toxicity On Day 1 ..................................... 52 
Table 7-6 Dose Reduction For Nonhematologic Toxicity On Day 8 ..................................... 52 
List of Figures 
Figure 5-1 Treatment Schema .................................................................................................. 38 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
1L 
first-line 
2L 
second-line 
5-HIAA
5-hydroxyindoleacetic acid
5-HT
serotonin
AE
adverse event
ALKP
alkaline phosphatase
ALT
alanine aminotransaminase
ANC
absolute neutrophil count
AST
aspartate aminotransaminase
BICR
blinded independent central review
BMI
body mass index
BTC
biliary tract cancer
C1
Cycle 1
C1D1
Cycle 1, Day 1; Baseline (Baseline value is defined as the last non-
missing data on or before the first dose of the study drug, unless
otherwise specified)
C10D1 
Cycle 10, Day 1 is intended as Month 6
C19D1 
Cycle 19 Day 1 is intended as Month 12
CA 19-9 
carbohydrate antigen 19-9
CBC 
complete blood count
CCA 
cholangiocarcinoma
CEA 
carcinogenic embryonic antigen
CFR 
Code of Federal Regulations
CI 
confidence interval
cis 
cisplatin
cis/gem 
cisplatin/gemcitabine: cisplatin 25 mg/m2 administered intravenously (iv)
over 60 to 90 minutes followed by gemcitabine iv 1000 mg/m2
administered iv over 30 minutes (also referred to as 1L therapy)
CMP 
complete metabolic profile
CR 
complete response
CRFg 
Case Report Form guideline
CS 
carcinoid syndrome or clinically significant
CT 
computed tomography
CTCAE 
Common Terminology Criteria for Adverse Events (v 5.0)
D1 
Day 1
DCR 
disease control rate defined as CR+PR+SD
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders 5th edition
ECG 
electrocardiogram
ECOG 
Eastern Cooperative Oncology Group
eCRF 
electronic Case Report Form
eGFR 
estimated glomerular filtration rate
EORTC 
European Organisation for Research and Treatment of Cancer
EOS 
End-of-Study
EOT 
End-of-Treatment
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Abbreviation 
Definition 
ERC 
Ethics Review Committee 
FDA 
US Food and Drug Administration 
FSH 
follicle stimulating hormone 
G-CSF
granulocyte-colony stimulating factor 
GBC
gall bladder carcinoma 
GCP
Good Clinical Practice 
gem
gemcitabine 
GGT
gamma-glutamyltransferase 
GINA
Genetic Information Nondiscrimination Act of 2008 
GLP
Good Laboratory Practice 
HbsAg
hepatitis B surface antigen 
HCV Ab
hepatitis C virus core antibody 
HDL
high-density lipoprotein 
HEENT
head, eyes, ears, nose, and throat 
Hgb
hemoglobin 
HIPAA
Health Insurance Portability and Accountability Act 
HIV
human immunodeficiency virus 
HRQoL
health-related quality of life 
IAC
Independent Adjudication Committee 
IB
Investigator Brochure 
ICH
International Council for Harmonisation 
IHC
immunohistochemical  
IND
Investigational New Drug 
INR
international normalized ratio 
IRB
Institutional Review Board 
iv
intravenously 
KPS
Karnofsky Performance Scale 
LDL
low-density lipoprotein 
MAO-A
monoamino-oxidase A 
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
magnetic resonance imaging 
NCCN
National Comprehensive Cancer Network® 
NCI
National Cancer Institute 
NCS
not clinically significant 
NYHA
New York Heart Association 
ORR
objective response rate defined as CR+PR 
OTC
over-the-counter 
OS
overall survival 
PD
progressive disease 
PE
physical examination 
PFS
progression-free survival 
PHI
protected health information 
PK
Pharmacokinetic 
PP
per-protocol population 
PR
partial response 
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Abbreviation 
Definition 
PT 
Preferred Term or prothrombin time 
QLQ-BIL21 
Cholangiocarcinoma and Gallbladder Cancer Module 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcB 
corrected QT interval using Bazett’s formula 
QTcF 
corrected QT interval using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease or standard deviation 
SFP 
Survival Follow-up Period 
SI 
Le Système international d'unités (The International System of Units) 
SOC 
System Organ Class 
SSA 
somatostatin analog(s) 
TEAE 
treatment-emergent adverse events 
TE 
telotristat ethyl 
tid 
3 times daily 
TPH 
tryptophan hydroxylase  
TPH-1 
tryptophan hydroxylase-1  
TTP 
time to tumor progression 
ULN 
upper limit of the normal reference range 
US 
United States 
v 
version 
WBC 
white blood cell 
Definitions of Investigational Product Terms 
Term 
Definition 
LX1606 Hippurate or telotristat 
etiprate 
salt form of the drug substance, LX1606 or telotristat 
ethyl 
LP-778902 or telotristat or 
LX1033 
active metabolite of LX1606 or telotristat ethyl 
telotristat ethyl or LX1606 
ethyl ester prodrug of the active metabolite 
LP-778902; XERMELO 
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3 
INTRODUCTION 
3.1 
Background on XERMELO and Biliary Tract Cancer 
Biliary tract cancer (BTC) is a group of malignancies that arise from the epithelium of the 
biliary tract. Classified by anatomical location, BTC includes cholangiocarcinoma (CCA), 
identified as intrahepatic or extrahepatic based on their location in relation to the liver, and 
gall bladder carcinoma (GBC) (Zhao, 2017). Approximately 10,000 new cases of BTC are 
diagnosed each year in the United States (US). Patients generally present with nonspecific 
abdominal symptoms that are bothersome, but not significantly burdensome for them to seek 
timely medical care. This most often results in a locally advanced, likely metastatic, BTC at 
the time of diagnosis (Marks, 2016). Demographically, the incidence of BTC increases with 
age. Patients are diagnosed later in life (between ages 40-70); there is a slight gender 
predominance in females for GBC and in males for CCA. A patient’s geographic location 
plays a significant role in associated risk. The incidence of BTC is relatively rare in the 
Western world as compared to Asian countries where the liver fluke (a risk factor for BTC) is 
endemic but the overall incidence of BTC is rising; possibly due to increased recognition of 
the disease by physicians, improved diagnostic capabilities, and active screening of patients 
at high risk (Bergquist, 2015; Kanthan, 2015; Razumilava, 2014). 
Management of risk factors and early detection of are key to improving survival in patients 
with BTC. Five years after diagnosis, 10% of patients with CCA and <5% with GBC remain 
alive. The 1-year survival rate for patients diagnosed with Stage 3 or 4 BTC is even lower. 
Only 10-15% of BTCs are amenable to surgery at initial presentation, and postresection 
recurrence rates remain at 50-60%. Given these statistics, it is apparent that these tumors are 
very aggressive malignancies with a very poor prognosis. Due to the rarity of this disease, 
evidence to support the role of adjuvant therapy is limited and available treatment options are 
not sufficient to address the poor survival rates in patients with locally advanced, recurrent, or 
metastatic BTC (Marks, 2016; Zhao, 2017).  
Available Treatment Options 
For patients presenting with unresectable BTC (locally advanced, recurrent, or metastatic) the 
current standard first-line (1L) therapy is a combination of cisplatin (cis) and gemcitabine 
(gem). The combination treatment (cis/gem) was found superior to gemcitabine alone in a 
randomized Phase 2 study (ABC-01) in 86 patients conducted in the United Kingdom 
(Valle, 2009). Treatment with cis/gem was associated with an improved disease control rate 
(DCR; complete response [CR] + partial response [PR] + stable disease [SD]; 75.0% vs 
58.0%), time to tumor progression ([TTP]; 8.0 months vs 4.0 months) and 6-month 
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progression-free survival ([PFS]; 57.1% vs 45.5%) when compared to gemcitabine alone. 
Following the positive results, the ABC-01 trial was extended into a randomized, Phase 3 
study (ABC-02) and powered to determine the effect of cis/gem or gemcitabine alone on 
overall survival (OS) and quality of life (QOL) (Valle, 2010).  
In the ABC-02 study, the treatment regimens and eligibility criteria mirrored the ABC-01 
study. A total of 410 patients were randomized (n=204 cis/gem vs. n=206 gem alone) and 
followed for a median of 8.2 months. Again, the combination treatment (cis/gem) was shown 
to be statically superior to gemcitabine alone; the median OS was 11.7 months vs 8.1 months, 
median PFS was 8.0 months vs 5.0 months, and DCR (CR + PR + SD) was 81.4% vs. 71.8%. 
Adverse events (AEs) were similar in the 2 groups with the exception of neutropenia, which 
was increased in the cis/gem group, although the number of neutropenia-associated infections 
was similar in the 2 groups (Valle, 2010). 
A second randomized Phase 3 study (BT-22) was conducted in Japan and enrolled 84 
Japanese patients (41 cis/gem vs 42 gem alone) with advanced BTC. For this study, the 
median OS was 11.2 vs 7.7 months, median PFS was 5.8 vs 3.7 months, and DCR (CR + PR 
+ SD) was 68.3% vs 50.0% (Okusaka, 2010).
Treatment options for patients with unresectable BTC following the failure of 1L therapy 
remain limited and are not supported by Phase 3 data. Other chemotherapy combinations (eg, 
oxaliplatin, 5-FU, capecitabine) have demonstrated only marginal improvements in survival 
and targeted therapies, such as antiEGFR or antiVEGF antibodies, have produced limited 
success in early stage studies. As such, second-line (2L) treatment regimens are highly 
variable and are influenced by the physician’s knowledge of available treatment options or, 
more likely, the availability of clinical trials (Zhao, 2017).  
In February 2017, the US Food and Drug Administration (FDA) approved the oral drug 
telotristat ethyl (XERMELO) as a 2L therapy to be used in combination with somatostatin 
analogs (SSAs) to help address inadequate control of diarrheal symptoms in patients with 
carcinoid syndrome (CS). XERMELO has been shown to lower serotonin (5-HT) levels in 
the peripheral system by inhibiting tryptophan hydroxylase (TPH). Through inhibition of 
TPH, XERMELO reduces the production of peripheral 5-HT and the frequency of CS 
diarrhea. This intracellular mechanism of action complements the extracellularly mediated 
action of SSAs, providing a more complete inhibition of 5-HT overproduction than SSA 
therapy alone (Lexicon Pharmaceuticals, Inc., 2017). 
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3.2 
XERMELO Pharmacology 
A complete package of safety pharmacology has been conducted for XERMELO. Details 
may be found in the Investigator's Brochure (IB). 
3.3 
XERMELO Toxicology 
A complete package of toxicology studies including Good Laboratory Practice (GLP)-
compliant mammalian toxicology, genetic toxicology, and safety pharmacology has been 
conducted with XERMELO. Details may be found in the IB. 
3.4 
Clinical Trials of XERMELO in Humans 
Detailed information regarding clinical studies may be found in the IB. 
3.5 
Rationale for Current Study 
While XERMELO is indicated for the treatment of CS diarrhea in combination with SSA 
therapy in adults inadequately controlled by SSA therapy, its mediation of 5-HT may provide 
a larger benefit. Serotonin (5-HT) plays a critical role in regulating several major 
physiological processes including cell proliferation. Literature suggests cell proliferation is 
autoregulated by endogenously produced 5-HT and that high levels of circulating 5-HT may 
exert a direct mitogenic effect on tumor cells, leading to tumor growth. Further, by 
modulating the amount of 5-HT exposure, tumor growth may be inhibited through 
vasoconstrictive action on the arterioles feeding the malignant growth, an antiangiogenic 
effect (Sarrouilhe, 2015).  
In vitro and in vivo studies have shown increased expression of TPH 1 and decreased 
expression of monoamino-oxidase A (MAO-A), the enzyme responsible for the degradation 
of serotonin, indicating that the metabolism of 5-HT is dysregulated. The result of this type of 
dysregulation is an increase in the production and secretion of 5-HT (Alpina, 2018; 
Huang, 2012; Sarroulilhe, 2015). In addition, treatment with 5-HT increased CCA cell 
growth in vivo and inhibition of 5-HT synthesis significantly blocked the growth of CCA in 
vivo and in vitro (Alpina, 2018; Huang, 2012; Sarroulilhe, 2015).  
A novel treatment approach that inhibits 5-HT production may provide clinical benefit to the 
significant number of patients with unresectable BTC. Adding a TPH inhibitor, like 
XERMELO to the treatment paradigm in combination with 1L therapy, may improve the 
physician’s armamentarium and fulfill the unmet medical need for patients with advanced 
BTC.  
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The AE profiles of XERMELO and the cis/gem combination are largely distinct and do not 
overlap, except for events related to elevations of liver function tests (LFTs). This is not 
surprising, as liver involvement occurs often in the setting of advanced BTC and in patients 
with advanced NETs. In order to address a potential risk to patients with liver involvement, 
the study will exclude patients with aspartate transaminase (AST) or alanine 
aminotransaminase (ALT) levels >5 x upper limit of normal (ULN) who have a documented 
history of hepatic metastases. Moreover, a Safety Run-in has been included in the design of 
the study since this will be the first time that these 3 agents will be used concomitantly in 
patients. A total of 6 patients with advanced BTC will be enrolled and treated with 
XERMELO plus 1L therapy for 1 cycle (21 days) to assess the safety of the triple 
combination before enrolling additional patients. Liver function will be closely monitored 
throughout the study and dose adjustment/modification rules are described in Section 7.5. 
The known and largely nonoverlapping safety profiles of XERMELO and the combination 
chemotherapy (cis/gem) suggest concomitant use is a rational approach to investigate the 
potential additive clinical benefit of XERMELO to 1L treatment, the current standard of care 
in eligible patients with advanced BTC. 
This study is intended to assess the effect of XERMELO in combination with 1L 
chemotherapy on PFS in patients with locally advanced, unresectable, recurrent or metastatic 
BTC who are naïve to tumor-directed therapy in the locally advanced or metastatic setting 
and for which treatment with 1L therapy is planned. 
3.6 
Rationale for Selection of Dose 
The dose level of XERMELO selected for this study is consistent with prior clinical study 
experience and is based upon clinical safety and pharmacodynamic (PD) data from Phase 2 
and Phase 3 multiple ascending-dose studies in patients with symptomatic CS. Dosages of 1L 
therapy are consistent with standard of care established by the ABC-02 trial (Valle, 2010). 
Based upon clinical study results, information for the XERMELO 500 mg tid dose level is 
more robust in terms of patient years of exposure and has an improved efficacy profile than 
the marketed dosage of 250 mg tid.  
As such, it is anticipated that the combination of therapies, at the dose levels proposed in this 
protocol, will be safe and well tolerated and may provide clinical benefit to patients with 
BTC. 
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3.7 
Rationale for Study Design  
An open-label study will allow for the assessment of the safety, tolerability, and efficacy 
XERMELO plus 1L therapy, herein referred to as “combination treatment” in a transparent 
manner. Should an efficacy signal be identified, additional studies may be undertaken to 
further assess the effect of the combination treatment in a larger patient population. 
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4 
STUDY OBJECTIVES 
4.1 
Primary Objective 
The primary objective of the study is to assess the safety and efficacy (PFS rate at Month 6) 
in the Safety population receiving the combination of XERMELO plus 1L treatment with 
cis/gem combination chemotherapy. Efficacy (PFS rate at Month 6) will also be evaluated in 
the Per Protocol Population (PP) and by treatment cycle. 
4.2 
Secondary Objectives 
To assess the effect of study treatment on the following: 
•
Overall survival (OS)
•
OS rate at Months 6 and 12
•
PFS rate at Month 12 and median PFS at Month 12
•
Disease control rate (DCR); defined as complete response (CR) + partial response
(PR) + stable disease (SD) at Months 6 and 12 and End of Study (EOS)
•
Objective response rate (ORR) defined as CR + PR at Months 6 and 12 and EOS
•
Local radiologist’s assessment of PFS, ORR, and DCR
•
Change from Baseline in
 Months 6 and 12 and EOS 
•
Change from Baseline in body weight at Months 6 and 12 and EOS
•
Change from Baseline in serum albumin at Months 6 and 12 and EOS
Note: Unless otherwise indicated, all radiologic endpoints will be based on Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent 
central review (BICR) and compared to published historical data of cisplatin/gemcitabine 
(cis/gem) alone. 
4.3 
Exploratory Objectives 
To assess the effect of study treatment on the following: 
•
Changes in health-related quality of life (HRQoL) as measured by European
Organisation for Research and Treatment of Cancer (EORTC) Quality of Life
Questionnaire Core 30 (QLQ-C30) and Cholangiocarcinoma and Gallbladder Cancer
(QLQ-BIL21) items at Baseline, Months 6 and 12
•
Change from Baseline in 
 fragment at Months
6 and 12 and EOS
•
Subgroup analyses of PFS, OS, ORR, and DCR using both BICR and local
radiologist’s assessment, based on categorical group of Baseline and change from
Baseline at Months 6 and 12 and EOS in:
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o
body weight
o
serum albumin
o
correlation between Baseline neutrophil:lymphocyte ratio and OS
•
Subgroup analyses in:
o
Patients with changes in liver function tests
o
Patients with Biliary stents
o
Location of disease (intrahepatic, extrahepatic, or gallbladder)
o
Extent of disease
o
Demographic groups
•
Subgroup analyses of patients by treatment cycles (such as patients who completed
 with combination treatment
4.4 
Pharmacokinetic (PK) Objective 
The pharmacokinetic (PK) objective is to identify intrinsic and extrinsic factors contributing 
to variability in exposure of XERMELO and the active metabolite, LP-778902, when dosed 
as a combination treatment with cisplatin and gemcitabine, including but not limited to, age, 
sex, race, and body mass index (BMI), as compared to historical data. 
4.5 
Substudy Objectives 
•
To assess the effect of study treatment based on characterization of tumor tissue by
immunohistochemical (IHC) staining (i.e., serotonin [5-HT] and tryptophan
hydroxylase-1 [TPH-1])
•
To determine the population PK profile among patients who participate in intensive
PK sampling
4.6 
Safety Objectives 
Evaluation of overall safety will be assessed by means of the following: 
•
Incidence of treatment-emergent adverse events (TEAEs) and severity assessment
using National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE) v5.0
•
Change from Baseline in clinical laboratory results including frequency of values
meeting CTCAE severity Grades >1, laboratory data toxicities as defined by NCI
CTCAE v5.0, physical examination (PE) findings, vital signs, and electrocardiogram
(ECG) findings
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5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design 
This study will be conducted as a multicenter, open-label, 2-stage study to assess the safety , 
tolerability, and efficacy of XERMELO in combination with first-line (1L) therapy (cisplatin 
plus gemcitabine) in patients with unresectable, locally advanced, recurrent or metastatic 
BTC (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer), who are naïve to 
tumor-directed therapy in the locally advanced or metastatic setting, and for which treatment 
with 1L therapy (defined as a combination of cis/gem) is planned.  
Note: 1L therapy will not be provided for this study by the Sponsor. 
5.1.1 Screening 
All patients are allowed a Screening Period of up to 21 days prior to Cycle 1 Day 1 (C1D1) 
when assessments for determining eligibility will be conducted per Appendix A. Written 
informed consent will be obtained from all patients before beginning any study related 
screening procedures. The collection of SAEs will begin after the patient has signed informed 
consent.  
Note: If radiological assessments have been completed within 6 weeks prior to Day 1, they 
are not required to be repeated at Day 1. 
5.1.2 Study Overview 
5.1.2.1 Treatment Period 
Stage 1 
Stage 1 enrollment will include a Safety Run-in cohort. Safety and tolerability data of the 
combination treatment from the first 6 patients who complete at least 21 days of safety 
follow-up after the first dose of combination treatment will be evaluated by the Coordinating 
Investigators, Sponsor, and Medical Monitor in accordance with established clinical stopping 
rules. This review will include all safety assessments from all patients obtained prior to the 
second chemotherapy cycle of the 6th patient enrolled. During this safety review, Stage 1 
enrollment will continue as per the study schema (Figure 5-1). It is anticipated that a total of 
20 patients will participate in Stage 1. 
Stage 2 
Stage 2 may initiate enrollment once Stage 1 enrollment has been completed, in the absence 
of significant or unresolved Grade 3 or higher toxicities considered related to the study drugs. 
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Approximately 33 additional patients are anticipated to participate in Stage 2. Study duration 
and assessments in this stage will be identical to Stage 1. From a total of 53 accrued patients 
from Stage 1 + Stage 2, if 34 or more (>60%) responses are observed (i.e., patients are alive 
and progression-free at Month 6), the study will be considered successful. 
Study Treatment (Stage 1 and Stage 2) 
On Day 1 (D1), eligible patients are to initiate Cycle 1 (C1), a 21-day cycle of XERMELO 
plus 1L therapy (herein referred to as “combination treatment”) as follows:  
•
XERMELO 250 mg (1 x 250-mg tablet) given as an oral dose 3 times daily (tid) for 7
days, plus
•
Cisplatin 25 mg/m2 administered intravenously (iv) over 60 to 90 minutes, followed
by
•
Gemcitabine 1000 mg/m2 administered iv over 30 minutes
On Day 8, patients will receive combination treatment as follows: 
•
XERMELO 500 mg (2 x 250-mg tablets) tid for 14 days, plus
•
Cis/Gem as described above
Every 21 days thereafter, patients will initiate a new 21-day cycle (eg, Cycle 2 [C2], Cycle 3 
[C3]) and will receive combination treatment, administered as:  
•
XERMELO 500 mg tid, plus
•
Cis/Gem regimen as described above on Day 1 and Day 8 of each cycle
Dose modification(s) and/or delay in treatment may be permitted as described in Section 7.5. 
During the Treatment Period, patients may discontinue cisplatin and continue treatment with 
XERMELO plus gemcitabine alone at the Investigator’s discretion. Gemcitabine should be 
administered on the same schedule as described above. 
Active symptom control will be permitted during the study as clinically indicated. 
Radiological assessment of the tumor by computed tomography (CT) or magnetic resonance 
imaging (MRI) will be conducted prior to initiating treatment on Cycle 1 Day 1(C1D1), then 
every 9 weeks (3 cycles) for the remaining duration of the Treatment Period. Note: If a 
radiological assessment has not been performed within 6 weeks prior to Day 1, a Screening 
assessment will also be required. 
All imaging will be evaluated by the local radiologist (or designee) for clinical management. 
If a change in response is noted by the local radiologist or Principal Investigator at any time 
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during the study a second radiological assessment should be performed within 4-6 weeks to 
confirm.    
All images will be sent to a central review facility for blinded, independent-parallel reading 
(i.e., BICR) for assessments of study endpoints (Section 8.2.1). No information regarding 
results of PD determination will be shared between central radiologic review and the local 
radiologist/Principal Investigator at any time during the study. 
Note: Management of biliary obstruction and/or ascending cholangitis will not be considered 
as PD in the absence of radiologically confirmed PD. 
Patients may continue to receive treatment as described above for as many cycles possible 
until progressive disease (PD) as determined by local review, unacceptable toxicity, or the 
patient withdraws from treatment. At this time, chemotherapy will be discontinued, End-of-
Treatment (EOT) assessments should occur, and the patient should enter the Follow-up 
Period. The Follow-up visit dates will be based off of the EOT date. 
5.1.2.2 Follow-up Periods  
All patients are expected to be followed for a total duration of 24 months after the Treatment 
Period unless they prematurely discontinue or voluntarily withdraw consent from future study 
visits or assessments. This 24-month phase is divided into 2 periods; the Post-treatment 
Follow-up Period (PTFP) where onsite visits occur every 3 months, and the Survival Follow-
up Period (SFP), where survival status will be collected by phone and no onsite visits are 
required. 
Post-treatment Follow-up Period 
All patients are expected to enter a PTFP at the time PD is confirmed locally or the patient is 
no longer able to tolerate chemotherapy plus XERMELO in the absence of PD. During the 
Post-treatment Follow-up Period, patients may continue treatment with XERMELO at the 
discretion of the treating physician. 
Patients will complete scheduled study visits every 3 months for a total duration of 24 months 
or until the patient begins a new tumor-directed therapy, prematurely discontinues, declines 
further treatment after progression, or withdraws consent from future study visits or 
assessments. At this time, the End of Study (EOS) procedures should be performed and the 
patient should enter the SFP (unless 24 months of follow-up after the last dose of 
chemotherapy has already occurred). 
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Note: For those patients who enter the PTFP prior to PD confirmed locally (i.e., those who 
experience an unacceptable toxicity or withdraw from chemotherapy), routine imaging 
assessments will continue to be performed every 3 months during the Post-treatment Follow-
up Period until PD is confirmed by local review. 
Note: Patients who enter PTFP prior to having their 6-month imaging assessment in the 
Treatment Period, will be asked to consent to provide their local scans and/or local scan 
report closest to the Treatment Period 6-month timepoint. This includes the possible 
reconsenting of patients previously prematurely discontinued or withdrew consent from the 
Treatment Period of the study. 
Survival Follow-up 
Once a new tumor-directed therapy begins, or a patient declines further treatment after 
progression, patients will enter the SFP. During this period, all patients (or caregivers, where 
appropriate) will be contacted by phone every 3 months to obtain the patient’s survival status 
until death, prematurely discontinue, withdrawal of consent, loss to follow-up, or for a period 
of 24 months following the last dose of chemotherapy, whichever occurs first. The site should 
make every attempt to document the date of death, if appropriate. 
Note: Patients who enter SFP without entering or completing PTFP and who entered SFP 
prior to having their 6-month imaging assessment in the Treatment Period, will be asked to 
consent to provide their local scans and/or local scan report closest to the Treatment Period 
6-month timepoint. This includes the possible reconsenting of patients previously
prematurely discontinued or withdrew consent from the Treatment Period of the study.
Note: The total duration of the PTFP and SFP combined should be no more than 24 months. 
Reconsent 
In cases when a patient has prematurely discontinued from the study and/or withdrawn 
consent from conducting further study assessments, these patients may be asked to re-consent 
to provide permission for their local imaging and imaging reports to be submitted to BICR.  
The treatment schema is summarized in Figure 5-1. 
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Figure 5-1 Treatment Schema 
Enroll Safety 
Cohort n=6
TE
1 + 1L
1 Cycle (21 days)
Enroll additional 
cohort n=6
TE
1 + 1L Reduced 
Dose
1 Cycle (21 Days)
Enroll remaining 
Stage 1 n=20
TE
1 + 1L
Terminate Study
Enroll remaining 
Stage 1 n=20
TE
1 + 1L Reduced 
Dose
If Clinically Significant AE*
 seen in ≥2 Patients
Treatment Period
Post Treatment 
Follow-up Period
Survival Follow-up 
Period
LX1606.207 
TE
1 + 1L in 
Patients with BTC 
N= 53
Enroll Stage 2 n=33
TE
1 + 1L Reduced 
Dose
If Clinically Significant AE* 
seen in ≤1 Patient
Enroll Stage 2 
n=33
TE
1 + 1L
If Clinically Significant AE*
 seen in ≤1 patient
If Clinically Significant AE*
 seen in ≥2 Patients
*Clinically Significant AE defined as unresolved, ≥Grade 3 non
hematological toxicity related to study drug (See Exclusions in
Protocol).
1 TE = Telotristat Ethyl
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6 
STUDY POPULATION 
It is anticipated that a total of 53 adult (>18 years of age) patients will be enrolled in 2 stages 
(n1=20 patients enrolled in Stage 1 and n2 = 33 patients enrolled in Stage 2) with 
unresectable, locally advanced, recurrent, or metastatic BTC (intrahepatic or extrahepatic 
cholangiocarcinoma, gallbladder cancer) naïve to tumor-directed therapy in the locally 
advanced or metastatic setting and are candidates to receive 1L therapy from approximately 
15 centers in the United States over an 18-month period.  
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria at Screening, or as otherwise indicated, to be 
considered eligible to participate in the study: 
1. Adults of either sex, ≥18 years of age. Patients of childbearing potential must
agree to use an adequate method of contraception during the study and for 30 days
after the last dose of XERMELO.
a.
Childbearing potential is defined as those who have not undergone surgical
sterilization (eg, documented hysterectomy, tubal ligation, or bilateral
salpingo-oophorectomy) or those who are not considered postmenopausal
(defined as 12 months of spontaneous amenorrhea). If necessary, follicular-
stimulating hormone (FSH) results >35 IU/L at Screening are confirmatory in
the absence of a clear postmenopausal history.
b. Adequate methods of contraception, defined as having a failure rate of <1%
per year, for patients or their partner include the following: condom with
spermicidal gel, diaphragm with spermicidal gel, intrauterine device, surgical
sterilization, vasectomy, oral contraceptive pill, depo-progesterone injections,
progesterone implant (i.e., Implanon®), patch (Ortho Evra®), NuvaRing®,
and abstinence. If a patient is not sexually active but becomes active, they or
their partner should use medically accepted forms of contraception.
2. Histopathologically or cytologically-confirmed, unresectable, locally advanced,
recurrent, or metastatic BTC (intrahepatic or extrahepatic cholangiocarcinoma,
gallbladder cancer)
3. Naïve to tumor-directed therapy in locally advanced, unresectable, or metastatic
setting. Note: Previous treatment with chemotherapy in the adjuvant setting
(including previous exposure to 1L therapy) will be permitted if PD is confirmed >6
months following treatment.
4. Measurable disease, defined as the presence of at least 1 measurable lesion as
determined by RECIST v1.1 using conventional imaging with CT or MRI
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5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
6. Plans to initiate treatment with 1L therapy; defined as cis/gem: cisplatin 25 mg/m2
administered iv over 60 to 90 minutes followed by gemcitabine1000 mg/m2
administered iv over 30 minutes as standard of care
7. Ability to provide written informed consent prior to participation in any study-related
procedure
6.2 
Exclusion Criteria 
Patients who meet any of the following criteria at Screening or as otherwise indicated, will be 
excluded from participating in the study:   
1. Prior exposure to XERMELO, telotristat ethyl, telotristat etiprate, LX1032, or
LX1606
2. Primary tumor site in the ampulla of Vater
3. Treatment with photodynamic therapy for localized disease or to relieve biliary
obstruction in the presence of metastatic disease within the past 30 days
4. Hematology laboratory values of:
a.
Absolute neutrophil count (ANC) ≤1,500 cells/mm3; or
b. Platelets ≤100,000 cells/mm3; or
c.
Hemoglobin (Hgb) ≤9 g/dL; or
d. White blood count (WBC) ≤3,000 cells/mm3
5. Hepatic laboratory values of aspartate transaminase (AST) or alanine
aminotransferase (ALT):
a.
>5 x upper limit of normal (ULN) if patient has documented history of
hepatic metastases; or
b. >2.5 x ULN if no liver metastases are present
6. Serum albumin <2.8 g/dL
7. Total bilirubin >1.5 x ULN or >1.5 mg/dL
8. Prothrombin time (PT) or international normalized ratio (INR) >1.5 x ULN. Note:
Patients receiving therapeutic doses of anticoagulant therapy may be considered
eligible if PT and INR are within the acceptable therapeutic limits for the institution.
9. Serum creatinine or serum urea >1.5 x ULN
10. Estimated glomerular filtration rate (eGFR) <50 mL/min
11. Positive pregnancy test, pregnant, or breastfeeding (female patients only)
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12. Any other clinically significant laboratory abnormality that would compromise patient
safety or the outcome of the study
13. Any clinically significant and/or uncontrolled cardiac-related abnormality that would
compromise patient safety or the outcome of the study including, but not limited to:
a.
Arrhythmia
b. Bradycardia
c.
Tachycardia
d. Symptomatic valvular disease
e.
Symptomatic congestive heart failure classified by New York Heart
Association (NYHA) as Class III or IV (Criteria Committee of the NYHA,
1994)
f.
Evidence of ischemia on ECG
g. Unstable angina pectoris
14. Myocardial infarction within the past 6 months
15. Active bleeding diathesis
16. Life expectancy ≤3 months
17. Current complaints of persistent constipation or history of chronic constipation, bowel
obstruction or fecaloma within the past 6 months
18. Receiving chronic treatment with corticosteroids of ≥5 mg/day of prednisone (or
equivalent), or other immunosuppressive agent(s)
19. Known history and/or uncontrolled hepatitis B surface antigen (HBsAg), hepatitis C
antibody (HCV Ab), or human immunodeficiency virus (HIV)-1 or HIV-2
Note:  Because of the possibility of spontaneous resolution of and success of 
treatment for hepatitis C, a clarification is being provided. Patients who have a 
history of hepatitis C will be allowed if their HCV RNA load is below the range that 
reflects infection with the virus at a time point that is at least 12 weeks after a 
spontaneous remission or 24 weeks after the end of treatment for hepatitis C. 
Hepatitis B patients will continue to be excluded based on having history of the 
disease. 
20. History of substance or alcohol abuse (Diagnostic and Statistical Manual of Mental
Disorders 5th edition [DSM-V] Criteria for Substance-Related Disorders) within the
past 2 years (American Psychiatric Association, 2013)
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21. History of galactose intolerance, deficiency of Lapp lactase, or glucose-galactose
malabsorption
22. History of malignancy or active treatment for malignancy (i.e., radiation or
chemotherapy, including monoclonal antibodies) within 5 years. Note: Patients with
squamous or basal cell carcinomas of the skin, carcinomas in situ of the cervix or
uterus, ductal breast cancer in situ, resected low-grade prostate cancer, or other
malignancies that in the opinion of the Investigator and the Medical Monitor are
considered cured, may participate.
23. Receipt of live, attenuated vaccine (eg, intranasal influenza, measles, mumps, rubella,
varicella) or close contact with someone who has received a live, attenuated vaccine
within the past 1 month. Note: Influenza vaccine will be allowed if administered >21
days.
24. Receipt of any investigational agent or study treatment (i.e., any treatment or therapy
not approved by the FDA for the treatment of BTC) within the past 30 days
25. Receipt of any protein or antibody-based therapeutic agents (eg, growth hormones or
monoclonal antibodies) within the past 3 months
26. Treatment with any tumor-directed therapy including, but not limited to,
chemotherapy or radiotherapy within the past 6 months with curative intent. Note:
Treatment (i.e., radiation, chemoembolization, radioembolization, or other local
ablative therapies, or hepatic resection) is permitted if received ≥4 weeks from
Screening and the patient has recovered to ≤Grade 1 toxicities as defined by NCI
CTCAE v5.0.
27. Existence of any surgical or medical condition that, in the judgment of the
Investigator, might compromise patient safety or the outcome of the study
28. Presence of any clinically significant findings (relative to the patient population)
during review of medical history or upon PE that, in the Investigator’s or Medical
Monitor’s opinion, would compromise patient safety or the outcome of the study (eg,
psychiatric illness/social situations that would limit compliance with study
requirements)
29. Evidence of brain metastases
30. Unable or unwilling to communicate or cooperate with the Investigator for any reason
31. Employee of Sponsor or clinical site, or relative of any member of a clinical site’s
staff
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6.3 
Criteria for Stopping Treatment/Study Withdrawal 
A patient may be discontinued from the study treatment and/or withdrawn from the study for 
the following medical or administrative reasons: 
•
Withdrawal of consent by the patient or legal guardian
•
Noncompliance, including failure to adhere to the study requirements as in the study
protocol, and/or lost to follow-up 
•
Investigator decides that, in the interest of the patient, it is not medically acceptable to
continue participation in the study 
•
The Sponsor terminates the study (Section 6.4)
•
Pregnancy (Section 9.3.1)
•
Progressive disease based on RECIST v1.1
•
Patient is unable to tolerate XERMELO following dosage reduction to 250 mg tid
•
Patient experiences:
○
Unresolved Grade 3 constipation as graded by the NCI CTCAE v5.0; or
○
Development of severe, persistent, or worsening abdominal pain
○
Continuing or recurrent Grade 4 toxicity (with the exception of alopecia, inadequately
treated nausea, vomiting, diarrhea, and transient electrolyte abnormalities that resolve
within 72 hours following institution of appropriate supportive care)
○
Suicidal ideation
○
Death
6.3.1 End-of-Treatment (EOT)/End-of-Study (EOS) Procedures 
6.3.1.1 End-of-Treatment Procedures 
The EOT procedures should occur as close to the last day of combination treatment whenever 
possible for all patients. Any assessments that have occurred <3 weeks prior to this visit will 
not be required to be repeated. See Appendix A for a list of all required EOT assessments. If a 
patient voluntarily withdraws consent from the study during the Treatment Period, or is 
discontinued prior to progressing, every attempt should be made to have the patient return to 
the clinic to complete all required EOT assessments and ask if the patient wishes to remain in 
the study by continuing into either Follow-up Period; PTFP where clinic visits occur every 3 
months, or SFP where phone calls occur instead of on-site visits. The date the patient 
discontinues the treatment, the treatment(s) discontinued, the primary reason for 
discontinuation (eg, AE, PD, protocol deviation, withdrawal of consent, lost to follow-up, 
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death) and whether they will continue in either Follow-up Period must be recorded on the 
electronic case report form (eCRF). The patient must agree to report any AEs, including 
serious adverse events (SAEs), see Section 9.4, for 30 days following their last dose of any 
study drug.  
Note: If the patient does not wish to enter the PTFP, EOS procedures should occur in the 
place of EOT procedures; see Appendix A for a list of all required EOS and EOT procedures. 
For those patients who enter PTFP prior to having their 6-month imaging assessment in the 
Treatment Period, will be asked to consent to provide their local scans and/or local scan 
report closest to the 6-month timepoint. 
6.3.1.2 End-of-Study Procedures 
The EOS procedures should occur at the final Post-treatment Follow-up visit whenever 
possible. Any assessments that have occurred ≤8 weeks prior to this visit will not be required 
to be repeated. See Appendix A for a list of all required EOS procedures. If a patient 
