A Phase I Trial of Triapine and Lutetium Lu 177 Dotatate in Combination for Well-Differentiated Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
Phase: PHASE1
Conditions: Metastatic Digestive System Neuroendocrine Neoplasm, Metastatic Neuroendocrine Tumor
Sponsor: National Cancer Institute (NCI)



NCI Protocol #:  10388 
Version Date:  17.May.2023 
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NCI Protocol #: 
10388 
 
Local Protocol #: 
NCI-CIRB-10388-PMC  
 
ClinicalTrials.gov Identifier:  NCT04234568 
 
TITLE:  A Phase I Trial of Triapine and Lutetium Lu 177 Dotatate in Combination for Well-
Differentiated Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors 
(GEP-NETs) 
 
Corresponding Organization: LAO-OH007 / Ohio State University Comprehensive Cancer 
Center LAO 
 
Principal Investigator:               Susanne Arnold, MD 
University of Kentucky 
800 Rose Street, CC445 
Ben Roach Bldg., Markey Cancer Center 
Lexington, KY 40536 
Telephone:859-323-8043   
Fax:  859-257-7715 
susanne.arnold@uky.edu 
 
Co-Principal Investigator: 
Aman Chauhan, M.D. 
                                                      dramanchauhan@gmail.com 
 
Translational PI: 
Jill Kolesar, PharmD  
  
University of Kentucky 
789 S. Limestone St. 
Lexington, Kentucky 40508 
Telephone:  859-323-4978 
jill.kolesar@uky.edu  
 
Participating Organizations:  Participating sites should have a track record of administering 
Lutetium Lu 177 dotatate and have required nuclear medicine logistical support. 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber – Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 

NCI Protocol #: 10388 
Version Date: 17.May.2023 
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Statistician: 
Co-Investigator, Interventional Radiology:  
      Heidi L. Weiss, Ph.D. 
Gaby E. Gabriel, M.D. 
 
800 Rose Street 
315 Chandler Medical Center 
 
Markey Cancer Center 
University of Kentucky 
 
Lexington, Kentucky 40536 
Lexington, KY 40536 
 
Telephone:  859-323-0577 
Telephone: 859-330-3321 
 
heidi.weiss@uky.edu  
gaby.gabriel@uky.edu 
 
 
 
Study Coordinator: 
 
Responsible Research Nurse: 
      Heather Heath, RN, CCRP 
Jeri Reynolds, RN, BSN, CCRC 
 
800 Rose Street Room 420 
789 South Limestone Street 
 
Markey Cancer Center 
Markey Cancer Center 
 
Lexington, Kentucky 40536 
Lexington, KY 40536 
 
Telephone:  859-323-6720 
Telephone:  859-218-0131 
 
Fax:  859-257-7715 
Fax:  859-257-0100 
 
heather.flynn@uky.edu  
jzreyn0@uky.edu  
 
Responsible Data Manager: 
Responsible Nuclear Medicine Physician: 
      Patrick Maloney 
Riham El Khouli, M.D. 
 
800 Rose Street Room CC420 
800 Rose Street, Hx302 
 
Lexington, KY 40536 
Chandler Hospital, University of Kentucky 
 
Telephone:  859-232-6370 
Telephone:  443-929-1877 
 
Fax:  859-272-7715 
rhel222@uky.edu  
 
Patrick.maloney@uky.edu  
 
Phase 1 Specialist: 
 
NET Specialist: 
 
Susanne Arnold, M.D. 
Lowell Anthony, M.D. 
 
800 Rose Street 
800 Rose Street, CC 454 
 
Lexington, Kentucky 40536 
Lexington, Kentucky 40536 
 
Telephone:  859-323-8043 
Telephone:  859-323-8043 
 
susanne.arnold@uky.edu  
lowell.anthony@uky.edu  
 
NET Basic Scientist: 
 
Responsible Radiation Oncologist: 
 
Mark Evers, M.D., F.A.C.S. 
Mahesh Kudrimoti 
 
800 Rose Street, CC 140 
800 Rose Street 
 
Lexington, Kentucky 40536 
Lexington, Kentucky 40536 
 
Telephone:  859-323-6556 
Telephone:  859-323-0283 
 
 
mark.evers@uky.edu  
mkudr0@email.uky.edu 
 
 
 
 
 

NCI Protocol #: 10388 
Version Date: 17.May.2023 
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NCI-Supplied Agent:  Triapine (NSC # 663249) 
Commercial Agent:  Lutetium Lu 177 Dotatate (NSC # 815530) 
 
 
IND #:   
 
IND Sponsor:  DCTD, NCI 
 
 
Protocol Type / Version # / Version Date: Original / October 30, 2019 
 
 
 
 
      Revision 1 / December 20, 2019 
 
 
 
      Revision 2a / February 14, 2020 
 
 
 
      Revision 3 / March 10, 2020 
 
 
 
      Revision 4 [ aka Amendment 1/ July 30, 2020 
 
 
 
      Revision 5 [aka Amendment 2] / October 14, 2020 
 
 
 
      Revision 6 [aka Amendment 3]/ January 6, 2021 
 
 
 
      Revision 7 [aka Amendment 4] / April 8, 2021 
 
 
 
      Revision 8 [aka Amendment 5] / June 16, 2021 
 
 
 
      Revision 9 [aka Amendment 6] / July 6, 2021 
                                                                        Revision 10 [aka Amendment 7] / December 7, 2021 
 
 
 
      Revision 11 [aka Amendment 8] / July 19, 2022 
                                                                        Revision 12 [aka Amendment 9] / Sept 29, 2022 
                                                                        Revision 13 [aka Amendment 10] /  Dec 14, 2022 
Revision 14 [aka Amendment 11] /  May 3, 2023 * 
           *CTEP disapproved the A 11 submission pvd 03MAY2023 
Revision 15 [aka Amendment 12] /  May 17, 2023 
 

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TABLE OF CONTENTS 
 
SCHEMA 
4 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives ...................................................................................................8 
1.2 
Secondary Objectives ...............................................................................................8 
1.3 
Correlative Objectives .............................................................................................8 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Study Disease ...........................................................................................................9 
2.2 
Triapine, CTEP IND Agent ...................................................................................10 
2.3 
Lutetium Lu 177 Dotatate ......................................................................................11 
2.4 
Rationale ................................................................................................................12 
2.5 
Correlative Studies Background ............................................................................13 
3. 
PATIENT SELECTION ....................................................................................................16 
3.1 
Eligibility Criteria ..................................................................................................16 
3.2 
Exclusion Criteria ..................................................................................................18 
3.3 
Inclusion of Women and Minorities ......................................................................19 
4. 
REGISTRATION PROCEDURES ...................................................................................20 
4.1 
Investigator and Research Associate Registration with CTEP ..............................20 
4.2 
Site Registration .....................................................................................................21 
4.3 
Patient Registration ................................................................................................24 
4.4 
General Guidelines .................................................................................................26 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................27 
5.1 
Summary Table for Specimen Collection ..............................................................27 
5.2 
Summary Table for Interventional Radiologist for Research Biopsies .................29 
5.3 
Specimen Procurement Kits and Scheduling .........................................................29 
5.4 
Specimen Tracking System Instructions ................................................................30 
5.5 
Specimen Collection ..............................................................................................34 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank ................................36 
5.7 
Shipping of Specimens from Clinical Site to Other Laboratories .........................40 
5.8 
Biomarker Plan ......................................................................................................43 
5.9 
Integrated Correlative Studies ................................................................................45 
5.10 
Exploratory/Ancillary Correlative Studies ............................................................46 
5.11 
Special Studies .......................................................................................................48 
6. 
TREATMENT PLAN ........................................................................................................49 
6.1 
Agent Administration in Dose Escalation Phase ...................................................49 
6.2 
Definition of Dose-Limiting Toxicity ....................................................................52 
6.3 
Triapine Administration: Dose Expansion Cohort ................................................52 
6.4 
General Concomitant Medication and Supportive Care Guidelines ......................53 
6.5 
Duration of Therapy ...............................................................................................54 

