Clinical trial NCT03453489
Conditions: Carcinoid Syndrome Metastatic Nonfunctional Well Differentiated Neuroendocrine Neoplasm
Sponsor: Barbara Ann Karmanos Cancer Institute
Start date: 2018-06-20; Completion date: 2020-10-15
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot trial studies how well telotristat etiprate works in treating participants with well differentiated neuroendocrine neoplasm that has spread to other places in the body and monitored by carbon C 11 alpha-methyltryptophan (AMT)-emission tomography (PET). Telotristat etiprate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Studying the changes within the tumor cells via AMT-PET may help doctors better understand how tumors respond to treatment with telotristat etiprate.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the effect of telotristat etiprate (telotristat ethyl) treatment in patients with advanced neuroendocrine tumors (NETs) using carbon C 11 alpha-methyltryptophan (alpha-\[11C\]methyl-?L-?tryptophan) (AMT)-?positron emission tomography (PET) as measured by changes in tumor maximum standardized uptake value (SUVmax).

SECONDARY OBJECTIVES:

I. Show that NETs will have increased AMT uptake on PET, as compared to surrounding non-tumor tissue at baseline.

II. Use compartmental modeling (in tumors with the left ventricle of the heart in the field-of-view) to measure change in AMT retention.

III. Measure change in AMT retention as mean standardized uptake value (SUVmean).

OUTLINE:

Participants undergo AMT-PET within 7 days prior to, and 9-14 days after start of telotristat etiprate treatment. Participants receive telotristat etiprate orally (PO) three times a day (TID) for 9-14 days.

After completion of study treatment, participants are followed up for 3 months.

Arms: arm 1: Participants undergo AMT-PET within 7 days prior to, and 9-14 days after start of telotristat etiprate treatment. Participants receive telotristat etiprate PO TID for 9-14 days.
Interventions: intervention 1: Carbon C 11 Alpha-methyltryptophan intervention 2: Laboratory Biomarker Analysis intervention 3: Positron Emission Tomography intervention 4: Telotristat Etiprate
Intervention descriptions: intervention 1: Undergo AMT-PET intervention 2: Correlative studies intervention 3: Undergo AMT-PET intervention 4: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
2017-144 Monitoring Telotristat Ethyl Inhibition of Tryptophan hydroxylase (TPH) in 
Neuroendocrine Tumors Using a-[11C]methyl-L-tryptophan (AMT)-PET 
Version 1: 11/27/17; Revised 09/10/19; Revised 05/26/20 
 
Table of contents: 
 
 
 Protocol summary 
 
 
 
 
2 
I. 
Objectives 
 
 
 
 
 
3 
II. 
Background 
 
 
 
 
 
3 
III. 
Patient selection 
 
 
 
 
6 
IV. 
Registration procedures 
 
 
 
7 
V. 
Treatment plan  
 
 
 
 
8 
VI. 
Adverse events  
 
 
 
 
8 
VII. 
Measurement of effect (AMT-PET) 
 
 
11 
VIII. 
Statistical plan  
 
 
 
 
12 
IX. 
Data and safety monitoring 
 
 
 
13  
X. 
References 
 
 
 
 
 
15 
 
Principal Investigator:  Anthony F. Shields, MD, PhD 
 
 
 
Tel: 313-576-8735; Fax: 313-576-8767 
 
 
 
Email: shieldsa@karmanos.org 
 
 
 
4100 John R Street, HW04HO 
 
 
 
Detroit, MI, 48201 
 
Co- Investigator:  
Csaba Juhasz, MD, PhD 
 
 
 
Philip A. Philip, MD, PhD 
 
 
 
Mohammed Al Hallak, MD 
 
 
 
Lynette M. Guziatek-Trojniak, RN, MSN, CNP 
 
 
 
Wei Chen, PhD - Biostatistician 
 
 
 
 
 
 
 
 
 
 
 
 


 
2 
PROTOCOL SUMMARY 
 
OBJECTIVES:  
Primary objective is to show that telotristat ethyl (Xermelo™), a recently FDA-approved TPH inhibitor drug, 
will decrease tumoral AMT uptake and trapping as compared to values measured at baseline before the 
start of treatment. Secondary objective is to show that neuroendocrine tumors (NETs) will have increased 
AMT uptake on positron emission tomography (PET), as compared to surrounding non-tumor tissue at 
baseline.  
 