voluntarily withdraws or is discontinued from the study prior to completing the 24-month 
Follow-up Period, every attempt should be made to have the patient return to the clinic to 
complete the EOS assessments. Patients who enter PTFP prior to having their 6-month 
imaging assessment in the Treatment Period, will be asked to consent to provide their local 
scans and/or local scan report closest to the 6-month timepoint.  See Appendix A for a list of 
all EOS assessments required. In addition, if a patient voluntarily ends participation in the 
study at any time, the primary reason for discontinuation (e.g., AE, PD, protocol deviation, 
withdrawal of consent, lost to follow-up, death)   must be recorded on the eCRF and 
document whether the patient  agrees to attend future study visits, allow contact by study 
personnel, and/or continued access to information and/or images about disease status and 
potential SAEs. The date the patient discontinues participation and the primary reason for 
discontinuation of participation (eg, AE, PD, protocol deviation, withdrawal of consent, lost 
to follow-up, death), must be recorded on the eCRF. 
After the EOS visit occurs, patients who have not completed 24 months of follow-up will 
enter the SFP where all patients (or caregivers, where appropriate) will be contacted by phone 
every 3 months to obtain their survival status until death, premature discontinuation, 
withdrawal of consent, loss to follow-up, or for a total duration of 24 months after the last 
dose of chemotherapy (including the duration of the PTFP), whichever occurs first. 
Note: Patients who enter SFP without entering or completing PTFP and who entered SFP 
prior to having their 6-month imaging assessment in the Treatment Period, will be asked to 
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consent to provide their local scans and/or local scan report closest to the 6-month timepoint. 
This includes the possible reconsenting of patients previously prematurely discontinued or 
withdrew consent from the Treatment Period of the study. 
6.3.1.3 Lost to Follow-up 
If a patient does not return to the clinic, attempts should be made to contact the patient (or a 
previously approved designee such as a caregiver, partner, or family member) to determine 
the reason for discontinuation. At minimum, 3 documented attempts, including 1 via certified 
mail, should be made to contact the patient before considering the patient lost to follow-up. If 
a patient is deemed lost to follow-up, every attempt should be made to obtain survival status 
through public records (eg, social security death index, obituaries) every 3 months for up to 
24 months after the last documented patient visit and record this data in the eCRF.  
6.4 
Criteria for Termination of the Study 
If the Sponsor, Investigator, study monitor, DSMB (if applicable), or regulatory officials 
discover conditions arising during the study that indicate that the study should be halted or 
that a study site’s participation in the study should be terminated, this action may be taken 
after appropriate consultation between the Sponsor and Investigator. Conditions that may 
warrant such action include, but are not limited to, the following: 
•
The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in
the study
•
A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or
development of the product
•
Failure of the Investigator to enroll patients into the study at an acceptable rate
•
Failure of the Investigator to comply with pertinent FDA regulations
•
Submission of knowingly false information from the research facility to the Sponsor,
study monitor, or the FDA
•
Insufficient adherence to protocol requirements
Study termination and follow-up would be performed in compliance with the conditions set 
forth in the following sections of the Code of Federal Regulations (CFR): 21 CFR 312.50 and 
21 CFR 312.56. 
6.5 
Clinical Stopping Rules 
While the combination treatment in this study is assumed safe due to minimal overlapping 
toxicities, untoward side effects may occur. Therefore, assessment of the safety and 
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tolerability data of all enrolled patients will occur once the 6th patient has completed 21 days 
of combination treatment and will include all safety assessments for all patients obtained 
prior to the second chemotherapy cycle of the 6th patient enrolled. The subsequent approach 
will be followed: 
•
If ≤1 patient has a clinically significant (CS) AE, the study will continue without a dose
adjustment.
•
If ≥2 patients have a CS AE, the dose level will be decreased to the Reduced Dose level
in accordance with Table 6-1, and 6 additional patients will be enrolled and treated with
the Reduced Dose for 1 full cycle.
○
If ≤1 of these patients has a CS AE at the Reduced Dose for the 1st cycle, the Reduced
Dose will be used for the study.
○
If ≥2 patients have a CS AE on the Reduced Dose, the study will be stopped.
Note: A CS AE is considered an unresolved ≥Grade 3 nonhematological toxicity, which is 
related to the study drugs, excluding: controllable nausea, vomiting, hypertension, diarrhea, 
constipation, transient electrolyte abnormalities, and alopecia; Grade 3 or higher febrile 
neutropenia.  
Table 6-1 Safety Run-in Dose Reduction 
Dose Level 
Gemcitabine 
Cisplatin 
XERMELO 
Starting Dose 
1000 mg/m2 
25 mg/m2 
500 mg tid 
Reduced Dose 
800 mg/m2 
20 mg/m2 
250 mg tid 
Note: If any patient experiences a Grade 4 toxicity during the Safety Run-in, the Sponsor, in 
consultation with the Investigator, will determine if additional patients should be enrolled at 
the Reduced Dose level. 
6.6 
Method of Assigning Patients to Treatment 
This is a nonrandomized study. Eligible patients will be assigned to treatment once eligibility 
has been confirmed.  
6.7 
Blinding and Unblinding of Study Drug 
This is an open-label study. 
6.8 
Replacement of Patients 
Patients who do not complete the study will not be replaced. 
6.9 
Rescreening of Patients 
Patients who are excluded during the Screening Period may be allowed to rescreen once. 
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7 
TREATMENT 
The concomitant chemotherapy (cis/gem) will not be supplied by TerSera. Initial dosing will 
be as defined in Section 5.1. Any dosage modification(s) should be performed in accordance 
with Section 6.3 and Section 7.5. 
7.1 
XERMELO (telotristat ethyl) 
For complete details on drug administration and storage, please refer to the IB. 
7.1.1 Identity 
Telotristat ethyl 250-mg tablets are white to off-white, coated, and oval with “T-E” debossed 
on 1 side and “250” debossed on the other side. 
7.1.2 Packaging, Labeling, and Storage 
Patients will receive 250-mg telotristat ethyl tablets packaged in 100-cc high-density 
polyethylene bottles with child-resistant polypropylene screw caps and heat-induction seal 
liners, as 100 tablet count per bottle. The drug product bottle contains desiccants. 
Telotristat ethyl should be stored at 25°C (77°F); excursions are permitted 15°C to 30°C 
(59°F to 86°F). 
7.2 
Prior and Concomitant Medications 
7.2.1 Prior Medication 
All medications and other treatments taken within 30 days prior to Screening will be recorded 
on the eCRF. 
7.2.2 Concomitant Medication 
All concomitant medications and other treatments taken during the study, including 
modifications to dosage and/or frequency, will be recorded on the eCRF, including 1L 
therapy. Each component of the combination chemotherapy, (i.e., cisplatin, gemcitabine) for 
each cycle should be recorded as a separate entry. 
Medical management of patients and their concomitant medications is allowed at the 
discretion of the Investigator. The list of concomitant medication therapy should be reviewed 
at each visit and continuance and/or adjustment of dosages should be evaluated based upon 
the patient’s clinical presentation and contraindication(s) of the assigned treatment. Specific 
attention should be paid to additive effects of concomitant therapies that may increase a 
patient’s risk of constipation and/or abdominal pain. Dosages of such concomitant treatments 
should be reduced or stopped, as appropriate, during the patient’s participation on study. 
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7.3 
Prohibited Medication or Concomitant Therapy 
Medication and other treatments are prohibited if they are: 
•
Identified as contraindicated in the package insert for XERMELO (TerSera Therapeutics
LLC, 2020), gemcitabine (Lilly USA, LLC, 2018), or cisplatin (Bristol-Myers Squibb
Company, 2010) or in best practice during the administration of 1L therapy; respectively.
•
Intended to produce an effect on tumor growth. No other tumor-directed therapy(ies) is
(are) permitted while taking combination treatment.
•
Chronic treatment with corticosteroids, ≥5 mg/day of prednisone (or equivalent), or other
immunosuppressive agent(s)
7.4 
Administration of Study Drug 
All patients will be instructed to take XERMELO with food. “With food” means taking 
XERMELO tablets within 15 minutes before or within 1 hour after a meal or large snack. 
Patients will be instructed to take XERMELO tid during waking hours, with doses spaced 
approximately 6 hours apart. 
Bottles of XERMELO and dosing instructions will be dispensed to patients on Day 1 of each 
cycle during the Treatment Period and at each visit during the Post-treatment Follow-up 
Period (if applicable), as described in Appendix A. Patients should be reminded to bring their 
bottles to the clinic on Day 8 of each cycle for dosing. 
Cisplatin and/or gemcitabine will be administered iv as described in Section 5.1.2 in 
accordance with institutional practice guidelines. 
7.4.1 Treatment Compliance  
Patients will be asked to bring their unused or unopened bottles of XERMELO to each visit 
(Appendix A). At each visit and in the presence of the patient, study site personnel will count 
returned tablets and reconcile the counts against planned number of doses for that interval. 
All dosages prescribed and dispensed to the patient, dose modification(s), and missed dose(s), 
including planned dose interruptions during the study must be recorded. Site personnel are to 
clarify any discrepancy and record this information within the eCRF.  
Patients will be asked to keep a Medication Diary on an electronic, hand-held device 
provided for the study. The patients will enter the number of tablets of XERMELO taken at 
breakfast, lunch, and dinner on the device. 
Patients must maintain at least 75% compliance in dosing to be deemed as compliant. In the 
event of a missed or vomited XERMELO dose, patients will take their subsequent dose at the 
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next scheduled time point, following the tid dosing regimen of approximately every 6 hours. 
A dose outside of a 3-hour window for XERMELO should be considered missed. A dose 
delay of more than 1 week for cis and gem should also be considered missed. Missed or 
vomited doses of XERMELO will not be made up. 
7.5 
Dose Adjustment/Modification 
For the purposes of this study the following definitions apply: 
•
Interruption: temporary stoppage of 1 or both treatments of the assigned combination
treatment (XERMELO and/or 1L) but then resuming the treatment(s) within 3 weeks for
XERMELO or at the next treatment cycle for 1L chemotherapy.
•
Discontinuation: premature withdrawal from 1 or both treatments of the assigned
combination treatment (XERMELO and/or 1L) defined as a dose interruption lasting for
>3 weeks (XERMELO) or a missed cycle (cis/gem)
•
Note: Discontinuation of cisplatin, but continuing treatment with gemcitabine alone, will
not be classified as a discontinuation.
Note: If gem is deferred, cis will also be deferred. Day 8 treatment may be deferred for toxic 
effect by 1 week only. If a second deferral is needed, the treatment will be omitted, and the 
patient will move on to the next treatment cycle.  
7.5.1 XERMELO (telotristat ethyl) 
XERMELO reduces bowel movement frequency and constipation was observed in clinical 
studies in patients with CS diarrhea. Monitor for the development of constipation and/or 
severe, persistent, or worsening abdominal pain in patients taking XERMELO. 
In general, 
 Toxicity will be 
assessed according to the NCI CTCAE v5.0 (Appendix G). 
Table 7-1  XERMELO Dose Modifications 
Grade of Event Management/Next XERMELO Dose2 
Grade 1 
No change in dose 
Grade 2 
Hold until ≤Grade 1. Resume at same dose level. 
Grade 3 
Hold until ≤Grade 1. Resume at 1 dose level lower (250 mg tid).1 
Grade 4 
Discontinue treatment 
1Patients unable to tolerate 250 mg tid should be discontinued from XERMELO. 
2Rechallenge may be permitted upon consultation with the Medical Monitor. 
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Recommended management for the following AEs: 
•
Nausea and/or vomiting: treat with antiemetics
•
Diarrhea: treat as indicated for underlying cause; examples of therapy(ies) include:
antidiarrheal agents (eg, loperamide, over-the-counter [OTC]), pancrealipase for
steatorrhea, cholestyramine for short gut syndrome
•
Gastrointestinal toxicity:
o
Monitor concomitant medication usage as described in Section 7.2.2.
o
Constipation (Grade 1 and above): initiate treatment as clinically indicated; examples
of therapy(ies) include: laxatives, enemas, suppositories, psyllium, hydration, OTC
agents
o
Abdominal pain (Grade 1 and above): initiate treatment as clinically indicated;
examples of therapy(ies) include: analgesics, anti-gas/bloating agents
o
Hold XERMELO for Grade 2 constipation or abdominal pain until ≤Grade 1. Resume
at 1 dose level lower (250 mg tid).
o
Discontinue XERMELO for Grade 3 constipation or abdominal pain
•
Suicidal ideation: Discontinue XERMELO
These dose modification rules should be followed for clinical laboratory abnormalities that 
are Clinically Significant as determined by the Investigator; the Investigator assessment can 
differ from the CTCAE severity grading stated on the laboratory report. 
Clinical interpretation is especially important for hepatic enzyme abnormalities. These may 
be elevated at Baseline, and CTCAE severity grades provided on the laboratory report may 
not account for this. Furthermore, GGT changes have been commonly observed with 
telotristat ethyl in patients with carcinoid syndrome, and these have been of uncertain clinical 
significance. 
Mean GGT changes in an oncology study were +130 U/L and +242 U/L on 250 mg tid and 
500 mg tid, respectively, of telotristat ethyl at Week 12. Increases in GGT were observed 
soon after telotristat initiation, and values remained elevated throughout the course of 
treatment (Kulke, 2017). 
In the same study, elevations in ALT were only +7 U/L and +17 U/L, respectively on these 
doses. No increase from Baseline in mean value of bilirubin levels was observed in any 
treatment group. Most adverse events of hepatic enzyme elevation were mild or moderate in 
intensity, the rate did not increase with long-term treatment, and a review concluded that 
these increases did not lead to Clinically Significant outcomes (Lexicon, 2018). 
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If there are laboratory changes without Clinical Significance, the Investigator can maintain 
treatment and continue to monitor. The drug may be interrupted at the Investigator's 
discretion in consultation with the Medical Monitor. 
7.5.2 Cisplatin/Gemcitabine 
In general, 
Toxicity will be assessed according to the NCI CTCAE v5.0. 
Table 7-2 Dose Reduction 
Dose Level 
Gemcitabine 
Cisplatin 
Starting Dose 
1000 mg/m2 
25 mg/m2 
Reduced Dose 
800 mg/m2 
20 mg/m2 
The following dose modification rules (Table 7-3) will be used with respect to hematologic 
toxicity on Day 1 of each treatment cycle believed to be related to cisplatin or gemcitabine: 
Table 7-3 Dose Reduction for Hematologic Toxicity on Day 1 
ANC 
Platelet Count 
Gemcitabine/Cisplatin 
≥1,000/mm3 
and 
≥100,000/mm3 
Treat as scheduled 
<1,000/mm3 
or/ 
and 
<100,000/mm3 
Defer treatment by 1 week. Reduce 
dose by 1 level for next treatment. 
The following dose modification rules will be used with respect to hematologic toxicity on 
Day 8 of each treatment cycle believed to be related to cisplatin or gemcitabine: 
Table 7-4 Dose Reduction for Hematologic Toxicity on Day 8 
ANC 
Platelet Count 
Gemcitabine/Cisplatin 
≥1,000/mm3 
and 
≥75,000/mm3 
Treat as scheduled 
<1,000/mm3 
or/ 
and 
<75,000/mm3 
Defer treatment 1 week. Reduce dose 
by 1 level for next treatment. If a 
second deferral is needed, treatment 
will be omitted 
Note: Administration of granulocyte-colony stimulating factor (G-CSF) is allowed, but 
discontinuation is required at least 2 days prior to the next administration of chemotherapy. If 
symptoms do not resolve after 28 days of uninterrupted G-CSF, chemotherapy treatment 
should be stopped.  
The following dose modification rules will be used with respect to nonhematologic toxicity 
on Day 1 of each treatment cycle believed to be related to cisplatin or gemcitabine.  
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Table 7-5 Dose Reduction for Nonhematologic Toxicity on Day 1 
Nonhematologic Toxicity1 
Gemcitabine/Cisplatin 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Defer treatment until resolves to ≤Grade 1. Reduce dose by 
1 level for next treatment.  
1Permissible exceptions to this rule are Grade 3 nausea, vomiting, hypertension, diarrhea, constipation, and 
transient electrolyte abnormalities that resolve within 72 hours following institution of appropriate supportive 
care, and alopecia. 
The 
Table 7-6 Dose Reduction for Nonhematologic Toxicity on Day 8 
Nonhematologic Toxicity1 
Gemcitabine/Cisplatin 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Defer treatment until resolves to ≤Grade 1. Reduce dose by 1 
level for next treatment. If deferral is needed for more than 1 
week, treatment will be omitted. 
1Permissible exceptions to this rule are Grade 3 nausea, vomiting, hypertension, diarrhea, constipation, and 
transient electrolyte abnormalities that resolve within 72 hours following institution of appropriate supportive 
care, and alopecia.  
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8 
STUDY PROCEDURES 
A schedule of study assessments is provided in Appendix A.  
8.1 
Restrictions during Study 
Patients should be advised to adhere to restrictions as described in the package insert for 
cisplatin (Bristol-Myers Squibb Company, 2010), gemcitabine, (Lilly USA, LLC, 2018) and 
XERMELO (TerSera Therapeutics LLC, 2020). 
8.2 
Description of Study Assessments 
8.2.1 Efficacy Assessments 
8.2.1.1 Imaging Assessment 
Each study site must have a designated radiologist or qualified individual who is responsible 
for the interpretation and evaluation of required images for this study according to RECIST 
v1.1 (Appendix J). If possible, the same radiologist/qualified individual should perform the 
evaluation for the entire duration of the study. All radiology evaluations will be performed 
initially by the local radiologist (or designee) with all images sent to a central reviewer.  
Independent central radiology review includes radiology assessments by BICR and an 
Independent Adjudication Committee (IAC). All scans will be reviewed and adjudicated as 
set forth in the Independent Review Charter. 
8.2.1.1.1 Computed Tomography (CT)/ Magnetic Resonance Imaging (MRI) 
Patients who have received previous treatment with chemotherapy in the adjuvant setting will 
be required to provide documentation of PD prior to study entry. This documentation requires 
least 2 evaluable CT or MRI studies performed ≥4 weeks apart and within 6 months prior to 
planned C1D1. For the purpose of this study, images submitted to BICR within 6 weeks prior 
to and including C1D1, i.e., which ever set was closest to C1D1 will be referred to as 
Baseline imaging. Copies of these images are to be sent to a central reviewer to use in the 
final analysis.  
All patients should have at least 1 measurable lesion by CT or MRI as determined by 
RECIST v1.1. For the purposes of this study, CT refers to a contrast enhanced image by CT 
of the chest, abdomen, pelvis, and/or other areas of known disease. The preferred method of 
imaging for this study is CT with contrast; MRI of the abdomen and/or pelvis with 
noncontrast CT of the chest will be acceptable for patients with medical contraindications to 
either the procedure itself or contrast agent used (eg, allergy to the contrast agent). Suspected 
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or known central nervous system involvement should be followed with MRI unless 
contraindicated. 
The same imaging technology and the same technique should be used to characterize each 
identified and reported lesion at Baseline and throughout the duration of the study. During the 
study, imaging studies will be performed as outlined in Appendix A.  
8.2.1.1.1.1 Measurement Technique 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. 
8.2.1.1.1.2 Tumor Response by Response Evaluation Criteria in Solid Tumors 
(RECIST) 
Measurable disease lesions must be accurately measured in at least 1 dimension in 
accordance with RECIST v1.1 (Appendix J). Changes in tumor measurements must be 
confirmed by repeat assessments within 4-6 weeks after the criteria for response, or 
progression, are first met. 
8.2.2 Clinical Laboratory Assessments  
Clinical laboratory assessments will include, at a minimum, blood chemistry (complete 
metabolic profile [CMP], liver function tests [alkaline phosphatase (ALKP), ALT, AST, total 
bilirubin], lipid panel [high-density lipoprotein (HDL), low-density lipoprotein (LDL), total 
cholesterol, triglycerides], coagulation parameters [PT, INR]), hematology (complete blood 
count [CBC] with differential, and platelet counts), and urinalysis.  
Additional assessments such as serum and urine pregnancy tests will be performed on 
females of childbearing potential only. Urine pregnancy tests will be performed by the site 
staff and will not be sent to the central laboratory. 
All other laboratory assessments will be performed by a central laboratory. Note: Central 
laboratory assessments for Day 8 are not required; sites may perform local laboratory 
assessments on Day 1 and/or Day 8 for patient management of chemotherapy infusion 
according to their practiced standard of care. In rare cases, laboratory results obtained from 
the local laboratory may be used to assess eligibility when the central laboratory lab result is 
unavailable. Authorization to use local laboratory results for determining eligibility must be 
obtained from the Sponsor prior to initiating study drug. 
Out of range values should be assessed by the Investigator for clinical significance relevant to 
the patient population. For this protocol, assessments will be defined as not clinically 
significant (NCS) or clinically significant (CS). The incidence of clinically significant 
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laboratory values, as well as clinically significant shifts in laboratory values, should be 
reported as an AE in the eCRF (Section 9.1.1) and followed as described in Section 9.5; 
retests should be performed as frequently as clinically indicated. 
8.2.3 Pharmacodynamic and Pharmacokinetic Assessments 
8.2.3.1 
Fasting (≥6 hours) blood samples for 
in plasma will be collected at 
the study sites and analyzed by Frontage Laboratories, Inc. All sample processing 
information will be supplied by the laboratory in a separate document. Efforts should be 
made to schedule these visits in the morning, with instructions to the patient to arrive in a 
fasted state and not dose prior to the blood draw. 
8.2.3.2 Other Tumor Biomarkers: Carbohydrate Antigen 19-9 (CA 19-9) and 
Carcinogenic Embryonic Antigen (CEA) 
Blood samples will be collected for measurement of 
throughout the 
duration of the study. 
Note: 
 Patients should be advised to avoid multivitamins or dietary 
supplements containing biotin (vitamin B7), which is commonly found in hair, skin, and nail 
supplements and multivitamins, for 12 hours prior to sample collection. 
8.2.3.3 Pharmacokinetic (PK) Assessments 
Blood samples for the purposes of determining trough levels of XERMELO and LP-778902 
concentrations in plasma will be collected for all patients as indicated in Appendix A. Efforts 
should be made to schedule these visits in the morning, with instructions to the patient to 
arrive in a fasted state and not dose prior to the blood draw.  
A separate, optional substudy will be conducted to collect additional samples from a subset of 
patients over a 6-hour timeframe as indicated in Appendix B for the purposes of a population 
PK analysis.  
Detailed procedures for the drawing, preparation, storage, and shipping of samples will be 
provided in a separate laboratory manual. 
8.2.4 Safety Assessments 
In addition to the clinical laboratory assessments described in (Section 8.2.2) and monitoring 
of AEs described in detail in Section 9.5, safety of patients will be monitored through vital 
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sign measurements (Section 8.2.4.1), PE findings (Section 8.2.4.2), and ECG findings 
(Section 8.2.4.3).  
Findings outside of the normal range and/or expectation should be assessed by the 
Investigator for clinical significance relevant to the patient population. For this protocol, 
assessments will be defined as NCS or CS. Clinically significant changes compared with 
Baseline (C1D1) findings for these variables should be reported as AEs on the eCRF and 
followed as described in Section 9.5; additional testing and/or retests should be performed as 
frequently as clinically indicated. 
8.2.4.1 Vital Sign Measurements 
Measurement of vital signs will include assessment of blood pressure, respiratory rate, pulse 
rate, and temperature. Vital sign measurements should not be conducted within the 
30 minutes immediately following any phlebotomy. 
Efforts should be made to standardize blood pressure collection across all patients and visits. 
Patients should be seated for at least 5 minutes prior to collection. All measurements should 
be assessed on the same arm, using the same equipment, and by the same technician where 
possible. 
Additional measurements may be obtained if clinically indicated. 
8.2.4.2 Physical Examination (PE), Height, and Weight 
A complete PE will be performed at specific time points as outlined in Appendix A. Physical 
examinations will include a minimum of a review of the patient’s general appearance and 
mental status; visual assessment of the head, eyes, ears, nose, and throat (HEENT), back, 
extremities, musculoskeletal, and skin; palpitation of the abdomen and neck including 
thyroid, and auscultation of the heart and lungs.  
Symptom-oriented PEs will be performed at all other time points and as clinically indicated. 
In addition, body weight will be captured at each clinic visit. Efforts should be made to 
standardize weight collection across all patients and visits. Patients should be instructed to 
remove shoes and heavy clothing (eg, heavy coats, jackets) prior to measurement. For weight 
collection, an effort should be made to use the same scale throughout the study where 
possible. In instances where multiple scales may be used, efforts should be made to reset the 
scale to zero prior to collection of weight measurement.  
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Height (without shoes) will be measured once, during Screening. Body Mass Index (BMI) 
will be calculated by the eCRF once height and weight have been entered (see Appendix F 
for calculation details). 
8.2.4.3 Electrocardiogram (ECG) 
Electrocardiograms (12-lead ECGs) will be performed to monitor cardiac function. Tracings 
must include a documented assessment of clinical significance (eg, NCS or CS), as applicable 
and the assessment must be signed and dated by the Investigator (or designee). 
8.2.4.4 Depression Detection 
Patients will be evaluated prior to initiating treatment on Day 1, then periodically throughout 
the remaining duration of the Treatment Period as outlined in Appendix A. During the 
Baseline visit, the patient will first be asked to respond to the question “During the past 
month, have you often been bothered by feeling down, depressed, or hopeless?” followed by 
“During the past month, have you often been bothered by little interest or pleasure in doing 
things?”. A positive response prior to Day 1 dosing will be evaluated by the Investigator in 
order to assess if the response is clinically significant. Positive responses assessed as 
clinically significant will be captured on the medical history CRF page.  
At all other timepoints, the patient will be asked to provide a response in relation to the last 
visit. “Since the last visit, have you often been bothered by feeling down, depressed, or 
hopeless?” followed by “Since the last visit, have you often been bothered by little interest or 
pleasure in doing things?”. A positive response following Day 1 dosing will be evaluated by 
the Investigator to determine if the response is clinically significant. Positive responses 
assessed as clinically significant are to be reported as an AE and captured on the AE page, 
additional reporting requirements are discussed in Section 9.3.2.  
The depression detection questions will automatically populate on the patient’s electronic 
device for them to complete on the evening prior to each study visit. A positive response to 
any question will send an automatic email to the site alerting them of the response so follow-
up with the patient can occur and clinical significance assessed. 
8.3 
Other Assessments 
8.3.1 Performance Status Based on Eastern Cooperative Oncology Group (ECOG) 
Performance status will be assessed throughout the duration of the study, the ECOG score 
will be recorded in the eCRF. Appendix G  provides scoring criteria and a conversion table 
for Investigators using the Karnofsky Performance Scale (KPS) scoring system. 
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8.3.2 Health-related Quality of Life (HRQoL) 
Health-related quality of life (HRQoL) will be evaluated using the 
 Module (Appendix I) at specific time points as outlined in 
Appendix A. These questionnaires will be completed by the patient at the clinic during the 
visit using the electronic device provided for the study; therefore, patients should be 
reminded to bring their electronic diaries with them to each study visit. 
8.3.3 Characterization of the Tumor - Substudy 
Baseline characterization of tumor tissue will be completed for a subset of patients in an 
optional substudy. Previously archived patient tumor biopsy samples will be requested, where 
available. These samples will be analyzed by IHC methods for 5-HT, TPH-1, and tumor 
fibrosis on patients who consent to participate. Additional markers may be added to this list if 
suggested by internal or external data. The purpose of these studies will be to further 
characterize the patient population. 
Specific requirements for tissue preparation and submission will be supplied by the 
laboratory in a separate document. 
8.4 
Appropriateness of Assessments 
The assessments used in this study conform to accepted clinical and laboratory assessments 
of patients with BTC in clinical trials and are typical of a Phase 2a study. 
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9 
SAFETY REPORTING 
It is the responsibility of the Investigator to document all AEs and special situations that 
occur during the study. 
Adverse events will be collected at all study visits as outlined in Appendix A. Each AE 
should be recorded using the medical diagnosis; if a diagnosis is not established at the time of 
the reporting, a symptom or sign described by standard medical terminology may be used. 
Adverse events should not be solicited with leading questions that suggest specific signs or 
symptoms. Rather, AEs should be solicited by asking the patient a nonleading question such 
as: “Do you feel different in any way since receiving the dose or since the last assessment?” 
Adverse events that occur after the signing of informed consent and before the first dose of 
study drugs should be recorded as medical history unless the event is an SAE that could be 
associated with the trial procedures and could modify the conduct of the trial, or as otherwise 
specified. 
9.1 
Definitions and Special Considerations 
9.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not it is considered drug related.  
An AE includes any noxious, pathological, or unintended change in anatomical, 
physiological, or metabolic functions as indicated by physical signs or symptoms occurring 
after a patient has provided informed consent, whether or not it is considered related to the 
study drugs.  
This definition includes an exacerbation of preexisting medical conditions or events, 
historical conditions not present prior to study treatment, which reappear following study 
treatment, intercurrent illnesses, hypersensitivity reactions, drug-drug or drug-food 
interactions, medication errors, overdose (both intentional or unintentional), drug 
misuse/abuse, false positive laboratory test, or the significant worsening of the disease under 
investigation.  
Anticipated day-to-day fluctuations of preexisting conditions that do not represent a clinically 
significant exacerbation or worsening need not be reported as AEs. 
Treatment-emergent AEs are defined as any AEs reported after the first dose of study drugs 
and for 30 days following the last dose of study drugs. 
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Any treatment-emergent abnormal laboratory result should be reported as an AE if it meets 1 
or more of the following conditions: 
•
Fulfills any of the criteria for an SAE (Section 9.1.2),
•
Results in discontinuation of study treatment,
•
Requires treatment, or
•
Is considered by the Investigator to be clinically significant.
9.1.2 Serious Adverse Events 
An SAE is defined as any AE that results in any of the following outcomes: 
1. Death;
2. A life-threatening AE - defined as an event, in the view of the Investigator, the
occurrence of which places the patient at immediate risk of death. It does not include
an AE that, had it occurred in a more severe form, might have caused death;
3. Hospitalization or prolonging of an existing hospitalization;
4. A persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions, or,
5. A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Hospitalization is defined as any inpatient overnight stay in a hospital. This does not include 
an emergency room visit or admission to an outpatient facility. 
A hospitalization in and of itself should not be reported as an SAE. 
Hospitalizations for preplanned or elective surgery or routine clinical procedures without 
worsening of the underlying condition, or for administrative/social reasons (such as 
convenience, logistics) should not be reported as SAEs; however, if an elective procedure has 
to be performed sooner than planned due to a worsening of the underlying medical condition 
and the patient is hospitalized for the procedure, the worsening medical condition should be 
reported as an SAE. 
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Any laboratory abnormality fulfilling any of the criteria for an SAE should be reported as 
such. 
9.1.3 Unexpected Adverse Events 
An unexpected AE is an AE that is not listed in the Reference Safety Information (eg, the IB) 
or is not listed at the specificity or severity that has been observed. “Unexpected” also refers 
to the AEs that are mentioned in the Reference Safety Information as occurring with the class 
of study drugs or as anticipated from the pharmacological properties of the study drugs but 
are not specifically mentioned as occurring with the study drugs. 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the IB referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents. 
It the responsibility of the Sponsor to assess whether an AE is expected or unexpected. 
9.2 
Assessment of Adverse Events 
The Investigator will evaluate all AEs with regards to the severity and relationship to each of 
the study drugs; XERMELO, cisplatin, and gemcitabine. 
9.2.1 Severity 
The Investigator will assess the severity of each AE using their clinical expertise and 
judgment using NCI CTCAE v5.0 criteria (Appendix H). 
9.2.2 Causality 
Causality assessment is a determination of whether there is a reasonable possibility that the 
study drug caused an AE. Factors that should be considered in causality assessment include, 
but are not limited to, temporal relationship, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease or concomitant medication, biological 
plausibility, and previous observation or lack of with study drug or other medication(s) in the 
same class. 
For each AE, the Investigator will assess the causal relationship between each of the study 
drugs and the AE using their clinical expertise and judgment according to the most 
appropriate description as follows: 
Note: In cases of elevated LFT(s), it may not be possible to differentiate which drug is 
causing the AE. If, based on clinical judgement, an increase in LFT(s) is attributed to drug 
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treatment, causality could be assigned to each of the study drugs. Dose modification should 
be performed in accordance with Section 7.5. 
•
Not related: The AE does not follow a reasonable temporal relationship to
administration of the study drug, or an alternative etiology (eg, underlying disease,
complications, concomitant drugs, or concurrent treatment) is more likely
•
Unlikely related: The AE has an improbable temporal relationship to administration
of the study drug, or an alternative etiology (eg, underlying disease, complications,
concomitant drugs, or concurrent treatment) is more likely
•
Possibly related: The AE follows a reasonable temporal relationship to
administration of the study drug (including the course after withdrawal of the drug),
and an alternative etiology (eg, underlying disease, complications, concomitant drugs,
or concurrent treatment) is equally or less likely
•
Probably related: The AE follows a reasonable temporal relationship to
administration of the study drug (including the course after withdrawal of the drug),
and an alternative etiology (eg, underlying disease, complications, concomitant drugs,
or concurrent treatment) is unlikely
•
Definitely related: The AE follows a plausible temporal relationship to
administration of the study drug (including the course after withdrawal of the drug)
and alternative etiology (eg, underlying disease, complications, concomitant drugs, or
concurrent treatment) can be ruled out. Positive rechallenge (i.e., reappearance or
worsening of the AE after study drug is reintroduced) or a response pattern known to
be associated with administration of the study drug provides further evidence of a
definitive causality assessment.
9.3 
Special Situations 
9.3.1 Pregnancy 
Any patient who becomes pregnant during the study must be discontinued from the study 
immediately. 
Any pregnancy during the study that occurs after administration of combination treatment, 
where the embryo or fetus may have been exposed to the study drugs (either through 
maternal exposure or transmission of a medicinal product via semen following paternal 
exposure), should be followed-up in order to collect information on the outcome of the 
pregnancy and development of the child after birth.  
The pregnancy exposure should be reported on the Pregnancy Questionnaire and captured on 
the eCRF page for AEs. The pregnant woman (patient or partner) should be followed for 
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pregnancy outcome through delivery or termination of the pregnancy. In any pregnancy that 
progresses to term, the infant should be followed until 6 months after birth and any 
congenital abnormalities/birth defects in the infant should be reported as an SAE.  
The outcome of a pregnancy, and the presence or absence of a congenital abnormality should 
be reported on the Pregnancy Outcome Form.  
After the study period, pregnancies should be collected by requesting that study patients 
notify the Investigator if a female patient or a female partner of a male patient becomes 
pregnant within 30 days after last dose of XERMELO. These pregnancies should be reported 
and followed in the same manner as pregnancies occurring during the study. 
9.3.2 Adverse Events of Special Interest (AESIs) 