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6.6 
Duration of Follow-Up ..........................................................................................55 
7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................56 
7.1 
Recommended Dose Modifications of Lutetium Lu 177 Dotatate for 
Adverse Reactions .................................................................................................56 
7.2 
Recommended Dose Modifications of Triapine ....................................................57 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................60 
8.1 
CTEP IND Agent - Triapine ..................................................................................60 
8.2 
Commercial Agent - Lutetium Lu 177 Dotatate (NSC 815530)............................62 
9. 
STATISTICAL CONSIDERATIONS...............................................................................64 
9.1 
Study Design/Endpoints.........................................................................................64 
9.2 
Sample Size/Accrual Rate ......................................................................................65 
9.3 
Stratification Factors ..............................................................................................66 
9.4 
Results of Phase 1: RP2D for the Dose Expansion Cohort ...................................66 
9.5 
Analysis of Secondary and Correlative Endpoints ................................................67 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................68 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPR) ...................68 
10.2 
Adverse Event Characteristics ...............................................................................73 
10.3 
Expedited Adverse Event Reporting ......................................................................74 
10.4 
Routine Adverse Event Reporting .........................................................................77 
10.5 
Pregnancy ...............................................................................................................77 
10.6 
Secondary Malignancy ...........................................................................................77 
10.7 
Second Malignancy ................................................................................................77 
11. STUDY CALENDAR .......................................................................................................78 
12. MEASUREMENT OF EFFECT........................................................................................83 
12.1 
Antitumor Effect – Solid Tumors ..........................................................................83 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................89 
13.1 
Study Oversight .....................................................................................................89 
13.2 
Data Reporting .......................................................................................................89 
13.3 
Data Quality Portal ................................................................................................92 
13.4 
CTEP Multicenter Guidelines ................................................................................92 
13.5 
Collaborative Agreements Language .....................................................................92 
14. REFERENCES ..................................................................................................................95 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ....................................................99 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING SERUM 
CREATININE..................................................................................................................100 
APPENDIX C 
PATIENT CLINICAL TRIAL WALLET CARD ....................................101 

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APPENDIX D 
PATIENT’S MEDICATION DIARY – ONCE DAILY (QD) .................102 
APPENDIX E 
PRE-BIOPSY ASSESSMENT ..................................................................103 
APPENDIX F 
PHARMACOKINETICS (PK) SHEET CYCLE 1, DAY 9 .....................104 
APPENDIX G 
IMAGE ACQUISITION AND ANALYSIS .............................................105 
APPENDIX H 
TISSUE BIOPSY VERIFICATION ......................................................109 
 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To evaluate the safety and to determine the recommended phase 2 dose (RP2D) of 
Lutetium Lu 177 Dotatate in combination with triapine. 
 
1.2 
Secondary Objectives 
 
1.2.1 To observe and record anti-tumor activity.  Although the clinical benefit of this 
combination has not yet been established, the intent of offering this treatment is to 
provide a possible therapeutic benefit, and thus the patient will be carefully monitored for 
tumor response and symptom relief in addition to safety and tolerability. 
 
1.2.2 To determine the overall response rate (ORR) by Response Evaluation Criteria In Solid 
Tumors (RECIST) 1.1 at 2, 4, 6, and 8 months post therapy in dose escalation cohort. 
 
1.2.3 To determine the Best overall response rate (ORR) by Response Evaluation Criteria In 
Solid Tumors (RECIST) 1.1 in dose expansion cohort.  
 
1.2.4 To measure duration of response (DOR) associated with the combination. 
 
1.2.5 To evaluate progression-free survival (PFS), 24-month PFS, and overall survival (OS). 
 
1.3 
Correlative Objectives 
 
1.3.1 Measure baseline 68gallium-dotatate (or Copper 64 dotatate) biodistribution. 
 
1.3.2 Evaluate oral triapine plasma pharmacokinetics and corresponding methemoglobin level 
by venous blood gas proportion. 
 
1.3.3 Collect blood at baseline and at disease progression to correlate result with clinical 
outcome. [NOTE: originally this blood was collected to analyze hPG80 but will now the 
frozen blood samples will be biobanked for future correlative analysis]  
 
1.3.4 Describe the tumor molecular profile using whole exome sequencing (WES), as well as 
RNAseq by the National Clinical Laboratory Network (NCLN), and correlate it with 
treatment outcome. 
 
1.3.5 Collect plasma for circulating DNA (ctDNA) assessment. 
 
1.3.6 Assess the effect of triapine on single deoxyribonucleoside concentrations by an 
LC/MSMS assay in baseline (pre-treatment) and disease progression blood samples 
(processed to plasma).  

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2. 
BACKGROUND 
 
2.1 
Study Disease 
 
Neuroendocrine tumors (NETs) are rare neoplasms which can arise anywhere in the body (Dasari 
et al., 2017).  However, a recent review of the Surveillance, Epidemiology, and End Results 
(SEER) database confirms a six-fold overall increase in the incidence of NETs (Figure 2).  Due to 
the indolent nature of NETs, the prevalence is disproportionate to the incidence.  Per the North 
American Neuroendocrine Society (NANETS.org) it is estimated that there are over 150,000 
gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients in the US.  In 2018, we 
published incidence rates of GEP-NETs in Kentucky and found that the incidence is higher than 
national average at 10 per 100,000 patients (Chauhan et al., 2018).  Despite the development of 
several effective targeted therapies, including everolimus and sunitinib, resistant disease is 
common and treatment options remain limited.  Peptide receptor radionuclide therapy using 
Lutetium Lu 177 Dotatate has recently been approved by the Food and Drug Administration (FDA) 
for metastatic, progressive GEP-NETs.  Despite an impressive PFS advantage over the control 
group, about 20% of patients do not respond to peptide receptor radionuclide therapy (Strosberg 
et al., 2017).  Moreover, 29-39% of patients who initially show objective radiological responses 
will eventually progress after peptide receptor radionuclide therapy treatment (Bodei et al., 2011; 
Brabander et al., 2017; van der Zwan et al., 2019).  Thus, there is an unmet medical need for the 
management of NET patients who have progressed on peptide receptor radionuclide therapy.  
 
 
Figure 2:  Increasing incidence of NETs in the US (Dasari et al., 2017). 
 
 
 

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2.2 
Triapine, CTEP IND Agent 
 
Triapine is a ribonucleotide reductase (RNR) inhibitor (Investigator’s Brochure, 2018).  RNR is 
an enzyme that is responsible for the reduction of ribonucleotides to deoxyribonucleotides in the 
biosynthesis of DNA.  This reduction process is a rate-limiting step due to the extremely low levels 
of deoxyribonucleotides in mammalian cells.  A direct relationship between tumor growth rate and 
specific RNR activity has been established.  RNR potentiates antitumor activity of DNA-damaging 
agents by inhibiting DNA repair by cheating the active site iron and thus inhibiting tyrosine free 
radical generation at the RNR active site.  Accordingly, an inhibitor of RNR is expected to be 
effective in treating cancer. 
 
Mammalian RNR is at least a heterodimer (α2, β2) consisting of two subunits, but higher order 
forms exist in humans (α2, β6 or α6, β6) (Investigator’s Brochure, 2018).  The M1 subunit contains 
the nucleotide binding site and the M2 subunit contains the metal binding site.  The M1-affecting 
RNR inhibitors are nucleoside analogs, several of which are currently under clinical development.  
One analog has recently been approved for the treatment of pancreatic cancer (i.e., gemcitabine).  
The M2 subunit contains non-heme iron and a tyrosine free radical, which are required for the 
enzymatic reduction of ribonucleotides.  Inhibitors of the M2 subunit act by destroying the free 
radical.  In the case of hydroxyurea (HU), which is the only clinically approved RNR inhibitor 
acting at the iron/free radical site (M2), the inhibition is reversible due to the ease in regenerating 
the tyrosine free radical by mammalian cells. 
 
Triapine is available in both intravenous (IV) and capsule formulations.  While the clinical activity 
of IV triapine in combination with standard chemoradiation therapy appears to be promising, it is 
quite time-intensive to perform a 2-hour infusion 3 times a week.  Additionally, the PK data from 
IV triapine indicated that peak serum concentrations occur 1-2 hours after a 2-hour infusion, 
suggesting only a potential transient therapeutic benefit.  It is conceivable, therefore, that daily 
dosing of triapine may yield greater clinical benefit.  Recently, a phase 1 trial evaluated single-
agent oral (PO) triapine in patients with a wide range of advanced solid tumors, enrolling 20 
patients (Chao et al., 2012).  Treatment consisted of 100 mg IV triapine on Day -7 with blood 
samples drawn over 8 hours to determine PK.  PO triapine was then administered every 12 hours 
for 5 consecutive doses on Days 1-3, 8-10, and 15-17 of an every 28-day cycle.  Triapine was 
initially dosed at 50 mg every 12 hours and then increased to dose levels of 100, 150, and 200 mg 
every 12 hours.  On this trial, grade 3 / 4 adverse events  were uncommon at the 50 mg (1 
hypertensive episode) and at the 100 mg (1 anemia) dose levels.  Three patients experienced (38%) 
grade 3 or 4 neutropenia at the 150 mg dose level.  At the 200 mg dose level, two grade 3-4 hypoxia 
events were reported; grade 3-4 anemia, neutropenia, thrombocytopenia, infection, fatigue, hepatic 
enzyme elevation, and anorexia adverse events were observed in one patient each.  The RP2D was 
150 mg every 12 hours for five consecutive doses on Days 1-3, 8-10, and 15-17 of each 28-day 
cycle.  Ultimately, 8 patients were treated at the 150 mg dose level with 1 dose limiting toxicity 
(DLT) observed.  PK analysis suggested that the 150 mg dose achieved a minimum inhibitory 
concentration of RNR for six hours, which is similar to what is observed with IV dosing.  In 
addition, the PK data suggested that the population average bioavailability of triapine was 
approximately 55-70%. 
 