 
PATIENT POPULATION:  
1. Histopathologically confirmed, well-differentiated metastatic NETs. 
2. Patients receiving stable-dose somatostatin analogs (SSAs, long-acting release [LAR], depot) for > 
3 months before enrollment.  
 
STUDY DESIGN:  
Imaging will be done with AMT-PET/CT, under separate protocol 2011-053, at baseline and after 9-14 days 
treatment on telotristat ethyl, 250 mg po three times daily.  
  
EVALUATION:  
Prior to PET imaging: Physical exam, CBC and Multiphasic (electrolytes, renal and liver function) drawn 
within 28 days of start of the study as part of routine care. Radiology testing to measure tumor size (for 
example, CT scans, MRI scans, PET scans) which are part of routine care. Scan may be done within 8 weeks 
of the start of the study. A negative urine or blood pregnancy test must be obtained in women with child 
bearing potential on the day of the first PET scan.  
 
PRIMARY and Secondary ENDPOINTS:  
The measurement of the uptake and retention of AMT will be quantitated by maximum standardized 
uptake values (SUVmax) and compartmental modeling (in tumors with the left ventricle of the heart in 
the field-of-view) before and after treatment with telotristat ethyl. The proportion of patients whose 
reduction in AMT uptake between baseline and follow-up is ≥20% will be the primary endpoint. We will 
also assess if the NET is visible above background at baseline and will also quantify the percent difference 
in AMT uptake between the tumor mass and background. Using time-activity curves, we will also identify 
the optimal time frame where tumoral AMT uptake peaks. 
 
STATISTICAL PLAN:  
This is a single arm single institution prospective proof-of-concept study. The proportion of patients, who 
achieved SUVmax reduction of 20% or more, will be estimated and exact (Clopper-Pearson) confidence 
interval will be calculated. Paired t test will be used for pre- and post- treatment SUVs if normality 
assumption holds. The relationship of one PET parameter to another will be visualized with scatter plot 
and measured using linear regression models.  
  
 


 
3 
I. OBJECTIVES 
 
1. Primary Objective: The primary objective of this pilot study is to evaluate the effect of 
telotristat ethyl treatment in patients with advanced neuroendocrine tumors (NETs) using a-
[11C]methyl-L-tryptophan (AMT)-positron emission tomography (PET) as measured by changes in 
tumor maximum standardized uptake value (SUVmax). 
2. 
Secondary Objectives: 
a. Show that NETs will have increased AMT uptake on PET, as compared to surrounding non-
tumor tissue at baseline 
b. Use compartmental modeling (in tumors with the left ventricle of the heart in the field-of-
view) to measure change in AMT retention.  
c.  Measure change in AMT retention as SUVmean 
 
II. BACKGROUND  
AMT-PET to study serotonin synthesis in vivo. Alpha-methyl-L-tryptophan (AMT) is an analog of 
tryptophan, the precursor of the neurotransmitter serotonin (5-HT, 5-hydroxytryptamine). In the early 
1990s, Diksic and colleagues at the Montreal Neurological Institute performed extensive animal studies 
of radiolabeled AMT to validate AMT as a tracer for the measurement of the rate of serotonin synthesis 
in vivo with positron emission tomography (PET) (Diksic et aI., 1990, 1991). After the administration of 
labeled AMT in rats, autoradiograms demonstrated a distribution of high tracer concentration in 
serotonergic cell bodies in the raphe nuclei. The synthesis of a-methyl-serotonin in brain after tracer 
administration was confirmed by high performance liquid chromatography (Missala and Sourkes, 1988; 
Diksic et aI., 1990). The [3H] a-methyl-serotonin synthesized in brain was localized to serotonergic 
neurons and nerve terminals by combined autoradiography and tryptophan hydroxylase (TPH) 
immunocytochemistry at the electron microscopic level (Cohen et aI., 1995). In addition, [11C]AMT, unlike 
tryptophan, was not incorporated into protein in significant amounts (Madras and Sourkes, 1965; Diksic 
et aI., 1990). These studies demonstrated that [11C]AMT was a suitable tracer for the measurement of 
serotonin synthesis in vivo in humans with PET. 
 