Based on the mechanism of action of telotristat etiprate, and observations in the clinical 
studies, events described in this section are considered AESIs. Monitoring of these AEs will 
be the responsibility of the Sponsor.  
Additional information will be collected if clinically significant episodes of events described 
in this section occur. 
9.3.2.1 Depression 
Refer to the Section 8.2.4.4 for additional details regarding depression detection. Below is a 
list of terms that will be considered a depression-related AESI if deemed clinically significant 
by the Investigator:  
•
Adjustment disorder with depressed
mood with or without mixed anxiety
•
Feeling guilty or feelings of despair,
worthlessness
•
Agitated depression
•
Helplessness
•
Anhedonia
•
Mixed anxiety and depressive
disorder
•
Antidepressant therapy
•
Assisted or completed suicide,
including suicide attempt or threat
•
Depressive symptom
•
Columbia suicide severity rating
scale abnormal
•
Decreased interest or depressed
mood
•
Depression suicidal
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•
Depression, including major,
menopausal, perinatal
•
Intentional overdose or self-injury
•
Depression postoperative
•
Poisoning deliberate
•
Dysphoria
•
Self-injurious ideation
•
Electroconvulsive therapy
•
Suicidal behavior or ideation
9.4 
Reporting of Serious Adverse Events and Pregnancies 
All SAEs, regardless of causal relationship to study drug, and pregnancies must be reported 
to the Sponsor within 24 hours of investigational site awareness of the event. Investigators 
should not wait for complete information on an event before notifying the Sponsor of an 
SAE. All SAEs, pregnancies, and other special situations should be recorded on the study 
participant’s eCRF page for AEs. 
Investigational site personnel must use the approved method of notification (eg, SAE Report 
form, Pregnancy Questionnaire form, eCRF page) provided by the Sponsor to report these 
events. Where applicable, information from relevant hospital records and autopsy reports 
should be obtained. 
If paper report forms are used or to provide redacted supporting documents, they, should be 
sent to:  
Safety Data Facsimile: 
or  
Email address (in case of fax failure): 
In case of failure of/lack of access to eCRF, email, or fax, the event can be reported to the 
TerSera Call Center 
If an SAE is reported via telephone, the telephone report should be followed by a written 
report using a reporting method described above (i.e., completion of eCRF or paper form). 
For questions on safety reporting, please contact TerSera Pharmacovigilance at 
For questions on study participant management related to AE, the Medical Monitor of the 
study should be contacted. 
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Additional information received after the initial SAE has been reported to the Sponsor should 
be reported as follow-up information following the same procedure and timeline as the initial 
SAE. 
An SAE that occurs after completion of the study and, in the opinion of the Investigator is 
related to study drug, should be reported following the same procedure and timeline as an 
SAE that occurs during the study. 
9.5 
Follow-up of Adverse Events 
All AEs should be followed until the event has resolved, the condition has stabilized, the 
patient is lost to follow-up, or at least 30 days following the last dose of any study drug (i.e., 
XERMELO, cisplatin, gemcitabine), whichever comes first. Final known outcome must be 
reported whenever possible.  
Medically significant abnormal laboratory test results should be repeated and followed until 
the test results have returned to the normal range or Baseline value, and/or an adequate 
explanation of the abnormality is determined.  
9.6 
Safety Oversight 
Safety review and oversight of this study will be the responsibility of the Sponsor according 
to the Sponsor’s Standard Operating Procedures. Safety and tolerability will be reviewed 
based on data entered into the eCRFs, reported SAEs, and results of laboratory assessments 
on an approximate monthly basis. The clinical stopping rules described in Section 6.5 will be 
followed. An independent DSMB will not be utilized for this study.  
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10 STATISTICAL METHODOLOGY 
10.1 Determination of Sample Size 
The sample size was computed by satisfying design assumptions for the primary endpoint of 
the study; which is to assess the PFS rate at Month 6.  
6-Month PFS rates of 70% and 55% are assumed for the XERMELO arm and historical
control arms. Simon's 2-stage design (Simon, 1989) will be used to test these rates. The null
hypothesis, that the true response rate is p0=0.55, will be tested against a 1-sided alternative.
In the first stage, n1=20 patients will be accrued. If there are r1=11 or fewer responses in
these n1=20 patients, the study will be stopped. Otherwise, 33 additional patients will be
accrued for a total n=53. The null hypothesis will be rejected if r2= 33 + 1 or more responses
are observed in 53 patients. This design yields a Type I error rate = 0.097 and statistical
power = 0.802 when the true response rate is p1= 0.70.
The target sample size of 53 patients is expected to be accrued over a period of 18 months, 
with the last enrolled patient followed for 6 months after the start of receiving study 
treatment. Under an exponential sampling process, the median follow-up time for the time-to-
event endpoints (e.g., PFS, OS) will be 15 months.  
10.2 Analysis Populations 
This is a single arm and open-label study. Safety data will be assessed periodically 
throughout the study in addition to the testing requirements of the Simon design. These 
safety-based interim analyses will not be used to assess efficacy; hence, there will be no 
inflation of the Type I error rate that would require an adjustment to the 53 patients sample 
size: 
Per-protocol (PP): A PP population will consist of those patients that 
and have no major protocol violation(s) that would interfere 
with the collection or interpretation of the efficacy data. Determination of the PP dataset will 
be made before database lock. 
Safety: The Safety population consists of all patients receiving any fraction of a dose of study 
drug. 
PK: The PK population will be made up of all patients treated with at least 1 dose of study 
drug and who have adequate samples taken to reliably estimate the parameters of interest. 
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10.3 Study Endpoints 
10.3.1 Efficacy Endpoints 
The primary efficacy endpoint is to assess the PFS rate at Month 6, where patient progression 
is defined as the time from Baseline until the first determination of PD by central radiologic 
reading using RECIST v1.1 (Eisenhauer, 2009) or death from any cause.  
Secondary efficacy endpoints include: 
•
OS
•
OS rate at Months 6 and 12
•
PFS rate at Month 12 median PFS
•
DCR; CR + PR + SD at Months 6 and 12 and EOS
•
ORR defined as CR + PR at Months 6 and 12 and EOS
•
Local radiologist’s assessment of PFS, ORR, and DCR
Exploratory efficacy endpoints include: 
•
Change from Baseline in plasma
at Months 6 and 12 and 
EOS
•
Change from Baseline in body weight at Months 6 and 12 and EOS
•
Change from Baseline in serum albumin at Months 6 and 12 and EOS
•
Subgroup analyses will be evaluated in:
o Patients with changes in liver function tests
o Patients with Biliary stents
o Location of disease (intrahepatic, extrahepatic, or gallbladder)
•
Efficacy will be evaluated by treatment cycles
 of combination treatment)
Note: Unless otherwise indicated, all radiologic endpoints will be based on RECIST v1.1 as 
determined by BICR and compared to published historical data of cis/gem alone. 
Exploratory efficacy endpoints include assessing the effect of XERMELO when used in 
combination with 1L therapy on the following endpoints: 
•
Changes in HRQoL as measured by
 items at 
Baseline, Months 6 and 12;
•
Change from Baseline in
 at Months 6 and 12 and EOS; 
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•
Subgroup analysis of PFS, OS, ORR, and DCR using both BICR and local radiologist’s
assessment based on categorical group of Baseline and change from Baseline at Months 6
and 12 and EOS in:
o serum albumin
o correlation between Baseline neutrophil:lymphocyte ratio and OS
10.3.2 Safety Endpoints 
Safety endpoints are as follows: 
•
Incidence of TEAEs, TEAEs by severity, TEAEs by relationship to each of the study
drugs, TEAEs by study drugs exposure time, TEAEs leading to discontinuation from the
study, SAEs, and deaths
•
Actual and change from Baseline in clinical laboratory results including frequency of
values meeting CTCAE Grades >1 for severity
•
Actual and change from Baseline in vital signs results
•
Actual and change from Baseline in weight
•
Actual and change from Baseline in 12-lead ECG findings
10.3.3 Pharmacokinetic Endpoints 
For patients with intensive PK assessments, the following PK parameters will be estimated, 
where possible, for XERMELO and its active metabolite, LP-778902, in plasma by non-
compartmental methods: 
Cmax 
maximum concentration in the sampled matrix (ng/mL), obtained 
directly from the observed concentration versus time data  
Cmin 
minimum concentration in the sampled matrix (ng/mL), obtained 
directly from the observed concentration versus time data 
tmax 
time of maximum concentration (h), obtained directly from the 
observed concentration versus time data  
AUC(0-6) 
area under the concentration-time curve in the sampled matrix from 
zero (predose) to 6 hours after dose administration.  
AUC(0-last) 
area under the concentration-time curve in the sampled matrix from 
zero (predose) to time of last measurable concentration (ng·h/mL), 
calculated by linear up/log down trapezoidal summation. 
Kel 
apparent first-order terminal rate constant 
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t½ 
apparent terminal elimination half-life 
Rac 
accumulation ratio at steady state 
PK structural models for telotristat (LP-778902) will be developed from already existing PK 
data in healthy subjects and patients. These models will be used, where possible, to develop a 
population PK analysis based on the data from this study. This analysis will include, where 
possible, an assessment of the effects of intrinsic and extrinsic factors on the PK of 
XERMELO. 
10.3.4 Characterization of Tumor Substudy Endpoint 
The endpoint of this substudy is to characterize the tumor tissue by IHC staining (i.e., 5-HT 
and TPH-1) at Baseline among patients who have consented to participate and for whom 
previously-banked tissue samples are available.  
10.4 Statistical Methods 
Demographic data, Baseline disease characteristics, prior and concomitant medications, 
treatment compliance, treatment exposure, AE, laboratory tests, vital signs, PE findings, 
12-lead ECG findings, and final disposition will be summarized descriptively.
Continuous variables will be summarized descriptively by the number of patients with non-
missing data, mean, standard deviation (SD), median, minimum, and maximum values. 
Categorical variables will be summarized descriptively by their counts and associated 
percentages. All summaries will be reported by study time point, as applicable.  
All data values will be provided in listings. 
A more detailed description of the analysis and reporting of data will be provided in the 
Statistical Analysis Plan. An overview of the main analysis strategy is provided in the 
following sections. 
10.4.1 Efficacy Analyses 
All imaging will be assessed by local radiologist and the BICR. The BICR will supersede the 
local radiologist’s assessment for the purpose of primary endpoint and all applicable key 
secondary objectives. A secondary analysis will be performed to further evaluate the primary 
and secondary efficacy endpoints using the local radiologist assessments.  
A Simon’s 2-stage design algorithm will be used to assess whether the study is successful at 
each stage of the analysis. In the Stage 1 Safety Population, if there are no clinically 
significant or unresolved Grade 3 or higher toxicities considered related to the study drug and   
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if 12 (60%) or more of the 20 patients enrolled who are deemed responders per the definition 
below after the 20th patient is censored, is alive and progression-free at the Month 6 
assessment, or has discontinued for any reason, the study will be declared successful and 
enrollment will continue in Stage 2. Efficacy will also be assessed in the PP population and 
by treatment cycle. 
Note: Patients are considered responders if they are alive and progression-free at the Month 6 
assessment; otherwise, they are considered non-responders. 
In Stage 2, an additional 33 patients will be enrolled. If 34 or more (>60%) of the 53 patients 
enrolled (Stage 1 + Stage 2) are deemed responders, the study will be considered successful. 
The primary and secondary efficacy endpoints will be analyzed based on the Safety 
population. Additional analyses for the primary and secondary efficacy endpoints will be 
performed using the PP population.  
For the primary endpoint, the Kaplan-Meier method (Kaplan, 1958) will also be used to 
estimate the survival function. The PFS rate at Month 6 and the corresponding 95% 
confidence interval (CI) will be presented. In addition, the median PFS value computed from 
this study will be compared with the historical/published median PFS time (published and 
clinically acceptable median PFS for cis/gem alone). Also, the PFS rate estimates and 95% 
CIs will be computed at Month 12. Patients without PD or death will be censored at the last 
confirmed radiographic assessment by the central reviewers prior to study completion or date 
of discontinuation from the study. The same methodology will be used to analyze the median 
OS and the OS rate at Months 6 and 12. 
Subgroup analysis may be performed based on the primary tumor site, prior therapy(ies), 
performance status, major demographic and prognostic subgroups, extent of disease, and 
Baseline biomarker levels. 
Radiographic assessments will incorporate standard and exploratory analyses. Additional 
secondary analyses will include assessment of ORR and DCR at Months 6 and 12 and EOS 
using RECIST v1.1. For binary endpoints estimated as binomial proportions, such as ORR 
and DCR, the frequency and proportion of patients assessed as responder and non-responder 
as an outcome will be presented at each assessed study time point. 
Other efficacy endpoints will be summarized descriptively by study time point. Change from 
Baseline for 
 will be summarized descriptively 
and 1-sample t-tests may be performed to test for significance.  
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10.4.2 Safety Analyses 
All safety summaries will be descriptive; no statistical significance tests will be performed on 
safety data.  
Summaries will be prepared by study time point. All safety data will be listed by patient. 
Treatment-emergent AE summaries will include the overall incidence (by System Organ 
Class [SOC] and Preferred Term [PT]), events by maximum severity, events by relationship 
to each study drug, events by length of exposure (at event onset) to each study drug, events 
leading to discontinuation from the study, and SAEs. 
Vital signs, 12-lead ECG findings, PE findings, (including height and weight) and laboratory 
parameters (hematology, chemistry, and urinalysis) will be summarized descriptively at each 
time point. For quantitative variables, both actual and change from Baseline data will be 
summarized. In addition, shift table analysis will be applied to the laboratory data. 
10.4.2.1 Adverse Events 
All AEs will be coded and listed by SOC and PT based on the Medical Dictionary for 
Regulatory Activities (MedDRA). Summaries will be provided for TEAEs, drug-related AEs, 
SAEs, TEAEs leading to study discontinuation, TEAEs by drug relationship, TEAEs by 
severity, and TEAEs by length of exposure (at event onset) to the study drugs. Treatment-
emergent AEs are those events not present at Day 1 but occurring after the first dose of study 
drug, or if existing on Day 1, increasing in severity after initiation of study drug. Summaries 
made by severity will select the event with the highest severity when multiple occurrences of 
the same event are reported for the same patient. In a similar manner, summaries prepared by 
drug relationship will select the event with the greatest degree of relationship when a patient 
reports multiple occurrences of the same event. On-study deaths will be reported for deaths 
occurring during study participation and the 30 days after stopping study drug. Also, deaths 
occurring outside the 30-day window, but secondary to an AE reported within the 30-day 
Follow-up Period, will be reported as well.  
Listings will be provided for deaths, SAEs, AESIs, and discontinuations due to AEs. 
Additional summaries or listings of AEs may also be provided. 
10.4.2.2 Clinical Laboratory Parameters 
Laboratory results will be reported in conventional units and International System of Units 
(SI) units in all tables, figures, and listings. Laboratory results falling out of the normal range 
will be marked as high or low in the listings. Actual and changes from Baseline in clinical 
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laboratory results will be summarized by time point using descriptive statistics. Summaries of 
shifts from Baseline, based on CTCAE severity grades, will be provided. 
10.4.2.3 Vital Sign Measurements 
Actual and change from Baseline in vital signs results will be summarized by time point 
using descriptive statistics. 
10.4.2.4 Electrocardiogram Findings 
Clinically significant changes in ECGs compared to Baseline, as determined by the 
Investigator, will be summarized by time point using descriptive statistics. Actual and change 
from Baseline (predose values) to each time point in corrected QT (QTc) interval using 
Fridericia’s formula (QTcF) and Bazett’s formula (QTcB) will be summarized.  
10.4.2.5 Physical Examination Findings, Height, and Weight 
Physical examination findings will be listed. Weight will be analyzed as change from 
Baseline at all time points, as appropriate. 
10.4.2.6 Eastern Cooperative Oncology Group (ECOG) Performance Status 
Actual and change from Baseline in ECOG will be summarized by time point using 
descriptive statistics. 
10.4.3 Pharmacodynamic Analyses 
Actual and change from Baseline in 
 will be 
summarized by time point using descriptive statistics. 
10.4.4 Pharmacokinetic Analyses 
For patients with intensive PK assessments, descriptive statistics will be used to summarize 
the plasma concentrations of XERMELO and LP-778902 at each time of collection. All PK 
parameters for XERMELO and LP-778902 will be listed and summarized using appropriate 
descriptive statistics. 
PK data will be summarized by n, arithmetic and geometric mean, standard deviation, 
median, minimum, and maximum values at various time points. Regression models may be 
used to evaluate the type and magnitude of associations between trough concentration of 
XERMELO and LP-778902 at selected time points. 
Based on intensive PK sampling from a subset of patients and sparse PK sampling (eg, 
trough concentrations) from the study population, Population PK analyses will explore the 
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effects of covariates including, but not limited to, age, sex, race, BMI on the systemic 
exposure to XERMELO and LP-778902. PK data from this study may be integrated with PK 
data from other clinical trials to further enhance the population PK analysis and/or support 
the development of an exposure-response model for safety and efficacy. Details of population 
PK analysis plan will be prepared in a separate document. 
Results from the population (overall) PK analysis will be documented in a separate report. 
10.4.5 Analysis of Health-related Quality of Life (HRQoL) 
Actual and change from Baseline for QLQ-C30 and QLQ-BIL21 total and subscale scores 
will be summarized by time point using descriptive statistics. 
10.4.6 Baseline Characteristics and Other Summaries 
Demographic data, prior and concomitant medications, treatment compliance, and final 
disposition will be summarized descriptively. 
10.4.7 Interim Analysis 
Periodic reviews of study data will be conducted as described in Section 9.6 throughout the 
study for the purposes of safety monitoring but will not serve as a formal analysis of study 
data. A Stage 1 analysis in a total of 20 patients will be conducted, Stage 1 enrollment will 
include a Safety Run-in cohort. Safety, tolerability and efficacy data of the combination 
treatment from the first 6 patients who complete at least 21 days of safety follow-up after 
the first dose of combination treatment will be evaluated. It is anticipated that a total of 20 
patients will participate in Stage 1. If there are no clinically significant or unresolved 
Grade 3 or higher toxicities considered related to the study drug, and if 12 (60%) or more 
of the 20 patients enrolled who are deemed PFS responders in the Safety population, 
enrollment will continue to Stage 2. In addition, efficacy will be assessed in the safety 
population with aim Efficacy will also be assessed in the per-protocol population and by 
treatment cycle. 
Three formal statistical interim analyses will be performed during this study as follows: 
•
Interim analysis 1: Conducted in Patients included in the Stage 1 analysis (first 20
patients enrolled) and will include safety, efficacy (PFS responder rate),
pharmacodynamic (biomarker) data and analysis by treatment cycle.
•
Interim analysis 2 added to (Stage 1+2) 6-month analysis: Conducted after all Patients
(Stage 1 + Stage 2) complete the Month 6 visit, and will include safety, efficacy (PFS
responder rate), pharmacodynamic (biomarker) data and analysis by treatment cycle.
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•
Interim Analysis 3 added to Stage (1+2) 12 month analysis: Conducted after all Patients
(Stage 1 + Stage 2) complete the Month 12 visit, and will include safety, efficacy (PFS
responder rate), pharmacodynamic (biomarker) data and analysis by treatment cycle.
These data will be used to help plan for future studies. 
10.4.8 Protocol Deviations 
Protocol deviations will be listed. 
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11 STUDY MANAGEMENT 
The Investigator is responsible for completing and maintaining adequate and accurate eCRFs 
and source documentation. Source documentation constitutes original records, which may 
include: progress notes, medication administration records, laboratory reports, ECG tracings, 
discharge summaries, etc.  
All data and corrections, if applicable, entered on to the eCRF must meet minimum 
requirements as specified in the case report form guidelines (CRFg). All eCRFs should be 
completed in their entirety and stored in accordance with International Council for 
Harmonisation (ICH) E6 Good Clinical Practice (GCP) guidance. The Investigator must sign 
the Investigator’s statement in each patient’s eCRF indicating that the data reported are 
accurate. 
At the study site, clinical research associates may verify up to 100% of eCRFs in their 
entirety against source documentation as specified in the Clinical Monitoring Plan. Computer 
programmed edit checks will be run against the database to check for discrepancies and 
reasonableness of the data, and the safety database will be reconciled with the clinical 
database. All issues resulting from the computer-generated checks and the safety database 
reconciliation will be resolved according to standard data management practices in 
conjunction with the Sponsor, clinical study personnel, and the study Investigator(s). 
11.1 Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
Sponsor’s study monitors will contact the study site via visits to the site, telephone calls, 
and/or letters in order to review study progress, eCRF completion, and address any concerns 
or questions regarding the study conduct. During monitoring visits, the following aspects of 
study conduct will be carefully reviewed: informed consent of patients, patient recruitment, 
patient compliance with the study procedures, source data verification, drug accountability, 
use of concomitant therapy by patients, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
The Investigator must make study data accessible to the clinical monitor, to other authorized 
representatives of the Sponsor, and to regulatory inspectors. 
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11.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Study 
Manual requirements. The noncompliance may be either on the part of the participant, the 
Investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
Prospective requests to deviate from the protocol (i.e., waivers) will not be approved unless 
the approval is required to protect the health or welfare of participants enrolled in the study. 
It is the responsibility of the Investigator and site staff to use continuous vigilance to identify 
and report deviations. In addition to notifying the Sponsor, protocol deviations are to be 
reported to the Institutional Review Board (IRB) as per applicable guidelines. The site study 
staff is responsible for knowing and adhering to IRB reporting requirements. Further details 
about the handling and reporting of protocol deviations will be included in a deviation plan. 
Detailed procedures for the documentation, definition, and escalation of protocol deviations 
will be defined within a separate document. 
11.3 Audits and Inspections 
The Sponsor, regulatory authority, or IRB may visit the study site at any time during the 
study or after completion of the study to perform audits or inspections. The purpose of a 
Sponsor audit or regulatory inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, ICH GCP guidelines (E6), and any other applicable regulatory 
requirements. Investigators should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection at their site. 
11.4 Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All 
amendments must be submitted to the IRB for approval prior to implementing the changes. In 
some instances, an amendment may require changes to the informed consent form, which 
also must be submitted for IRB approval prior to administration to patients. If any changes to 
the eCRF are required, the Sponsor will issue supplemental or revised eCRF pages. 
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11.5 Record Keeping 
11.5.1 Drug Accountability  
The Investigator must maintain accurate records of XERMELO receipt, dispensing 
information, and disposition. If the Investigator cannot account for all clinical supplies at the 
termination of the study, a written explanation must be provided. 
11.5.2 Health Insurance Portability Accountability Act of 1996 and Subsequent 
Updates 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 CFR Parts 160 and 164 
(the Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy Regulation 
and any applicable updates). The Investigator shall ensure that study patients authorize the 
use and disclosure of protected health information (PHI) in accordance with HIPAA Privacy 
Regulation and in a form satisfactory to the Sponsor. 
The Department of Health and Human Services updated a final rule to modify HIPAA. The 
new rule has been in effect since 26 Mar 2013, and strengthens the privacy and security 
protection for individual’s health information; modifies the rule for Breach Notification for 
Unsecured PHI (Breach Notification Rule) under the HITECH Act to address public 
comment received on the interim final rule; modifies the HIPAA Privacy Rule to strengthen 
the privacy protections for genetic information by implementing section 105 of Title I of the 
Genetic Information Nondiscrimination Act of 2008 (GINA); and makes certain other 
modifications to the HIPAA Privacy, Security, Breach Notification, and Enforcement Rules 
(the HIPAA Rules) to improve their workability and effectiveness and to increase the 
flexibility for and decrease burden on the regulated entities. 
The full text of the rule can be found at: 
11.5.3 Financial Disclosure 
The Investigator shall provide to the Sponsor sufficient accurate financial information to 
allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the FDA. The Investigator shall promptly update this information if any 
relevant changes occur in the course of the study or for 1 year following completion of the 
study. 
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11.5.4 Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation (see examples in Section 11) to ensure data integrity. “Original” in this 
context is defined as the first documentation of an observation and does not differentiate 
between hard copy and electronic records. 
11.5.5 Retention of Study Documents 
The new EU clinical trial regulation (Regulation (EU) No 536/2014 of the European 
Parliament and of the Council of 16 April 2014 (Article 58) mandates a new minimum 
retention period for the trial master file of 25 years after the end of the clinical trial”. This 
establishes a more specific time period than with internationally accepted practice of ICH 
GCP.  
The Investigator must not destroy any study-related records without receiving approval from 
the Sponsor. The Investigator must notify the Sponsor in the event of accidental loss or 
destruction of any study records. If the Investigator leaves the institution where the study was 
conducted, the Sponsor must be contacted to arrange alternative record storage options. 
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12 ADMINISTRATIVE STRUCTURE OF THE STUDY 
The study will be monitored by Sponsor personnel or the Sponsor’s representative. The 
following functions for this study will be performed by organizations designated by the 
Sponsor: data management and statistical analysis, including pharmacodynamic analysis and 
reporting. 
Specific functions designated by the Sponsor to another organization are to be defined via a 
formal transfer of obligations. 
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13 APPENDIX A – SCHEDULE OF EVENTS: 
Procedure 
Treatment Period2,3,4  
(1 cycle = 21 days, with Cis/Gem treatment on D1 & D8 and XERMELO treatment daily) 
Screening1 
(Up to 21 days)
C1 
D1 
C2 
D1 
C3 
D1 
C4 
D1 
C5 
D1 
C6 
D1 
C7 
D1 
C8 
D1 
C9 
D1 
C10 
D1
C11 
D1 
C12 
D1 
C13 
D1 
C14 
D1 
C15 
D1 
C16 
D1 
C17 
D1 
C18 
D1 
C19 
D1 
EOT
5,6
Window 
(days) 
NA 
NA 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
Assess IE 
criteria 
X 
X 
Medical 
history and 
demographics 
X 
Full physical 
exam7
X 
X 
X 
Symptom-
oriented, brief 
physical 
exam7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
pregnancy 
test8 
X 
Urine 
pregnancy 
test8 
X 
X 
Hematology9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
Blood 
chemistry9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
Serum CA 
19-99,11
X 
X 
X 
X 
X 
X 
X 
X10 
Serum CEA9 
X 
X 
X 
X 
X 
X 
X 
X10 
Plasma 5-
HIAA9 
X 
X 
X 
X 
X 
X 
X 
X10 
PK trough 
sample9,12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
Tumor 
Assessment13 
 (CT or MRI) 
X1 
X1 
X 
X 
X 
X 
X 
X 
X10 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
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Procedure 
Treatment Period2,3,4  
(1 cycle = 21 days, with Cis/Gem treatment on D1 & D8 and XERMELO treatment daily) 
Screening1 
(Up to 21 days)
C1 
D1 
C2 
D1 
C3 
D1 
C4 
D1 
C5 
D1 
C6 
D1 
C7 
D1 
C8 
D1 
C9 
D1 
C10 
D1
C11 
D1 
C12 
D1 
C13 
D1 
C14 
D1 
C15 
D1 
C16 
D1 
C17 
D1 
C18 
D1 
C19 
D1 
EOT
5,6
Window 
(days) 
NA 
NA 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
ECOG 
Performance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Depression 
detection 
(ePRO) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EORTC 
QLQ-30 and 
QLQ-BIL21 
(ePRO) 
X 
X 
Record 
concomitant 
medications14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record AEs 
and AESIs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense 
Xermelo4,15
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X16 
Cis/Gem 
Infusion17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intensive PK 
substudy18 
X 
X 
X 
X 
X 
X 
X 
Tumor 
characterizati
on substudy19 
X 
1.
The Screening Visit allows for up to 21 days prior to C1D1 if needed; however, if radiological assessments have been completed within 6 weeks prior to Day 1, they are not required to
be repeated at Day 1.
2.
All assessments, including laboratory assessments, ECGs and questionnaires should be performed prior to initiating treatment regimen.
3.
Treatment visit dates will be scheduled based on the date of enrollment.
4.
All cycles are 21 days, with Cis/Gem treatment on D1 and D8 and XERMELO treatment daily. Patients are not required to complete a specific amount of cycles, patients may continue
combination treatment for as many cycles possible until PD, unacceptable toxicity, or patient withdraws from treatment.
5.
EOT procedures should be completed once the patient has confirmed PD, unacceptable toxicity, or withdraws from combination treatment. The patient will then begin the Post-
treatment Follow-up Period (PTFP) where patients return to the site every 3 months to complete the required assessments until a new tumor directed therapy begins, the patient declines
further treatment after progression, or withdraws from any further study visits. At that time, the EOS procedures should be completed and the patient should enter the Survival Follow-
up Period (SFP) until the patient has completed a full 24 months of combination Post-treatment/Survival Follow-up.  During SFP patients are to be contacted by phone every 3 months
to obtain survival status; see Section 5.1.2.2 for details.
6.
Procedures should not be repeated if end of treatment (EOT)/end of study (EOS) occurs during scheduled study visit; however, all EOT/EOS assessments should be completed; with
those required by the scheduled visit to be recorded on the scheduled visit eCRF and additional assessments required by EOT/EOS recorded in the EOS eCRF.
7.
A complete physical examination will include, at minimum, a review of the patient’s general appearance, head, eyes, ears, nose, throat, neck, heart, lungs, abdomen, back, extremities,
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skin and general neurological system. A symptom-related brief physical exam will only occur if the patient is experiencing symptoms or AEs. If a symptom-related brief physical exam 
is required, it should include a review of all body systems that relate to the symptoms and/or AE the patient is experiencing. 
8.
Females of childbearing potential only
9.
Day 8 labs are optional (at the discretion of the Investigator) and will be analyzed by the local lab.
10. EOT assessments are not required if the last assessment occurred <3weeks prior; EOS assessments are not required if last assessment occurred ≤8weeks prior.
11. Patients should avoid multivitamins or dietary supplements containing biotin (vitamin B7) for 12 hours prior to sample collection.
12. PK trough samples are required to be drawn for ALL patients. Patients should be in a fasted state and should not have dosed prior to blood draw.
13. Tumor assessments are not required if progressive disease has been confirmed by CT/MRI at previous visit.
14. Prior medications taken within 30 days of screening will be recorded within the patient’s medical history. Any medications that are ongoing at the time of screening should be recorded
within the patient’s concomitant medication page.
15. Xermelo will be dispensed on D1 of each cycle. The patient should be reminded to bring their bottles back on D8 of each cycle in order for dosing of Xermelo to be given with the
chemotherapy infusion.
16. Xermelo can continue to be dispensed during the Post-treatment Follow-up Period, at the discretion of the Investigator, until the patient begins new tumor-directed therapy, declines
further treatment after progression, or withdraws from any further study visits.
17. Cis/Gem are not being provided by TerSera. If cisplatin is stopped, gemcitabine may be continued alone at the Investigator’s discretion.
18. Intensive PK is an optional substudy. These samples are only required for those patients who have consented to participate in this substudy and will be drawn on Day 1 and Day 8 of
each cycle where collected; refer to Appendix B for additional details.
19. Archived tissue samples can be submitted at any time during the Treatment Period. Fresh biopsies will not be collected.
20. Total duration of the 2 combined Follow-up Periods should be no more than 24 Months.
21. Follow-up visits dates should be scheduled based on the EOT date.
22. Phone call to patient or caregiver, where appropriate, to obtain survival status.
23. Patients who enter PTFP and imaging assessments are not required, or who enter SFP without entering or completing PTFP prior to having their 6-month imaging assessment in the Treatment
Period, will be asked to consent to provide their local scans and/or local scan report closest to the 6-month timepoint.  Reconsenting the patient may be required if previously prematurely
discontinued or withdrew consent from the Treatment Period of the study.
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APPENDIX A – SCHEDULE OF EVENTS 
AE = adverse event; AESI = adverse event of special interest; CT = computed tomography; Cis = cisplatin; ECG = electrocardiogram; EOS = End of Study; EOT = End of Treatment; Gem 
= gemcitabine; IE = inclusion/exclusion; MRI = magnetic resonance imaging; SAE = serious adverse event; PK = pharmacokinetic 
Procedure 
Follow-up Period20,21 
Post-treatment Follow-up 
 Survival Follow-up 
3 
Month 
6 
Month 
9 
Month 
12 
Month 
15 
Month 
18 
Month 
21 
Month 
24 
Month / 
EOS6 
3 
Month 
6 
Month
9 
Month
12 
Month
15 
Month
18 
Month
21 
Month
24 
Month
Window (days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Phone patient22 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical exam7
X 
Symptom-oriented brief 
physical exam7
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test8 
X 
Hematology9 
X 
X 
X 
X 
X 
X 
X 
X10 
Blood chemistry9 
X 
X 
X 
X 
X 
X 
X 
X10 
Serum CA 19-99,11 
X 
X 
X 
X 
X 
X 
X 
X10 
Serum CEA9 
X 
X 
X 
X 
X 
X 
X 
X10 
Plasma 5-HIAA9 
X 
X 
X 
X 
X 
X 
X 
X10 
PK trough sample9,12 
X 
X 
X 
X 
X 
X 
X 
X10 
Urinalysis 
X10 
Tumor Assessment13
 (CT or MRI) 
X23 
X23 
X 
X 
X 
X 
X23 
X10,23 
ECG 
X10
ECOG Performance 
X 
X 
X 
X 
X 
X 
X 
X 
Depression detection 
(ePRO) 
X 
EORTC QLQ-30 and 
QLQ-BIL21 (ePRO) 
X 
X 
Record concomitant 
medications18 
X 
X 
X 
X 
X 
X 
X 
X 
Record SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
Record AEs and AESIs 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Xermelo4,15
X16
X16
X16
X16
X16
X16
X16
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1.
The Screening Visit allows for up to 21 days prior to C1D1 if needed; however, if radiological assessments have been completed within 6 weeks prior to Day 1, they are not
required to be repeated at Screening.
2.
All assessments, including laboratory assessments, ECGs and questionnaires should be performed prior to initiating treatment regimen.
3.
Treatment visit dates will be scheduled based on the date of enrollment.
4.
All cycles are 21 days, with Cis/Gem treatment on D1 and D8 and XERMELO treatment daily. Patients are not required to complete a specific amount of cycles, patients may
continue combination treatment for as many cycles possible until PD, unacceptable toxicity, or patient withdraws from treatment.
5.
EOT procedures should be completed once the patient has confirmed PD, unacceptable toxicity, or withdraws from combination treatment. The patient will then begin the
Post-treatment Follow-up Period (PTFP) where patients return to the site every 3 months to complete the required assessments until a new tumor directed therapy begins, the
patient declines further treatment after progression, or withdraws from any further study visits. At that time, the EOS procedures should be completed and the patient should
enter the Survival Follow-up Period (SFP) until the patient has completed a full 24 months of combination Post-treatment/Survival Follow-up.  During SFP patients are to be
contacted by phone every 3 months to obtain survival status; see Section 5.1.2.2 for details.
6.
Procedures should not be repeated if end of treatment (EOT)/end of study (EOS) occurs during scheduled study visit; however, all EOT/EOS assessments should be