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2.3 
Lutetium Lu 177 Dotatate 
 
Lutetium Lu 177 Dotatate binds to somatostatin receptors with highest affinity for subtype 2 
receptors (SSTR2) (Package Insert, 2018).  Upon binding to SSTR expressing cells, including 
malignant SSTR-positive tumors, the compound is internalized.  The beta emission from Lu 177 
induces cellular damage by formation of free radicals in SSTR-positive cells and in neighboring 
cells. 
 
The PK of Lutetium Lu 177 Dotatate have been characterized in patients with progressive, SSTR-
positive NETs (Package Insert, 2018).  The mean blood exposure (area under the concentration-
time curve [AUC]) of Lutetium Lu 177 Dotatate at the recommended dose is 41 ng.h/mL 
(coefficient of variation [CV] 36 %).  The mean maximum blood concentration (Cmax) for Lutetium 
Lu 177 Dotatate is 10 ng/mL (CV 50%), which generally occurred at the end of the Lutetium Lu 
177 Dotatate infusion.  The mean volume of distribution for Lutetium Lu 177 Dotatate is 460 L 
(CV 54%). 
 
Within 4 hours after administration, Lutetium Lu 177 Dotatate distributes in kidneys, tumor 
lesions, liver, spleen, and, in some patients, pituitary gland and thyroid (Package Insert, 2018).  
The co-administration of amino acids reduced the median radiation dose to the kidneys by 47% 
(34% to 59%) and increased the mean beta-phase blood clearance of Lutetium Lu 177 Dotatate by 
36%.  The non-radioactive form of lutetium dotatate is 43% bound to human plasma proteins.  The 
mean clearance (CL) is 4.5 L/h (CV 31%) for Lutetium Lu 177 Dotatate.  The mean (± standard 
deviation) effective blood elimination half-life is 3.5 (±1.4) hours and the mean terminal blood 
half-life is 71 (±28) hours.  Lutetium Lu 177 Dotatate does not undergo hepatic metabolism.  
 
Lutetium Lu 177 Dotatate is primarily eliminated renally with cumulative excretion of 44% within 
5 hours, 58% within 24 hours, and 65% within 48 hours following Lutetium Lu 177 Dotatate 
administration (Package Insert, 2018).  Prolonged elimination of Lutetium Lu 177 Dotatate in the 
urine is expected; however, based on the half-life of Lutetium Lu 177 D and terminal half-life of 
Lutetium Lu 177 Dotatate, greater than 99% will be eliminated within 14 days after administration 
of Lutetium Lu 177 Dotatate. 
 
The efficacy of Lutetium Lu 177 Dotatate in patients with foregut, midgut, and hindgut GEP-NETs 
was assessed in 360 patients in the ERASMUS study (Package Insert, 2018).  In ERASMUS, 
Lutetium Lu 177 Dotatate was initially provided as expanded access under a general peptide 
receptor radionuclide therapy protocol at a single site in the Netherlands.  A subsequent Lutetium 
Lu 177 Dotatate-specific protocol written eight years after study initiation did not describe a 
specific sample size or hypothesis testing plan but allowed for retrospective data collection.  A 
total of 1214 patients received Lutetium Lu 177 Dotatate in ERASMUS, of which 601 (50%) were 
assessed per RECIST criteria.  Of the 601 patients evaluated by investigators using RECIST 
criteria, 360 (60%) had GEP-NETs.  Lutetium Lu 177 Dotatate 200 mCi was administered every 
6 to 13 weeks for up to 4 doses concurrently with the recommended amino acid solution.  The 
major efficacy outcome was investigator-assessed ORR.  The median age in the efficacy subset 
was 61 years (25 to 88 years), 52% were male, 61% had a baseline Karnofsky performance status 
≥90 (60 to 100), 60% had progressed within 12 months of treatment, and 15% had received prior 
chemotherapy.  Fifty five percent of patients received a concomitant somatostatin analog.  The 
median dose of Lutetium Lu 177 Dotatate was 800 mCi.  Baseline tumor assessments were 

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obtained in 39% of patients.  The investigator assessed ORR was 16% (95% CI 13, 20) in the 360 
patients with GEP-NETs.  Three complete responses (CRs) were observed (<1%).  Median DOR 
in the 58 responding patients was 35 months (95% CI: 17, 38). 
 
 
2.4 
Rationale 
 
NETs are a very heterogeneous group of tumors that develop predominantly in the gastrointestinal 
and pulmonary systems (Dasari et al., 2017).  Clinical detection and diagnosis occur more 
frequently at late stages when metastatic spread has occurred.  Patients with advanced disease may 
suffer from complications of uncontrolled hormone secretion and usually succumb due to tumor 
progression.  Patients with advanced NETs have a median survival of 33 months (Kwekkeboom 
et al., 2008).  Conventional therapies such as radiation and chemotherapy are not effective in NET 
and first-line systemic therapy usually consists of a somatostatin analogue for the control of both 
hormonal secretion and tumor growth (Kvols et al., 1986; Rinke et al., 2009; Caplin et al., 2014).  
With the exception of everolimus and Lutetium Lu 177 Dotatate for the treatment of nonfunctional 
NETs (Yao et al., 2016), no standard second-line systemic treatment options are currently FDA 
approved.  Radiolabeled somatostatin analogues provide a means of delivering targeted radiation 
with a high therapeutic index to NETs that express SSTRs.  This targeted form of systemic 
radiotherapy allows for the delivery of radionuclides directly to tumor cells.  Radiolabeled 
somatostatin analogue Lutetium Lu 177 Dotatate is a beta- and gamma-emitting radionuclide (van 
der Zwan et al., 2015).  In a single-group trial of Lutetium Lu 177 Dotatate involving 310 patients 
who had GEP-NETs, CR occurred in 2% of the patients and partial response (PR) in 28% 
(Kwekkeboom et al., 2008).  Despite these initial responses, high relapse rates following Lutetium 
Lu 177 Dotatate radionuclide indicate the urgent requirement for novel radio sensitizing strategies 
(van der Zwan et al., 2015). 
 
Radiation is a potent inducer of DNA double-strand breaks (DSBs) (Begg et al., 2011); targeting 
signaling networks involved in DSB repair is a promising approach for enhancing cellular radio 
sensitivity.  RNR is the rate-limiting enzyme in the synthesis and repair of DNA, and it is directly 
involved in the cellular response to radiation, making RNR-targeted therapy to enhance radiation 
treatment a rational therapeutic strategy.  There is an unmet therapeutic need to improve 
radiological responses during peptide receptor radionuclide therapy-based treatments.  RNR is the 
only enzyme responsible for conversion of ribonucleoside diphosphate to deoxyribonucleotide 
diphosphate (dNDP), the key building blocks for DNA synthesis.  RNR is composed of a 
heterodimeric tetramer comprised of two dimers M1:M2 or M1:M2b.  When RNR is inhibited, the 
supply of dNDPs and deoxyribonucleotide triphosphates (dNTPs) is reduced.  Inhibition of key 
nucleotide precursors for DNA biosynthesis results in a protracted repair of damaged DNA, which 
in turn, enhances the potential cytotoxic effects of chemotherapy and radiation therapy.  As such, 
RNR inhibitors have been developed as potential radiation sensitizers over the past 30 years.  
While the initial data was promising, the older inhibitor compounds had displayed mixed clinical 
effectiveness, and they were associated with significant toxicity.  However, there was sufficient 
proof of concept to suggest that an RNR inhibitor may be efficacious when used in combined 
modality therapy.  Newer RNR inhibitors have increased potency and improved binding 
characteristics, which has significantly renewed interest in their clinical development.  The RNR 
inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP, triapine, NSC # 663249) 
was developed by the Sartorelli laboratory at the Yale Cancer Center, and extensive pre-clinical 
studies have shown this agent to be an equipotent inhibitor of M2b and M2 (Kunos et al., 2010; 

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Kunos et al., 2013).  Kunos et al. have studied triapine in both TP53-mutated and wild type human 
cancer cell lines and have found that inhibition of RNR by triapine enhances radiation-mediated 
cytotoxicity independent of p53 regulation by impairing DNA repair processes that rely on 
deoxyribonucleotide production, thereby substantially increasing the radiation sensitivity of 
human cancers (Kunos et al., 2009).  
 
This study will test the hypothesis that triapine is an effective radiation sensitizer which can be 
safely combined with peptide receptor radionuclide therapy and can improve antitumor activity of 
Lutetium Lu 177 Dotatate.  Ninety-nine percent of radiation is excreted by Day 14 after Lutetium 
Lu 177 Dotatate administration.  Since most of the DNA damage from Lutetium Lu 177 Dotatate 
happens in the first 7-14 days, 14 days of triapine administration should be adequate treatment as 
a radiation sensitizer. 
 