Effect of inhibition of tryptophan hydroxylase (TPH) on AMT trapping. Autoradiographic studies with 
alpha-[14C]methyl-L-tryptophan in rats have demonstrated that trapping of this radiotracer in the brain 
was drastically reduced (by 40-80%) following treatment with p-chlorophenylalanine (PCPA), a TPH 
inhibitor (Tohyama et al., 2002). In contrast, the inhibition of protein synthesis with CXM did not have a 
significant effect on the global brain trapping of AMT and 5-HT synthesis. In another study, the TPH 
activation inhibitor AGN-2979 has led to an up to 35% decrease of AMT trapping in the raphe nuclei 
(Hasegawa et al., 2005). These studies provided proof-of-principle data that measurement of AMT 
trapping may be useful to assess TPH activity in living tissue. 
 
Imaging epileptic foci and human tumors by AMT-PET. Our group at Wayne State University introduced 
the use of [11C]AMT-PET for the detection of epileptogenic lesions (Chugani et al., 1998; Juhasz et al., 
2003; 2004) and a variety of cerebral and extracerebral tumors (Juhasz et al., 2006; 2009; 2012; 2014; 


 
4 
Bosnyak et al., 2015; 2016; 2017). High AMT transport and trapping was detected in cerebral gliomas, 
meningiomas as well as lung cancers and breast cancers, with various tumor types showing differences in 
tryptophan uptake and kinetics. Importantly, increased AMT uptake was commonly detected even in low-
grade gliomas and meningiomas (Juhasz et al., 2006; 2011; Alkonyi et al., 2012; Bosnyak et al., 2015). 
Increased uptake and trapping of AMT in various tumors may have been affected by increased transporter 
activity as well as increased activity of enzymes converting tryptophan to its metabolites. 
 
Tryptophan PET imaging in carcinoid tumors. Most NETs have an overactive serotonin pathway with 
increased TPH activity, thus inducing carcinoid syndrome, a condition associated with tumoral secretion 
of serotonin and clinical symptoms of diarrhea, flushing, bronchial constriction, as well as the 
development of cardiac valvular fibrosis. Diarrhea is one of the most prominent symptoms of carcinoid 
syndrome. Imaging TPH activity in vivo by PET would be useful to visualize these tumors and evaluate 
baseline TPH enzyme activity as well as monitor efficacy of TPH inhibitor drugs. Although AMT-PET has 
not been tested in carcinoid tumors, studies with other amino acid PET radiotracers, including a 
tryptophan derivative (11C-5-hydroxy-tryptophan) demonstrated high sensitivity to detect carcinoid 
tumors as small as 5mm in diameter (Koopmans et al., 2008). Highest sensitivities (81-92%) were achieved 
in lesions located in bone, abdomen/pelvis, liver, head and neck regions. These data make it likely that 
AMT-PET will be able to detect carcinoid tumors in various locations, and it is reasonable to assume that 
its uptake and kinetic properties will be modulated by changes in tumoral TPH activity. 
 
Serotonin and cancer proliferation. Many studies have demonstrated that serotonin may a play an 
important role in tumor growth and vascularity of breast, prostate, and many other tumor types (Siddiqui 
et al., 2006; Sonier et al., 2006; Dizeyi et al., 2011; Sarrouilhe et al., 2015). At high levels serotonin may 
promote tumor proliferation, while at lower levels it may even inhibit growth, in part from decreasing 
tumor blood supply. This is evident in studies using a number of serotonin receptor agonists and 
antagonists, which have stimulated or inhibited growth depending on the concentration.  
 