completed; with those required by the scheduled visit to be recorded on the scheduled visit eCRF and additional assessments required by EOT/EOS recorded in the EOS
eCRF.
7.
A complete physical examination will include, at minimum, a review of the patient’s general appearance, head, eyes, ears, nose, throat, neck, heart, lungs, abdomen, back,
extremities, skin and general neurological system. A symptom-related brief physical exam will only occur if the patient is experiencing symptoms or AEs. If a symptom-
related brief physical exam is required, it should include a review of all body systems that relate to the symptoms and/or AE the patient is experiencing.
8.
Females of childbearing potential only
9.
Day 8 labs are optional (at the discretion of the Investigator) and will be analyzed by the local lab.
10. EOT assessments are not required if the last assessment occurred <3weeks prior; EOS assessments are not required if last assessment occurred ≤8weeks prior.
11. Patients should avoid multivitamins or dietary supplements containing biotin (vitamin B7) for 12 hours prior to sample collection.
12. PK trough samples are required to be drawn for ALL patients. Patients should be in a fasted state and should not have dosed prior to blood draw.
13. Tumor assessments are not required if progressive disease has been confirmed by CT/MRI at previous visit.
14. Prior medications taken within 30 days of screening will be recorded within the patient’s medical history.  Any medications that are ongoing at the time of screening should be
recorded within the patient’s concomitant medication page.
15. Xermelo will be dispensed on D1 of each cycle. The patient should be reminded to bring their bottles back on D8 of each cycle in order for dosing of Xermelo to be given
with the chemotherapy infusion.
16. Xermelo can continue to be dispensed during the Post-treatment Follow-up Period, at the discretion of the Investigator, until the patient begins new tumor-directed therapy,
declines further treatment after progression, or withdraws from any further study visits.
17. Cis/Gem are not being provided by TerSera. If cisplatin is stopped, gemcitabine may be continued alone at the Investigator’s discretion.
18. Intensive PK is an optional substudy. These samples are only required for those patients who have consented to participate in this substudy and will be drawn on Day 1 and
Day 8 of each cycle where collected; refer to Appendix B for additional details.
19. Archived tissue samples can be submitted at any time during the Treatment Period. Fresh biopsies will not be collected.
20. Total duration of the 2 combined Follow-up Periods should be no more than 24 Months.
21. Follow-up visits dates should be scheduled based on the EOT date.
22. Phone call to patient or caregiver, where appropriate, to obtain survival status.
23. Patients who enter PTFP and imaging assessments are not required, or who enter SFP without entering or completing PTFP prior to having their 6-month imaging assessment
in the Treatment Period, will be asked to consent to provide their local scans and/or local scan report closest to the 6-month timepoint.  Reconsenting the patient may be
required if previously prematurely discontinued or withdrew consent from the Treatment Period of the study.
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14 APPENDIX B – INTENSIVE PK SUBSTUDY SCHEDULE 
Schedule of Intensive PK Assessments1 
Predose 
Morning 
Dose2 
1 hr 
2 hr 
3 hr 
4 hr 
6 hr 
Midday 
Dose 
Intensive PK 
Assessments 
X 
X4 
X4 
X4 
X4 
Time of Day 
(Example) 
Predose3 
8:00 
9:00 
10:00 
11:00 
12:00 
14:00 
14:01 
1Patients who have consented to the intensive PK substudy should have PK samples collected at all 
time points shown above on Day 1 and Day 8 of all required cycles; see Appendix A. 
2With food
3Fasted 
4Samples should be collected within 15 minutes of scheduled 
collection time 
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15 APPENDIX C – ESTIMATED AMOUNT OF BLOOD TO BE 
COLLECTED FROM EACH PATIENT 
Assessment 
Sample 
volume 
(mL) 
Number 
of 
samples* 
Estimated total 
volume (mL) 
Safety 
Hematology 
4 
19 
76 
Blood chemistry 
6 
19 
114 
Serum hCG 
2 
1 
2 
Pharmacokinetic 
XERMELO and LP-
788902 
4 
42 
168 
4 
16 
64 
4 
16 
64 
4 
16 
64 
Total 
552 
* Maximum number of samples is indicated.
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16 APPENDIX D – ETHICAL STANDARDS 
Ethics and Regulatory Considerations 
This study will be conducted according to GCP, 21 CFR Part 50, (Protection of Human 
Subjects), 21 CFR Part 56 (Institutional Review Boards), ICH Guidance for Industry, E6 
GCP: Consolidated Guidance, the Nuremberg Code, and the Declaration of Helsinki.  
General Instructions 
The FDA regulates studies of drugs, biologics, and medical devices. Consequently, these 
studies are patient to GCP regulations and guidance issued by the FDA and are included in, 
but not limited to, the following parts of the CFR and guideline document: 
•
21 CFR Part 11 – Electronic Records
•
21 CFR Part 50 – Protection of Human Patients
•
21 CFR Part 54 – Financial Disclosure
•
21 CFR Part 56 – Institutional Review Boards
•
21 CFR Part 312 – Investigational New Drug Application
•
Current FDA Guideline for the Monitoring of Clinical Investigations
•
Current FDA Guideline for Institutional Review Boards and Clinical Investigators
•
Current FDA Guideline for Good Clinical Practice
Copies of these materials are available from the Sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper 
conduct of clinical trials that have been developed by the medical, scientific, and regulatory 
communities. They are not intended to impede or restrict clinical research.  
The ethical standards defined within GCP are intended to ensure that: 
•
human patients are provided with an adequate understanding of the possible risks of
their participation in the study, and that they have a free choice to participate or not;
•
the study is conducted with diligence and in conformance with the protocol in such a
way as to ensure the integrity of the findings;
•
the potential benefits of the research justify the risks.
TerSera Therapeutics LLC is the Sponsor of the Investigational New Drug Application 
(IND). The Sponsor is responsible for the following: 
•
selecting qualified Investigators,
•
providing Investigators with the information they need to properly conduct an
investigation,
•
ensuring proper monitoring of the investigation,
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•
ensuring that the study is conducted according to the general investigational plan and
protocols contained in the IND,
•
maintaining the IND, and
•
ensuring that FDA and all participating Investigators are properly informed of
significant new information regarding adverse effects or risks associated with the drug
being studied.
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17 APPENDIX E – INVESTIGATOR OBLIGATIONS 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56, 
the study protocol and the final version of the patient informed consent form will be approved 
by the IRB before enrollment of any patients. The opinion of the IRB will be dated and given 
in writing. A copy of the letter of approval from the IRB and a copy of the approved informed 
consent form will be received by the Sponsor prior to shipment of XERMELO supplies to the 
Investigator. 
The Investigator will ensure that the IRB will be promptly informed of all changes in the 
research activity and of all unanticipated problems including risk to patients. The Investigator 
will also ensure that no changes will be made to the protocol without IRB approval. 
As a part of the IRB requirement for continuing review of approved research, the Investigator 
will be responsible for submitting periodic progress reports to the IRB at intervals appropriate 
to the degree of patient risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every patient prior to 
clinical trial participation. The rights, safety, and well-being of the trial patients are the most 
important considerations and should prevail over interests of science and society. 
As described in GCP guidelines, study personnel involved in conducting this trial will be 
qualified by education, training, and experience to perform their respective task(s). Study 
personnel will not include individuals against whom sanctions have been invoked after 
scientific misconduct or fraud (eg, loss of medical licensure, debarment). Quality assurance 
systems and procedures will be implemented to assure the quality of every aspect of the 
study. 
Principal Investigators in the US must provide the Sponsor with a fully executed Form FDA 
1572 (statement of Investigator) and all updates on a new fully executed Form FDA 1572. 
Principal Investigators must provide the Sponsor with their own curriculum vitae and current 
curriculum vitae for each subinvestigator listed on the Form FDA 1572. 
Protection of Human Patients (21 CFR Part 50) 
Informed consent must be obtained from every patient before entry into a clinical study. It 
must be given freely and not under duress. Consent must be documented by use of an IRB-
approved consent form and signed by the patient or the patient’s legally authorized 
representative. The Department of Health and Human Services suggests that when minors are 
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involved, a parent or guardian should sign the consent form. If the minor is an adolescent, 
their signature should also be included. Non-English-speaking patients must be presented 
with a consent form written in a language that they understand. A copy of the signed consent 
form must be given to the patient signing it. Another copy must be kept in the Investigator’s 
files and made available to FDA representatives upon request. If, for any reason, patient risk 
is increased as the study progresses, a revised, IRB-approved consent form must be signed by 
the patient. Before the study begins, a sample of the consent form must be provided to the 
Sponsor for review. The FDA may reject otherwise scientifically valid studies if proper 
informed consent has not been obtained from all patients. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the Investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB within 5 working 
days. In this situation, the Investigator may not administer any subsequent product to that 
patient until informed consent and IRB approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each patient prior to entry in the study. One 
copy of the signed informed consent document will be given to the patient, and another will 
be retained by the Investigator. Additionally, the participant must be allowed adequate time to 
consider the potential risks and benefits associated with his/her participation in the study.  
In situations where the participant is not legally competent to provide consent (i.e., mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the Sponsor and 
by the Investigator’s IRB prior to the initiation of the study. The document must contain the 8 
basic elements of informed consent and may contain the 6 additional elements described in 
21 CFR Part 50. Every consent form must include the following 8 elements: 
•
A statement that the study involves research, an explanation of the purpose of the
research and the expected duration of the patient’s participation, a description of the
procedures to be followed, and identification of any procedures that are experimental
•
A description of any reasonably foreseeable risks or discomforts to the patient
•
A description of any benefits to the patient or to others that may reasonably be
expected from the research
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•
A disclosure of appropriate alternative procedures or course of treatment, if any, that
might be advantageous to the patient
•
A statement describing the extent, if any, to which confidentiality of records
identifying the patient will be maintained and noting the possibility that the FDA and
representatives may inspect the records
•
An explanation as to whether any compensation or medical treatments are available if
injury occurs for research involving more than minimal risk. The explanation should
involve a description of the compensation or treatment available, or a statement
describing where further information may be obtained
•
An explanation of whom to contact for answers to pertinent questions about the
research and the patient’s rights and whom to contact in the event of a research related
injury
•
A statement that participation is voluntary, that refusal to participate will involve no
penalty or loss of benefits to which the patient is otherwise entitled, and that the
patient may discontinue participation at any time without penalty or loss of benefits to
which the patient is otherwise entitled.
When appropriate, 1 or more of the following elements of information shall also be included 
in the consent form: 
•
A statement that the particular treatment or procedure may involve risks to the patient
(or to the embryo or fetus, if the patient is or may become pregnant), which are
currently unforeseeable
•
Anticipated circumstances under which the patient’s participation may be terminated
by the Investigator without regard to the patient’s consent
•
Any additional costs the patient may incur from participation in the research
•
The consequences of a patient’s decision to withdraw from the research and
procedures for orderly termination of participation by the patient
•
A statement that significant new findings developed during the course of the research
that may relate to the patient’s willingness to continue participation will be provided
to the patient
•
The approximate number of patients involved in the study
The Declaration of Helsinki includes further details regarding the specific requirements for 
informed consent.  
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
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The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective. Some states, such as California and Oregon, 
require further action on the Investigator’s part concerning patient consent. 
Study Documentation 
The protocol and informed consent form(s) for this study, including advertisements used to 
recruit participants, must be reviewed and approved by an appropriate IRB/Ethics Review 
Committee (ERC) prior to enrollment of participants in the study. It is the responsibility of 
the Investigator to assure that all aspects of the ethical review are conducted in accordance 
with the current Declaration of Helsinki, ICH GCP, and/or local laws, whichever provide the 
greatest level of protection. A letter documenting the IRB/ERC approval, which specifically 
identifies the study/protocol and a list of the committee members, must be received by the 
Sponsor prior to initiation of the study. Amendments to the protocol will be subject to the 
same requirements as the original protocol. 
A progress report with a request for reevaluation and reapproval will be submitted by the 
Investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the Sponsor.  
When the Sponsor provides the Investigator with a Safety Report, the Investigator must 
promptly forward a copy to the IRB/ERC. 
After completion or termination of the study, the Investigator will submit a final report to the 
IRB/ERC and to the Sponsor, if required. This report should include: deviations from the 
protocol, the number and types of participants evaluated, the number of participants who 
discontinued (with reasons), results of the study, if known, and significant AEs, including 
deaths. 
Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current GCP standards and all applicable federal, state, and local laws, rules, 
and regulations related to the conduct of a clinical study. Study documents include, but are 
not limited to, the IB, drug accountability records, Sponsor/Investigator correspondence, IRB 
correspondence, protocol and amendments, information regarding monitoring activities, 
patient exclusion records, eCRFs, and data queries. 
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Confidentiality 
The anonymity of participating patients must be maintained. Patients will be identified by an 
assigned patient number on eCRFs and other documents submitted to the clinical monitor. 
Documents that will be submitted to the clinical monitor and that identify the patient (eg, the 
signed informed consent document) must be maintained in strict confidence by the Principal 
Investigator, except to the extent necessary to allow auditing by the FDA, the clinical 
monitor, or Sponsor personnel. 
All information regarding the nature of the proposed investigation provided by the Sponsor to 
the Investigator (with the exception of information required by law or regulations to be 
disclosed to the IRB, the patient, or the FDA) must be kept in confidence by the Investigator. 
Drug Accountability 
The Investigator or designee is responsible for accountability of XERMELO at the site. The 
Investigator or designee must maintain records of the product’s delivery to the site, inventory 
at the site, use by each patient, and return to the Sponsor or alternative disposition of any 
unused product. These records must include dates, quantities, batch/serial/lot numbers, and 
expiration dates (if applicable). 
The Investigator should ensure that XERMELO is used only in accordance with the protocol. 
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18 APPENDIX F – CALCULATIONS 
Cockcroft-Gault equation: 
The equation for calculation of creatinine clearance, as an estimation of glomerular filtration 
rate, using the method of Cockcroft and Gault is: 
     [(140-age) x weight (in kg)]___ 
[72 x serum creatinine (in mg/dL)]  
If the patient is female, multiply the above by 0.85  
For an online calculator, please use: http://www.nephron.com/cgi-bin/CGSI.cgi. 
Source:  Cockcroft D, Gault MD. Prediction of Creatinine Clearance from Serum Creatinine. 
Nephron. 1976;16:31-41. 
Body Mass Index equation: 
For an online calculator, please use: 
From the Centers for Disease Control and Prevention site: 
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Reference: 
National Cancer Institute – Cancer Therapy Evaluation Program. Clinical Data Update System (CDUS) 
Instructions and Guidelines version 3.0 Release 4. Capital Technology Information Services, Inc. 15 January 
2008. 
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20 APPENDIX H – NATIONAL CANCER INSTITUTE (NCI) 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) V5.0 
The NCI CTCAE v5.0 can be found at: 
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22 APPENDIX J – RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) 
The RECIST Guidelines can be found at: 
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23 APPENDIX K - DETAILED SUMMARY OF PROTOCOL CHANGES 
Section 
Former Text 
New Text (in Bold) 
Rationale 
Cover Page 
Added Amendment 3 Date: 
15 November 2020 
Cover Page 
Sponsor 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Sponsor 
TerSera Therapeutics LLC 
 520 Lake Cook Road, Suite 500 
Deerfield, IL 60015 
Investigator 
Signature 
Page 
Added Amendment 3 Date: 
15 November 2020 
Investigator 
Signature 
Page 
Sponsor 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Sponsor 
TerSera Therapeutics LLC 
 520 Lake Cook Road, Suite 500 
Deerfield, IL 60015 
Investigator 
Signature 
Page 
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Section 
Former Text 
New Text (in Bold) 
Rationale 
Protocol 
Amendment 
Changes 
Added: 
Protocol Amendment Summary Of Key Changes 
Synopsis-
Primary 
Objective 
Section 4.1-
Primary 
Objective 
The primary objective of the study is to 
assess the safety and efficacy (progression-
free survival rate at Month 6) of XERMELO 
in combination with cisplatin (cis) plus 
gemcitabine (gem) 
The primary objective of the study is to assess the 
safety and efficacy (PFS rate at Month 6) in the 
Safety population receiving the combination of 
XERMELO plus 1L treatment with cis/gem 
combination chemotherapy. Efficacy (PFS rate at 
Month 6) will also be evaluated in the Per 
Protocol Population (PP) and by treatment cycle. 
Synopsis-
Second 
Objectives 
Section 4.2-
Secondary 
Objective 
Section 10.3-
Study 
Endpoints 
•
PFS rate at Month 12 and median PFS
•
PFS rate at Month 12 and median PFS at
Month 12
Synopsis-
Exploratory 
Objectives 
Section 4.3-
Exploratory 
Objectives 
Section 10.3-
Study 
Endpoints 
•
Change from Baseline in
•
Subgroup analyses of PFS, OS, ORR,
and DCR using both BICR and local
radiologist’s assessment, based on
categorical group of Baseline and
change from Baseline
•
Change from Baseline in
 at 
Months 6 and 12 and EOS; 
•
Subgroup analyses of PFS, OS, ORR, and
DCR using both BICR and local
radiologist’s assessment, based on
categorical group of Baseline and change
from Baseline at Months 6 and 12 and
EOS in:
Added the following new objectives: 
•
Subgroup analyses in:
o
Patients with changes in liver
function tests
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Section 
Former Text 
New Text (in Bold) 
Rationale 
o
Patients with Biliary stents
o
Location of disease (intrahepatic,
extrahepatic, or gallbladder)
•
Efficacy analyses by treatment cycles
(such as in patients who completed
 with combination
treatment)
Synopsis-
Methodology 
Section 
5.1.2.1-
Treatment 
Period 
If 12 or more patients have survived and 
remain progression-free at Month 6, Stage 1 
of the study will be considered successful 
and enrollment will continue in Stage 2. 
From a total of 53 accrued patients from 
Stage 1 + Stage 2, if 34 or more responses 
are observed (ie, patients are alive and 
progression-free at Month 6) the study will 
be declared successful 
Added: 
Note: Efficacy (PFS rate at Month 6) will also 
be assessed in the Per Protocol population and 
by treatment cycle. 
Note: For statistical purposes and most 
analyses, Cycle 1 Day 1 is intended as 
Baseline, Cycle 10 Day 1 is intended as 
Month 6, and Cycle 19 Day 1 is intended 
as Month 12.  
If there are no clinically significant or 
unresolved Grade 3 or higher toxicities 
considered related to the study drug, and if 
efficacy in 12 (60%) or more of the 20 patients 
are deemed responders, in the Safety 
population, enrollment will continue to Stage 2. 
In addition, efficacy will be assessed in the Per-
Protocol (PP) population and by treatment 
cycle. 
From a total of 53 accrued patients from Stage 1 + 
Stage 2, if 34 (>60%) or more responses are 
observed (i.e., patients are alive and progression-
free at Month 6) in the Safety population, the 
study will be declared successful. Efficacy will 
also be assessed in the PP population and by 
treatment cycle. 
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Section 
Former Text 
New Text (in Bold) 
Rationale 
Section 
5.1.2.2-
Follow-up 
Periods 
Note: If a radiological assessment has not 
been performed within 6 weeks prior to Day 
1, an assessment at Screening will also be 
required. 
All patients are expected to be followed for a 
total duration of 24 months after the 
Treatment Period unless they voluntarily 
withdraw consent from future study visits or 
assessments. 
Patients will complete scheduled study visits 
every 3 months for a total of 24 months or 
until the patient begins a new tumor-directed 
therapy, declines further treatment after 
progression, or withdraws consent from 
future study visits or assessments. 
Note: If a radiological assessment has 
performed within 6 weeks prior to Day 1, a 
Day 1 assessment will not be required. 
All patients are expected to be followed for a total 
duration of 24 months after the Treatment Period 
unless they prematurely discontinue or 
voluntarily withdraw consent from future study 
visits or assessments. 
Patients will complete scheduled study visits 
every 3 months for a total of 24 months or until 
the patient begins a new tumor-directed therapy, 
prematurely discontinues, declines further 
treatment after progression, or withdraws consent 
from future study visits or assessments. 
Added: 
Note: For those patients who enter PTFP prior 
to having their 6-month imaging assessment in 
the Treatment Period, will be asked to consent 
to provide their local scans and/or local scan 
report closest to the Treatment Period 6-month 
timepoint. This includes the possible 
reconsenting of patients previously 
prematurely discontinued or withdrew consent 
from the Treatment Period of the study. 
Note: Patients who enter SFP without entering 
or completing PTFP and who entered SFP 
prior to having their 6-month imaging 
assessment in the Treatment Period, will be 
asked to consent to provide their local scans 
and/or local scan report closest to the 
Treatment Period 6-month timepoint. This 
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Section 
Former Text 
New Text (in Bold) 
Rationale 
includes the possible reconsenting of patients 
previously prematurely discontinued or 
withdrew consent from the Treatment Period 
of the study. 
Synopsis-
Direction of 
Treatment 
Added: 
Note: Patients may continue to receive 
treatment for as many cycles possible, until 
progressive disease (PD) (up to 19 cycles 
during the Treatment Period), and during the 
Post Treatment Follow-up Period (up to an 
additional 24 months) at the discretion of the 
Investigator. 
Synopsis-
Interim 
Analysis 
New Section: 
A formal statistical interim analysis will be 
performed on patients included in the Stage 1 
analysis. The interim analysis results will include 
safety, efficacy (PF responder rates), and 
pharmacodynamic (biomarker) data. These data 
will be used to help plan for future studies. 
Interim Analysis will be conducted: 
•
In addition to (Stage 1 + Stage 2) analysis,
after all 53 patients complete Month 6
In addition to (Stage 1 + Stage 2) analysis after, 
all 53 patients complete Month 12 
Synopsis-
Statistical 
Methods 
In Stage 1, if 12 or more of the 20 patients 
enrolled are deemed responders per the 
clinically significant or unresolved Grade 3 or 
higher toxicities considered related to the study 
drug and if 12 or more (≥60%) of the 20 
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Rationale 
definition below after the 20th patient is 
censored, is alive and progression-free at the 
Month 6 assessment, or has discontinued for 
any reason, the first stage of the study will be 
declared successful and enrollment will 
continue in Stage 2. 
In Stage 2, an additional 33 patients will be 
enrolled. If 34 or more of the 53 patients 
enrolled (Stage 1 + Stage 2) are deemed 
responders, the study will be considered 
successful. 
patients enrolled are deemed responders per the 
definition below after the 20th patient is censored, 
is alive and progression-free at the Month 6 
assessment, or has discontinued for any reason, 
the first stage of the study will be declared 
successful and enrollment will continue in Stage 
2. Efficacy will also be assessed in the PP
populations and by treatment cycle.
In Stage 2, an additional 33 patients will be 
enrolled. If 34 (>60%) or more of the 53 patients 
enrolled (Stage 1 + Stage 2) are deemed 
responders, the study will be considered 
successful. Efficacy will also be assessed in the 
PP populations and by treatment cycle. 
Synopsis-PK 
Analysis 
Section 
10.4.4-PK 
Analyses 
PK data will be summarized by n, mean, 
standard deviation, median, minimum, and 
maximum values at various time points. 
PK data will be summarized by n, arithmetic and 
geometric mean, standard deviation, median, 
minimum, and maximum values at various time 
points. 
Abbreviations 
C1D1 Cycle 1, Day 1; Baseline 
C1D1 Cycle 1, Day 1; Baseline (Baseline value 
is defined as the last non-missing data on or 
before the first dose of the study drug, unless 
otherwise specified) 
Added: 
C10D1 Cycle 10, Day 1 is intended as Month 6  
C19D1 Cycle 19 Day 1 is intended as Month 12 
Section 5.1.1-
Screening 
Note: If radiological assessments have been 
completed within 6 weeks prior to Day 1, 
they are not required to be repeated during 
the Screening Period 
Note: If radiological assessments have been 
completed within 6 weeks prior to Day 1, they are 
not required to be repeated at Day 1. 
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Section 
5.1.2.2-
Follow-up 
Periods 
Added: 
Reconsent 
In cases when a patient has prematurely 
discontinued from the study and/or withdrawn 
consent from conducting further study 
assessments, these patients may be asked to re-
consent to provide permission for their local 
imaging and imaging reports to be submitted to 
BICR.  
Section 
6.3.1.1-End-
of-Treatment 
Procedures 
Added: 
For those patients who enter PTFP prior to having 
their 6-month imaging assessment in the 
Treatment Period, will be asked to consent to 
provide their local scans and/or local scan report 
closest to the 6-month timepoint. 
Section 
6.3.1.2-End-
of-Study 
Procedures 
In addition, if a patient voluntarily ends 
participation in the study, it must be recorded 
on the eCRF the extent of withdrawal (eg, 
Does the patient agree to attend future study 
visits, allow contact by study personnel, 
and/or continued access to information about 
potential SAEs?). The date the patient 
discontinues participation and the primary 
reason for termination of participation (eg, 
AE, PD, protocol deviation, withdrawal of 
consent, lost to follow-up, death), must be 
recorded on the eCRF. 
Added: 
Patients who enter PTFP prior to having their 6-
month imaging assessment in the Treatment 
Period, will be asked to consent to provide their 
local scans and/or local scan report closest to the 
6-month timepoint.
In addition, if a patient voluntarily ends 
participation in the study at any time, the 
primary reason for discontinuation (e.g., AE, 
PD, protocol deviation, withdrawal of consent, 
lost to follow-up, death) must be recorded on the 
eCRF and document whether the patient agrees 
to attend future study visits, allow contact by 
study personnel, and/or continued access to 
information and/or images about disease status 
and potential SAEs. The date the patient 
discontinues participation and the primary reason 
for discontinuation of participation (eg, AE, PD, 
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After the EOS visit occurs, patients who 
have not completed 24 months of follow-up 
will enter the SFP where all patients (or 
caregivers, where appropriate) will be 
contacted by phone every 3 months to obtain 
their survival status until death, withdrawal 
of consent, loss to follow-up, or for a total 
duration of 24 months after the last dose of 
chemotherapy (including the duration of the 
PTFP), whichever occurs first. 
protocol deviation, withdrawal of consent, lost to 
follow-up, death), must be recorded on the eCRF. 
After the EOS visit occurs, patients who have not 
completed 24 months of follow-up will enter the 
SFP where all patients (or caregivers, where 
appropriate) will be contacted by phone every 3 
months to obtain their survival status until death, 
premature discontinuation, withdrawal of 
consent, loss to follow-up, or for a total duration 
of 24 months after the last dose of chemotherapy 
(including the duration of the PTFP), whichever 
occurs first. 
Added: 
Note: Patients who enter SFP without entering 
or completing PTFP and who entered SFP 
prior to having their 6-month imaging 
assessment in the Treatment Period, will be 
asked to consent to provide their local scans 
and/or local scan report closest to the 6-month 
timepoint. This includes the possible 
reconsenting of patients previously 
prematurely discontinued or withdrew consent 
from the Treatment Period of the study. 
Section 7-
Treatment 
Lexicon 
TerSera 
Section 7.3-
Prohibited 
Medication or 
Concomitant 
Therapy 
(Lexicon Pharmaceuticals, Inc., 2017), 
(TerSera Therapeutics LLC. 2020)), 
Added: 
•
Chronic treatment with corticosteroids, ≥5
mg/day of prednisone (or equivalent), or other
immunosuppressive agent(s)
Section 8-
Study 
Procedures 
(Lexicon Pharmaceuticals, Inc., 2017), 
(TerSera Therapeutics LLC, 2020). 
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Section 
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Section 
8.2.1.1.1-
CT/MRI 
For the purpose of this study, C1D1 will be 
referred to as Baseline. 
For the purpose of this study, images submitted 
to BICR within 6 weeks prior to and including 
C1D1, i.e., which ever set was closest to C1D1 
will be referred to as Baseline imaging. 
Section 8.2.2-
Clinical 
Laboratory 
Assessments 
Added: 
In rare cases, laboratory results obtained from 
the local laboratory may be used to assess 
eligibility when the central laboratory lab 
result is unavailable. Authorization to use local 
laboratory results for determining eligibility 
must be obtained from the Sponsor prior to 
initiating study drug. 
Section 9.4-
Reporting of 
SAEs and 
Pregnancies 
If paper report forms are used, the form(s) 
should be sent to:  
Safety Data Facsimile: (832) 442-5462 or  
Email address (in case of fax failure): 
In case of failure of/lack of access to eCRF, 
email, or fax, the event should be reported 
using Safety Hotline:
If an SAE is reported via telephone, the 
telephone report should be followed by a 
written report using a reporting method 
described above (ie, completion of eCRF of 
paper form).  
For questions on safety reporting, the Safety 
Physician of the study should be contacted 
at: 
 Pharmacovigilance and 
Drug Safety 
Email: 
Phone: 
Added: 
All SAEs, pregnancies, and other special 
situations should be recorded on the study 
participant’s eCRF page for AEs. 
Moved: 
Where applicable, information from relevant 
hospital records and autopsy reports should be 
obtained. 
If paper report forms are used or to provide 
redacted supporting documents, they, should be 
sent to:  
Safety Data Facsimile:
 or 
Email address (in case of fax failure): 
In case of failure of/lack of access to eCRF, email, 
or fax, the event can be reported to the TerSera 
Call Center
If an SAE is reported via telephone, the telephone 
report should be followed by a written report 
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Section 
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Rationale 
For questions on study participant 
management related to AE, the Medical 
Monitor of the study should be contacted. 
All SAEs, pregnancies, and other special 
situations should also be recorded on the 
study participant’s eCRF page for AEs. 
using a reporting method described above (i.e., 
completion of eCRF or paper form).  
For questions on safety reporting, please contact 
Section 
10.4.1-
Efficacy 
Analyses 
A Simon’s 2-stage design algorithm will be 
used to assess whether the study is successful 
at each stage of the analysis. In the Stage 1 
Safety Population, if there are no clinically 
significant or unresolved Grade 3 or higher 
toxicities considered related to the study drug 
and   if 12 (60%) or more of the 20 patients 
enrolled who are deemed responders per the 
definition below after the 20th patient is 
censored, is alive and progression-free at the 
Month 6 assessment, or has discontinued for 
any reason, the study will be declared 
successful and enrollment will continue in 
Stage 2. Efficacy will also be assessed in the 
PP population and by treatment cycle. 
In Stage 2, an additional 33 patients will be 
enrolled. If 34 or more (>60%) of the 53 
patients enrolled (Stage 1 + Stage 2) are 
deemed responders, the study will be 
considered successful. 
A Simon’s 2-stage design algorithm will be used 
to assess whether the study is successful at each 
stage of the analysis. In the Stage 1 Safety 
Population, if there are no clinically significant 
or unresolved Grade 3 or higher toxicities 
considered related to the study drug and   if 12 
(60%) or more of the 20 patients enrolled who are 
deemed responders per the definition below after 
the 20th patient is censored, is alive and 
progression-free at the Month 6 assessment, or has 
discontinued for any reason, the study will be 
declared successful and enrollment will continue 
in Stage 2. Efficacy will also be assessed in the 
PP population and by treatment cycle. 
In Stage 2, an additional 33 patients will be 
enrolled. If 34 or more (>60%) of the 53 patients 
enrolled (Stage 1 + Stage 2) are deemed 
responders, the study will be considered 
successful. 
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Section 
10.4.7-Interim 
Analysis 
Periodic reviews of study data will be 
conducted as described in Section 9.6 
throughout the study for the purposes of 
safety monitoring but will not serve as a 
formal analysis of study data. No formal 
interim analysis will be performed. 
Periodic reviews of study data will be conducted 
as described in Section 9.6 throughout the study 
for the purposes of safety monitoring but will not 
serve as a formal analysis of study data: 
Added: 
A Stage 1 analysis in a total of 20 patients will 
be conducted.  Stage 1 enrollment will include 
a Safety Run-in cohort. Safety, tolerability and 
efficacy data of the combination treatment 
from the first 6 patients who complete at least 
21 days of safety follow-up after the first dose 
of combination treatment will be evaluated. It 
is anticipated that a total of 20 patients will 
participate in Stage 1. If there are no clinically 
significant or unresolved Grade 3 or higher 
toxicities considered related to the study drug, 
and if 12 (60%) or more of the 20 patients 
enrolled who are deemed PFS responders in 
the Safety population, enrollment will continue 
to Stage 2. In addition, efficacy will be assessed 
in the safety population with aim Efficacy will 
also be assessed in the per-protocol population 
and by treatment cycle. 
Three formal statistical interim analyses will be 
performed during this study as follows: 
•
Interim analysis 1: Conducted in Patients
included in the Stage 1 analysis (first 20
patients enrolled) and will include safety,
efficacy (PFS responder rate),
pharmacodynamic (biomarker) data and
analysis by treatment cycle.
•
Interim analysis 2 added to (Stage 1+2) 6-
month analysis: Conducted after all
Patients (Stage 1 + Stage 2) complete the
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Month 6 visit, and will include safety, 
efficacy (PFS responder rate), 
pharmacodynamic (biomarker) data and 
analysis by treatment cycle.  
•
Interim Analysis 3 added to Stage (1+2) 12
month analysis: Conducted after all
Patients (Stage 1 + Stage 2) complete the
Month 12 visit, and will include safety,
efficacy (PFS responder rate),
pharmacodynamic (biomarker) data and
analysis by treatment cycle.
These data will be used to help plan for future 
studies. 
Appendix A-
Schedule of 
Events 
#1: The Screening Visit allows for up to 21 
days prior to C1D1 if needed; however, if 
radiological assessments have been 
completed within 6 weeks prior to Day 1, 
they are not required to be repeated at 
Screening 
#17: Lexicon 
#22 Phone call to patient or caregiver, where 
appropriate, to obtain survival status. 
Added footnotes to tumor assessment 
First table 
#1: The Screening Visit allows for up to 21 days 
prior to C1D1 if needed; however, if radiological 
assessments have been completed within 6 weeks 
prior to Day 1, they are not required to be 
repeated at Day 1. 
#17:TerSera 
Added: 
#23 Patients who enter PTFP and imaging 
assessments are not required, or who enter SFP 
without entering or completing PTFP prior to 
having their 6-month imaging assessment in the 
Treatment Period, will be asked to consent to 
provide their local scans and/or local scan report 
closest to the 6-month timepoint.  Reconsenting 
the patient may be required if previously 
prematurely discontinued or withdrew consent 
from the Treatment Period of the study. 
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Second Table 
Added: 
#22. Phone call to patient or caregiver, where 
appropriate, to obtain survival status. 
#23. Patients who enter PTFP and imaging 
assessments are not required, or who enter SFP 
without entering or completing PTFP prior to 
having their 6-month imaging assessment in the 
Treatment Period, will be asked to consent to 
provide their local scans and/or local scan report 
closest to the 6-month timepoint.  Reconsenting 
the patient may be required if previously 
prematurely discontinued or withdrew consent 
from the Treatment Period of the study. 
Appendix D-
Ethical 
Standards 
Lexicon Pharmaceuticals, Inc. 
TerSera Therapeutics LLC 
Appendix K-
Summary of 
Changes 
New Section 
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SAP_001.pdf: 
 