 
2.5 
Correlative Studies Background 
 
2.5.1 Integrated Correlative Studies 
 
2.5.1.1 
Whole Exome Sequencing (WES) 
 
Biological rationale:  Molecular and genomic characterization of NETs is still in its infancy.  
Recently some studies have looked into WES of NETs however limited sample size often restricts 
interpretation of these results.  Moreover, validation of mutation pattern needs to come from a 
different geographical pool of patient population.  Our study will add to the limited data on NET 
WES and will explore potential targetable mutations.  
 
Hypothesis:  To explore potential targetable mutations and hypothesis generating mutational 
biomarkers of response.  
 
Preclinical and clinical data:  Some of the prevalent genomic alterations in seen in pancreatic NETs 
(PNETs) include MEN1 (43%), DAXX (28%), ATRX (11%), TSC2 (6%), and PTEN (5%) (Yao et 
al., 2019).  Data on genomic alteration of small bowel NETs is less robust as compared to PNETs.  
However, it seems that a marked intra-tumoral genetic heterogeneity exists in small bowel NETs, 
but mutational pattern seems to be concordant between primary site and metastatic site (Walter et 
al., 2018). 
 
2.5.1.2 
Triapine Pharmacokinetics 
 
Biological rationale:  Triapine, an α-heterocyclic carboxaldehyde thiosemicarbazone (HCT), is a 
RNR inhibitor that acts on the M2 (R2) subunit.  Triapine has never been combined with Lutetium 
Lu 177 Dotatate radionuclide.  Based on the metabolism and mechanism of elimination of both study 
drugs, we do not anticipate that the combination would result in alterations in individual drug 
pharmacokinetics nor heightened toxicities.  Triapine has a direct toxicity of generating higher 
circulating blood levels of methemoglobin, and so, methemoglobin levels by venous blood gas 
proportion are obtained to monitor this adverse event after oral triapine administration. 
Hypothesis:  The PK of PO triapine can be appropriately documented and concentrations comparable 
with previous reports can be achieved with this new formulation when administered concurrently with 
Lutetium Lu 177 Dotatate. 
Preclinical and clinical data:  Currently no preclinical or clinical data exist pertaining to the 

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14 
combination of triapine and Lutetium Lu 177 Dotatate.  
 
2.5.1.3 
Methemoglobin Determination 
 
Previous studies of triapine have shown methemoglobinemia as a potential side-effect. 
Therefore, we will perform studies to monitor the percentage of methemoglobin at the same 
time points for triapine PK, which will allow us to correlate this effect with exposure. 
 
 
2.5.2 Exploratory Correlative Studies 
 
2.5.2.1 
Frozen blood samples for biobanking 
 
NOTE: Originally, blood was collected and frozen on all enrolled patients for 1.3.3 correlative 
endpoint (i.e., hPG80 assay). After the study closed to accrual, it was determined that frozen 
blood is inadequate for hPG80 analysis. Thus, it was decided that these collected samples of 
frozen blood will be biobanked with NCI for future analysis. The text below is retained for 
clarity and transparency of collection of these blood samples underlying original exploratory 
endpoint 1.3.3. Note that in addition to 1.3.3 and this section, the Study Calendar and Section 5 
also retain text/language regarding hPG80, in order to maintain transparency on collection, 
handling and processing of these now-frozen biobanked blood samples. The retention of this 
language should support utilization of these frozen samples in a future analysis).  
 
hPG80 Assay:  
Rationale: Current blood based biomarkers for neuroendocrine neoplasms (NENs) lack both 
sensitivity and specificity. Human circulating progastrin (hPG80) is a novel biomarker that can be 
easily measured in plasma by ELISA. Recent examination of hPG80 in NENs was presented at 
ENETS 2021 and the findings published in Cancers [Chauhan 2022]. Plasma hPG80 was 
quantified from 95 stage IV NEN patients, using DxPG80 technology (ECS Progastrin, 
Switzerland) and compared with hPG80 concentrations in two cohorts of healthy donor controls 
aged 50-80 (n=252) and 18-25 (n=137). Median hPG80 in NENs patients was 5.54 pM compared 
to 1.5 pM for the 50 80 controls and 0.29 pM the 18 25 cohort (p<0.0001). Subgroup analysis 
revealed median hPG80 levels significantly higher than for either control cohort in 
neuroendocrine carcinoma (NEC; n=25) and neuroendocrine tumors (NET; n=70) including the 
small cell lung cancer (SCLC) sub cohort (n=13). Diagnostic accuracy, estimated by AUCs, was 
high for NENs, as well as both sub-groups (NEC/NET) when compared to the younger and older 
control groups. Plasma hPG80 in NENs may be a diagnostic blood biomarker for both low and 
high grade NENs.  Hypothesis:  To prospectively validate the efficacy of plasma hPG80 as a 
diagnostic biomarker in NETs. NOTE: This planned analysis was not conducted, per rationale 
above.  
 
 
2.5.2.2 
RNAseq 
 
Biological rationale:  RNA can be a potential biomarker for tumor characterization.  In this 
exploratory analysis, we would like to evaluate differences in RNA expression between various 
grades of NETs and between PNET and small bowel NETs.  
 

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15 
Hypothesis:  To explore differences in RNA expression of NETs based on the grade and site of 
origin.  
 
Preclinical and clinical data:  There are data which suggest that RNA sequencing can help classify 
NETs and add as a valuable adjunct to morphological classification of NETs (Panarelli, et al., 
2019).  More studies are needed to validate the role of RNA sequencing in characterizing NETs.   
 
 
2.5.2.3 
ctDNA Sequencing 
 
Biological rationale:  The role of ctDNA has grown exponentially in the field of oncology.  ctDNA 
provides an easy avenue to explore not only potential targetable mutations but to also monitor 
disease status.  Studies looking at ctDNA in NETs are extremely limited.  We would like to 
evaluate tumor specific genetic alterations in ctDNA. Our data can help future studies to evaluate 
most prevalent genomic alterations found in ctDNA as biomarker of treatment response.  
 
Hypothesis:  To explore tumor specific genetic alterations in ctDNA   
 
Preclinical and clinical data:  Boons et al. (2018) were first one to detect tumor specific genetic 
alteration in cell free DNA in pancreatic neuroendocrine tumor patients. More recently Starr and 
colleagues looked into circulating tumor DNA in neuroendocrine tumor patients.  Of 27 patients 
evaluated for ctDNA, 19 (70%) were reported to have genomic alterations (Starr et al., 2019).  
Both these studies suggest that ctDNA can be evaluated in metastatic neuroendocrine tumor 
patients. We would like to prospectively validate these smaller studies and generate pilot data to 
support that tumor specific mutation can be detected on ctDNA.  
 
 
 
2.5.3 Imaging Correlative Studies 
 
2.5.3.1 
Gallium-68 dotatate Scan and Copper-64 dotatate (64Cu) scan 
 
Theranostics is a new term that describes the utility of targeting the same biological marker for 
both diagnosis and therapy by radiolabeling it once with a diagnostic radioisotope (gamma or 
positron emitter) and the other time using a therapeutic radioisotope (beta emitter).  The main 
purpose of that is the ability to assess binding and efficiency of the targeted agent prior to 
administration of therapy.  Gallium-68 Dotatate, Copper-64 Dotatate and Lutetium Lu 177 
Dotatate are prominent examples of theranostics.  They share the same biological targeting part, 
Dotatate, which is a SSTR analogue.  A study by Boy et al., investigated correlation between 
maximum standardized uptake value (SUVmax) of lesion on Gallium-68 Dotatoc and SSTR 
expression on normal human tissues.  The study found correlation between SUVmax and SSTR2 
expression in normal human tissues (Boy et al., 2011).  The NETTER clinical trial (Strosberg et 
al., 2017) proved significant survival benefit of Lutetium Lu 177 Dotatate in patients with midgut 
NET, which facilitated its FDA approval.  One of the inclusion criteria for the Lutetium Lu 177 
Dotatate treatment arm was confirmation of SSTR expression on target lesions by 111In-
Octreoscan.  Gallium-68 Dotatate is a PET/CT radiopharmaceutical that binds to SSTRs and has 
widely replaced 111In-Octreoscan in assessment of well differentiated low grade NETs.  
 
The Krenning score was used to evaluate SSTR binding in NETTER trial.  It is based on 
comparing the uptake level of target and nontarget lesions to liver, spleen, and kidneys.  
 

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3.1.3 Patients must have progressive disease based on RECIST Criteria, Version 1.1 evidenced 
with CT scans/MRI obtained within 24 months from enrollment. 
 
3.1.4 Patients must have measurable disease per RECIST 1.1. 
 
3.1.5 No prior exposure to peptide receptor radionuclide therapy. 
 
3.1.6 Recovered from adverse events of previously administered therapeutic agents to Grade 1 
or less toxicity according to CTCAE version 5.0. 
 