Telotristat ethyl is an oral small-molecule TPH inhibitor that has a high molecular weight and acidic 
moieties, which inhibit it from crossing the blood-brain barrier (Liu et al., 2008; Lapuerta et al., 2015). As 
the drug has recently become available for clinical treatment of carcinoid-related diarrhea, there is an 
urgent need to evaluate non-invasive techniques to assess drug effects. 
 
Telotristat ethyl has been shown to inhibit tumor growth in a retrospective study of 200 patients with 
NET (Morse et al., 2020).  After initiation of telotristat ethyl they observed a mean decrease of 0.6 cm in 
tumor size (p = 0.006) and decrease in tumor growth (p = 0.045). It will be of interest to determine using 
AMT-PET if we can measure inhibition of serotonin synthesis and serve as a biomarker in studies assess 
this activity of this pathway. The use of telotristat ethyl may inhibit tumor proliferation and the image of 
AMT uptake may provide a predictive marker of this effect. If promising, PET imaging with AMT or an 
18F-labeled analog (with a longer half-life) (see, e.g., Michelhaugh et al., 2016; Giglio et al., 2017) could 
be useful to monitor effectiveness of TPH inhibition in future multicenter studies and clinical trials.  
 


 
5 
The central hypothesis of this pilot study is that (i) that telotristat ethyl (Xermelo™) (Kulke et al., 2017), a 
recently FDA-approved TPH inhibitor drug, will decrease tumoral AMT uptake and trapping as compared 
to values measured at baseline before the start of treatment. (ii) carcinoid tumors will show increased 
AMT uptake on PET, as compared to surrounding non-tumor tissue at baseline. 
 
As a first step, in this pilot study we will perform AMT-PET imaging in 6 evaluable patients with previously 
diagnosed mNETs, not previously treated with TPH inhibitor, to characterize the baseline and post-
treatment uptake patterns of these tumors and test the feasibility to use AMT-PET for evaluating activity 
of TPH after inhibitor treatment. 
 
III. PATIENT SELECTION 
 
Inclusion: 
1. Eligible patients must be > 18 years of age. 
2. Histopathologically confirmed, well-differentiated metastatic NETs 
3. Receiving stable-dose somatostatin analog (long-acting release [LAR], depot) for > 3 months 
before enrollment.  
4. Patients with 5-HIAA levels above or below the upper limit of normal range and those with 
unknown values at baseline are allowed to participate.  
5. Able to lie within the PET scanner for at least 70 minutes while undergoing scanning. 
6. ECOG performance status of 2 or better. 
7. Physical exam, CBC and Multiphasic (including electrolytes, BUN, creatinine, total bilirubin, AST, 
and ALT) must be done within 28 days of PET imaging and demonstrate adequate renal and liver 
function. Creatinine ≤ 2.5, total bilirubin ≤ 1.5 x upper limit of normal (ULN). AST and ALT ≤ 2.5 
ULN.  
8. Patient must have a least one lesion greater than 2 cm on standard imaging (CT, MR, octreotide, 
or dotatate imaging within 8 weeks of the start of the study) that is judged amenable to AMT-PET.  
9. Women of child bearing potential must not be pregnant or breastfeeding. A negative urine or 
blood pregnancy test must be obtained in women with child bearing potential. Men and women 
with reproductive potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) on study entry and for the duration of study participation.  
10. Eligible and consent signed for imaging with AMT PET under protocol 2011-053. 
 
Exclusion: 
1. Because of the risk of acute complications from severe diarrhea, patients experiencing more than 
12 watery bowel movements per day associated with volume contraction, dehydration, or 
hypotension, or showing evidence of enteric infection are excluded. 
2. Patients are excluded if they had undergone tumor-directed therapy within 3 months. 
3. Patients cannot be on a targeted agent (e.g., sunitinib or everolimus) or receiving cytotoxic 
chemotherapy (e.g., capecitabine or temozolimide). They can’t be on telotristat ethyl. Previous 
use is acceptable if the patient has been off for over one month. 
 