SAP Title:   A Phase 2, Multicenter, Open-label, Safety and Efficacy Study of 
XERMELO® (Telotristat Ethyl) plus First-line Chemotherapy in Patients with Locally 
Advanced, Unresectable, Recurrent or Metastatic Biliary Tract Cancer (BTC) 
 
 
NCT Number: 03790111 
 
SAP Approval Date:   February 3, 2021 
 
Certain information within this statistical analysis plan has been redacted (ie, 
Specific content is masked irreversibly from view with a black bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
• Named persons or organizations associated with the study. 
 
• Proprietary information, such as scales or coding systems, which are 
considered confidential information under prior agreements with license 
holder. 
 
• Other information as needed to protect confidentiality of TerSera or 
partners, personal information, or to otherwise protect the integrity of the 
clinical study. 
 
The information contained in the following document is the property of TerSera 
Therapeutics LLC and should not be shared or used for any purpose other than for 
which it was provided. 
 
 


i 
TerSera Therapeutics LLC 
LX1606.1-207-BTC 
A Phase 2, Multicenter, Open-label, Safety and Efficacy Study of 
XERMELO® (Telotristat Ethyl) plus First-line Chemotherapy in Patients 
with Locally Advanced, Unresectable, Recurrent or Metastatic Biliary Tract 
Cancer (BTC) 
03FEB2021 
Final Statistical Analysis Plan 
Version 2.0 
Prepared by: 
PPD 
929 North Front Street 
Wilmington, NC 28401 
and 
TerSera 
Therapeutics 
LLC 
520 Lake Cook 
Road, Suite 500 
Deerfield, IL 
60015 


PPD Biostatistics and Programming 
Statistical Analysis Plan (SAP) Client Approval Form 
SOP-BST-05ar06  
Effective Date:   19 September 2019 
Page 1 of 1
Client: 
TerSera Therapeutics LLC 
Protocol Number: 
LX1606.1-207-BTC 
Document Description: 
Final Statistical Analysis Plan 
SAP Title: 
A Phase 2, Multicenter, Open-label, Safety and Efficacy 
Study of XERMELO® (Telotristat Ethyl) plus First-line 
Chemotherapy in Patients with Locally Advanced, 
Unresectable, Recurrent or Metastatic Biliary Tract 
Cancer (BTC) 
SAP Version Number: 
2.0 
Effective Date: 
03FEB2021 
Author(s): 
For PPD: 
 <Client>: <Name>, <Title> 
 <add more lines as required> 
Approved by: 
Date (DD-MMM-YYYY) 
Date (DD-MMM-YYYY) 
DocuSign Envelope ID: 0A8F9DBE-D16B-422F-813E-0F916030986A
2/3/2021
2/3/2021
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SIGN


ii 
TABLE OF CONTENTS 
SUMMARY OF CHANGES .............................................................................................. V
LIST OF ABBREVIATIONS .............................................................................................. I
1.
INTRODUCTION ....................................................................................................4
2.
OBJECTIVES ...........................................................................................................5
2.1.
Primary Objective ................................................................................................. 5
2.2.
Secondary Objective ............................................................................................. 5
2.3.
Exploratory Objective ........................................................................................... 5
2.4.
Pharmacokinetic Objective ................................................................................... 6
2.5.
Substudy Objective ............................................................................................... 6
2.6.
Safety Objective .................................................................................................... 6
3.
INVESTIGATIONAL PLAN ..................................................................................6
3.1. OVERALL STUDY DESIGN AND PLAN ........................................................................ 6
3.2. STUDY ENDPOINTS .................................................................................................... 8
3.2.1
Primary Endpoint .............................................................................................. 8
3.2.1.1 Primary Efficacy Endpoint .......................................................................... 8
3.2.2 
Secondary Endpoints ......................................................................................... 9
3.2.3
Exploratory Endpoints ...................................................................................... 9
3.2.4
Pharmacokinetic Endpoints ............................................................................ 10
3.2.5
Substudy Endpoints ......................................................................................... 10
3.2.6
Safety Endpoints .............................................................................................. 10
3.3. TREATMENTS .......................................................................................................... 11
3.4. DOSE ADJUSTMENT/MODIFICATIONS ...................................................................... 12
3.4.1
Dose Modification – XERMELO ..................................................................... 13
3.4.2
Dose Modification – Cisplatin/Gemcitabine ................................................... 13
3.4.3
Clinical Stopping Rules ................................................................................... 14
4.
GENERAL STATISTICAL CONSIDERATIONS .............................................15
4.1. SAMPLE SIZE ........................................................................................................... 16
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING ............................................... 17
4.2.1.
Randomization and Stratification .................................................................... 17
4.2.2.
Blinding ........................................................................................................... 17
4.3. ANALYSIS POPULATION .......................................................................................... 17
4.3.1.
Enrolled Population ........................................................................................ 17
4.3.2.
Per Protocol (PP) Population ......................................................................... 18
4.3.3.
By Treatment Cycle Population ...................................................................... 18
4.3.4.
Safety Population ............................................................................................ 18
4.3.5.
PK Population ................................................................................................. 18
5.
PATIENT DISPOSITION .....................................................................................18
5.1. DISPOSITION ........................................................................................................... 18


iii 
5.2.
PROTOCOL DEVIATIONS .......................................................................................... 19
6.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ..........................19
6.1.
DEMOGRAPHICS ...................................................................................................... 19
6.2.
BASELINE DISEASE CHARACTERISTICS ................................................................... 20
6.3.
MEDICAL HISTORY ................................................................................................. 20
6.3.1. 
General Medical History ................................................................................. 20
6.4 INCLUSION AND EXCLUSION CRITERIA ........................................................................ 21
7.
TREATMENTS AND MEDICATIONS ..............................................................22
7.1. PRIOR AND CONCOMITANT MEDICATIONS .............................................................. 22
7.1.1.
Prior Medications ........................................................................................... 22
7.1.2.
Concomitant Medications ............................................................................... 22
7.2. CONCOMITANT PROCEDURES .................................................................................. 23
7.3. STUDY TREATMENTS .............................................................................................. 23
7.3.1.
Extent of Exposure .......................................................................................... 23
7.3.2.
Treatment Compliance and Modifications ...................................................... 23
8.
EFFICACY ANALYSIS ........................................................................................24
8.1. PRIMARY EFFICACY ANALYSIS ............................................................................... 25
8.1.1
Progression-free Survival (PFS) ..................................................................... 25
8.1.2
Sensitivity Analysis .......................................................................................... 27
8.2. SECONDARY EFFICACY ANALYSIS .......................................................................... 27
8.2.1
PFS Rate at Month 12 and Median PFS ......................................................... 27
8.2.2
Overall Survival (OS) ...................................................................................... 28
8.2.3 Disease Control Rate (DCR) ............................................................................... 28
8.2.4 Overall Response Rate (ORR) ............................................................................. 28
8.2.5 Local Radiologist’s Assessment (PFS, ORR, and DCR) ..................................... 30
8.2.6  Change in Tumor Size ......................................................................................... 30
8.2.7  Sensitivity Analysis ............................................................................................. 30
9.
EXPLORATORY ANALYSIS ..............................................................................30
9.1
Health-Related Quality of Life (HRQoL) ........................................................... 30
9.2
Subgroup Analysis .............................................................................................. 32
9.3
Sensitivity Analysis ............................................................................................. 32
10.
SAFETY ANALYSIS .............................................................................................32
10.1.
ADVERSE EVENTS ................................................................................................ 33
10.1.1.
Incidence of Adverse Events ........................................................................ 34
10.1.2.
Treatment Emergent Adverse Events Summary by SOC and PT ................. 34
10.1.3.
Relationship of Adverse Events to Study Drug ............................................ 35
10.1.4.
Severity of Adverse Event ............................................................................. 35
10.1.5.
Adverse Events by Length of Exposure to Each Study Drug ....................... 36
10.1.6.
Serious Adverse Events ................................................................................ 36


iv 
10.1.7.
Adverse Events Leading to Study Discontinuation ...................................... 37
10.1.8.
Adverse Events Leading to Treatment Discontinuation ............................... 37
10.1.9.
Adverse Events Leading to Dose Reduction ................................................ 37
10.1.10.
Adverse Events Leading to XERMELO Reduction ................................... 38
10.1.11.
Adverse Events Leading to XERMELO Interruption ................................ 38
10.1.12.
Adverse Events of Special Interest ............................................................ 39
10.1.13.
Deaths ....................................................................................................... 39
10.2.
CLINICAL LABORATORY EVALUATIONS .............................................................. 39
10.2.1.
Serum Albumin ............................................................................................. 40
10.2.2.
Pregnancy Test ............................................................................................. 40
10.3.
VITAL SIGN MEASUREMENTS .............................................................................. 40
10.4.
PHYSICAL EXAMINATION .................................................................................... 41
10.5.
ELECTROCARDIOGRAM ........................................................................................ 41
10.6.
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS ... 41
10.7.
DEPRESSION DETECTION ..................................................................................... 41
10.8.
OTHER SAFETY DATA .......................................................................................... 42
11.
PHARMACOKINETICS ......................................................................................42
12.
PHARMACODYNAMICS ....................................................................................43
13.
INTERIM ANALYSIS ...........................................................................................43
14.
REFERENCES .......................................................................................................45
15.
APPENDICES ........................................................................................................46
15.1.
SCHEDULE OF STUDY PROCEDURES ..................................................................... 46
15.2.
TERMS CONSIDERED DEPRESSION-RELATED AESI, IF CLINICALLY SIGNIFICANT 51
15.3.
IMPUTATION ........................................................................................................ 52
15.4.
EORTC QLQ – BIL21 ........................................................................................ 54
15.5.
VISIT CYCLES AND ANALYSIS TIMEPOINTS ......................................................... 56
15.6.
DETAILED SUMMARY OF SAP CHANGES ............................................................. 58


v 
Summary of Changes 
Statistical Analysis Plan Revision History 
Version 
Date 
Summary of Changes 
2.0 
03Feb2021 
Updated according to new protocol amendment dated on 23NOV2020 and 
instruction from TerSera. 


List of Abbreviations 
1L 
first-line 
2L 
second-line 
5-HIAA
plasma 5-hydroxyindoleacetic acid 
5-HT
serotonin 
AE
adverse event 
ALKP
alkaline phosphatase 
ALT
alanine aminotransaminase 
ANC
absolute neutrophil count 
AST
aspartate aminotransaminase  
AUC
area under the plasma concentration-time curve 
AUC(0-6)
AUC from time zero to 6 hours after dose administration 
AUC(0-last)
AUC from time zero to time of last measurable concentration 
BICR
blinded independent central review 
BLQ
below the limit of quantification 
BMI
body mass index 
BTC
biliary tract cancer 
C1
Cycle 1  
C1D1
Cycle 1, Day 1; Baseline (Baseline value is defined as the last non-
missing data on or before the first dose of the study drug, unless 
otherwise specified) 
C10D1 
Cycle 10 Day 1 is intended as Month 6  
C19D1 
Cycle 19 Day 1 is intended as Month 12 
CA 19-9 
serum carbohydrate antigen 19-9 
CCA 
cholangiocarcinoma 
CEA 
carcinogenic embryonic antigen 
CI 
confidence interval 
cis 
cisplatin 
cis/gem 
cisplatin/gemcitabine: cisplatin 25 mg/m2 administered 
intravenously (iv) over 90 minutes followed by gemcitabine iv 
1000 mg/m2 administered iv over 30 minutes (also referred to as 1L 
therapy)  
CMP 
complete metabolic profile 
Cmax 
observed maximum plasma concentration 
CR 
complete response 
CRF 
case report form 
CS 
clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events (v5.0) 
Ctrough 
trough plasma concentration (predose concentration) 
CV 
coefficient of variation 
DCR 
disease control rate defined as CR+PR+SD 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EORTC 
European Organisation for Research and Treatment of Cancer  
EOS 
End-of-Study 
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EOT 
End-of-Treatment 
FDA 
United States Food and Drug Administration 
GBC 
gall bladder carcinoma 
gem 
gemcitabine 
HDL 
high-density lipoprotein 
HEENT 
head, ears, eyes, nose, throat 
HRQoL 
health-related quality of life 
IHC 
immunohistochemical 
INR 
international normalized ratio 
iv 
intravenously 
Kel 
apparent first-order terminal rate constant  
KM 
Kaplan-Meier 
LDL 
low-density lipoprotein 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NCS 
not clinically significant 
ORR 
objective response rate defined as CR+PR 
OS 
overall survival 
PD 
progressive disease 
PE 
physical examination 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PP 
Per Protocol Population 
PR 
partial response  
PT 
Preferred Term or prothrombin time 
PTFP 
post-treatment follow-up period 
QLQ-BIL21 
Cholangiocarcinoma and Gallbladder Cancer Module  
QLQ-C30 
Quality of Life Questionnaire Core 30 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcB 
corrected QT interval using Bazett’s formula 
QTcF 
corrected QT interval using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RS 
raw score 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease or standard deviation 
SFP 
survival follow-up period  
SOC 
System Organ Class 
SSAs 
somatostatin analogs 
t1/2 
apparent terminal elimination half-life  
TEAE 
treatment-emergent adverse events 
tid 
3 times daily 
tmax 
time of maximum observed plasma concentration 
TPH 
tryptophan hydroxylase 


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TPH-1 
tryptophan hydroxylase-1 
TPR 
time point response 
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1. Introduction
This Statistical Analysis Plan (SAP) describes the analysis and the data presentations to be 
applied to data gathered for Protocol No. LX1606.1-207-BTC to assess the safety, 
tolerability, and efficacy of XERMELO® (telotristat ethyl) plus first-line chemotherapy in 
patients with locally advanced, unresectable, recurrent or metastatic biliary tract cancer 
(BTC).  
Collectively, BTC is a group of malignancies that arise from the epithelium of the biliary 
tract and includes cholangiocarcinoma (CCA) and gall bladder carcinoma (GBC). 
Management of risk factors and early detection of are key to improving survival in patients 
with BTC. These tumors are very aggressive malignancies with a very poor prognosis. The 
rarity of the disease limits the evidence to support role of adjuvant therapy. The available 
treatment options are also not sufficient to address the poor survival rates in patients with 
locally advanced, recurrent, or metastatic BTC. 
For patients presenting with unresectable BTC (locally advanced, recurrent, or metastatic) 
the current standard first-line (1L) therapy is a combination of cisplatin (cis) and 
gemcitabine (gem). While there are studies showing that combination treatment (cis/gem) 
is superior to gemcitabine alone as 1L therapy, treatment options for patients with 
unresectable BTC following the failure of 1L therapy remain limited and are not supported 
by Phase 3 data.  
In February 2017, the US Food and Drug Administration (FDA) approved the oral drug 
telotristat ethyl (XERMELO) as a second-line (2L) therapy to be used in combination with 
somatostatin analogs (SSAs) to help address inadequate control of diarrheal symptoms in 
patients with carcinoid syndrome (CS). While XERMELO is indicated for the treatment of 
CS diarrhea in combination with SSA therapy in adults inadequately controlled by SSA 
therapy, its mediation of serotonin (5-HT) may provide a larger benefit. A novel treatment 
approach that inhibits 5-HT production may provide clinical benefit to the significant 
number of patients with unresectable BTC. Adding a tryptophan hydroxylase (TPH) 
inhibitor, like XERMELO to the treatment paradigm in combination with 1L therapy, may 
improve the physician’s armamentarium and fulfill the unmet medical need for patients 
with advanced BTC. 
This study is intended to assess the safety and the effect of XERMELO in combination 
with 1L chemotherapy on progression-free survival (PFS) in patients with locally 
advanced, unresectable, recurrent or metastatic BTC who are naïve to tumor-directed 
therapy in the locally advanced or metastatic setting and for which treatment with 1L 
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2. Objectives
2.1. Primary Objective
The primary objective of the study is to assess the safety and efficacy (PFS rate at Month 6) 
in the Safety population receiving the combination of XERMELO plus 1L treatment with 
cis/gem combination chemotherapy. Efficacy (PFS rate at Month 6) will also be evaluated 
in the Per Protocol Population (PP) and by treatment cycle.  
2.2. Secondary Objective 
To assess the effect of study treatment on the following: 
•
Overall survival (OS)
•
OS rate at Months 6 and 12
•
PFS rate at Month 12 and median PFS
•
Disease control rate (DCR); defined as complete response (CR) + partial response (PR)
+ stable disease (SD) at Months 6, 12 and End-of-Study (EOS)
•
Objective response rate (ORR) defined as CR + PR at Months 6, 12 and EOS
•
Local radiologist’s assessment of PFS, ORR, and DCR
•
Change from Baseline in plasma 5-hydroxyindoleacetic acid (
at Months 6, 12 and EOS 
•
Change from Baseline in body weight at Months 6, 12 and EOS
•
Change from Baseline in serum albumin at Months 6, 12 and EOS
Note: Unless otherwise indicated, all radiologic endpoints will be based on Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent 
central review (BICR).  
2.3. Exploratory Objective 
 To assess the effect of study treatment on the following: 
•
Changes in health-related quality of life (HRQoL) as measured by European
Organization for Research and Treatment of Cancer (EORTC) Quality of Life
Questionnaire Core 30 (QLQ-C30) and Cholangiocarcinoma and Gallbladder Cancer
(QLQ-BIL21) items from Baseline, at Months 6 and 12
•
Change from Baseline in carcinogenic embryonic antigen (CEA) fragment at Months
6, 12 and EOS
•
Subgroup analyses of PFS, OS, ORR, and DCR using both BICR and local
radiologist’s assessment, based on categorical group of Baseline and change from
Baseline in:
o
body weight
o
serum albumin
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o
correlation between Baseline neutrophil:lymphocyte ratio and OS
•
Subgroup analyses in:
o
Patients with changes in liver function tests
o
Patients with Biliary stents
o
Location of disease (intrahepatic, extrahepatic , or gallbladder)
o
prior therapy
o
ECOG performance status
•
Efficacy analysis by treatment cycle population.
2.4. Pharmacokinetic Objective 
 The pharmacokinetic (PK) of XERMELO and the active metabolite, LP-778902 will be 
characterized, where possible, when dosed as a combination treatment with cisplatin and 
gemcitabine. In addition, where possible, intrinsic and extrinsic factors contributing to 
variability in exposure of XERMELO and the active metabolite, LP-778902, might be 
explored. 
2.5. Substudy Objective 
•
To assess the effect of study treatment based on characterization of tumor tissue by
immunohistochemical (IHC) staining (ie, 5-HT and tryptophan hydroxylase-1 [TPH-
1])
•
To determine the population PK profile among patients who participate in intensive PK
sampling
•
The population PK modeling objective is outside the scope of this analysis plan; it will be
performed by a different vendor and submitted as a separate report.
2.6. Safety Objective  
Evaluation of overall safety will be assessed by means of the following: 
•
Incidence of treatment-emergent adverse events (TEAEs) and severity assessment
using National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE) v5.0
•
Change from Baseline in clinical laboratory results including frequency of values
meeting NCI CTCAE Grades >1, laboratory data toxicities as defined by NCI CTCAE
v5.0, physical examination (PE) findings, vital signs, and electrocardiogram (ECG)
findings
3. Investigational Plan
3.1. Overall Study Design and Plan


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This study is a multicenter, open-label, 2-stage study to assess the safety, tolerability, and 
efficacy of XERMELO in combination with 1L therapy (cisplatin plus gemcitabine) in 
patients with unresectable, locally advanced, recurrent or metastatic BTC (intrahepatic or 
extrahepatic cholangiocarcinoma, gallbladder cancer), who are naïve to tumor-directed 
therapy in the locally advanced or metastatic setting, and for which treatment with 1L 
therapy (defined as a combination of cis/gem) is planned. 
The study involves: Screening, Treatment Period with Stages 1 and 2, Post-treatment 
Follow-up Period (PTFP), and Survival Follow-up. The schedule of events to be performed 
from Screening to End-of-Study (EOS) is presented in Appendix 15.1.  
Prior to the conduct of any study-related screening procedure, written consent is to be 
obtained from all patients. The collection of serious adverse events (SAEs) will begin after 
the patient has signed the informed consent. 
Stage 1 enrollment will include a Safety Run-in cohort. Safety and tolerability data will be 
evaluated for the first 6 patients who complete at least 21 days of safety follow-up after the 
first dose of combination treatment. Safety and tolerability data  will be evaluated by the 
Coordinating Investigators, Sponsor, and Medical Monitor in accordance with established 
clinical stopping rules as described in Section 3.4.  The evaluation will include all safety 
assessments from all patients obtained prior to the second chemotherapy cycle of the 6th 
patient enrolled. During this safety evaluation, Stage 1 enrollment will continue as per the 
study schema as described in Section 3.3. It is anticipated that a total of 20 patients will 
participate in Stage 1. If there are no clinically significant or unresolved Grade 3 or higher 
toxicities considered related to the study drug, and if 12 or more (≥60%) of the 20 patients 
enrolled who are deemed responder, enrollment will continue to Stage 2.   
Stage 2 may initiate enrollment once Stage 1 enrollment has been completed, in the 
absence of significant or unresolved Grade 3 or higher toxicities considered related to the 
study drugs. Approximately 33 additional patients are anticipated to participate in Stage 2. 
Study assessments in this stage will be identical to Stage 1. 
From a total of 53 accrued patients from Stage 1 + Stage 2, if 34 ( >60%) or more 
responses are observed (i.e., patients are alive and progression-free at Month 6) in the 
Safety population, the study will be declared successful. Efficacy will also be assessed in 
the PP population and by treatment cycle population. 
All patients are expected to be followed for a total duration of 24 months after the Treatment 
Period, unless they prematurely discontinue or voluntarily withdraw consent from future study 
visits or assessments. This 24-month phase is divided into 2 periods; the Post-treatment 
Follow-up Period (PTFP) and the Survival Follow-up Period.  
All patients are expected to enter PTFP at the time progressive disease (PD) is confirmed 
locally, or the patient is no longer able to tolerate chemotherapy plus XERMELO in the 
absence of PD. During the Post-treatment Follow-up Period, patients may continue treatment 


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with XERMELO at the discretion of the treating physician. Patients will complete scheduled 
study visits every 3 months for a total duration of 24 months, or until the patient begins a 
new tumor-directed therapy, declines further treatment after progression, prematurely 
discontinue, or withdraws consent from future study visits or assessments. At this time, the 
End-of-Study (EOS) procedures should be performed and the patient should enter the 
Survival Follow-up Period (unless 24 months of follow-up after the last dose of 
chemotherapy has already occurred).  
Once a new tumor-directed therapy begins, or the patient declines further treatment after 
progression, the patient enters the Survival Follow-up Period. During this period, all 
patients (or caregivers, where appropriate) will be contacted by phone every 3 months to 
obtain the patient’s survival status until death, prematurely discontinue, withdrawal of 
consent, loss to follow-up, or for a period of 24 months following the last dose of 
chemotherapy, whichever occurs first. The site should make every attempt to document the 
date of death, if appropriate.  
Note: Patients who enter PTFP prior to having their 6-month imaging assessment in the 
Treatment Period, will be asked to consent to provide their local scans and/or local scan 
report closest to the Treatment Period 6-month timepoint. This includes the possible 
reconsenting of patients previously prematurely discontinued or withdrew consent from the 
Treatment Period of the study. 
Note: Patients who enter SFP without entering or completing PTFP and who entered SFP 
prior to having their 6-month imaging assessment in the Treatment Period, will be asked to 
consent to provide their local scans and/or local scan report closest to the Treatment Period 
6-month timepoint. This includes the possible reconsenting of patients previously
prematurely discontinued or withdrew consent from the Treatment Period of the study.
3.2. Study Endpoints 
3.2.1 Primary Endpoint 
The primary endpoint of the study is to assess the safety, tolerability and efficacy of 
XERMELO in combination with cisplatin (cis) plus gemcitabine (gem). 
3.2.1.1 Primary Efficacy Endpoint
The primary efficacy endpoint is PFS rate at Month 6, where patient disease progression is 
defined as the time from first dose date until the first determination of PD by central 
radiologic reading using RECIST v1.1 (Eisenhauer, 2009) or death from any cause. 


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3.2.2  Secondary Endpoints 
The secondary efficacy endpoints include: 
•
OS
•
OS rate at Months 6 and 12
•
PFS rate at Month 12 and median PFS at Month 12
•
DCR defined as CR + PR + SD at Months 6, 12 and EOS
•
ORR defined as CR + PR at Months 6, 12 and EOS
•
Local radiologist’s assessment of PFS, ORR and DCR
•
Change from Baseline in
•
Change from Baseline in body weight at Months 6, 12 and EOS
•
Change from Baseline in serum albumin at Months 6, 12 and EOS
3.2.3 Exploratory Endpoints 
Note: Unless otherwise indicated, all radiologic endpoints will be based on RECIST v1.1 
as determined by BICR. 
To evaluate the effect of XERMELO when used in combination with 1L therapy, the 
following exploratory efficacy endpoints will be assessed: 
•
Changes in HRQoL as measured by EORTC QLQ-C30 and QLQ-BIL21 items at
Baseline, Months 6 and 12
•
Change from Baseline in CEA fragment at month 6, 12 and EOS
•
Subgroup analysis of PFS, OS, ORR, and DCR using both BICR and local
radiologist’s assessment based on categorical group of Baseline and change from
Baseline in:
o
body weight
o
serum albumin
o
correlation between Baseline neutrophil:lymphocyte ratio and OS
•
Subgroup analyses in:
o
Patients with changes in liver function tests
o
Patients with Biliary stents
o
Location of disease (Histology: intrahepatic, extrahepatic , or gallbladder)
o
prior therapy
o
ECOG performance status
•
Efficacy analysis by treatment cycle (such as in patients who completed
 with combination treatment.
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3.2.4 Pharmacokinetic Endpoints 
For patients with intensive PK assessments on Cycle 1 Day 1 and Cycle 1 Day 8, the 
following plasma PK parameters will be estimated by non-compartmental analysis, where 
possible, for XERMELO and its active metabolite LP-778902.  Additionally, trough 
plasma concentration (Ctrough) values for additional cycles will be reported for all patients 
to the extent data are available. 
Table 1 
Pharmacokinetic Parameters 
PK Parameter 
Definition 
Cmax 
observed maximum plasma concentration 
Ctrough 
trough plasma concentration (predose concentration) 
tmax 
time of maximum observed plasma concentration 
AUC(0-6)  
area under the plasma concentration-time curve from time zero to 6 
hours after dose administration. 
AUC(0-last)  
area under the plasma concentration-time curve from time zero to 
time of last measurable concentration 
Kel 
apparent first-order terminal rate constant 
t½ 
apparent terminal elimination half-life 
3.2.5 Substudy Endpoints 
One substudy is conducted in parallel to the main study. The endpoint of this study is the 
characterization of the tumor tissue by IHC staining (ie, 5-HT and TPH-1) at Baseline 
among patients in whom tissue samples are available. 
3.2.6 Safety Endpoints 
Safety endpoints are as follows: 
•
Incidence of TEAEs, TEAEs by severity, TEAEs by relationship to each of the
study drugs, TEAEs by study drugs exposure time, TEAEs leading to
discontinuation from the study, TEAE leading to dose reduction, TEAE leading to
XERMELO reduction, TEAE leading to XERMELO interruption, TEAE leading to
discontinuation from treatment, SAEs, and deaths
•
Actual and change from Baseline in clinical laboratory results including frequency
of values meeting NCI CTCAE Grades >1, laboratory data toxicities as defined by
NCI CTCAE v5.0
•
Actual and change from Baseline in vital signs results
•
Actual and change from Baseline in PE findings
•
Actual and change from Baseline in 12-lead ECG findings


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3.3. Treatments  
The treatment schema is summarized in Figure 1. 
Figure 1 
Treatment Schema 
In both Stages 1 and 2, study treatment is administered to patients in the following manner: 
1) On Day 1 (D1), eligible patients are to initiate Cycle 1 (C1), a 21-day cycle of
XERMELO plus 1L therapy (herein referred to as “combination treatment”) as
follows:
•
XERMELO 250 mg (1 x 250-mg tablet) given as an oral dose 3 times daily
(tid) for 7 days, plus
•
Cisplatin 25 mg/m2 administered intravenously (iv) over 60 to 90 minutes,
followed by
•
Gemcitabine 1000 mg/m2 administered iv over 30 minutes
2) On Day 8, patients receive combination treatment as follows:
•
XERMELO 500 mg (2 x 250-mg tablet) tid for 14 days, plus
•
Cis/gem as described above
3) Every 21 days thereafter, patients initiate a new 21-day cycle (eg, Cycle 2 [C2],
Cycle 3 [C3]) and receive combination treatment, administered as:
•
XERMELO 500 mg tid, plus
•
Cis/gem as described above on Day 1 and Day 8 of each cycle
Patients are expected to undergo approximately 6 months of combination treatment. 


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Note: Patients may continue to receive treatment for as many cycles possible, until 
progressive disease (PD) (up to 19 cycles during the Treatment Period), and during the 
Post Treatment Follow-up Period (up to an additional 24 months) at the discretion of the 
Investigator. 
Dose modification(s) and/or delay in treatment may be permitted as described in Section 
3.4. During the Treatment Period, patients may discontinue cisplatin and continue 
treatment with XERMELO plus gemcitabine alone at the Investigator’s discretion. 
Gemcitabine should be administered on the same schedule as described above. 
Patients may continue to receive combination treatment as described above for as many 
cycles as possible until PD as determined by local review, unacceptable toxicity, 
prematurely discontinue, or the patient withdraws from treatment. At this time, 
chemotherapy is discontinued, the End-of-Treatment (EOT) assessments should occur, and 
the patient should enter the PTFP. Visit dates for Follow-up period are based off the EOT 
date. During PTFP, patients may continue treatment with XERMELO at the discretion of 
the treating physician. 
3.4. Dose Adjustment/Modifications 
Dose modification(s) and/or delay in treatment may be permitted as described in Sections 
3.4.1 and 3.4.2. Section 3.4.3 describes the clinical stopping rules during Stage 1 Safety 
Run-in of the Treatment Period.  
For the purposes of this study, the following definitions apply: 
•
Interruption: temporary stoppage of 1 or both treatments of the assigned
combination treatment (XERMELO and/or 1L) but then resuming the treatment(s)
within 3 weeks for XERMELO or at the next treatment cycle for 1L chemotherapy
•
Discontinuation: prematurely discontinue or prematurely withdrawal from 1 or
both treatments of the assigned combination treatment (XERMELO and/or 1L)
defined as a dose interruption lasting for >3 weeks (XERMELO) or a missed cycle
(cis/gem). Note, however, that discontinuation of cisplatin, but continuation of
treatment with gemcitabine alone, will not be classified as discontinuation.
If gemcitabine is deferred, cisplatin will also be deferred. Day 8 treatment may be deferred 
for toxicity reasons by 1 week only. If a second deferral is needed, the treatment will be 
omitted, and the patient will move on to the next treatment cycle. 