3.1.7 Archival tissue no longer than 6 months old should be present, otherwise baseline 
research biopsy is needed for WES. 
 
3.1.8 Age ≥18 years.   
 
Because no dosing or adverse event data are currently available on the use of triapine in 
combination with Lutetium Lu 177 Dotatate in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials.   
 
3.1.9 ECOG performance status 0,1, or 2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.10 Patients must have adequate organ and marrow function as defined below: 
 
− 
leukocytes  
 
≥2,000/mcL 
− 
absolute neutrophil count 
 
≥1,500/mcL 
− 
platelets  
 
≥75,000/mcL 
− 
total bilirubin 
 
≤3 × institutional upper limit of normal (ULN) 
− 
AST(SGOT)/ALT(SGPT) 
 
≤3 × institutional ULN 
− 
glomerular filtration rate (GFR) ≥50 mL/min using Cockcroft-Gault method (see 
Appendix B) 
− 
hemoglobin 
 
 
 
≥8.0 g/dL 
 
3.1.11 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 
therapy with undetectable viral load within 6 months are eligible for this trial. 
 
3.1.12 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
 
3.1.13 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured.  For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
3.1.14 Patients with treated brain metastases are eligible if follow-up brain imaging after central 
nervous system (CNS)-directed therapy shows no evidence of progression.  
 
3.1.15 Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen, in the opinion of the enrolling physician, are eligible for this 

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trial. 
 
3.1.16 Pregnancy Precaution:  Men and women should avoid pregnancy for seven months after 
the date of their last treatment with Lutetium Lu 177 Dotatate.  It is noteworthy that β-HCG 
may be secreted by a small percentage of NETs, such that, in addition to being a pregnancy 
marker, it also is a tumor marker.  Consequently, NET female patients with positive β-
HCG (>5 mIU/mL) at baseline can be eligible to enter the study and receive treatment if 
pregnancy can be excluded by lack of expected doubling of β-HCG and negative pelvic 
ultrasound.  Normally, in pregnant subjects β-HCG doubles every 2 days during the first 4 
weeks of pregnancy and every 3.5 days by Weeks 6 to 7.  Women of childbearing potential 
include any female who has experienced menarche and who has not undergone successful 
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral ovariectomy) or is 
not postmenopausal (defined as amenorrhea >12 consecutive months, and for women on 
hormone replacement therapy, only with a documented plasma follicle-stimulating 
hormone (FSH) level >35 mIU/mL).  Even women who are using oral, implanted, or 
injected contraceptive hormones, an intrauterine device (IUD), or barrier methods 
(diaphragm, condoms, spermicidal) to prevent pregnancy, are practicing abstinence or 
where the partner is sterile (e.g., vasectomy) should be considered to be of childbearing 
potential.  Postmenopausal women who have fertilized eggs implanted are also considered 
to be of childbearing potential.  Acceptable methods of contraception may include total 
abstinence at the discretion of the Investigator in cases where the age, career, lifestyle, or 
sexual orientation of the patient ensures compliance.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  Reliable contraception (hormonal or barrier method of birth 
control; abstinence) should be maintained throughout the study and for 7 months after study 
treatment discontinuation.  All women of childbearing potential and male partners must 
use a double-barrier method of birth control or practice continuous abstinence from 
heterosexual contact throughout the study and for seven months after the end of the last 
treatment. 
 
3.1.17 Ability to understand and the willingness to sign a written informed consent document.  
Participants with impaired decision-making capacity (IDMC) who have a legally-
authorized representative (LAR) and/or family member available will also be eligible. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had major surgical procedures in the prior 6 weeks. 
 
3.2.2 Patients with an inability to swallow oral medications or gastrointestinal disease limiting 
absorption of oral agents. 
 
3.2.3 Patients who have received prior external beam radiotherapy to more than 50% of bone 
marrow, as determined by a radiation medicine physicist who will calculate the volume 
of bone marrow exposure in prior radiotherapy portals divided by the volume of total 
bone marrow harboring tissues.  This ratio must be less than 50 percent. 
 

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3.2.4 Uncontrolled congestive heart failure (NYHA III, IV). 
 
3.2.5 Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the 
study. 
 
3.2.6 Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1) with the exception of alopecia.   
 
3.2.7 Patients who are receiving any other investigational agents. 
 
3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to triapine or Lutetium Lu 177 Dotatate. 
 
3.2.9 Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection; symptomatic decompensated congestive heart failure; unstable angina 
pectoris; cardiac arrhythmia; and known inadequately controlled hypertension. 
 
3.2.10 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.11 Pregnant women are excluded from this study because triapine is an RNR inhibitor and 
Lutetium Lu 177 Dotatate is a peptide receptor radionuclide therapy with the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with triapine and 
Lutetium Lu 177 Dotatate, breastfeeding should be discontinued if the mother is treated 
with triapine and Lutetium Lu 177 Dotatate and for 2.5 months following the last 
treatment.  
 
3.2.12 Discontinue long-acting somatostatin analogs (e.g., long-acting octreotide) for at least 4 
weeks prior to initiating Lutetium Lu 177 dotatate. Long-acting somatostatin analog will 
be allowed to continue if patient has history of carcinoid syndrome and requires long-
acting somatostatin analog for control of his/her functional syndrome. 
 
 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-defined 
clinical research unless a clear and compelling rationale and justification establishes to the 
satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate with 
respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of childbearing 
potential should not be routinely excluded from participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
 

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21 
In addition, all investigators act as the Site-Protocol PI (Investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the Clinical Investigator (CI) on 
the DTL must be rostered at the enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.   
For questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
 
4.2 
Site Registration 
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network.  Site preferences can be set at the network or 
protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website.  
Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation, 
• IRB-signed CTSU IRB Certification Form, and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) 
and on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
1. An active Federal-wide Assurance (FWA) number, 
2. An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO), and 
3. Compliance with all protocol-specific requirements (PSRs). 
 

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4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment.  To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a PO on the protocol.  One 
way to search for a protocol is listed below.  
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-OH007, and 
protocol number 10388, 
• Click on Documents, select Site Registration, and download and complete the forms 
provided.  (Note:  For sites under the CIRB initiative, IRB data will load automatically to 
the CTSU as described above.)  
 
4.2.2 Protocol Specific Requirements For 10388 Site Registration 
 
Upon University of Kentucky (UK) approving the RTI provider for the study modality, UK will 
send the approval to the Regulatory Support System (RSS) to comply with the protocol specific 
requirement.  Participating sites will send de-identified Gallium-68 (or Copper-64) dotatate scan 
images/discs to Dr. Aman Chauhan at amanchauhan@uky.edu or 800 Rose Street, CC 447, Ben 
Roach Building, Markey Cancer Center, 40536, Lexington Kentucky.  This imaging (Gallium-68 
or Copper-64 dotatate scan) is collected for correlative analysis on all enrolled participants.   
 
▪ Specimen Tracking System Training Requirement: 
▪ All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
▪ Theradex will provide a certificate of completion, which will need to be submitted to the 
CTSU through the Regulatory Submission Portal. 
▪ The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study, the training does not need 
to be completed again nor does the certificate of completion need to be resubmitted to 
the CTSU.  However, new versions of the Specimen Tracking System may require new 
training. 
▪ This training will need to be completed before the first patient enrollment at a given site. 
▪ Please contact STS Support at Theradex for the training (STS.Support@theradex.com, 
Theradex phone: 609-799-7580). 
 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to the 
Regulatory section, and select Regulatory Submission. 

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Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application in the Delegation Log 
section on the CTSU members’ website.  The Clinical Investigator (CI) is required to review and 
electronically sign the DTL prior to the site receiving an Approved site registration status and 
enrolling patients to the study.  To maintain an approved site registration status the CI must re-
sign the DTL at least annually and when a new version of the DTL is released; and activate new 
task assignments requiring CI sign-off.  Any individual at the enrolling site on a participating roster 
may initiate the site DTL.  Once the DTL is submitted for CI approval, only the designated DTL 
Administrators or the CI may update the DTL.  Instructions on completing the DTL are available 
in the Help Topics button in the DTL application and include a Master Task List, which describes 
DTL task assignments, CI signature, and CTEP registration requirements. 
The DTL for this study has training requirements as follows: 
 
• At least one authorized user physician investigator of lutetium Lu177 for medical use 
must be registered with CTEP at the Investigator level and be listed on the site DTL with 
the appropriate task(s). 
 
Authorized user physician investigators should be identified as such by the site Radiation Material 
License or site Radiation Safety Officer authorized list indicating their authority as an authorized 
user of lutetium Lu177 for medical use. 
 
Study investigators and staff must review initial site initiation slides and/or attend site initiation 
webinar, as well as reviewing all amendments. 
 
 
The individual initiating the DTL for the site should upload the above listed training 
documentation when making the task assignment.  The designated reviewer will accept or reject 
the documentation.  A note regarding rejection of any training documents will display on the Site 
DTL Browser next to the task assignment.  The DTL cannot be submitted for CI sign-off until the 
minimum number of individuals is assigned to the task and have met the training requirements.   
 