 
6 
IV. REGISTRATION PROCEDURES  
 
General Guidelines 
Eligible patients will be entered on the study centrally at the clinical trials office of the Karmanos Cancer 
Center/Wayne State University by the study coordinator.  
 
At the time of registration: 
• 
Patients must have signed an informed consent form.  
• 
Confirm that all required prestudy history and physical examination, and laboratory tests have 
been collected.  
• 
Document demographic information including smoking history. Also document medications.  
• 
Patients should be scheduled for pre-treatment AMT-PET scans if patients have provided 
appropriate consent.  
• 
Inform patients about all necessary follow-up including laboratory tests and further PET imaging.  
 
Following registration, patients should begin protocol treatment within 7 days of baseline AMT PET 
imaging. Issues that would cause treatment delays should be discussed with the Principal Investigator, 
Dr. Anthony Shields at 313-576-8735; shieldsa@karmanos.org, or contact the study coordinators. If a 
patient does not receive protocol therapy following registration, the patient’s registration on the study 
may be cancelled. The study coordinator should be notified of cancellations as soon as possible.  
 
Registration Process 
To register a patient, the following documents should be completed by the research nurse or data 
manager and faxed or emailed to the study coordinator: 
• 
Copies of required laboratory tests, scans.  
• 
Signed patient consent form. 
• 
HIPAA authorization form. 
• 
Eligibility checklist. 
• 
Completed registration form. 
 
To complete the registration process, the study coordinator will: 
• 
Register the patient on the study 
 
Off-Study Criteria 
• 
Patients will be considered to have gone off of study following the completion of the second 
AMT-PET scan. They may elect to continue telotristat ethyl therapy under the supervision of 
their physician as part of standard treatment. Cost of continued standard treatment will be 
charged to the patient’s insurance and patient. 
 
 
 


 
7 
V. TREATMENT PLAN 
 
AMT-PET Imaging 
• 
Scan 1: Baseline within 7 days prior to the start of telotristat ethyl treatment. 
• 
Scan 2: On day 9-14 of telotristat ethyl administration. 
• 
Patients cannot eat protein containing foods for 6 hours prior to the AMT-PET studies, to ensure 
stable plasma tryptophan and large neutral amino acid levels during the duration of the study. 
They can have water and soft drinks.  
• 
The final dose of telotristat ethyl on day 9-14 should be taken within 6 hours of the scan and 
should be taken along with high fat foods, but no protein. This may include oils, olives, low 
protein breads with margarine. The choice of such foods will be discussed with the patient at 
the time of enrollment. Note that this dietary restriction only applies for scan 2 since patients 
need to take telotristat ethyl with fat. 
• 
Blood (approximately 3 tsp) will be drawn to measure drug levels and tumor hormone levels 
(including serotonin) in the blood prior to each scan. These will be done by the hospital and 
company laboratories. 
 
Agent Administration 
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks for 
telotristat ethyl are described in Section VI. No investigational or commercial agents or therapies other 
than telotristat ethyl may be administered with the intent to treat the patient’s malignancy other than 
somatostatin analog (long-acting release [LAR], depot.  
 
Agent 
Dose 
Route 
Schedule 
Telotristat 
ethyl 
250 mg 
Oral 
Three times daily for 9-14 days prior to the second scan, with 
one dose or two doses depending on the time of Scan 2.* 
 
*Patients may elect to stay on telotristat ethyl (250 mg tid) indefinitely following the completion Scan 2 
if it is considered to provide benefit by their treating physician as part of the standard of care. As part of 
the study the patient will received 28 days of drug and may continue to use it and then obtain standard 
treatment on the agent if desired by the patient and their physician.  
 