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3.4.1 Dose Modification – XERMELO 
In general, the following dose modification rules will be used with respect to potential 
toxicity and management of TEAEs believed to be related to XERMELO. Toxicity will be 
assessed according to the NCI CTCAE v5.0.  
Table 2 
Toxicity Grade of TEAE and Corresponding XERMELO Dosing 
Action 
Grade of Event 
Management/Next XERMELO Dose1 
Grade 1 
No change in dose 
Grade 2 
Hold until ≤Grade 1. Resume at same dose level. 
Grade 3 
Hold until ≤Grade 1. Resume at 1 dose level lower (250 mg tid).2 
Grade 4 
Discontinue treatment 
1Rechallenge may be permitted upon consultation with the Medical Monitor. 
2Patients unable to tolerate 250 mg tid should be discontinued from XERMELO. 
The details on recommended management of specific adverse events (AEs) are presented 
on Section 7.5.1 of the Protocol. 
3.4.2 Dose Modification – Cisplatin/Gemcitabine 
In general, 
Toxicity will be assessed according to the NCI CTCAE v5.0. 
Table 3 
Dose Reduction 
Dose Level 
Gemcitabine 
Cisplatin 
Starting Dose 
1000 mg/m2 
25 mg/m2 
Reduced Dose 
800 mg/m2 
20 mg/m2 
The following tables show the dose modification rules that will be used with respect to 
hematologic/nonhematologic toxicity on Day 1/8 of each treatment cycle believed to be 
related to cisplatin or gemcitabine. 
Table 4 
Dose Reduction for Hematologic Toxicity on Day 1 
ANC 
Platelet 
Count 
Gemcitabine/Cisplatin 
≥1,000/mm3 and 
≥100,000/mm3 Treat as scheduled
<1,000/mm3 or/and <100,000/mm3 Defer treatment by 1 week. Reduce dose by 1 
level for next treatment. 
Table 5 
Dose Reduction for Hematologic Toxicity on Day 8 
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ANC 
Platelet 
Count 
Gemcitabine/Cisplatin 
≥1,000/mm3 and 
≥75,000/mm3 Treat as scheduled
<1,000/mm3 or/and <75,000/mm3 Defer treatment by 1 week. Reduce dose by 1 
level for next treatment. If a second deferral is 
needed, treatment will be omitted. 
Table 6 
Dose Reduction for Nonhematologic Toxicity on Day 1 
Nonhematologic 
Toxicity1 
Gemcitabine/Cisplatin 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Defer treatment until resolves to ≤Grade 1. Reduce dose by 
1 level for next treatment.  
1Permissible exceptions to this rule are Grade 3 nausea, vomiting, hypertension, diarrhea, 
constipation, and transient electrolyte abnormalities that resolve within 72 hours following 
institution of appropriate supportive care and alopecia.  
Table 7 
Dose Reduction for Nonhematologic Toxicity on Day 8 
Nonhematologic 
Toxicity1 
Gemcitabine/Cisplatin 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Defer treatment until resolves to ≤Grade 1. Reduce dose by 
1 level for next treatment. If deferral is needed for more 
than 1 week, treatment will be omitted. 
1Permissible exceptions to this rule are Grade 3 nausea, vomiting, hypertension, diarrhea, 
constipation, and transient electrolyte abnormalities that resolve within 72 hours following 
institution of appropriate supportive care and alopecia.  
3.4.3 Clinical Stopping Rules 
The rules described below will include all safety assessments for all patients obtained prior 
to the second chemotherapy cycle of the 6th patient enrolled. The subsequent approach will 
be followed: 
•
If ≤1 patient has a clinically significant (CS) AE, the study will continue without a
dose adjustment.
•
If ≥2 patients have a CS AE, the dose level will be decreased to the Reduced Dose
level in accordance with Table 7, and 6 additional patients will be enrolled and
treated at the Reduced Dose level for 1 full cycle.
o
If ≤1 patient has a CS AE at the Reduced Dose level for the 1st cycle, the
Reduced Dose level will be used for the study.
o
If ≥2 patients have a CS AE at the Reduced Dose level, the study will be
stopped.


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Note that a CS AE is considered an unresolved ≥Grade 3 nonhematological toxicity, which 
is related to the study drugs, excluding: controllable nausea, vomiting, hypertension, 
diarrhea, constipation, transient electrolyte abnormalities, and alopecia; Grade 3 or higher 
febrile neutropenia. 
Table 8 
Safety Run-in Dose Reduction 
Dose Level 
Gemcitabine 
Cisplatin 
XERMELO 
Starting Dose 
1000 mg/m2 
25 mg/m2 
500 mg tid 
Reduced Dose 
800 mg/m2 
20 mg/m2 
250 mg tid 
Note that if a patient experiences a Grade 4 toxicity during the Safety Run-in, the Sponsor, 
in consultation with the Investigator, will determine if additional patients should be 
enrolled at the Reduced Dose level.  
4. General Statistical Considerations
Continuous data will be summarized using descriptive statistics (ie, n, mean, standard 
deviation (SD), median, minimum and maximum). For the summary statistics of all 
numerical variables unless otherwise specified, minimum and maximum will be displayed 
to the same level of precision as reported.  Mean, median and 95% confidence intervals 
(CIs) will be displayed to 1 level of precision greater than the data collected. Standard 
deviation will be displayed to 2 levels of precision greater than the data collected. 
Categorical variables will be summarized descriptively by their counts and associated 
percentages. The denominator for all percentages will be the number of patients within the 
combination treatment for the population of interest, unless otherwise stated. Percentages 
will be presented to 1 decimal place. When count data are presented, the percentage will be 
suppressed when the count is zero in order to draw attention to the non-zero counts. A row 
denoted “Missing” will be included in count tabulations where specified on the shells to 
account for dropouts and missing values.  
Baseline value is defined as the last non-missing data on or before the first dose of the 
study drug, unless otherwise specified.  
For the purpose of statistical analyses, Cycle 10 Day 1 is intended as Month 6, and Cycle 
19 Day 1 is intended as Month 12. 
All summaries will be reported by study time point, as applicable. 
Demographic data, Baseline disease characteristics, prior and concomitant medications, 
treatment compliance, treatment exposure, AE, laboratory tests, vital signs, PE findings, 
12-lead ECG findings, and final disposition will be summarized descriptively. In addition,


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shift table analyses will be applied to the laboratory data. No statistical tests will be 
performed. Analyses will be based on the Safety population. 
The primary and secondary efficacy endpoints will be analyzed based on the Safety 
population. Additional analyses for the primary and secondary efficacy endpoints will be 
performed using the PP population.  
For PFS and OS, the Kaplan-Meier (KM) method will be used to estimate the survival 
function. The distribution of PFS and OS will be used to estimate the survival rates and 
corresponding 95% CI at Month 6 and Month 12. Patients without PD or death will be 
censored at the last adequate confirmed radiographic assessment by the central reviewers 
prior to the study completion, date of discontinuation from the study, date of 
discontinuation from the treatment (if there is no 6-month assessment) or the start date of 
new line of anticancer treatment.  
Subgroup analyses may be performed based on the primary tumor site, prior therapy(ies), 
performance status, major demographic and prognostic subgroups, extent of disease, and 
Baseline biomarker levels.  
For binary endpoints estimated as binomial proportions, such as ORR and DCR, the 
frequency and proportion of patients assessed as responder and non-responder as an 
outcome will be presented at each assessed study time point.  
Other efficacy endpoints will be summarized descriptively by study time point. Change 
from Baseline for 
 will be summarized
descriptively and 1-sample t-tests may be performed to test for significance using a 5% 
level of significance. 
All data values will be provided in listings. 
During the programming period, the table/listing/figure shell format and footnote might be 
edited. And this kind of change is not be considered as analysis changes or impact the 
analysis results. 
4.1. Sample Size 
The sample size was computed by satisfying design assumptions for the primary efficacy 
endpoint of the study; which is to assess the PFS responder rate at Month 6.  
Month 6 PFS responder rates of 70% and 55% are assumed for the XERMELO arm and 
historical control arms, respectively. Simon's 2-stage optimal design (Simon, 1989) is used 
to test these rates. The null hypothesis, that the true response rate is p0=0.55, will be tested 
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against a 1-sided alternative. In the first stage, n1=20 patients will be accrued. If there are 
r1=11 or fewer responses in these n1=20 patients, the study will be stopped. Otherwise, 33 
additional patients will be accrued for a total sample size of n=53. The null hypothesis will 
be rejected if r2= 33 + 1 or more responses are observed in 53 patients. This design yields a 
Type I error rate = 0.097 and statistical power = 0.802 when the true response rate is p1= 
0.70. 
In the Stage 1 Safety population, if there are no clinically significant or unresolved Grade 3 
or higher toxicities considered related to the study drug and if 12 (60%) or more of the 20 
patients enrolled who are deemed responders per the definition in Section 8.1.1 after the 
20th patient is censored, is alive and progression-free at the Month 6 assessment in the 
Safety Population, enrollment will continue to Stage 2.  
The target sample size of 53 patients is expected to be accrued over a period of 18 months, 
with the last enrolled patient followed for 6 months after the start of receiving study 
treatment. Under an exponential sampling process, the median follow-up time for the time-
to-event endpoints (eg, PFS, OS) will be 15 months. 
4.2. Randomization, Stratification, and Blinding 
4.2.1. Randomization and Stratification 
Randomization and stratification are not applicable. This is a nonrandomized study. 
Eligible patients will be assigned to treatment once eligibility has been confirmed. 
4.2.2. Blinding 
Blinding is not applicable. This is an open-label study. 
4.3. Analysis Population 
The primary and secondary efficacy endpoints will be analyzed based on the Safety 
population. Additional analyses for the primary and secondary efficacy endpoints will be 
performed using the Per Protocol (PP) population. 
4.3.1. Enrolled Population 
The enrolled population will consist of those patients with informed consent date. 
All listings and disposition tables will be based on the Enrolled population. 


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4.3.2. Per Protocol (PP) Population 
The Per Protocol population will consist of those patients that 
and who have no major protocol violation(s) that would
interfere with the collection or interpretation of the efficacy data. Determination of the PP 
population will be made before database lock.  
The analysis population will be used for analysis of primary and secondary efficacy 
endpoints. 
4.3.3. By Treatment Cycle Population 
The by treatment cycle population consist of all patients who completed 
combination treatment. 
The by treatment cycle population will be used for analysis of all efficacy endpoints as 
exploratory analysis as well as all AE outputs. 
4.3.4. Safety Population 
The Safety population will consist of all patients receiving any fraction of a dose of any of 
the study drugs (any of the study drug components).  
The Safety population will be used for analysis of primary and secondary efficacy 
endpoints as well as safety endpoints. 
4.3.5. PK Population 
The PK population will consist of all patients treated with at least 1 dose of study drug and 
who have adequate samples taken to reliably estimate at least 1 of the PK parameters of 
interest. Determination of the PK population will be reviewed after all PK concentration 
data are made available. 
This population will be used for estimation of PK endpoints. 
5. Patient Disposition
5.1. Disposition
The number of patients enrolled in the study will be tabulated. Tables will indicate the 
number of patients who were enrolled into the study, the number of patients who 
completed the treatment period, the number of patients who completed the study, and the 
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number of patients who prematurely discontinued treatment period or study (early 
termination) for any of, but not limited to, the following reasons: 
•
Adverse event
•
Protocol deviation
•
Screen failure
•
Lost to follow-up
•
Withdrawal by patient (withdrawal of consent)
•
Non-compliance
•
Investigator’s decision
•
Study terminated by Sponsor (sponsor decision)
•
Pregnancy
•
Disease progression
•
Suicidal ideation
•
Death
•
Other
All percentages will be based on the number of enrolled patients. 
Patient disposition data will be presented in a listing.  
5.2. Protocol Deviations 
Protocol deviations will be presented in a listing. 
6. Demographics and Baseline Characteristics
6.1. Demographics
All baseline patient characteristics of demographics data will be presented for the Safety 
population. Demographic characteristics will be collected at Screening. 
The following variables will be summarized: 
1. Continuous baseline demographic variables:
•
Age at time of consent (years)
•
Height (in inches)
•
Weight (in kg)
•
BMI (in kg/m2)
2. Categorical baseline demographic variables:
•
Age: <Median and ≥ Median age
•
Sex (male, female)
•
Childbearing potential (if female) (Yes, No)


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•
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
•
Race: All races (White, African American, Asian, American Indian or Alaska
Native, Native Hawaiian or Other Pacific Islander, Other) and White vs Non-
white
Patient demographics will be presented in a listing. 
6.2. Baseline Disease Characteristics 
Baseline values from the parameters below, but not limited to, will be tabulated: 
•
Eastern Cooperative Oncology Group (ECOG) performance status
•
Cancer history information (Type of biliary tract cancer, histology, stage of
cancer at study entry, duration of cancer at study entry, primary tumor
location and metastases location)
•
Patients with changes in liver function tests
•
Patients with Biliary stents
•
Prior therapy
Duration of cancer at study entry is defined as the date of inform consent minus the date of 
diagnosis + 1 and will be presented in months. Incomplete dates will be derived following 
the same rules for medical history. 
Patients with changes in liver function tests will be identified using "Drug related hepatic 
disorders - comprehensive search" PT coding terms based on AE records. Patients with 
Biliary stents will be identified using “Biliary stent”, “Biliary Tract stent”, “Bile duct 
stent” from Medical history term. Patients with prior therapy will be identified using the 
leading question “Is Condition or Term associated with BTC?” in Medical history CRF 
page. 
Baseline disease characteristics will be summarized in table and also will be presented in a 
listing. C1D1 images or images being obtained within 6 weeks prior to Day 1, or whichever 
images were closest in date to C1D1 are submitted to BICR for establishment of Baseline. 
6.3. Medical History 
6.3.1. General Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.1 or higher and actual version number will be denoted in the 


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outputs. The number and percentage of patients with any medical history at Baseline will 
be summarized overall and for each system organ class and preferred term. Percentages 
will be calculated based on number of patients in the Safety population. Incomplete dates 
will be imputed following rules in Section 15.3.  
Patient medical history data including specific details will be presented in a listing. 
6.4 Inclusion and Exclusion Criteria 
Inclusion and exclusion data will be listed only for patients that did not meet 
inclusion/exclusion criteria.  
6.5 Subgroups 
The following subgroups will be defined: 
•
•
body weight – Subgroup categories: <Median and ≥ Median baseline weight 
•
serum albumin - Subgroup categories: Normal and Abnormal baseline albumin
Demographics and disease characteristics will be considered as subgroups including: 
•
major demographic
o
Age: <Median and ≥ Median age
o
Sex: Male vs Female
o
Race: White vs Non-white
•
Subgroup analyses in:
o
Patients with changes in liver function tests
o
Patients with Biliary stents
o
Location of disease (Histology: intrahepatic, extrahepatic, or gallbladder)
o
Prior therapy
o
ECOG performance status
Subgroups mentioned in the protocol based on correlation between Baseline 
neutrophil:lymphocyte ratio and OS, prognostic subgroups, extent of disease are not 
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planned but might be performed upon reviewing the data. Such analyses will be defined in 
the Clinical Study Report. 
Patients with changes in liver function tests will be identified using "Drug related hepatic 
disorders - comprehensive search" PT coding terms based on AE records. Patients with 
Biliary stents will be identified using “Biliary stent”, “Biliary Tract stent”, “Bile duct 
stent” from Medical history term. Patients with prior therapy will be identified using the 
leading question “Is Condition or Term associated with BTC?” in Medical history CRF 
page. 
Subgroup analyses of PFS, OS, ORR, and DCR will be evaluated for exploratory 
endpoints. 
7. Treatments and Medications
7.1. Prior and Concomitant Medications
Information on prior and concomitant medications taken by patients are recorded in the 
electronic Case Report Form (eCRF). Incomplete dates will be imputed following rules in 
Section 15.3. All medications will be listed. 
7.1.1. Prior Medications 
Prior medications are defined as all medications and treatments taken prior to initiation of 
study medication. Any medications and treatments taken prior and not stopped prior to the 
first study medication will be counted in both prior medication and concomitant 
medication. The total number of prior medications and the number and percentages of 
patients with at least 1 prior medication will be summarized. The number and percentages 
of all prior medications will be summarized by drug class and preferred term. All 
summaries will be performed using the Safety population. 
Medications will be coded using the WHODRUG 20180901 or higher and actual version 
number will be denoted in the outputs. 
7.1.2. Concomitant Medications 
All concomitant medications and other treatments taken during the study, including 
modifications to dosage and/or frequency, will be recorded in eCRF.  
Information on concomitant medications will be summarized similarly to how prior 
medications will be summarized in Section 7.1.1.  


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7.2. Concomitant Procedures 
The following patient information on prior surgeries or procedures will be presented in 
frequency tabulations: 
•
Number of patients with any prior surgeries or procedures
•
Type of procedure (surgery, radiation therapy, chemotherapy, imaging, other)
Incomplete dates will be imputed following rules in Section 15.3. 
Patient information on prior surgeries or procedures will be presented in a listing. 
7.3. Study Treatments 
Administration of XERMELO, gemcitabine, and cisplatin will be documented at each visit 
as described in Section 15.1.  
7.3.1. Extent of Exposure 
The treatment schema is discussed in detail in Section 3.3.  
The following variables will be summarized by XERMELO, cisplatin and gemcitabine 
separately: 
1. Continuous drug exposure variables:
•
Duration of treatment exposure (days) is defined as the total number of
days a patient was exposed to the study drug. It will be calculated as (last
dose date – first dose date + 1), where the first dose date is assumed to be
Cycle 1 Day 1 for each drug.
•
Cumulative dose (mg) is defined as the sum of all doses taken per drug
during the treatment period for XERMELO only based on drug accountability. 
2. Categorical drug exposure variable:
•
Dosing status (dosed, not dosed) per cycle
Overall treatment duration and dose status will also be presented in the table. 
Patient drug exposure will be presented in a listing. 
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Patients must maintain at least 75% compliance in dosing to be deemed as compliant. In 
the event of a missed or vomited XERMELO dose, patients will take their subsequent dose 
at the next scheduled time point, following the tid dosing regimen of approximately every 
6 hours. A dose outside of a 3-hour window for XERMELO should be considered missed. 
A dose delay of more than 1 week for cisplatin and gemcitabine should also be considered 
missed. Missed or vomited doses will not be made up. 
The following variables will be summarized: 
1. Continuous drug exposure variables:
•
Number of dose modifications per cisplatin and gemcitabine
•
Number of dose interruptions or missed doses per cisplatin and gemcitabine
•
Compliance (%) defined as [(actual number of tablets taken over the study
period prior to EOT) / (designated total number of tablets that should have
been taken over the study period prior to EOT)] * 100 for XERMELO.
Actual number of tablets taken will be calculated using the dispensed and
returned count from the XERMELO Dispensation CRF page. All the tablets
not returned will be considered as taken by patient. Designated total number
of tablets will be based on exact days patients were put under treatment
cycles (250 mg tid starting on Day 1 and 500 mg tid staring on Day 8 in
cycle 1 and 500 mg tid in cycle 2 and after) regardless dose interruptions
and/or modifications.
2. Categorical drug exposure variable:
•
At least 1 dose modification (yes, no)
•
Reason for dose modification per cisplatin and gemcitabine
•
Reason for dose interruption per cisplatin and gemcitabine
•
Compliance category (<75%, ≥75%) for XERMELO
8. Efficacy Analysis
The primary and secondary efficacy endpoints will be analyzed based on the Safety 
population. Additional analyses for the primary and secondary efficacy endpoints will be 
performed using the PP population.  
All imaging will be assessed by local radiologist and the BICR. The BICR will supersede 
the local radiologist’s assessment for the purpose of primary efficacy analysis and all 
applicable key secondary objectives. A secondary analysis will be performed to further 
evaluate the primary and secondary efficacy endpoints using the local radiologist 
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PFS and OS will be summarized using Kaplan-Meier method in both summary tables and 
figures. 
8.1. Primary Efficacy Analysis 
8.1.1 Progression-free Survival (PFS) 
Progression-free survival (PFS) will be defined as the time from first dose of study 
treatment until the first date of either disease progression or death due to any cause. The 
date of disease progression will be defined as the earliest date of radiological disease 
progression, as assessed through the radiographic assessment by the central reviewers 
using RECIST version 1.1 (v1.1). Duration of progression-free survival (PFS) in days is 
defined as the time between the date of first dose of study drug and the date of the first 
occurrence of one of the following events: 
•
Radiological disease progression per RECIST v1.1 as assessed by the central
reviewers
•
Death due to any cause
For patients who do not experience one of these events by the time of data cutoff, PFS will 
be right censored at the date of last adequate disease assessment.  An adequate disease 
assessment is a non-missing, valid scan where the overall assessment is defined by 
RECIST v1.1 criteria.  For patients who do not experience disease progression, and do not 
have any adequate post-Baseline disease assessments, PFS will be right censored at first 
dose date. For patients who start a new line of anticancer treatment, PFS will be censored 
at the date of last adequate disease assessment prior to the start date of new line of 
anticancer treatment. If no such assessment is made, then censoring is applied on the first 
dose date. A Safety physician from TerSera will identify the anticancer treatments and first 
date of their administration from the concomitant medication records. 
The full event and censoring rules for deriving PFS are specified in Table 9 below. Cycle 
10 Day 1 is considered the Month 6 timepoint and Cycle 19 Day 1 is considered the Month 
12 timepoint for analysis purposes. Patients who prematurely discontinued from Treatment 
Period or withdrew consent from Treatment Period prior to Month 6 of the Treatment 
Period, will be asked to reconsent to allow for images and or imaging reports, obtained 
locally, to be submitted to BICR. 
Table 9 
Censoring Conventions for PFS


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Situation 
Date of Progression or 
Censoring 
Outcome 
Disease progression 
Date of scan confirming progression 
Event 
Disease progression documented from an 
assessment made after missing 2 or more 
consecutive scheduled radiological 
assessments 
Latest of: 
➢
Last adequate disease
assessment prior to the missing
2 or more consecutive scheduled
radiological assessments
➢
The first dose date
Censored 
Death 
Date of death 
Event 
Death after missing 2 or more consecutive 
scheduled radiological assessments 
Latest of: 
➢
Last adequate disease
assessment prior to the missing
2 or more consecutive scheduled
radiological assessments
➢
The first dose date
Censored 
Treatment discontinuation for toxicity or 
other reasons (except death) prior to 
disease progression and Month 6 
radiological assessment is not available 
Latest of: 
➢
Last adequate disease
assessment
➢
The first dose date
Censored 
No death and no disease progression after 
first dose date 
Latest of: 
➢
Last adequate disease
assessment
➢
The first dose date
Censored 
Start a new line of anticancer treatment 
Latest of: 
➢
Last adequate disease
assessment
➢
The first dose date
Censored 
The primary efficacy endpoint is the PFS response rate at 6 months and scheduled cycle 10 
day 1 disease assessment results will be used for this purpose. This is a binomial variable 
in which the numerator is derived as the number of patients at 6 months who are alive and 
event-free. Event-free means that a valid radiologic assessment of disease (ie, radiological 
scan of the tumor) at 6 months shows that the patient has no progressive disease (PD) per 
RECIST 1.1 criteria. Such patients will be classified as "successes" or "responders" for the 
PFS response rate outcome. This may apply to patients that dropped 
from the study before 6 months, but returned to the clinic and had a valid scan performed 
at the Month 6 visit. Patients with radiologic evidence of PD or who died from any cause 
before the 6-month assessment will be classified as "failures" or "non-responders". Patients 
lacking a valid radiologic assessment at Month 6, for any reason, will also be classified as 
"failures" or "non-responders". This includes patients stopping study treatment for any 
reason (eg, adverse event) and who do not return for the 6-month scan. Assessments made 
after initiation of a new line of anticancer treatment will be censored in the analysis, 
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responder status for the study regimen. In cases that initiation of other anticancer 
treatments starts before the 6-month disease assessment, such patients will be classified as 
"failures" or "non-responders" in the analysis. The Safety population is used as the 
denominator in deriving the PFS rate.  
In addition to the PFS response rate, the PFS rate at Month 6 derived as a function of a 
time-to-event outcome, and the corresponding 95% confidence interval (CI), will be 
presented. The Kaplan-Meier method will be used to estimate the survival function of this 
measure of the PFS variable.  
In the first stage of Simon’s 2-stage design, PFS tables and associated listings will be 
provided after 20 patients are accrued with Month 6 assessment results. If 12 or more of 
the 20 patients enrolled are deemed responders per the PFS response rate definition 
provided above, enrollment will continue to the maximum sample size of 53 patients. 
Observation of 11 or fewer PFS responders at the Stage 1 analysis will result in the 
termination of patient accrual. Should data show that, via routine trial monitoring, the 
number of patients reaching the 6-month disease assessment will not allow for a positive 
PFS result at either Stage of the design (eg, excessive number of patients discontinuing the 
study), consideration will be given to stop patient accrual at that time. 
8.1.2 Sensitivity Analysis 
Addition to original PFS definition, clinical disease progression can be also considered as 
evidence of disease progression when there is no supportive radiographic assessment of 
PD. The date of clinical/symptomatic disease progression assessed by the investigator will 
be used as the event date in a sensitivity analysis. It can be either the last dose date when 
the primary reason of study drug discontinuation is disease progression or study 
termination date when the primary reason for discontinuation is disease progression, 
whichever earlier. Also, PD or death after missing 2 or more consecutive scheduled 
radiological assessments is considered as an event in the sensitivity analysis. This 
sensitivity analysis will be based on the Safety population. 
A separate sensitivity analysis will also be performed on the PFS response rate as defined 
in Section 8.1.1 based on the PP population as well as by treatment cycle population.  
8.2. Secondary Efficacy Analysis 
8.2.1 PFS Rate at Month 12 and Median PFS 


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The PFS response rate at month 12 and this measure derived as a time-to-event outcome, 
will be calculated in the same manner as the primary endpoint (see Section 8.1.1).  
Scheduled disease assessment at cycle 19 day 1 will be used to determine PFS response 
rate at month 12. 
8.2.2 Overall Survival (OS) 
Overall survival (OS) will be defined as the time from first dose of study treatment until 
the date of death due to any cause. For patients who have not died at the time of the 
analysis, censoring will be performed using the date the patient was last known to be alive. 
OS will be calculated in days as OS = Date of death (or date of last known alive) - Date of 
first dose + 1.  
The Kaplan-Meier method used in analyzing PFS will be used to summarize the median 
OS and the OS rate at Months 6 and 12. 
8.2.3 Disease Control Rate (DCR) 
Disease control rate (DCR) is defined as the proportion of patients with best overall 
response of SD longer than 6 weeks from first dosing, confirmed PR, or confirmed CR. 
The best overall response is defined in Section 8.2.4. DCR will be summarized at Month 6, 
Month 12, and EOS. Patients without an event will be considered as non-DCR. Associated 
2-sided 95% CI will be presented by using the exact method (ie, Clopper-Pearson).
8.2.4 Overall Response Rate (ORR) 
Overall response rate (ORR) is defined as the proportion of patients with best overall 
response of confirmed PR or confirmed CR. The best overall response is the best overall 
response recorded from the start of study treatment until the EOS considering any 
requirement for confirmation. In general, the patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. Patients who 
have obtained a response (PR or CR) will have a confirmatory scan at a minimum of 4 
weeks following the initial scan. When stable disease (SD) is believed to be the best 
response, it must be a minimum of 6 weeks (42 days) ± 7 days for a minimum time on-
study of 35 days from the first dose to documented evidence of SD. If the subject is on-
study less than 35 days, any tumor assessment indicating stable disease before this time 
period will have a best response of NE unless PD is identified. Otherwise, the patient’s best 
response depends on the subsequent assessment. The best overall response when 
confirmation of CR and PR is required is presented in Table 10. Patients without an event 
will be considered as non-ORR. 


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The ORR will be evaluated at Months 6 and 12, and at EOS. 
Table 10 
Best overall response when confirmation of CR and PR required
First Time Point 
Response** 
Second Time Point 
Response 
Confirmed Response 
(Best Response)* 
PD 
No further evaluation 
PD 
NE 
PD 
PD 
CR 
PD 
SD or PD (1) 
PR 
PD 
SD or PD (1) 
SD 
PD 
SD or PD (1) 
CR 
CR 
CR 
CR 
NE ** 
SD or NE (2) 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD (3)** 
SD 
PR 
NE ** 
SD or NE (2) 
SD 
CR 
SD 
SD 
PR 
SD 
SD 
SD 
SD 
SD 
NE 
SD or NE (2) 
NE 
CR 
SD 
NE 
PR 
SD 
NE 
SD 
SD 
NE 
NE 
NE 
Source: Independent Review Charter v1.0 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, and NE = not evaluable. 
*
A Best response of SD can only be made after the subject is on-study for a minimum of six (6)
weeks (42 days).  If the subject is on-study less than six (6) weeks (42 days)  seven (7) days, for a


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minimum time on-study of thirty-five (35) days, any tumor assessment indicating stable disease 
before this time period will have a Best response of NE unless PD is identified. 
** 
Subsequent documentation of CR may provide confirmation of a previously identified CR for 
subjects where the second integrated response was NE.  Subsequent documentation of PR may 
provide confirmation of a previously identified PR for subjects where the second integrated 
response was NE or SD. If the third time point response (TPR) confirms the CR (or PR) then the 
confirmed response will be CR (or PR).  For this study, only 1 intervening NE is allowed between 
CRs/PRs. For example: CR NE CR = CR; PR NE PR = PR. Additionally, 1 SD is allowed between 
PRs (eg, PR SD PR = PR).  Note: in the following scenario, PR SD NE PR, the second PR is not a 
confirmed PR. 
(1)
Best response will be SD if the first TPR is after 35 days on-study.  Otherwise, the best response
will be PD.
(2)
Best response will be SD if the first TPR is after 35 days on-study.  Otherwise, the best response
will be NE.
(3)
TPR is SD if the increase from the first to the second assessment does not qualify for PD.
8.2.5 Local Radiologist’s Assessment (PFS, ORR, and DCR)
Secondary sensitivity analysis will be performed to further evaluate the primary and 
secondary efficacy endpoints PFS, ORR, and DCR using the local radiologist’s 
assessments. In addition, subgroup analysis will be applied PFS, ORR and DCR using the 
same method as described in Section 8.1.1, Section 8.2.3, Section 8.2.4, and Section 9.2. 
8.2.6  Change in Tumor Size 
A waterfall plot will be provided of change in tumor size (as of % of baseline) from 
baseline to Month 6 response for all patients for whom primary lesion data are available 
and will be displayed based on Safety population. Associated change from baseline 
summary table will be also provided. 
8.2.7  Sensitivity Analysis 
A separate sensitivity analysis will also be performed on all secondary efficacy tables as 
defined in Section 8.2 based on the PP population as well as by treatment cycle population. 
9. Exploratory Analysis
Exploratory analyses will be performed on the Safety population.
9.1 
Health-Related Quality of Life (HRQoL) 


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Quality of Life (QoL) will be assessed using the EORTC QLQ-C30 and QLQ-BIL21. 
Analyses will be based on the Safety population. Actual and change from Baseline for 
QLQ-C30 and QLQ-BIL21 total and subscale scores will be summarized at Baseline, 
Months 6 and 12 using descriptive statistics.  
Each of the 30 scores of the EORTC QLQ-C30, as well as the 5 functional scales 
(physical, role, emotional, cognitive, social), and 9 symptom scales (fatigue, nausea and 
vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial 
difficulties) will be summarized by visit. The analyses of the EORTC QLQ-C30 will be 
based on all treated patients who completed the Baseline assessment and had at least 1 
post-Baseline assessment with the EORTC QLQ-C30. Actual values and changes from 
Baseline will be summarized for all patients overall. 
The standard scoring procedures as suggested by the EORTC v3.0 will be followed. All of 
the scales and single item measures range in score from 0 to 100. A high scale score 
represents a high response level. For all scales, the raw score (RS) is the mean of the 
component items. The functional scales will be calculated as: 
        Score =  (1- (RS-1)/range) x100, and 
For symptom scales/items and global health status/QoL: 
       Score = ((RS-1) /range) x 100. 
where range is the difference between the maximum possible value of RS and the 
minimum possible value. 
Each of the 21 items of the EORTC QLQ-BIL21, as well as the 5 functional scales (eating, 
jaundice, tiredness, pain, anxiety) will be summarized by visit. The analyses of the EORTC 
QLQ-BIL21will be based on all treated patients who completed the Baseline assessment 
and had at least 1 post-Baseline assessment with the EORTC QLQ-BIL21. Actual values 
and changes from Baseline will be summarized for all patients overall. 
The standard scoring procedures are in a similar fashion to the scoring for the EORTC 
QLQ-C30. All of the scales and single item measures range in score from 0 to 100. A high 
scale score represents a worse or more problems. For all scales, the raw score (RS) is the 
mean of the component items.  
        Score= (RS-1)/rangex100 


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Range is the difference between the maximum and minimum possible value of the raw 
score. All items are scored from 1 to 4, giving a range=3. 
For each scale, the raw score will be calculated by the addition of item responses divided 
by the number of items. Then a linear transformation is used to standardize the raw score, 
so that scores range from 0 to 100. Please refer to Section 15.4 for the details of EORTC 
QLQ-BIL21 scoring. 
The calculation of scores and methods to deal with missing data will be handled according 
to the respective questionnaires’ standard scoring guidelines for both EORTC QLQ-C30 
and QLQ-BIL21. If at least half of the items from the scale have been answered, all of the 
items that were completed are used and apply the standard equations given above: ignore 
any items with missing values when making the calculations. If less than half of the items 
from the scale have been answered, the scale score is set to missing. For single-item 
measures with missing response, the score is set to missing. 
9.2 
Subgroup Analysis 
Subgroup analyses of PFS, OS, ORR, and DCR may be performed using both BICR and 
local radiologist’s assessment, based on categorical subgroup group variables. Subgroup 
definition details are specified in Section 6.5. 
9.3 
Sensitivity Analysis 
All efficacy analyses will be also conducted based on the PP population as well as by 
treatment cycle population. 
10. Safety Analysis
Safety and tolerability will be evaluated through the collection and review of treatment-
emergent adverse events (TEAEs), as graded by CTCAE v5.0, vital signs measurement, 
12-lead electrocardiogram (ECG) findings, physical examination (PE) findings, and
clinical laboratory parameters (chemistry, hematology, and urinalysis) including changes
from Baseline and frequency of values meeting CTCAE Grades >1, CTCAE Grades 3/4
separately. In addition, shift table analyses will be applied to the laboratory data. All
summaries will be performed using the Safety population.
All safety summaries will be descriptive; no statistical significance tests will be performed 
on the safety data. 