 
4.2.4 Checking Site Registration Status 
 
Site’s registration status may be verified on the CTSU website.  
• Click on Regulatory at the top of the screen, 
• 
Click on Site Registration, and 
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 

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24 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol.  It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
 
 
 
4.3 
Patient Registration 
 
 
4.3.1 OPEN / IWRS 
 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment.  OPEN or IWRS will populate the 
patient enrollment data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access:   
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Must be on an LPO roster, ETCTN 
corresponding roster, or PO roster with the role of Registrar.  Registrars must hold a 
minimum of an Associate Plus (AP) registration type. 
• If a DTL is required for the study, the registrar must hold the OPEN Registrar task on the 
DTL for the site. 
• Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  IWRS system also sends an email confirmation of the registration.  You 
may print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  

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Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System or the IWRS Slot 
Reservation System to ensure that a slot on the protocol is available to the patient.  Once a slot 
reservation confirmation is obtained, site staff may then proceed to enroll the patient to this 
study. 
 
 
 
4.3.2 Special Instructions for Patient Enrollment 
 
This Study will use the ETCTN Specimen Tracking System (STS).  
 
1. All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   
2. The system is accessed through special Rave user roles:  “Rave CRA” “Rave CRA 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the 
Biorepository.   
3. Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section under the Rave Home tab and then 
under Rave Resource Materials. 
4. Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Detailed instructions can be found in Section 5.4. 
 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN link of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
609-619-7862 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
 
 
 

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4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 30 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
 

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5.2 
Summary Table for Interventional Radiologist for Research Biopsies 
 
Biopsy #:  1 
Trial Time Point:  Pretreatment  
IR Biopsy Definition:  Research – No Clinical Impact (All cores from a single biopsy 
procedure impact research goals, but do not directly impact patient care or benefit the patient.) 
Core 
Priority 
Use in the 
Trial 
Biomarker 
Name(s) 
Tumor 
Content 
Required 
Post-Biopsy Processing 
1 
Integrated 
WES 
25-50%  
Formalin 
2 
Integrated 
WES 
5-25% 
Formalin 
 
Note:  Pre-biopsy assessments will be reported and tracked through a trial-specific CRF within 
the CTEP Medidata Rave system (see Appendix E).  
 
 
5.3 
Specimen Procurement Kits and Scheduling 
 
5.3.1 Specimen Procurement Kits  
 
Kits for the collection and shipment of specimens to the EET Biobank can be ordered online via 
the Kit Management system: https://kits.bpc-apps.nchri.org/.  
 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit.  Please note that protocol may include more than 
one type of kit.  Each user may order two kits per kit type per day (daily max = 6 kits).  Kits are 
shipped ground, so please allow 5-7 days for receipt.  A complete list of kit contents for each kit 
type is located on the Kit Management system website. 
 
Note:  Kits or supplies are only provided for specimens shipped to the Biorepository. 
Institutional supplies must be used for all other specimen collection and processing.  
 
 
5.3.2 Scheduling of Specimen Collections to the EET Biobank 
 
Please adhere to the following guidelines when scheduling procedures to collect tissue:  
• Tumor tissue specimens collected during biopsy procedures and fixed in formalin must 
be shipped on the same day of collection. 
• Tissue in formalin can be collected Monday through Wednesday and shipped overnight 
for arrival on Tuesday through Thursday at the EET Biobank at Nationwide Children’s 
Hospital. 
 
• Specimens submitted frozen, such as frozen whole blood and frozen plasma, can be 
collected on any day but must be stored frozen and shipped to the EET Biobank on 
Monday through Thursday.  In the event that frozen specimens cannot be shipped 
immediately, they must be maintained in a -70°C to -80°C freezer. 
 
 
• Fresh blood specimens may be collected and shipped Monday through Friday.  
 

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5.3.3 Scheduling of Specimen Collections to the Beumer Laboratory 
 
Beumer Laboratory: Blood samples will be collected at the timepoints specified in Section 5.1.  
Frozen plasma/serum will be shipped overnight on either Monday, Tuesday, or Wednesday (and 
not before a federal or university holiday) to the Beumer Laboratory at the University of Pittsburgh. 
 
5.4 
Specimen Tracking System Instructions 
 
5.4.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and unique 
identification numbers to the patient, a Universal patient ID (UPID) and a Treatment patient ID.  
The UPID is associated with the patient and used each and every time the patient engages with the 
portion of this or any other protocol that uses the ETCTN Specimen Tracking System.  The UPID 
contains no information or link to the treatment protocol.  IWRS will maintain an association 
between the UPID for ETCTN biobanking and molecular characterization and any treatment 
protocols the patient participates in, thereby allowing analysis of the molecular characterization 
results with the clinical data.   
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave.  Important:  Remove any personally identifying 
information, including, but not limited to, the patient’s name, date of birth, initials, medical 
record number, and patient contact information from the institutional pathology report 
prior to submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com. 
 
 The Shipping List report must be included with all sample submissions. 

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5.4.2 Specimen Labeling 
 
5.4.2.1 Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date (and time for PK samples) (to be added by hand) 
 
5.4.2.2 Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers (e.g., formalin jar):  
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., formalin-fixed paraffin-embedded [FFPE] Block, Formalin 
Fixed Tissue, Fresh Tissue in Media, etc.) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number (when applicable)    
• Block number from the corresponding pathology report (archival only) 
• Collection date (to be added by hand) 
• Slide section number (only if archival tissue is submitted as slides) (to be added by 
hand) 
 
5.4.2.3 Example of Specimen Label Generated by STS 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens 
folder. A generated PDF is emailed to the user as a result of saving that form.  
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide. 
 

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The QR code in the above example is for the Specimen ID shown on the second line.   
Labels may be printed on a special purpose label printer, one label at a time, or on a standard 
laser printer, multiple labels per page. Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers: https://www.labtag.com/shop/product/cryo-laser-
labels-1-28-x-0-5-cl-23-colors-available/ 
The last line item on the label includes the following data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification 
Space is provided at the bottom of the label for the handwritten date and optional time.   
 
 
5.4.3 Overview of Process at Treating Site 
 
5.4.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system.  OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments.  If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
 

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5.4.3.2 Rave Specimen Tracking Process Steps 
 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate participant. 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a specimen  
            label can be applied to them) and the Baseline forms regarding Prior Therapies.  Enter  
            the initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded).  CRF generates unique 
Specimen ID.  
 
Step 2:  Print labels using the Print Labels CRF located in the All Specimens folder, then 
             collect specimen. 
• Label specimen containers and write collection date (and time for PK samples) on each 
label.   
• After collection, store labeled specimens as described in Section 5.4.2. 
• Apply an extra specimen label to each report before scanning.  Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
4), Surgical (or Operative) reports.  Return to Specimen Tracking Enrollment CRF to 
upload any molecular report (one per specimen) and/or specimen specific pathology or 
related report (one per specimen) and/or Tissue Biopsy Verification form (when 
applicable).  Uploaded reports should have protected health information (PHI) data, like 
name, date of birth, mailing address, medical record number or social security number 
(SSN), redacted.  Do not redact SPID, block number, diagnosis or relevant dates (such as 
collection date), and include the UPID and patient study ID on each document (either by 
adding a label or hand writing).  
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form:  Enter collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, recipient, 
number of sample containers and ship date once for the first specimen in a shipment. 
• Copy Shipping CRF:  In the specimen folders for additional specimens (if any) that will 
be shipped with the initial specimen, please use the Copy Shipping form to derive 
common data into additional Shipping Status forms. A few unique fields will still need 
to be entered in Shipping Status.   
 
Step 5:  Print shipping list report and prepare to ship.  
• Shipping List report is available at the site level. 
• Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
• Print pathology or other required reports to include in the box.  Be sure the printed copy 
includes the specimen label. 
 
Step 6:  Send email notification.  

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• For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 
Step 8:  Monitor the Receiving Status form located in each specimen folder for acknowledgment  
          of receipt and adequacy. 
 
 
5.5 
Specimen Collection  
 
5.5.1 Archival or Formalin-Fixed Paraffin-Embedded (FFPE) Tumor Specimen  
 
If previously-collected FFPE tissue will be submitted, then the following criteria must be met: 
 
• Tissue must have been collected within 6 months prior to registration  
• FFPE tumor tissue block must be submitted.  The optimal block is at least 70% tumor.  
Specimen size requirement is as follows: 
o Surface area:  25 mm2 is optimal.  Minimum is 5 mm2. 
o Volume:  1 mm3 optimal.  Minimum volume is 0.2 mm3, however the success of 
DNA extraction decreases at suboptimal tissue volume. 
 
If an existing block cannot be submitted, the following are requested, if available: 
• One (1) H&E slide (3-5 µm), 
• Thirty to fifty (30 – 40) 10 µm unstained air-dried, uncharged slides. 
 