Benefits: 
Telotristat ethyl (250 mg tid) daily compared to placebo has been shown to improve cancer related 
diarrhea (Kulke et al., 2017) and may slow tumor growth (Morse et al., 2020). 
 
VI. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
This study will use the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE can be 


 
8 
downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
 
Reporting Adverse Events 
In the unlikely event that any immediate toxicity is found during the course of treatment, it will be 
recorded and reported as described below. Given the dose of drug, no measurable delayed toxicity is 
expected.  
 
Reaction 
Reporting Obligation for A, B, and 
C 
A. All life-threatening events (Grade 4), which may be due to 
drug 
Within 24 hours (note 1) 
B. All fatal events (Grade 5) while on study (or within 24 hours
of treatment). 
Written report to follow within 10 
working days (note 1). 
C. First occurrence of any previously  unknown clinical event 
(regardless of grade). 
(Note 2 and 3) 
 
 
• 
Note 1:  Telephone number available 24 hours daily: A. Shields page 313-745-5111 beeper  
 
1049, (313)-576-8770 (Recorder after hours). Also may report to  
 
 
 
SAE@Karmanos.org and ShieldsA@karmanos.org  
• 
Note 2:  A list of all known toxicities can be found in the protocol document or consent form. 
• 
Note 3: Reactions judged definitely not treatment-related should not be reported.  
• 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded on the Adverse Event Case Report Form and followed as 
appropriate. An adverse event is any undesirable sign, symptom or medical condition occurring 
after starting even if the event is not considered to be related.  
• 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment (any procedures specified in the 
protocol).  
• 
Any serious adverse event occurring after the patient has provided informed consent and until 4 
weeks after the second scan of must be reported. 
• 
Adverse events occurring before starting study treatment but after signing the informed consent 
form are recorded on the Medical History/Current Medical Conditions Case Report Form.  
• 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms or require therapy, and are recorded on the Adverse Events Case Report 
Form under the signs, symptoms or diagnosis associated with them.  
 
Adverse Event (AE) Characteristics  
Serious adverse events  
A serious adverse event is an undesirable sign, symptom or medical condition which:  


 
9 
1. Is fatal or life-threatening.  
2. Required or prolonged hospitalization  
3. Results in persistent or significant disability/incapacity  
4. Constitutes a congenital anomaly or a birth defect  
5. Are medically significant, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above  
 
Not considered to be serious adverse events are hospitalizations for the:  
1. Routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition.  
2. Treatment, which was elective or pre-planned, for a pre-existing condition that did not worsen  
3. treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of 
serious given above and not resulting in hospital admission 
  
Commonly Reported Side Effects of telotristat ethyl 
 From the package insert. 
• 
nausea 13%,  
• 
headache 11% 
• 
increased liver function test (GGT) 9%, possibly indicating liver damage 
• 
depression 9% 
• 
peripheral edema (leg swelling) 7% 
• 
flatulence 7% 
• 
decreased appetite 7% 
• 
fever 7% 
 
In another placebo-controlled clinical trial of patients with carcinoid syndrome diarrhea and less than 4 
bowel movements per day, the following additional adverse reactions, not listed above, of abdominal 
pain (including upper and lower abdominal pain, abdominal distention and gastrointestinal pain) and 
constipation were reported in at least 5% of patients in the telotristat ethyl treated group and at an 
incidence greater than placebo. Discontinue telotristat ethyl if severe constipation or severe persistent 
or worsening abdominal pain develops  
 
Less Common Adverse Reactions:  
The following is a list of adverse reactions occurring in less than 5% of patients receiving telotristat ethyl 
during the 12-week placebo-controlled period of the clinical trial:  
 
Investigations: increased alkaline phosphatase, increased alanine aminotransferase, and increased 
aspartate aminotransferase.  
 
Fecaloma was reported in one patient treated with telotristat ethyl during the 36-week open-label 
extension period following the 12-week double-blind period of the trial.  