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Summaries will be prepared by study time point. Adverse events will also be prepared by 
PP population as well as by treatment cycle population.  Adverse events will also be 
displayed by study drug cycle based on Safety population. All safety data will be listed by 
patient. 
10.1. 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not it is considered drug related. 
Treatment-emergent AEs (TEAEs) are defined as any AEs reported after the first dose of 
study drugs (XERMELO, cisplatin, and/or gemcitabine) and for 30 days following the last 
dose of study drugs. 
Any treatment-emergent abnormal laboratory result should be and reported as an AE if it 
meets 1 or more of the following conditions:  
•
Fulfills any of the criteria for an SAE,
•
Results in discontinuation of study treatment,
•
Requires treatment, or
•
Is considered by the Investigator to be clinically significant.
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be 
imputed based on Appendix 15.3. 
All AEs will be classified by System Organ Class (SOC) and Preferred Term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA, version 21.1 or 
later). 
Patients with at least 1 TEAE will be summarized for the following: 
•
Overall summary of TEAEs
•
Summary of TEAEs by SOC and PT
•
Summary of TEAEs by PT by decreasing frequency
•
Summary of TEAEs by relationship to each study drug (XERMELO, cisplatin, and
gemcitabine), SOC and PT
•
Summary of TEAEs by relationship to each study drug (XERMELO, cisplatin, and
gemcitabine) and PT
•
Summary of TEAEs by maximum severity by SOC and PT
•
Summary of TEAEs by study drug cycle
•
Serious TEAEs by SOC and PT
•
Death by SOC and PT
•
TEAEs that leading to discontinuation from the study by SOC and PT
•
TEAEs that leading to discontinuation from treatment by SOC and PT


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•
TEAEs that leading to treatment reduction by SOC and PT
•
TEAEs that leading to XERMELO reduction by SOC and PT
•
TEAEs that leading to XERMELO interruption by SOC and PT
•
TEAEs with severity grade ≥ 1 by SOC and PT
•
TEAEs with severity grade ≥ 2 by SOC and PT
•
TEAEs with severity grade 3 and 4 by SOC and PT
•
Adverse events of special interest (AESI) by SOC and PT
Summaries made by severity will select the event with the highest severity when multiple 
occurrences of the same event are reported for the same patient. In a similar manner, 
summaries prepared by drug relationship will select the event with the greatest degree of 
relationship when a patient reports multiple occurrences of the same event.  
On-study deaths will be reported for deaths occurring during study participation and the 30 
days after stopping study drug. Also, deaths occurring outside the 30-day window, but 
secondary to an AE reported within the 30-day Follow-up Period, will be reported as well. 
All AE tables will be displayed based on safety population, PP population as well as by 
treatment cycle population. All AE tables by study drug cycle will also be displayed based 
on safety population. 
10.1.1. Incidence of Adverse Events 
An overall summary of TEAEs will be presented in a table and will include the number 
and incidence of patients with any TEAE, number of TEAEs, patients with serious TEAEs, 
patients with severe TEAE (≧ Grade 3), patients that discontinued from study due to 
TEAEs, TEAE leading to dose reduction, TEAE leading to discontinuation from treatment, 
and deaths. In addition, the table will include the number and percentage of patients in 
each category of severity (ie, Grade 1 to Grade 5) for all TEAEs and the number and 
percentage of patients in each category of relationship to each study drug (ie, “Related” 
and “Not Related”). 
A related AE is an event where the investigator determined that the relationship to study 
drug was “Possibly Related”, “Probably Related” or “Definitely Related”. For summaries 
by relationship, adverse events with missing relationship are counted as “Possibly 
Related”. For summaries by CTCAE grade, adverse events with missing CTCAE grade are 
counted as CTCAE Grade 3 (Severe). 
10.1.2. Treatment Emergent Adverse Events Summary by SOC and PT 


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Summaries of the total number of TEAEs and the number and percentage of patients with 
at least 1 TEAE will be provided. TEAEs will be presented by SOC and PT. At each level 
of patient summarization, a patient is counted once if the patient reported 1 or more events. 
Percentages will be calculated out of the number of patients in the Safety population.  
The summary of TEAEs will be presented in descending order from the SOC with the 
highest total incidence to the SOC with the lowest total incidence. If the total incidence for 
any 2 or more SOCs is equal, the SOCs will be presented in alphabetical order. Within 
each SOC, the PTs will be presented in descending order.  
Additional summary of TEAEs will be presented in descending order from the PT with the 
highest total incidence to the PT with the lowest total incidence. 
All TEAEs will be presented in a listing. 
10.1.3. Relationship of Adverse Events to Study Drug 
A summary of total number of TEAEs and number and percentage of patients with at least 
1 TEAE by relationship (ie, “Related” and “Not Related”) to each study drug, will be 
presented in a table by incidence of occurrence. If the relationship is missing, it will be 
considered as related in the summary table. 
For each AE, the Investigator will assess the causal relationship between each of the study 
drugs and the AE using their clinical expertise and judgment. In the TEAE relationship 
table, if a patient reports multiple occurrences of the same TEAE, only the most closely 
related occurrence will be presented. Percentages will be calculated out of the number of 
patients in the Safety population. 
The TEAE data will be categorized and presented by SOC, PT, and relationship. 
Additional summary of TEAEs will be presented by PT and relationship. 
10.1.4. Severity of Adverse Event 
A summary of total number of TEAEs and number and percentage of patients with at least 
1 TEAE by severity will be presented in a table.  
The severity that will be presented represents the most extreme severity captured on the 
CRF page. The possible severities are Grade 1 to Grade 5 (ie, “Mild”, “Moderate”, 
“Severe”, “Life-threatening”, and “Death”, respectively). If the severity is missing, it will 
be considered as severe in the summary table. In the TEAE severity table, if a patient 


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reported multiple occurrences of the same TEAE, only the most severe will be presented. 
Percentages will be calculated out of the number of patients in the Safety population. 
The TEAE data will be categorized and presented by SOC, PT, and severity. 
In addition, similar tables will be produced for TEAEs that have severity of Grade ≥ 1, 
Grade ≧ 2, and Grade 3/4 separately. 
10.1.5. Adverse Events by Length of Exposure to Each Study Drug 
TEAEs will be summarize separately by the total exposure cycles of XERMELO, cisplatin, 
and gemcitabine. TEAE will be categorized into 6 subgroups:  
•
exposure=0 or exposure ≦ C1;
•
C1 < exposure ≦ C3;
•
C3 < exposure ≦ C6;
•
C6 < exposure ≦ C9;
•
C9 < exposure ≦ C12;
•
exposure > C12
Additional analysis by different exposure range (eg, every 4 cycles) might be performed 
upon reviewing the data. 
10.1.6. Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in death, is life-threatening, is a congenital anomaly/birth defect, requires in-
patient hospitalization or prolongation, or results in significant disability/incapacity. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
Summaries of the total number of SAEs and the number and percentage of patients with at 
least 1 SAE will be provided. SAEs will be presented by SOC and PT. At each level of 
patient summarization, a patient is counted once if the patient reported 1 or more events. 
Percentages will be calculated out of the number of patients in the Safety population.  
The summary of SAEs will be presented in descending order from the SOC with the 
highest total incidence to the SOC with the lowest total incidence. If the total incidence for 


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any 2 or more SOCs is equal, the SOCs will be presented in alphabetical order. Within 
each SOC, the PTs will be presented in descending order.  
All SAEs will be presented in a listing by patient using the Safety population. If there are 
no SAEs at the end of the study, the tables or listings will state that there are no SAEs in 
the study. 
10.1.7. Adverse Events Leading to Study Discontinuation 
A summary of the total number of TEAEs leading to study discontinuation and the number 
and percentage of patients with at least 1 TEAE that caused study discontinuation will be 
presented. TEAEs leading to study discontinuation will be presented by SOC and PT. At 
each level of patient summarization, a patient is counted once if the patient reported 1 or 
more events. Percentages will be calculated out of the number of patients in the Safety 
population within the subgroup category.  
The summary of TEAEs that caused study discontinuation will also be presented in 
descending order of frequency from the SOC with the highest total incidence to the SOC 
with the lowest total incidence. If the total incidence for any 2 or more SOCs is equal, the 
SOCs will be presented in alphabetical order.  Within each SOC, the PTs will be presented 
in descending order. 
10.1.8. Adverse Events Leading to Treatment Discontinuation 
A summary of total number of TEAEs leading to treatment discontinuation and number 
and percentage of patients with at least 1 TEAE that caused treatment discontinuation will 
be presented. TEAEs leading to treatment discontinuation will be defined as TEAEs 
leading to treatment discontinuation of either one of study drugs. TEAEs leading to 
treatment discontinuation will be presented by SOC and PT. At each level of patient 
summarization, a patient is counted once if the patient reported 1 or more events. 
Percentages will be calculated out of the number of patients in the Safety population within 
the subgroup category.  
The summary of TEAEs that caused treatment discontinuation will also be presented in 
descending order of frequency from the SOC with the highest total incidence to the SOC 
with the lowest total incidence. If the total incidence for any 2 or more SOCs is equal, the 
SOCs will be presented in alphabetical order.  Within each SOC, the PTs will be presented 
in descending order. 
10.1.9. Adverse Events Leading to Dose Reduction 


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A summary of total number of TEAEs leading to dose reduction and number and 
percentage of patients with at least 1 TEAE that caused dose reduction will be presented. 
TEAEs leading to dose reduction will be defined as TEAEs leading to dose reduction of 
either one of study drugs. TEAEs leading to dose reduction will be presented by SOC and 
PT. At each level of patient summarization, a patient is counted once if the patient reported 
1 or more events. Percentages will be calculated out of the number of patients in the Safety 
population within the subgroup category.  
The summary of TEAEs that caused dose reduction will also be presented in descending 
order of frequency from the SOC with the highest total incidence to the SOC with the 
lowest total incidence. If the total incidence for any 2 or more SOCs is equal, the SOCs 
will be presented in alphabetical order.  Within each SOC, the PTs will be presented in 
descending order. 
10.1.10. 
Adverse Events Leading to XERMELO Reduction 
A summary of total number of TEAEs leading to XERMELO reduction and number and 
percentage of patients with at least 1 TEAE that caused XERMELO reduction will be 
presented. TEAEs leading to XERMELO reduction will be presented by SOC and PT. At 
each level of patient summarization, a patient is counted once if the patient reported 1 or 
more events. Percentages will be calculated out of the number of patients in the Safety 
population within the subgroup category.  
The summary of TEAEs that caused XERMELO reduction will also be presented in 
descending order of frequency from the SOC with the highest total incidence to the SOC 
with the lowest total incidence. If the total incidence for any 2 or more SOCs is equal, the 
SOCs will be presented in alphabetical order.  Within each SOC, the PTs will be presented 
in descending order. 
10.1.11. 
Adverse Events Leading to XERMELO Interruption 
A summary of total number of TEAEs leading to XERMELO interruption and number and 
percentage of patients with at least 1 TEAE that caused XERMELO interruption will be 
presented. TEAEs leading to XERMELO interruption will be presented by SOC and PT. 
At each level of patient summarization, a patient is counted once if the patient reported 1 
or more events. Percentages will be calculated out of the number of patients in the Safety 
population within the subgroup category.  
The summary of TEAEs that caused XERMELO interruption will also be presented in 
descending order of frequency from the SOC with the highest total incidence to the SOC 
with the lowest total incidence. If the total incidence for any 2 or more SOCs is equal, the 


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SOCs will be presented in alphabetical order.  Within each SOC, the PTs will be presented 
in descending order. 
10.1.12. 
Adverse Events of Special Interest 
Based on the mechanism of action of telotristat etiprate, and observations in the clinical 
studies, monitoring of depression-related AEs will be the responsibility of the Sponsor. 
Refer to Section 15.2 for a list of preferred terms that will be considered as a depression-
related AESI if deemed clinically significant by the Investigator. 
Depression-related adverse events will be presented in frequency tables for number and 
percentage of patients with any depression-related adverse events and by SOC and PT. 
Similarly, Suicide/Self injury-related adverse events and liver-related AEs will be 
presented in frequency tables by SOC and PT separately. In addition, hepatic enzyme 
increase safety analysis will be addressed and presented in part by summarizing the 
number and percentage of subjects who had AEs that relate to liver function. A list of 
preferred terms that correspond to depression, suicide/self-injury and hepatic enzyme 
increase related adverse events will be identified using a subset of PTs selected from 
narrow scope PTs in the SMQ. 
10.1.13. 
Deaths 
On-study deaths will be reported for deaths occurring during study participation and the 30 
days after stopping study drug. Also, deaths occurring outside the 30-day window, but 
secondary to an AE reported within the 30-day Follow-up Period, will be reported as well.  
Deaths will be presented in frequency tables for number and percentage of patients with 
any death and by SOC and PT. Listings will be provided for deaths. 
10.2. 
Clinical Laboratory Evaluations 
Clinical laboratory assessments will include, at a minimum, blood chemistry (complete 
metabolic profile [CMP], liver function tests [alkaline phosphatase (ALKP), ALT, AST, 
total bilirubin], lipid panel [high-density lipoprotein (HDL), low-density lipoprotein 
(LDL), total cholesterol, triglycerides], coagulation parameters [PT, INR]), hematology 
(complete blood count [CBC] with differential, and platelet counts), and urinalysis.  
Out of range values should be assessed by the Investigator for clinical significance relevant 
to the patient population. For this protocol, assessments will be defined as not clinically 
significant (NCS) or clinically significant (CS). 


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Summary tabulations (ie, n, mean, SD, median, minimum, and maximum) for the observed 
values and changes from Baseline will be presented for clinical laboratory evaluations with 
numeric values for patients in the Safety population. Observed results at each visit and 
changes from Baseline for each scheduled post-Baseline visit will be presented.  
All relevant clinical laboratory tests will be classified as Low, Normal, and High according 
to the normal ranges. This categorical data will be summarized in shift tables based on 
normal range comparing the results at worst post-Baseline value (minimum or maximum 
value of any post-Baseline visit) with those at the Baseline visit. 
Summaries by visit will include data from scheduled assessments only, and all data will be 
reported according to the nominal visit date for which it was recorded (ie, no visit windows 
will be applied). Unscheduled data will be included in the shift table summaries, which 
will capture a worst case across all scheduled and unscheduled visits after the first dose of 
study treatment. 
All individual laboratory values will be listed by visit. 
10.2.1. Serum Albumin 
Actual, and change from Baseline in serum albumin results will be summarized in a 
separate table by Baseline, Month 6, Month 12, and EOS using descriptive statistics. 
10.2.2. Pregnancy Test 
Additional assessments such as serum and urine pregnancy tests will be performed on 
females of childbearing potential only. The urine pregnancy test will be performed by the 
site staff with the provided laboratory kit.  
Pregnancy test details will be listed. 
10.3. 
Vital Sign Measurements 
Measurement of vital signs will include assessment of blood pressure, respiratory rate, 
pulse rate, temperature, and body weight.  
Summary tabulations (ie, n, mean, SD, median, minimum, and maximum) for the observed 
values and changes from Baseline will be presented for vital sign data for patients in the 
Safety population. Changes from Baseline to each scheduled post-Baseline time point and 


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visit will be presented. Baseline is defined as last measurement before first dose of study. 
Figure for mean weight change over time will be provided. 
For weight, the proportions with stable weight, weight gain, weight loss will also be 
summarized. Stable weight is defined as a change from baseline to week 24 of less than 
3%. Weight gain is an increase of at least 3%, and weight loss is a reduction of at least 3%. 
All vital sign data by patient will be presented in a listing. 
10.4. 
Physical Examination 
Physical examination findings will be listed. 
10.5. 
Electrocardiogram 
Summary of actual value and change from Baseline will be presented in a summary table 
for patients in the Safety population. Overall interpretation is assessed as normal, 
abnormal, not clinically significant, clinically significant. A shift table from Baseline to 
current visit will be presented for the overall interpretation. The categories of QTcB and 
QTcF (≤450 msec, >450-480 msec, >480-500 msec, >500 msec) and the categories of 
change from Baseline for QTcB and QTcF (≥30 msec and ≥60 msec) will be summarized 
by visit. 
ECG data for all patients will be presented in a listing. 
10.6. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Actual and change from Baseline in ECOG will be summarized by time point using 
descriptive statistics. 
All measurements will be displayed in a data listing. 
10.7. 
Depression Detection 
Patients will be evaluated for depression prior to initiating treatment on Day 1, then 
periodically throughout the remaining duration of the study as outlined in Section 15.1. 
Frequency tables on responses to depression detection questions per visit will be presented. 
The responses of patients will also be listed. 


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10.8. 
Other Safety Data 
Observed values at Baseline for serotonin [5-HT] and tryptophan hydroxylase-1 [TPH-1] 
will be summarized using descriptive statistics to assess the effect of study treatment based 
on characterization of tumor tissue by immunohistochemical (IHC) staining. 
Immunohistochemical (IHC) staining details will be listed. 
11. Pharmacokinetics
11.1 Pharmacokinetic Sample Concentrations
Blood samples for plasma PK analysis of XERMELO and the active metabolite, LP-
778902 will be collected at the following time points:  
Predose, 1, 2, 4, and 6 hours on C1D1 and C1D8. 
Predose on C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, and EOT 
Plasma concentration and time deviation data will be presented in data listings by cycle, 
day, and nominal time point for the Safety population. Plasma concentration data will be 
summarized by cycle, day, and nominal time point for the PK population using descriptive 
statistics: number of patients with non-missing data (n), mean, SD, coefficient variance 
(CV), median, minimum, and maximum. All plasma concentration values below the limit 
of quantification (BLQ) will be set to zero when calculating summary statistics. 
Mean plasma concentration versus nominal time profiles on C1D1 and C1D8 will be 
presented on both linear and semilogarithmic scales for the PK population. Individual 
plasma concentration versus actual time profiles on C1D1 and C1D8 will be presented on 
both linear and semilogarithmic scales by dose for the Safety population. In addition, mean 
and individual trough concentration on Day 1 of each cycle versus time profiles will be 
presented on linear scale. 
11.2 Pharmacokinetic Parameters 
Where possible, the individual plasma concentration versus actual time data for 
XERMELO and LP-778902 will be used to derive the following PK parameters, by 
noncompartmental methods using Phoenix® WinNonlin® Version 8.0 or higher (Certara 
USA, Inc., Princeton, NJ). 
PK Parameter 
Definition 
Cmax 
observed maximum plasma concentration 


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Ctrough 
trough plasma concentration (predose concentration) 
tmax 
time of maximum observed plasma concentration 
AUC(0-6)  
area under the plasma concentration-time curve from time zero to 6 
hours after dose administration. 
AUC(0-last)  
area under the plasma concentration-time curve from time zero to 
time of last measurable concentration 
Kel 
apparent first-order terminal rate constant 
t½ 
apparent terminal elimination half-life 
For the calculation of PK parameters, all plasma concentrations that are BLQ prior to the 
first measurable concentration will be set to zero and treated as missing thereafter. 
Ctrough values will also be listed and summarized, and mean trough values will be plotted. 
Individual PK parameters will be presented in data listings for the PK population. The PK 
parameters will be summarized for the PK population using the following descriptive 
statistics: n, mean, SD, CV, geometric mean, geometric CV, median, minimum, and 
maximum. For tmax, only n, median, minimum, and maximum will be reported. 
12. Pharmacodynamics
Pharmacodynamic assessments include the determination of 
will be summarized at Month 6, Month 12, and EOS using descriptive statistics and 1-
sample t-tests may be performed to test for significance using a 5% level of significance. 
Pharmacodynamics data for all patients will be presented in a listing. 
13. Interim Analysis
Stage 1 analysis 
Stage 1 enrollment will include a Safety Run-in cohort. Safety and tolerability data of the 
combination treatment from the first 6 patients who complete at least 21 days of safety 
follow-up after the first dose of combination treatment will be evaluated. During this 
review, Stage 1 enrollment will continue. It is anticipated that a total of 20 patients will 
participate in Stage 1. If there are no clinically significant or unresolved Grade 3 or higher 
toxicities considered related to the study drug and if of 12 (60%) or more of the 20 patients 
enrolled are deemed PFS responders in the Safety population, enrollment will continue to 
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Stage 2. In addition, selected efficacy will be assessed in the per-protocol population and 
by treatment cycle. 
Stage (1 + 2) analysis and Interim Analyses: 
Formal statistical interim analyses will be performed during this study as follows: 
•
Interim analysis 1 : Conducted in Patients included in the Stage 1 analysis (first 20
patients enrolled) and will include safety, efficacy (PFS responder rate),
pharmacodynamic (biomarker) data.
•
Interim analysis 2 added to (Stage 1+2) 6 month analysis : Conducted after all 53
Patients (Stage 1 + Stage 2) complete the Month 6 visit, and will include safety,
efficacy (PFS responder rate), pharmacodynamic (biomarker) data and analysis by
treatment cycle population.
•
Interim Analysis 3 added to (Stage 1+2) 12 month analysis: Conducted after all 53
Patients (Stage 1 + Stage 2) complete the Month 12 visit, and will include safety,
efficacy (PFS responder rate), pharmacodynamic (biomarker) data and analysis by
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14. References
1. TerSera LX1606.1-207-BTC Protocol: A Phase 2, Multicenter, Open-label, Safety
and Efficacy Study of XERMELO® (Telotristat Ethyl) plus First-line Chemotherapy
in Patients with Locally Advanced, Unresectable, Recurrent or Metastatic Biliary
Tract Cancer (BTC)
2. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical
Trials. 1989 Mar;10(1):1-10.
3. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in
solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–
247.
4. National Comprehensive Cancer Network®. NCCN Guidelines® v 1.2018
Neuroendocrine and Adrenal Tumors. March 29, 2018.
5. Sarrouilhe D, Clarhaut J, Defamie N, Mesnil M. Serotonin and cancer: what is the
link? Curr Mol Med. 2015;15(1):62-77.
6. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on
behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual
(3rd Edition).Brussels 2001.


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15. Appendices
15.1. 
Schedule of Study Procedures 
Schedule of Events: 


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Schedule of Events Footnotes 
1.
The Screening Visit allows for up to 21 days prior to C1D1 if needed; however, if radiological assessments have been completed within 6 weeks prior to
Day 1, they are not required to be repeated at Day 1.
2.
All assessments, including laboratory assessments, ECGs and questionnaires should be performed prior to initiating treatment regimen.
3.
Treatment visit dates will be scheduled based on the date of enrollment.
4.
All cycles are 21 days, with Cis/Gem treatment on D1 and D8 and XERMELO treatment daily. Patients are not required to complete a specific amount of
cycles, patients may continue combination treatment for as many cycles possible until PD, unacceptable toxicity, or patient withdraws from treatment.
5.
EOT procedures should be completed once the patient has confirmed PD, unacceptable toxicity, or withdraws from combination treatment. The patient
will then begin the Post-treatment Follow-up Period (PTFP) where patients return to the site every 3 months to complete the required assessments until a
new tumor directed therapy begins, the patient declines further treatment after progression, or withdraws from any further study visits. At that time, the
EOS procedures should be completed and the patient should enter the Survival Follow-up Period (SFP) until the patient has completed a full 24 months of
combination Post-treatment/Survival Follow-up.  During SFP patients are to be contacted by phone every 3 months to obtain survival status; see Section
5.1.2.2 of protocol for details.
6.
Procedures should not be repeated if end of treatment (EOT)/end of study (EOS) occurs during scheduled study visit; however, all EOT/EOS assessments
should be completed; with those required by the scheduled visit to be recorded on the scheduled visit eCRF and additional assessments required by
EOT/EOS recorded in the EOS eCRF.
7.
A complete physical examination will include, at minimum, a review of the patient’s general appearance, head, eyes, ears, nose, throat, neck, heart, lungs,
abdomen, back, extremities, skin and general neurological system. A symptom-related brief physical exam will only occur if the patient is experiencing
symptoms or AEs. If a symptom-related brief physical exam is required, it should include a review of all body systems that relate to the symptoms and/or
AE the patient is experiencing.
8.
Females of childbearing potential only
9.
Day 8 labs are optional (at the discretion of the Investigator) and will be analyzed by the local lab.
10. EOT assessments are not required if the last assessment occurred <3weeks prior; EOS assessments are not required if last assessment occurred ≤8weeks
prior.
11. Patients should avoid multivitamins or dietary supplements containing biotin (vitamin B7) for 12 hours prior to sample collection.
12. PK trough samples are required to be drawn for ALL patients. Patients should be in a fasted state and should not have dosed prior to blood draw.
13. Tumor assessments are not required if progressive disease has been confirmed by CT/MRI at previous visit.
14. Prior medications taken within 30 days of screening will be recorded within the patient’s medical history. Any medications that are ongoing at the time of
screening should be recorded within the patient’s concomitant medication page.
15. Xermelo will be dispensed on D1 of each cycle. The patient should be reminded to bring their bottles back on D8 of each cycle in order for dosing of
Xermelo to be given with the chemotherapy infusion.
16. Xermelo can continue to be dispensed during the Post-treatment Follow-up Period, at the discretion of the Investigator, until the patient begins new
tumor-directed therapy, declines further treatment after progression, or withdraws from any further study visits.
17. Cis/Gem are not being provided by TerSera. If cisplatin is stopped, gemcitabine may be continued alone at the Investigator’s discretion.
18. Intensive PK is an optional substudy. These samples are only required for those patients who have consented to participate in this substudy and will be
drawn on Day 1 and Day 8 of each cycle where collected; refer to Intensive PK Substudy Schedule of protocol for additional details.
19. Archived tissue samples can be submitted at any time during the Treatment Period. Fresh biopsies will not be collected.
20. Total duration of the 2 combined Follow-up Periods should be no more than 24 Months.
21. Follow-up visits dates should be scheduled based on the EOT date.


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22. Phone call to patient or caregiver, where appropriate, to obtain survival status.
23. 23. Patients who enter PTFP and imaging assessments are not required, or who enter SFP without entering or completing PTFP prior to having their 6-month
imaging assessment in the Treatment Period, will be asked to consent to provide their local scans and/or local scan report closest to the 6-month timepoint.
Reconsenting the patient may be required if previously prematurely discontinued or withdrew consent from the Treatment Period of the study.
Intensive PK Substudy Schedule 
1Patients who have consented to the intensive PK substudy should have PK samples collected at all time points shown above on Day 1 
and Day 8 of all required cycles; see Schedule of Events.  
2With food 
3Fasted  
4Samples should be collected within 15 minutes of scheduled collection time 


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15.2. 
Terms Considered Depression-related AESI, if Clinically Significant 
Please see below narrow PTs based on the Depression (excl suicide and self injury) SMQ 
and Suicide/self-injury (SMQ). MedDRA v. 22.1. The PTs might be updated if later 
MedDRA version is used for the study. 
Depression 
•
Adjustment disorder with depressed mood
•
Adjustment disorder with mixed anxiety and depressed mood
•
Agitated depression
•
Anhedonia
•
Antidepressant therapy
•
Childhood depression
•
Decreased interest
•
Depressed mood
•
Depression
•
Depression postoperative
•
Depressive symptom
•
Dysphoria
•
Electroconvulsive therapy
•
Feeling guilty
•
Feeling of despair
•
Feelings of worthlessness
•
Helplessness
•
Major depression
•
Menopausal depression
•
Mixed anxiety and depressive disorder
•
Perinatal depression
•
Persistent depressive disorder
Assisted suicide
•
Columbia suicide severity rating scale abnormal
•
Completed suicide
•
Depression suicidal
•
Intentional overdose
•
Intentional self-injury
•
Poisoning deliberate
•
Self-injurious ideation
•
Suicidal behaviour
•
Suicidal ideation
•
Suicide attempt
•
Suicide threat
•
Suspected suicide
•
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15.3. 
Imputation  
Adverse Event and Concomitant Medications 
Missing onset dates (where UK and UKN indicate unknown or missing day and month 
respectively): 
•
UK-MMM-YYYY: If the month and year are different from the month and year of
the first dose of study drug, assume 01-MMM-YYYY. If the month and year are the
same as the first dose of study drug month and year, and the end date (after any
imputation) is on or after the first dose of study drug, then assume the date of the first
dose of study drug. If the month and year are the same as the first dose of study drug
month, and year and the end date (after any imputation) is prior to the first dose of
study drug, then assume the end date for the onset date
•
DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of first
dose of study drug, assume 01-JAN-YYYY of the collected year. If the year is the
same as the first dose of study drug year, and the end date (after any imputation) is
on or after the first dose of study drug, then assume the date of the first dose of study
drug. If the year is the same as the first dose of study drug, and the end date (after
any imputation) is prior to the first dose of study drug, then assume the end date for
the onset date
•
If onset date is completely missing and the end date (after any imputation) is on or
after the first dose of study drug, then onset date is set to date of first dose.
Missing end dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
• UK-MMM-YYYY: Assume the last day of the month
• DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY
Medical History and Disease Diagnosis 
Missing onset dates/diagnosis date (where UK and UKN indicate unknown or missing day 
and month respectively): 
•
UK-MMM-YYYY: If the month and year are different from the month and year of
the first dose of study drug, assume 01-MMM-YYYY. If the month and year are the
same as the first dose of study drug month and year, and the end date (after any
imputation) is on or after the first dose of study drug, then assume the date of the first
dose of study drug - 1. If the month and year are the same as the first dose of study
drug month, and year and the end date (after any imputation) is prior to the first dose
of study drug, then assume the end date for the onset date.
•
DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of first
dose of study drug, assume 01-JAN-YYYY of the collected year. If the year is the
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on or after the first dose of study drug, then assume the date of the first dose of study 
drug - 1. If the year is the same as the first dose of study drug, and the end date (after 
any imputation) is prior to the first dose of study drug, then assume the end date for 
the onset date  
•
If onset date is completely missing and the end date (after any imputation) is on or
after the first dose of study drug, then onset date is set to date of first dose.
Missing end dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
• UK-MMM-YYYY: Assume the last day of the month
• DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY
• If the end date after any imputation is on or after the first dose of study drug, then set
to date of first dose - 1.


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15.5. 
Visit Cycles and Analysis Timepoints 
Table 11: Visit Cycles and Analysis Timepoints 
Cycle (Number)  
Day 1 
Number of Days (± window 
days*) 
Analysis 
Timepoint 
Cycle 1 Day 1 
21 days (± 0) 
Baseline 
Cycle 2 Day 1 
42 days (± 4) 
Cycle 3 Day 1 
63 days (± 4) 
Cycle 4 Day 1 
84 days (± 4) 
Cycle 5 Day 1 
105 days (± 4) 
Cycle 6 Day 1 
126 days (± 4) 
Cycle 7 Day 1 
147 days (± 4) 
Cycle 8 Day 1 
168 days (± 4) 
Cycle 9 Day 1 
189 days (± 4) 
Cycle 10 Day 1 
210 days (± 4) 
Month 6 
Cycle 11 Day 1 
231 days (± 4) 
Cycle 12 Day 1 
252 days (± 4) 
Cycle 13 Day 1 
273 days (± 4) 
Cycle 14 Day 1 
294 days (± 4) 
Cycle 15 Day 1 
315 days (± 4) 
Cycle 16 Day 1 
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Cycle 17 Day 1 
357 days (± 4) 
Cycle 18 Day 1 
378 days (± 4) 
Cycle 19 Day 1 
399 days (± 4) 
Month 12 
End of Treatment 
(± 4) 
* Nominal visit window pre-specified in protocol and the visit windows are not
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15.6. 
Detailed Summary of SAP Changes 
Section 
Former Text 
New Text (in Bold) 
Rationale 
Cover Page 
Lexicon Pharmaceuticals, Inc. 
TerSera Therapeutics LLC 
Sponsor changed 
Cover Page 
Prepared by: 
PPD 
929 North Front Street 
Wilmington, NC 28401 
Prepared by: 
PPD 
929 North Front Street 
Wilmington, NC 28401 
and 
TerSera Therapeutics LLC 
520 Lake Cook Road, Suite 500 
Deerfield, IL 60015 
Sponsor changed 
List of Abbreviations, 
C1D1 
Cycle 1, Day 1; Baseline 
Cycle 1, Day 1; Baseline (Baseline value 
is defined as the last non-missing data 
on or before the first dose of the study 
drug, unless otherwise specified) 
Clarificaiton 
requested by 
TerSera 
List of Abbreviations, 
C10D1 
Cycle 10 Day 1 is intended as Month 6 
New abbreviation 
List of Abbreviations, 
C19D1 
Cycle 19 Day 1 is intended as Month 12 
New abbreviation 
List of Abbreviations, DCR disease control rate defined as 
CR+PD+SD 
disease control rate defined as CR+PR+SD Fixed the error 
List of Abbreviations, LFT 
liver function test 
New abbreviation 
List of Abbreviations, 
PTFP 
post-treatment follow-up 
post-treatment follow-up period 
Fixed the error 
List of Abbreviations, SFP 
survival follow-up period 
New abbreviation 
Section 1, Introduction 
This study is intended to assess the 
effect of XERMELO in combination 
with 1L chemotherapy on 
progression-free survival (PFS) in 
patients with locally advanced, 
This study is intended to assess the safety 
and the effect of XERMELO in 
combination with 1L chemotherapy on 
progression-free survival (PFS) in patients 
with locally advanced, unresectable, 
Updated based on 
protocol 
amendment 3, 
Section 4.1 
Primary Objective 


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unresectable, recurrent or metastatic 
BTC who are naïve to tumor-
directed therapy in the locally 
advanced or metastatic setting and 
for which treatment with 1L therapy 
is planned. 
recurrent or metastatic BTC who are naïve 
to tumor-directed therapy in the locally 
advanced or metastatic setting and for 
which treatment with 1L therapy is 
planned. 
Section 2.1, Primary 
Objective 
The primary objective of the study is 
to assess the safety and efficacy 
(PFS rate at Month 6) of 
XERMELO in combination with 
cisplatin (cis) plus gemcitabine 
(gem). 
The primary objective of the study is to 
assess the safety and efficacy (PFS rate at 
Month 6) in the Safety population 
receiving the combination of 
XERMELO plus 1L treatment with 
cis/gem combination chemotherapy. 
Efficacy (PFS rate at Month 6) will also 
be evaluated in the Per Protocol 
Population (PP) and by treatment cycle. 
Updated based on 
protocol 
amendment 3, 
Section 4.1 
Primary Objective 
Section 2.2, Secondary 
Objective 
To assess the effect of study 
treatment on the following:  
... 
•
Disease control rate (DCR);
defined as complete response (CR) +
partial response (PR) + stable
disease (SD) at Months 6 and 12 and
End-of-Study (EOS)
•
Objective response rate
(ORR) defined as CR + PR at
Months 6 and 12 and EOS
...
•
Change from Baseline in
 at Months 6 
and 12 and EOS 
To assess the effect of study treatment on 
the following:  
... 
•
Disease control rate (DCR);
defined as complete response (CR) +
partial response (PR) + stable disease (SD)
at Months 6, 12 and End-of-Study (EOS)
•
Objective response rate (ORR)
defined as CR + PR at Months 6, 12 and
EOS
...
•
Change from Baseline in
at Months 6, 12 and EOS 
•
Change from Baseline in body
weight at Months 6, 12 and EOS
•
Change from Baseline in serum
albumin at Months 6, 12 and EOS
Grammar updated 
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•
Change from Baseline in
body weight at Months 6 and 12 and
EOS
•
Change from Baseline in
serum albumin at Months, 6 and 12
and EOS
Note: Unless otherwise indicated, all 
radiologic endpoints will be based 
on Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 as 
determined by blinded independent 
central review (BICR) and compared 
to published historical data of 
cisplatin/gemcitabine (cis/gem) 
alone.). 
Note: Unless otherwise indicated, all 
radiologic endpoints will be based on 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 as determined by 
blinded independent central review 
(BICR).  
Section 2.3, Exploratory 
Objective 
To assess the effect of study 
treatment on the following:  
•
Changes in health-related
quality of life (HRQoL) as measured
by European Organization for
Research and Treatment of Cancer
(EORTC) Quality of Life
Questionnaire Core 30 (QLQ-C30)
and Cholangiocarcinoma and
Gallbladder Cancer (QLQ-BIL21)
items at Baseline, Months 6 and 12
•
Change from Baseline in
 To assess the effect of study treatment on 
the following:  
•
Changes in health-related quality
of life (HRQoL) as measured by European
Organization for Research and Treatment
of Cancer (EORTC) Quality of Life
Questionnaire Core 30 (QLQ-C30) and
Cholangiocarcinoma and Gallbladder
Cancer (QLQ-BIL21) items from
Baseline, at Months 6 and 12
•
Change from Baseline in
 at Months 6, 12 and EOS 
Added: 
•
Subgroup analyses in:
o
Patients with changes in liver
function tests
Updated based on 
protocol 
amendment 3, 
Section 4.3 
Exploratory 
Objectives 
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o
Patients with Biliary stents
o
Location of disease
(intrahepatic, extrahepatic , or
gallbladder)
o
prior therapy
o
ECOG performance status
•
Efficacy analysis by treatment
cycle population.
Section 3.1, Overall Study 
Design and Plan 
The study involves: Screening, 
Treatment Period with Stages 1 and 
2, Post-treatment Follow-up (PTFP), 
and Survival Follow-up. 
The study involves: Screening, Treatment 
Period with Stages 1 and 2, Post-treatment 
Follow-up Period (PTFP), and Survival 
Follow-up.  
Added: 
If there are no clinically significant or 
unresolved Grade 3 or higher toxicities 
considered related to the study drug, 
and if 12 or more (≥60%) of the 20 
patients enrolled who are deemed 
responder, enrollment will continue to 
Stage 2.   
Updated based on 
protocol 
amendment 3, 
Synopsis, 
Methodology 
Section 3.1, Overall Study 
Design and Plan 
Stage 2 may initiate and continue 
enrollment upon completion of the 
Stage 1 enrollment. If fewer than 12 
PFS responders are observed at 
Stage 1, patient accrual will be 
halted, and the study regimen 
declared “inactive”.  In the case that 
12 or more PFS responders are 
observed at Stage 1, an additional 33 
patients will be enrolled for Stage 2. 
Study duration and assessments in 
Stage 2 may initiate enrollment once Stage 
1 enrollment has been completed, in the 
absence of significant or unresolved 
Grade 3 or higher toxicities considered 
related to the study drugs. 
Approximately 33 additional patients are 
anticipated to participate in Stage 2. 
Study assessments in this stage will be 
identical to Stage 1. 
From a total of 53 accrued patients from 
Stage 1 + Stage 2, if 34 ( >60%) or more 
Updated based on 
protocol 
amendment 3, 
Section 
5.1.2.1, Treatment 
Period and Section 
5.1.2.2, Follow-up 
Periods 


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this stage will be identical to Stage 
1. From a total of 53 accrued
patients from Stage 1 + Stage 2, if
34 or more positive responses are
observed (ie, patients are alive and
progression-free at Month 6), the
study will be considered successful.
All patients are expected to be
followed for a total duration of 24
months after the Treatment Period,
unless they voluntarily withdraw
consent from future study visits or
assessments.
responses are observed (i.e., patients are 
alive and progression-free at Month 6) in 
the Safety population, the study will be 
declared successful. Efficacy will also be 
assessed in the PP population and by 
treatment cycle population. 
All patients are expected to be followed for 
a total duration of 24 months after the 
Treatment Period, unless they 
prematurely discontinue or voluntarily 
withdraw consent from future study visits 
or assessments.  
.... 
Added: 
Note: Patients who enter PTFP prior to 
having their 6-month imaging 
assessment in the Treatment Period, will 
be asked to consent to provide their 
local scans and/or local scan report 
closest to the Treatment Period 6-month 
timepoint. This includes the possible 
reconsenting of patients previously 
prematurely discontinued or withdrew 
consent from the Treatment Period of 
the study. 
Note: Patients who enter SFP without 
entering or completing PTFP and who 
entered SFP prior to having their 6-
month imaging assessment in the 
Treatment Period, will be asked to 
consent to provide their local scans 
and/or local scan report closest to the 
Treatment Period 6-month timepoint. 