Process and number slides sequentially (e.g., H&E stained slide should be created first and 
labeled with “1,” and additional unstained slides should be processed next and be labeled 2 – n). 
 
See Section 5.4.2 for labeling instructions. 
 
 
5.5.2 Formalin-Fixed Tumor Biopsies  
 
1. Label formalin-filled containers according to instructions in Section 5.4.2.  
2. Obtain 2 16-gauge or 18-gauge core needle biopsy specimens, and place one core in each 
cassette.  
3. Snap the cassette lids closed and place cassettes into a formalin-filled pre-labeled 
container as soon as possible after collection to prevent air drying.  Up to two cassettes 
may be placed in one formalin jar. 
4. Secure the container lids and package containers into the shipping kit according to 
instructions in Section 5.6.2.3.  Keep tissue in formalin jars at room temperature until 
shipment to the EET Biobank.  
 
 
5.5.3 Blood Collection  
 
5.5.3.1 Collection of Blood in Streck cfDNA tube for ctDNA and germline sequencing 
 
1. Label two 10 mL Streck cfDNA tube according to the instructions in Section 5.4.2.  
2. Collect 10 mL of blood into the pre-labeled tube and gently invert to mix.  Note:  blood 
must be thoroughly mixed to ensure preservation of specimen.  If patients may have an 

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indwelling catheter:  heparin should be avoided in pre-collection flush procedures.  If 
therapeutic heparin dosing contamination is a possibility, then venipuncture is 
recommended as a first choice collection method.  If a Streck cfDNA tube immediately 
follows a heparin tube in the draw order, then collecting an EDTA tube as a waste tube 
prior to collection in the Streck Cell-Free DNA BCT is recommended. 
3. After collection, blood in Streck cfDNA tubes should never be refrigerated, as this 
will compromise the specimen.  Blood collected in Streck cfDNA tubes is stable at room 
temperature until shipment to the EET Biobank.  
 
 
5.5.3.2 
Collection of Blood in EDTA Tubes for Plasma Processing for PK Studies 
 
General 
 
Blood samples to be obtained through a peripheral or central line blood draw.  EDTA Vacutainer 
tubes shall be prepared for this purpose.   
 
Processing 
Document exact administration time and exact times of blood draws per Appendix F. 
 
1. Collect in a 3 or 4 mL purple top tube (e.g.,  BD vacutainer 367861 plastic 13 x 75 4 mL 
tube). 
2. Invert the vacutainer tubes several times to mix blood with EDTA anticoagulant and 
immediately place on ice. 
3. Processing should begin preferably within 30 minutes of collection (note that within 2-hours 
is allowable). 
4. Samples should be centrifuged for 10 min at approximately 1000-2000 x g in a refrigerated 
tabletop centrifuge so as to produce plasma. 
5. The resulting plasma should be aspirated from the tubes, placed into appropriately-labeled 
microcentrifuge tubes, and stored at -70 °C until shipment. 
 
 
5.5.3.3 
Collection of Peripheral Venous Blood 
 
1. 1 × 2mL collections (peripheral venous blood) per institutional standards. 
2. Immediately place the sample on ice and route to institutional lab. 
3. Sample should be analyzed within 30 minutes (up to 2 hours) of being drawn per 
institutional SOPs. 
 
 

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5.5.3.4 Collection of Blood in Purple-top EDTA Tubes for future Studies (1.3.3)  
 
NOTE: Originally collected to analyze hPG80, but instead will be biobanked (as of  
            12/13/2022) for use in future correlative analysis. We retained the instructions 
            on collection and processing/handling of these now-frozen biobanked blood  
            samples for transparency in future analysis.   
 
1. Collect 5 mL of peripheral blood in an EDTA tube (purple top)  
2. After collection thoroughly mixed by inverting (8 -10 times) 
3. Immediately freeze at -80°C and store frozen until shipment to the EET Biobank.  
4. If blood cannot be frozen immediately then it can be stored on ice up to 2 
hours before freezing. 
 
 
5.5.3.5 Collection of Blood in EDTA Tubes for Deoxyribonucleoside Studies  
 
1. Collect 16 mL of peripheral blood in two K2 EDTA tubes (8mL each, white top)  
2.  Invert the vacutainer tubes several times to mix blood with EDTA anticoagulant and 
immediately place on ice. Processing should begin preferably within 30 minutes of collection 
(note that within 2-hours is allowable). 
3. Samples should be centrifuged for 12 min at approximately 1700 x g in a refrigerated tabletop 
centrifuge so as to produce plasma. 
4. The resulting plasma should be aspirated from the tubes, placed into four appropriately-
labeled microcentrifuge tubes, and stored at -70 °C until shipment. 
 
 
 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank  
 
5.6.1 General Shipping Information 
 
Core biopsies that are fixed in formalin should be shipped in the single chambered kit that is 
provided, whenever possible.  The shipping container sent with kit contents should be used to ship 
specimens to the EET Biobank.  In winter months, please include extra insulation, such as bubble 
wrap, inside the shipping container. 
 
For new biopsies, the Tissue Biopsy Verification Form (Appendix H) and a copy of the radiology 
and/or operative reports from the tissue removal procedure and the diagnostic anatomic pathology 
report must be sent with the tissue to the EET Biobank.    
For all archival tissue, the corresponding anatomical clinical pathology report is required both in 
the package and uploaded in the ETCTN specimen tracking system.  If this is not available at the 
time of shipment, then it must be uploaded to the ETCTN specimen tracking system, or the 
specimen will not be processed.  The pathology report must state the disease diagnosis made by 
the reviewing pathologist. 
 

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5.6.1.1 
Required Forms for Specimen Submissions: 
 
Each document submitted with the specimen must be labeled with a label printed from the 
STS, or the Universal ID and Patient Study ID. 
 
Tissue  
Required Forms 
Archival 
1. Shipping List 
2. Corresponding Pathology Report 
 
Tumor biopsies in formalin 
1. Shipping List 
2. Tissue Biopsy Verification Form 
3. Diagnostic Pathology Report  
4. Surgical and/or Radiology Report 
Blood in Streck cDNA tubes or purple 
top EDTA tubes 
1. Shipping List 
 
5.6.2 Specimen Shipping Instructions 
 
Tissue in formalin must be shipped on the day of collection.  Collect and ship on Monday 
through Wednesday. 
 
Frozen specimens and archival (FFPE) tissue may be shipped on Monday through Thursday.  
 
Fresh blood may be shipped on Monday through Friday.  Please select “Saturday Delivery” 
when shipping fresh blood on a Friday.  
 
5.6.2.1 
Shipping of FFPE Blocks and Glass Slides  
 
1. Before packaging slides, verify that slides are labeled according to Section 5.4.2.2. 
2. Blocks should be placed in a hard-sided container, preferably a special block holder, to 
protect the specimen.  Glass slides are to be placed in plastic slide holders.  Place tissue 
paper on top of the separated slides prior to closing the slide holder to reduce slide 
movement during shipment. 
3. Place the blocks or slides in a reinforced cardboard shipping box with appropriate 
packaging filler to minimize movement of specimens within the shipping box. 
4. Include a copy of the forms listed above and a shipping manifest from the Specimen 
Tracking System with each shipment.  
5. Please include a cold pack when shipping on hot days and extra insulation on cold days. 
6. Ship specimens to the address listed below.  FedEx Priority Overnight is strongly 
recommended to prevent delays in package receipt.  
 
5.6.2.2 
Shipping Blood in an Ambient Shipper  
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed.   

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2. Prepare the SAF-T-TEMP Gel Pak for shipment.  Note: If contents of the Pak are 
crunchy, place Pak in a warm water bath until gel is smooth.  Do not refrigerate, freeze, 
or microwave.  
3. Place the SAF-T-TEMP Pak in bottom of insulated chest.  Note:  The insulated chest 
must be shipped inside the provided cardboard box(es).  
4. Place the blood collection tubes in zip-lock bags.   
5. Next, place blood into a biohazard envelope with absorbent material.  Expel as much air 
as possible and seal the envelope securely.  
6. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 
7. Place packaged blood collection tube(s) and a copy of the shipping manifest from the 
Sample Tracking System on top of SAF-T-TEMP Pak.  
8.  Place the lid on the insulated chest.  
9. Close the outer flaps of the shipping box and tape shut. 
10. Attach a shipping label to the top of the shipping container.  
11. Attach an Exempt Human Specimen sticker to the side of the box. 
12. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.6.2.3 
Shipping Ambient Formalin-Fixed Tissue in a Single-Chamber Kit 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed.  The lids of formalin jars should be wrapped in parafilm.  Absorbent material 
must be placed around each primary container that holds liquid.   
2. Place the specimens in zip-lock bags.  Use a separate bag for each specimen type. 
3. Place specimens into the secondary pressure vessel surrounded by bubble wrap.  Place 
the lid on the secondary pressure vessel and set it inside the kit chamber.  
4. Place a copy of the shipping manifest and corresponding reports such as pathology, 
surgical, or radiology reports into the insulated shipping container.  
5. Set the lid on top of the container.  Close the outer flaps and tape shut. 
6. Attach a shipping label to the top of the shipping container.  
7. Attach an Exempt Human Specimen sticker to the side of the container. 
8. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
 
5.6.2.4 
Shipping Frozen Specimens in Your Own Container 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are tightly 
sealed.  
2. Place the specimens in zip-lock bags.  Use a separate zip-lock bag for each specimen type 
and time point.  
3. Place the zip-lock bags in a biohazard envelope containing absorbent material.  Expel as 
much air as possible and seal securely.  