 
10 
‘Attribution’ of the AE will be defined by the investigative team  
• 
Definite – The AE is clearly related to the study treatment  
• 
Probable – The AE is likely related to the study treatment  
• 
Possible – The AE may be related to the study treatment  
• 
Unlikely – The AE is doubtfully related to the study treatment  
• 
Unrelated – The AE is clearly NOT related to the study treatment  
 
VII. MEASUREMENT OF EFFECT: AMT PET SCAN ACQUISTION AND ANALYSIS  
 
Baseline AMT-PET scan will be obtained within 7 days of the start of telotristat ethyl 250 mg po tid and 
then again 9-14 days after the start of treatment under protocol 2011-053 as described below. 
 
PET imaging will be performed using a GE Discovery STE PET/CT system (GE Medical Systems, Milwaukee, 
WI), located at the PET Center, Children’s Hospital of Michigan. Patients will be imaged in a supine (on 
their back) position on a PET/CT scanner in a high-sensitivity mode.  
 
Patients cannot eat protein containing foods for 6 hours prior to the AMT-PET studies, to ensure stable 
plasma tryptophan and large neutral amino acid levels during the duration of the study. The final dose of 
telotristat ethyl should be taken within 6 hours of the scan and should be taken along with high fat foods, 
but no protein (as described in the Treatment Plan). 
 
A venous line will be established for injection of AMT tracer (0.1 mci/kg). All PET images will be corrected 
for attenuation using the CT scan. After injection a CT scan is performed, immediately followed by a 60-
minute dynamic PET scan of the area of interest that includes the tumor. The total dose for the PET/CT 
scan will be in compliance with guidelines for research studies prescribed by the Code of Federal 
Regulation.  
 
Quantitative assessment of AMT tumor uptake. The AMT uptake in ROIs representing tumor and non-
tumor tissue will be characterized in the following two ways: 
 
1. Standardized uptake values (SUVs): The SUV calculation relates tracer concentration in tissue to the 
dose injected and the subject's mass (SUV = tissue concentration in ROI /injected dose per weight). First, 
decay-corrected time-activity curves will be generated to evaluate the tumoral accumulation and wash-
out of the tracer during the scanning period. Since all subjects receive the same injected dose based upon 
weight (0.1 mCi/kg), the SUV images will be directly obtained by averaging values from frames of the 
dynamic image sequence during which time there is the most metabolic product. The timing of these 
frames will be determined after examination of the time-activity curves to identify the optimal time frame 
when tracer uptake reaches a plateau. The Standard Uptake Value maximum (SUVmax) will measure the 
most active pixel in the tumor and the two adjacent planes. Change in SUVmax will serve as the primary 
aim. Regions of Interest (ROIs) for the SUVmean will be drawn using isocontours set at 50% of the SUVmax. 
Results will be indicated as percent change in the uptake between the two scans.  


 
11 
2. Compartmental modeling (in tumors with the left ventricle of the heart in the field-of-view). In addition 
to the semi-quantitative SUV analysis, in tumors where the left ventricle of the heart is in the field-of-
view, we will also assess the data with tracer kinetic analysis using a 3-compartment model, as described 
in our previous studies in lung and breast tumors (Juhasz et al., 2009; 2012). This analysis will allow a more 
detailed analysis of tumoral tracer transport and trapping parameters at baseline and their changes after 
TPH inhibitor treatment. 
 
 3. Primary endpoint and secondary endpoints:  
The proportion of patients who achieved SUVmax reduction of 20% or more between baseline and follow-
up will be the primary measurement. We will also assess if the NET is visible above background at baseline 
and will also quantify the percent difference in AMT uptake between the tumor mass and background. In 
addition, using time-activity curves, we will also identify the optimal time frame where tumoral AMT 
uptake peaks. The change in SUVmean will also be measured. 
 