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This includes the possible reconsenting 
of patients previously prematurely 
discontinued or withdrew consent from 
the Treatment Period of the study. 
Section 3.2.1, Primary 
Endpoint 
3.2.1 
Primary Endpoint 
The primary efficacy endpoint is 
PFS rate at Month 6, where patient 
progression is defined as the time 
from Baseline until the first 
determination of PD by central 
radiologic reading using RECIST 
v1.1 (Eisenhauer, 2009) or death 
from any cause. 
3.2.1 
Primary Endpoint 
The primary endpoint of the study is to 
assess the safety, tolerability and 
efficacy of XERMELO in combination 
with cisplatin (cis) plus gemcitabine 
(gem). 
3.2.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS rate 
at Month 6, where patient disease 
progression is defined as the time from 
first dose date until the first determination 
of PD by central radiologic reading using 
RECIST v1.1 (Eisenhauer, 2009) or death 
from any cause. 
Updated based on 
protocol 
amendment 3, 
Section 4.1 
Primary Objective 
Section 3.2.2, Secondary 
Endpoints 
•
PFS rate at Month 12 and
median PFS
•
DCR defined as CR + PR +
SD at Months 6 and 12 and EOS
•
ORR defined as CR + PR at
Months 6 and 12 and EOS
•
Local radiologist’s
assessment of PFS, ORR and DCR
•
Change from Baseline in
 at 
Months 6 and 12 and EOS 
•
Change from Baseline in
body weight at Months 6 and 12 and
EOS
•
PFS rate at Month 12 and median
PFS at Month 12
•
DCR defined as CR + PR + SD at
Months 6, 12 and EOS
•
ORR defined as CR + PR at
Months 6, 12 and EOS
•
Local radiologist’s assessment of
PFS, ORR and DCR
•
Change from Baseline in
 at Months 6, 12 and 
EOS 
•
Change from Baseline in body
weight at Months 6, 12 and EOS
Updated based on 
protocol 
amendment 3, 
Section 4.2, 
Secondary 
Objective 
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•
Change from Baseline in
serum albumin at Months 6 and 12
and EOS
•
Change from Baseline in serum
albumin at Months 6, 12 and EOS
Section 3.2.3, Exploratory 
Endpoints 
•
Changes in HRQoL as
measured by EORTC QLQ-C30 and
QLQ-BIL21 items at Baseline,
Months 6 and 12
•
Added: 
Note: Unless otherwise indicated, all 
radiologic endpoints will be based on 
RECIST v1.1 as determined by BICR. 
… 
•
Changes in HRQoL as measured
by EORTC QLQ-C30 and QLQ-BIL21
items at Baseline, Months 6 and 12
•
Change from Baseline in CEA
fragment at month 6, 12 and EOS
...
Added:
•
Subgroup analyses in:
o
Patients with changes in liver
function tests
o
Patients with Biliary stents
o
Location of disease (Histology:
intrahepatic, extrahepatic , or
gallbladder)
o
prior therapy
o
ECOG performance status
•
Efficacy analysis by treatment
cycle (such as in patients who completed
 with
combination treatment.
Updated based on 
protocol 
amendment 3, 
Section 4.3 
Exploratory 
Objectives 
Section 3.2.6, Safety 
Endpoints 
•
Incidence of TEAEs,
TEAEs by severity, TEAEs by
relationship to each of the study
drugs, TEAEs by study drugs
exposure time, TEAEs leading to
•
Incidence of TEAEs, TEAEs by
severity, TEAEs by relationship to each of
the study drugs, TEAEs by study drugs
exposure time, TEAEs leading to
discontinuation from the study, TEAE
leading to dose reduction, TEAE leading
Added per 
TerSera's request 
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discontinuation from the study, 
SAEs, and deaths  
•
Actual and change from
Baseline in clinical laboratory
results including frequency of values
meeting NCI CTCAE Grades >1
to XERMELO reduction, TEAE leading 
to XERMELO interruption, TEAE 
leading to discontinuation from 
treatment, SAEs, and deaths  
•
Actual and change from Baseline
in clinical laboratory results including
frequency of values meeting NCI CTCAE
Grades >1, laboratory data toxicities as
defined by NCI CTCAE v5.0
Section 3.3, Treatments  
… 
Patients may continue to receive 
combination treatment as described 
above for as many cycles as possible 
until PD as determined by local 
review, unacceptable toxicity, or the 
patient withdraws from treatment.  
Added: 
Note: Patients may continue to receive 
treatment for as many cycles possible, 
until progressive disease (PD) (up to 19 
cycles during the Treatment Period), 
and during the Post Treatment Follow-
up Period (up to an additional 24 
months) at the discretion of the 
Investigator. 
... 
Patients may continue to receive 
combination treatment as described above 
for as many cycles as possible until PD as 
determined by local review, unacceptable 
toxicity, prematurely discontinue, or the 
patient withdraws from treatment.  
Updated based on 
protocol 
amendment 3, 
Section 
5.1.2.1, Treatment 
Period  
Section 3.4, Dose 
Adjustment/Modifications 
•
Discontinuation: premature
withdrawal from 1 or both
treatments of the assigned
combination treatment (XERMELO
and/or 1L) defined as a dose
interruption lasting for >3 weeks
(XERMELO) or a missed cycle
(cis/gem). Note, however, that
discontinuation of cisplatin, but
•
Discontinuation: prematurely
discontinue or prematurely withdrawal
from 1 or both treatments of the assigned
combination treatment (XERMELO and/or
1L) defined as a dose interruption lasting
for >3 weeks (XERMELO) or a missed
cycle (cis/gem). Note, however, that
discontinuation of cisplatin, but
continuation of treatment with gemcitabine
Updated based on 
protocol 
amendment 3, 
Section 5.1.2.2, 
Follow-up 
Periods 


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continuation of treatment with 
gemcitabine alone, will not be 
classified as discontinuation.  
alone, will not be classified as 
discontinuation.  
Section 4, General 
Statistical Considerations 
... 
Demographic data, Baseline disease 
characteristics, prior and 
concomitant medications, treatment 
compliance, treatment exposure, AE, 
laboratory tests, vital signs, PE 
findings, 12-lead ECG findings, and 
final disposition will be summarized 
descriptively. No statistical tests will 
be performed. Analyses will be 
based on the Safety population. 
Added: 
For the purpose of statistical analyses, 
Cycle 10 Day 1 is intended as Month 6, 
and Cycle 19 Day 1 is intended as Month 
12. 
… 
Demographic data, Baseline disease 
characteristics, prior and concomitant 
medications, treatment compliance, 
treatment exposure, AE, laboratory tests, 
vital signs, PE findings, 12-lead ECG 
findings, and final disposition will be 
summarized descriptively. In addition, 
shift table analyses will be applied to the 
laboratory data. No statistical tests will 
be performed. Analyses will be based on 
the Safety population. 
Updated based on 
protocol 
amendment 3, 
Synopsis, 
Methodology and 
Section 10.4.2, 
Safety Analyses 
Section 4.1, Sample Size 
The sample size was computed by 
satisfying design assumptions for the 
primary endpoint of the study; 
which is to assess the PFS responder 
rate at Month 6.  
The sample size was computed by 
satisfying design assumptions for the 
primary efficacy endpoint of the study; 
which is to assess the PFS responder rate at 
Month 6.  
… 
Added: 
In the Stage 1 Safety population, if there 
are no clinically significant or 
unresolved Grade 3 or higher toxicities 
considered related to the study drug and 
if 12 (60%) or more of the 20 patients 
enrolled who are deemed responders per 
Updated based on 
protocol 
amendment 3, 
Synopsis, 
Methodology 


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the definition in Section 8.1.1 after the 
20th patient is censored, is alive and 
progression-free at the Month 6 
assessment in the Safety Population, 
enrollment will continue to Stage 2.  
Section 4.3.2, Per Protocol 
(PP) Population 
This analyses population will be 
used for analysis of primary and 
secondary efficacy endpoints. 
The analysis population will be used for 
analysis of primary and secondary efficacy 
endpoints. 
Grammar updated 
Section 4.3.3, By 
Treatment Cycle 
Population 
Added: 
4.3.3. By Treatment Cycle Population 
The by treatment cycle population 
consist of all patients who completed at 
least a 3 cycles of combination 
treatment.  
The by treatment cycle population will 
be used for analysis of all efficacy 
endpoints as exploratory analysis as well 
as all AE outputs. 
Updated based on 
protocol 
amendment 3, 
Section 4.3 
Exploratory 
Objectives 
Section 4.3.5, PK 
Population 
The PK population will consist of all 
patients treated with study drug and 
who have adequate samples taken to 
reliably estimate at least 1 of the PK 
parameters of interest. 
Determination of the PK population 
will be reviewed after all PK 
concentration data are made 
available. 
The PK population will consist of all 
patients treated with at least 1 dose of 
study drug and who have adequate samples 
taken to reliably estimate at least 1 of the 
PK parameters of interest. Determination 
of the PK population will be reviewed after 
all PK concentration data are made 
available. 
Updated based on 
protocol 
amendment 3, 
Section 10.2, 
Analysis 
Populations 
Section 6.1, Demographics 
The following variables will be 
summarized: 
1.
Continuous baseline
demographic variables:
1.
Continuous baseline demographic
variables:
•
Age at time of consent (years)
•
Height (in inches)
•
Weight (in kg)
Specified all 
subgroup 
categories based 
on demographic 
data 


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•
Age at time of consent
(years)
•
Height (in inches)
2.
Categorical baseline
demographic variables:
•
Sex (male, female)
•
Childbearing potential (if
female) (Yes, No)
•
Ethnicity (Hispanic or
Latino, Not Hispanic or Latino)
•
Race (White, African
American, Asian, American Indian
or Alaska Native, Native Hawaiian
or Other Pacific Islander, Other)
•
BMI (in kg/m2)
2.
Categorical baseline demographic
variables:
•
Age: <Median and ≥ Median age
•
Sex (male, female)
•
Childbearing potential (if female)
(Yes, No)
•
Ethnicity (Hispanic or Latino, Not
Hispanic or Latino)
•
Race: All races (White, African
American, Asian, American Indian or
Alaska Native, Native Hawaiian or Other
Pacific Islander, Other) and White vs
Non-white
Section 6.2, Baseline 
Disease Characteristics 
Baseline values from the parameters 
below, but not limited to, will be 
tabulated:  
... 
Duration of cancer at study entry is 
defined as the date of inform consent 
minus the date of diagnosis and will 
be presented in months. Incomplete 
dates will be derived following the 
same rules for medical history. 
Baseline disease characteristics will 
be presented in a listing. 
Baseline values from the parameters 
below, but not limited to, will be tabulated: 
... 
•
Patients with changes in liver
function tests
•
Patients with Biliary stents
•
Prior therapy
Duration of cancer at study entry is defined
as the date of inform consent minus the
date of diagnosis + 1 and will be presented
in months. Incomplete dates will be
derived following the same rules for
medical history.
Patients with changes in liver function 
tests will be identified using "Drug 
related hepatic disorders - 
comprehensive search" PT coding terms 
based on AE records. Patients with 
Biliary stents will be identified using 
Specified all 
subgroup 
categories and 
definitions based 
on baseline 
disease 
characteristics 
data 


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“Biliary stent”, “Biliary Tract stent”, 
“Bile duct stent” from Medical history 
term. Patients with prior therapy will be 
identified using the leading question “Is 
Condition or Term associated with 
BTC?” in Medical history CRF page. 
Baseline disease characteristics will be 
summarized in table and also will be 
presented in a listing. C1D1 images or 
images being obtained within 6 weeks 
prior to Day 1, or whichever images 
were closest in date to C1D1 are 
submitted to BICR for establishment of 
Baseline. 
Section 6.5, Subgroups 
Added: 
6.5 Subgroups 
The following subgroups will be defined: 
• 
Added subgroup 
section and 
definition here. 
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 the change from baseline 
at Month 6, Month 12 and EOS will be 
categorized into “decrease >= 30%” and 
“decrease < 30%”. 
•
body weight – Subgroup
categories: <Median and ≥ Median
baseline weight
•
serum albumin - Subgroup
categories: Normal and Abnormal
baseline albumin
Demographics and disease 
characteristics will be considered as 
subgroups including:  
•
major demographic
o
Age: <Median and ≥ Median age
o
Sex: Male vs Female
o
Race: White vs Non-white
•
Subgroup analyses in:
o
Patients with changes in liver
function tests
o
Patients with Biliary stents
o
Location of disease (Histology:
intrahepatic, extrahepatic, or
gallbladder)
o
Prior therapy
o
ECOG performance status
Subgroups mentioned in the protocol
based on correlation between Baseline
neutrophil:lymphocyte ratio and OS,
prognostic subgroups, extent of disease
are not planned but might be performed
upon reviewing the data. Such analyses
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will be defined in the Clinical Study 
Report. 
Patients with changes in liver function 
tests will be identified using "Drug 
related hepatic disorders - 
comprehensive search" PT coding terms 
based on AE records. Patients with 
Biliary stents will be identified using 
“Biliary stent”, “Biliary Tract stent”, 
“Bile duct stent” from Medical history 
term. Patients with prior therapy will be 
identified using the leading question “Is 
Condition or Term associated with 
BTC?” in Medical history CRF page. 
Subgroup analyses of PFS, OS, ORR, 
and DCR will be evaluated for 
exploratory endpoints. 
Section 7.3.1, Extent of 
Exposure 
•
Cumulative dose (mg) is
defined as the sum of all doses taken
per drug during the treatment period
for XERMELO only.
•
Cumulative dose (mg) is defined
as the sum of all doses taken per drug
during the treatment period for
XERMELO only based on drug
accountability.
…
Overall treatment duration and dose
status will also be presented in the table.
Added 
clarification for 
XERMELO 
cumulative dose 
calculation and 
specify the table 
will be 
summarized. 
Section 7.3.2, Treatment 
Compliance and 
Modifications 
•
Compliance (%) defined as
[(actual number of tablets taken over
the study period) / (designated total
number of tablets that should have
been taken over the study period)] *
100 for XERMELO. Actual number
of tablets taken will be calculated
•
Compliance (%) defined as
[(actual number of tablets taken over the
study period prior to EOT) / (designated
total number of tablets that should have
been taken over the study period prior to
EOT)] * 100 for XERMELO. Actual
number of tablets taken will be calculated
Specified the 
XERMELO 
compliance 
calculation 
duration and 
details. 


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using the dispensed and returned 
count from the XERMELO 
Dispensation CRF page. All the 
tablets not returned will be 
considered as taken by patient. 
Designated total number of tablets 
will be based on exact days patients 
were put under treatment cycles 
(250 mg tid starting on Day 1 and 
500 mg tid staring on Day 8) 
regardless dose interruptions and/or 
modifications. 
using the dispensed and returned count 
from the XERMELO Dispensation CRF 
page. All the tablets not returned will be 
considered as taken by patient. Designated 
total number of tablets will be based on 
exact days patients were put under 
treatment cycles (250 mg tid starting on 
Day 1 and 500 mg tid staring on Day 8 in 
cycle 1 and 500 mg tid in cycle 2 and 
after) regardless dose interruptions and/or 
modifications. 
Section 8.1, Primary 
Efficacy Analysis  
Section 8.1, Primary Efficacy 
Endpoint 
Section 8.1, Primary Efficacy Analysis 
Section 8.1.1, Progression-
free Survival (PFS) 
A Safety physician from Lexicon 
will identify the anticancer 
treatments and first date of their 
administration from the concomitant 
medication records. 
The full event and censoring rules 
for deriving PFS are specified in 
Table 9 below. 
A Safety physician from TerSera will 
identify the anticancer treatments and first 
date of their administration from the 
concomitant medication records. 
The full event and censoring rules for 
deriving PFS are specified in Table 9 
below. Cycle 10 Day 1 is considered the 
Month 6 timepoint and Cycle 19 Day 1 is 
considered the Month 12 timepoint for 
analysis purposes. Patients who 
prematurely discontinued from 
Treatment Period or withdrew consent 
from Treatment Period prior to Month 
6 of the Treatment Period, will be asked 
to reconsent to allow for images and or 
imaging reports, obtained locally, to be 
submitted to BICR. 
Changed the 
sponsor name to 
TerSera and add 
details of Month 6 
and Month 12 
definition per 
protocol 
amendment 3 


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Table 9, Censoring 
Conventions for PFS 
Treatment discontinuation for 
toxicity or other reasons prior to 
disease progression and Month 6 
radiological assessment is not 
available 
Treatment discontinuation for toxicity or 
other reasons (except death) prior to 
disease progression and Month 6 
radiological assessment is not available 
Add clarification 
for the exception 
of treatment 
discontinuation 
due to death is not 
considered as 
censored. 
Section 8.1.1, Progression-
free Survival (PFS) 
The primary efficacy endpoint is the 
PFS response rate at 6 months. This 
is a binomial variable in which the 
numerator is derived as the number 
of patients at 6 months who are alive 
and event-free. Event-free means 
that that a valid radiologic 
assessment of disease (ie, 
radiological scan of the tumor) at 6 
months shows that the patient has no 
progressive disease (PD) per 
RECIST 1.1 criteria.  
… 
In addition to the PFS response rate, 
the PFS rate at Month 6 derive as a 
function of a time-to-event outcome, 
and the corresponding 95% 
confidence interval (CI), will be 
presented. The Kaplan-Meier 
method will be used to estimate the 
survival function of this measure of 
the PFS variable.  
The primary efficacy endpoint is the PFS 
response rate at 6 months and scheduled 
cycle 10 day 1 disease assessment results 
will be used for this purpose. This is a 
binomial variable in which the numerator 
is derived as the number of patients at 6 
months who are alive and event-free. 
Event-free means that a valid radiologic 
assessment of disease (ie, radiological scan 
of the tumor) at 6 months shows that the 
patient has no progressive disease (PD) per 
RECIST 1.1 criteria.  
... 
In addition to the PFS response rate, the 
PFS rate at Month 6 derived as a function 
of a time-to-event outcome, and the 
corresponding 95% confidence interval 
(CI), will be presented. The Kaplan-Meier 
method will be used to estimate the 
survival function of this measure of the 
PFS variable.  
Clarification 
added based on 
protocol 
amendment 3, 
Synopsis, 
Methodology 
Section 8.1.2, Sensitivity 
Analysis 
A separate sensitivity analysis will 
also be performed on the PFS 
response rate as defined in Section 
8.1.1 based on the PP population.  
A separate sensitivity analysis will also be 
performed on the PFS response rate as 
defined in Section 8.1.1 based on the PP 
population as well as by treatment cycle 
population.  
Updated based on 
protocol 
amendment 3, 
Section 4.1 
Primary Objective 


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Section 8.2, Secondary 
Efficacy Analysis  
Section 8.1, Secondary Efficacy 
Endpoint 
Section 8.1, Secondary Efficacy Analysis 
Section 8.2.1, PFS Rate at 
Month 12 and Median PFS 
Added: 
Scheduled disease assessment at cycle 19 
day 1 will be used to determine PFS 
response rate at month 12. 
Updated based on 
protocol 
amendment 3, 
Synopsis, 
Methodology  
Section 8.2.6, Change in 
Tumor Size 
Added: 
A waterfall plot will be provided of 
change in tumor size (as of % of 
baseline) from baseline to Month 6 
response for all patients for whom 
primary lesion data are available and 
will be displayed based on Safety 
population. Associated change from 
baseline summary table will be also 
provided. 
Added per 
TerSera's request 
Section 8.2.7, Sensitivity 
Analysis 
Added: 
A separate sensitivity analysis will also 
be performed on all secondary efficacy 
tables as defined in Section 8.2 based on 
the PP population as well as by 
treatment cycle population.  
Updated based on 
protocol 
amendment 3, 
Section 4.3 
Exploratory 
Objectives 
Section 9.2, Subgroup 
Analysis 
Subgroup analyses of PFS, OS, 
ORR, and DCR may be performed 
using both BICR and local 
radiologist’s assessment, based on 
categorical group of Baseline in:  
• 
Subgroup analyses of PFS, OS, ORR, and 
DCR may be performed using both BICR 
and local radiologist’s assessment, based 
on categorical subgroup group variables. 
Subgroup definition details are specified 
in Section 6.5. 
Moved the 
subgroup 
definition to 
section 6.5. 
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Subgroup analyses mentioned in the 
protocol based on correlation 
between Baseline 
neutrophil:lymphocyte ratio and OS, 
the primary tumor site, prior 
therapy(ies), performance status, 
prognostic subgroups, extent of 
disease are not planned but might be 
performed upon reviewing the data. 
After reviewing the data, additional 
subgroup analysis may be 
performed. Such analyses will be 
defined in the Clinical Study Report. 
Section 9.3, Sensitivity 
Analysis 
Added: 
9.3 
Sensitivity Analysis 
All efficacy analyses will be also 
conducted based on the PP population 
as well as by treatment cycle population. 
Added Sensitivity 
Analysis section 
under exploratory 
analysis per 
TerSera's request 
Section 10, Safety Analysis Safety and tolerability will be 
evaluated through the collection and 
review of treatment-emergent 
adverse events (TEAEs), as graded 
by CTCAE v5.0, vital signs 
measurement, 12-lead 
electrocardiogram (ECG) findings, 
physical examination (PE) findings, 
and clinical laboratory parameters 
(chemistry, hematology, and 
urinalysis) including changes from 
Baseline and frequency of values 
meeting CTCAE Grades >1, 
CTCAE Grades 3/4 separately. All 
Safety and tolerability will be evaluated 
through the collection and review of 
treatment-emergent adverse events 
(TEAEs), as graded by CTCAE v5.0, vital 
signs measurement, 12-lead 
electrocardiogram (ECG) findings, 
physical examination (PE) findings, and 
clinical laboratory parameters (chemistry, 
hematology, and urinalysis) including 
changes from Baseline and frequency of 
values meeting CTCAE Grades >1, 
CTCAE Grades 3/4 separately. In 
addition, shift table analyses will be 
applied to the laboratory data. All 
Added 
clarification for 
lab shift table. 
Added AE 
additional 
analyses per 
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summaries will be performed using 
the Safety population. 
... 
Summaries will be prepared by 
study time point. All safety data will 
be listed by patient. 
summaries will be performed using the 
Safety population. 
... 
Summaries will be prepared by study time 
point. Adverse events will also be 
prepared by PP population as well as by 
treatment cycle population.  Adverse 
events will also be displayed by study 
drug cycle based on Safety population. 
All safety data will be listed by patient. 
Section 10.1, Adverse 
Events 
Added: 
•
TEAEs that leading to treatment
reduction by SOC and PT
•
TEAEs that leading to
XERMELO reduction by SOC and PT
•
TEAEs that leading to
XERMELO interruption by SOC and
PT
•
TEAEs with severity grade ≥ 1 by
SOC and PT
•
TEAEs with severity grade ≥ 2 by
SOC and PT
•
TEAEs with severity grade 3 and 4
by SOC and PT
•
Adverse events of special interest
(AESI) by SOC and PT
…
All AE tables will be displayed based on
safety population, PP population as well
as by treatment cycle population. All AE
tables by study drug cycle will also be
displayed based on safety population.
Added AE 
additional 
analyses per 
TerSera's request 
Section 10.1.1, Incidence 
of Adverse Events 
An overall summary of TEAEs will 
be presented in a table and will 
An overall summary of TEAEs will be 
presented in a table and will include the 
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include the number and incidence of 
patients with any TEAE, number of 
TEAEs, patients with serious 
TEAEs, patients with severe TEAE 
(≧ Grade 3), patients that 
discontinued from study due to 
TEAEs, and deaths. In addition, the 
table will include the number and 
percentage of patients in each 
category of severity (ie, Grade 1 to 
Grade 5) for all TEAEs and the 
number and percentage of patients in 
each category of relationship to each 
study drug (ie, “Related” and “Not 
Related”). 
number and incidence of patients with any 
TEAE, number of TEAEs, patients with 
serious TEAEs, patients with severe TEAE 
(≧ Grade 3), patients that discontinued 
from study due to TEAEs, TEAE leading 
to dose reduction, TEAE leading to 
discontinuation from treatment, and 
deaths. In addition, the table will include 
the number and percentage of patients in 
each category of severity (ie, Grade 1 to 
Grade 5) for all TEAEs and the number 
and percentage of patients in each category 
of relationship to each study drug (ie, 
“Related” and “Not Related”). 
analyses per 
TerSera's request 
Section 10.1.9, Adverse 
Events Leading to Dose 
Reduction 
New Section 
Added new 
section per 
TerSera's request 
Section 10.1.10, Adverse 
Events Leading to 
XERMELO Reduction 
New Section 
Added new 
section per 
TerSera's request 
Section 10.1.11, Adverse 
Events Leading to 
XERMELO Interruption 
New Section 
Added new 
section per 
TerSera's request 
Section 10.1.12, Adverse 
Events of Special Interest 
Section 10.1.9.Adverse Events of 
Special Interest 
Section 10.1.12.Adverse Events of Special 
Interest 
Section 10.1.13, Deaths 
Section 10.1.10. Deaths 
Section 10.1.13. Deaths 
Section 10.3, Vital Sign 
Measurements 
Added: 
For weight, the proportions with stable 
weight, weight gain, weight loss will also 
be summarized. Stable weight is defined 
as a change from baseline to week 24 of 
less than 3%. Weight gain is an increase 
Added additional 
analyses per 
TerSera's request 


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of at least 3%, and weight loss is a 
reduction of at least 3%. 
Section 12, 
Pharmacodynamics 
Actual and change from Baseline for 
 will be summarized 
at Month 6, Month 12, and EOS 
using descriptive statistics. 
Actual and change from Baseline for 
will be summarized at Month 6, 
Month 12, and EOS using descriptive 
statistics and 1-sample t-tests may be 
performed to test for significance using 
a 5% level of significance. 
Added 
clarification based 
on protocol 
section 10.4.1, 
Efficacy Analyses 
Section 13, Interim 
Analysis 
An interim analysis will be 
performed at Stage 1 once 20 
patients are accrued, treated with 
study medication, and either have a 
6-month scan for determination of
PFS response or stopped the study
early regardless of having a scan for
disease assessment. Patients beyond
the initial 20 patient cohort will be
allowed to enroll while the data
accumulates for the Stage 1 analysis.
If fewer than 12 PFS responders are
observed at Stage 1, patient accrual
is to stop, and the study regimen
declared “inactive”. In the case that
12 or more PFS responders are
observed at Stage 1, patient
enrollment will continue to the
maximum sample size of 53
patients. If at the end of Stage 2 the
number of PFS responders at Month
6 exceeds 34 patients, then the null
hypothesis will be rejected, and the
study treatment labeled a “success”.
Should an excessive number of PFS
Added: 
Stage 1 analysis 
Stage 1 enrollment will include a Safety 
Run-in cohort. Safety and tolerability 
data of the combination treatment from 
the first 6 patients who complete at least 
21 days of safety follow-up after the first 
dose of combination treatment will be 
evaluated. During this review, Stage 1 
enrollment will continue. It is 
anticipated that a total of 20 patients 
will participate in Stage 1. If there are 
no clinically significant or unresolved 
Grade 3 or higher toxicities considered 
related to the study drug and if of 12 
(60%) or more of the 20 patients 
enrolled are deemed PFS responders in 
the Safety population, enrollment will 
continue to Stage 2. In addition, selected 
efficacy will be assessed in the per-
protocol population and by treatment 
cycle. 
Stage (1 + 2) analysis and Interim 
Analyses: 
Updated based on 
protocol 
amendment 3, 
Section 10.4.7, 
Interim Analysis 
CCI
CCI
CCI
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response “failures” occur at any time 
over the course of the study such 
that the sampling rule cannot be 
successfully achieved at either 
Stage, consideration will be given to 
stop patient accrual at that time.  
Formal statistical interim analyses will 
be performed during this study as 
follows: 
•
Interim analysis 1 : Conducted
in Patients included in the Stage 1
analysis (first 20 patients enrolled) and
will include safety, efficacy (PFS
responder rate), pharmacodynamic
(biomarker) data.
•
Interim analysis 2 added to
(Stage 1+2) 6 month analysis :
Conducted after all 53  Patients (Stage 1
+ Stage 2) complete the Month 6 visit,
and will include safety, efficacy (PFS
responder rate), pharmacodynamic
(biomarker) data and analysis by
treatment cycle population.
•
Interim Analysis 3 added to
(Stage 1+2) 12 month analysis:
Conducted after all 53 Patients (Stage 1
+ Stage 2) complete the Month 12 visit,
and will include safety, efficacy (PFS
responder rate), pharmacodynamic
(biomarker) data and analysis by
treatment cycle population.
Section 14, References 
1.
Lexicon LX16061207BTC
Protocol: A Phase 2, Multicenter,
Open-label, Safety and Efficacy
Study of XERMELO® (Telotristat
Ethyl) plus First-line Chemotherapy
in Patients with Locally Advanced,
Unresectable, Recurrent or
1.
TerSera LX1606.1-207-BTC
Protocol: A Phase 2, Multicenter, Open-
label, Safety and Efficacy Study of
XERMELO® (Telotristat Ethyl) plus First-
line Chemotherapy in Patients with
Locally Advanced, Unresectable,
updated based on 
protocol 
amendment 3 


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Metastatic Biliary Tract Cancer 
(BTC)  
Recurrent or Metastatic Biliary Tract 
Cancer (BTC)  
Section 15.1, Schedule of 
Study Procedures 
Update Schedule of Study Procedures table 
and footnote based on protocol amendment 
3. 
updated based on 
protocol 
amendment 3 
Section 15.5, Visit Cycles 
and Analysis Timepoints 
Added: 
Table 11 Visit Cycles and Analysis 
Timepoints 
Added new table 
per TerSera's 
request 
Section 15.6, Detailed 
Summary of SAP Changes 
New Section