VIII. STATISTICAL PLAN  
 
Design This is a single arm single institution prospective proof-of-concept study. Primary endpoint is the 
proportion of patients who achieved SUVs reduction of 20% or more. The primary endpoint will be 
reported with a one-sided, 90% confidence limit. The other categorical endpoints will be reported as 
proportions with two-sided exact 95% confidence intervals. All continuous endpoints will be reported with 
mean and standard deviation. Paired t test will be used for pre- and post- treatment SUVs if normality 
assumption holds. The relationship of one PET parameter to another will be visualized with scatter plot 
and measured using linear regression models. Statistical analysis will be performed using R version 3.3.2. 
Power calculation: This is a Proof-of-Concept trial where the goal is to demonstrate the feasibility and to 
show the proportion of patients who achieved SUVs reduction is at least 0.2 or higher. Hence, we will 
calculate the minimum sample size to achieve a confidence lower limit no less than 0.2. A sample size of 
6 produces a one-sided 90% lower-limit confidence interval at (0.201, 1) using Clopper-Pearson formula 
when the expected proportion is 0.5. Study Duration: The accrual rate is 6/year and minimum follow -up 
for each patient will be 3 months. The study will require 15-18 months to complete. 
 
IX. DATA AND SAFETY MONITORING/STUDY AUDITS/STUDY ETHICS  
 
Data and Safety Monitoring 
1. Scheduled meetings will be held monthly or more frequently depending on the activity of the 
protocol. These meetings will include the protocol investigators and research staff involved with 
the conduct of the protocol. 
2. During these meetings the investigators will discuss: 
• 
Safety of protocol participants (adverse events and reporting) 
• 
Validity and integrity of the data (data completeness on case report forms and complete 
source documentation) 


 
12 
• 
Enrollment rate relative to expectation of target accrual, (eligible and ineligible 
participants) 
• 
Retention of participants, adherence to the protocol and protocol deviations 
• 
  Protocol amendments 
3. Data and Safety Monitoring Reports (DSMR) of the research meetings will be completed by the 
Study Coordinator and submitted to the Data and Safety Monitoring Committee quarterly for 
review.  
4. The Barbara Ann Karmanos Cancer Institute, Data and Safety Monitoring Committee (DSMC) 
provide the primary oversight of data and safety monitoring for KCI Investigator-initiated trials.  
 
 
Data Management 
Study data including patient images and blood sample results will be maintained by the Shields’ 
laboratory. In addition, a KCI CTO monitor specialist will remotely review the clinical trial data. 
Frequency of monitoring will be based on accrual but will occur at least once every 2 months if a patient 
has been enrolled. Monthly screening and enrollment logs will be sent to the KCI lead Study 
Coordinator.  
  
 
 
Study Audits 
Authorized representatives of FDA, a regulatory authority or Wayne State University Institutional Review 
Board (IRB) may visit the center to perform audits or inspections, including source data verification. The 
investigator should contact Clinical Trials Office immediately if contacted by a regulatory agency about 
an inspection at his center regarding this study. 
 
Ethics  
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable regulatory 
requirements.  
 
The final study protocol, including the final version of the Written Informed Consent Form, must be 
approved in writing by Wayne State University IRB. 
 
The principal investigator is responsible for informing the Wayne State University IRB of any 
amendments to the protocol. The protocol must be re-approved by the IRB annually. Progress reports 
and notifications of serious, unexpected adverse drug reactions will be provided to the IRB. The Principal 
Investigator is also responsible for providing the IRB with reports of any serious adverse drug reactions 
from any other study conducted with the investigational product.  
 
The principal investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Subjects must also be 
notified that they are free to discontinue from the study at any time. The subject should be given the 
opportunity to ask questions and allowed time to consider the information provided. In accordance with 


 
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the Health Information Portability and Accountability Act (HIPAA), the Written Informed Consent Form 
must include a subject authorization to release medical information to Karmanos Cancer Institute, 
Wayne State University, the Detroit Medical Center, University Physician Group, or McLaren Health Care 
or Institutional Review Board access to subject’s medical information that includes all hospital records 
relevant to the study, including subjects’ medical history. 
 
The principal investigator must store the original, signed written informed consent form. A copy of the 
signed written informed consent form must be given to the subject. 
 
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