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4. Put the secondary envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely.  
5. Place frozen specimens in the insulated shipping container with dry ice.  Layer the 
bottom of the container with dry ice until it is approximately one-third full.  Place the 
frozen specimens on top of the dry ice.  Cover the specimens with the dry ice until the 
container is almost completely full.  When packaging specimens, ensure that you leave 
enough room to include at least 5 pounds of dry ice in the shipment.  
6. Insert a copy of the required forms into a plastic bag and place in the container. 
7. Close the container and tape it shut with durable sealing tape.  Do not completely seal the 
container. 
8. Complete a FedEx air bill and attach to top of shipping container. 
9. Complete a dry ice label. 
10. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
11. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
 
5.6.3 Shipping Address 
 
Ship to the address below.  Ship formalin-fixed and fresh blood specimens the same day of 
specimen collection.  Do not ship specimens the day before a holiday. 
 
EET Biobank 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive, WA1340 
Columbus, Ohio 43205 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.   
 
NOTE:  The EET Biobank FedEx Account will not be provided to submitting institutions. 
 
 
5.6.4 Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
EET Biobank  
Toll-free Phone:  (800) 347-2486 
E-mail:  BPCBank@nationwidechildrens.org 
 
 
 

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5.7 
Shipping of Specimens from Clinical Site to Other Laboratories  
 
5.7.1 Shipping of Specimens to Beumer Laboratory 
 
5.7.1.1 
Specimen Shipping Instructions 
 
Preparing the shipment: 
1.  Samples should be stored in cardboard boxes (5 1/8” × 5 1/8” × 2”, L × W × H). 
2.  Organize the samples by Patient and Time point in the box. 
3.  Do not store in plastic bags (they break on dry-ice and labels will detach). 
4.  A copy of each of the pharmacokinetic sample collection forms for the respective patients 
should be included with each shipment (see Appendix F).  To prevent problems with illegible 
writing on tubes, consider numbering them and numbering samples on the sample sheet. 
• Note the study number, PI, and the drugs used/to be measured. 
A name, phone number, and email address should be included with the samples so 
that receipt can be acknowledged.  Please notify the lab by email (pitt-
pk@upmc.edu), telephone (412-623-3248), or fax (412-623-1212) at least 24 hours 
prior to shipment. 
 
Regulations:  Shipment of samples must comply with appropriate regulations as specified by the 
carrier.  At a minimum, all samples must be packaged within two containers with absorbent 
material between containers to control any spill or leakage.  The outer container must be 
puncture-resistant (e.g.  cardboard mailing tube, corrugated cardboard box).  A biohazard sticker 
must be affixed to both the inner and outer containers. 
 
Shipping Restrictions:  All samples should be shipped via overnight express courier in insulated 
containers with enough dry ice to maintain the samples in a frozen state.  All specimens are to be 
shipped on either Monday, Tuesday, or Wednesday, and not before federal or university 
holidays. 
 
5.7.1.2 
Shipping Address 
 
Jan Beumer, University of Pittsburgh  
Cancer Pharmacokinetics and Pharmacodynamics Facility 
UPMC Hillman Cancer Center 
Room G27E, Hillman Research Pavilion 
5117 Centre Avenue 
Pittsburgh, PA 15213 
 
5.7.1.3 
Contact Information for Assistance 
 
Lab phone:  412-623-3248 
Lab fax:  412-623-1212 
PK Lab email: PITT-PK@upmc.edu  
PK director email: beumerjh@upmc.edu 

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5.7.2 Shipping of Specimens to Kolesar Laboratory 
 
5.7.2.1 
Schedule of Shipment 
 
Frozen specimens (plasma) may be shipped on Monday through Thursday. Frozen specimens are 
batch shipped every 6 months.  
 
5.7.2.2 
Packing Instructions for Frozen Plasma 
Frozen plasma samples should be batch shipped using the instructions below:  
1. Place the plasma specimens in zip-lock bags. Use a separate zip-lock bag for each time 
point and collection.  
2. Place the zip-lock bags in a biohazard envelope containing absorbent material. Expel as 
much air as possible and seal the envelope.  
3. Put the secondary envelope into a Tyvek envelope. Expel as much air as possible and seal 
the envelope.  
4. Place the Tyvek envelope in a Styrofoam container filled with dry ice. Layer the bottom 
with dry ice until it is approximately one-third full. Place the Tyvek envelope containing 
frozen specimens on top of the dry ice. Cover the specimens with the dry ice until the 
compartment is almost completely full.  
5. Insert a copy of the specimen manifest from the Specimen Tracking System into a plastic 
bag and place in the container.  
6. Place the Styrofoam lid on top to secure specimens during shipment.  
7. Close the lid with filament or other durable sealing tape. Do not completely seal the container.  
8. Complete a FedEx air bill and attach to top of shipping container.  
9. Complete a dry ice label.  
10. Attach the dry ice UN1845 label and an Exempt Human Specimen sticker or UN3373 
sticker to the side of the shipping container.  
11. Arrange for courier pickup. Note: FedEx Priority Overnight is strongly recommended for 
next day delivery to prevent delays in package receipt.  
 
5.7.2.3 
Shipping Address 
 
Ship plasma for PK analysis overnight courier on dry ice to the University of Kentucky for   
       processing and storage.  
 
Attn: Rob McCorkle, Ph.D. Kolesar Lab 
B0551-02 HKRB 
760 Press Avenue 
Lexington, KY 40536  
 

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5.7.2.4 
Contact Information for Assistance 
 
Phone: 859 323-4978 
Fax: 859 323-3561 
Email: jill.kolesar@uky.edu  

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5.9 
Integrated Correlative Studies 
 
5.9.1 Whole Exome Sequencing 
 
5.9.1.1 
Specimens Receipt and Processing at the EET Biobank  
 
Archival formalin-fixed paraffin-embedded (FFPE) or pre-treatment formalin-fixed tumor will be 
processed for this assay. Tumor tissue received in formalin will be paraffin-embedded.  All FFPE 
blocks will be sectioned to generate an initial H&E-stained slide for pathology QA review. As 
needed, tumor tissues may be annotated for macrodissection to enrich tumor content  
DNA and RNA will be co-extracted from tumor tissue.  Germline DNA will be extracted from 
blood collected in the Streck cfDNA tube at C1D1, following plasma processing.  The nucleic 
acids will be analyzed to determine concentration and quality.  Aliquots of tumor and germline 
DNA will be shipped to the central sequencing laboratory for analysis. 
 
5.9.1.2 
Site Performing Correlative Study 
 
This study will be conducted at the MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) under the supervision of Mickey Williams, Ph.D. (mickey.williams@nih.gov).  
 
  
5.9.1.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.9.1.4 
Contact Information for Notification of Specimen Shipment 
 
Thomas Forbes (mochasamplereceiving@nih.gov) 
 
5.9.2 Triapine PK Studies 
 
5.9.2.1 
Specimen(s) Receipt and Processing at the Beumer lab 
 
Frozen Plasma aliquots will be received at the Beumer laboratory for storage and analysis. 
 
An LC-MS/MS assay to quantitate triapine was developed and validated in the UPMC Hillman 
Cancer Center, Cancer Pharmacokinetics and Pharmacodynamics Facility (Matsumoto et al., 
2017). 
 
5.9.2.2 
Site(s) Performing Correlative Study   
 

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This study will be performed in the Beumer laboratory under the supervision of Jan Beumer, 
Ph.D. (beumerjh@upmc.edu).  
 
5.9.2.3 
Contact information for notification of specimen shipment 
 
 
Refer to section 5.7.1.2 and 5.7.1.3. 
 
5.9.3 Methemoglobin Determination 
 
5.9.3.1 
Specimen(s) Receipt and Processing at Local Labs 
 
Local labs should process these samples per institutional SOPs as part of standard of care. 
 
5.9.3.2 
Site(s) Performing Correlative Study   
 
This study will be conducted at local labs. 
 
5.10 
Exploratory/Ancillary Correlative Studies 
 
5.10.1 Blood-Based Predictive Assay (1.3.3) 
 
5.10.1.1 
Specimen Receipt and Processing at the EET Biobank  
 
Frozen blood (5mL purple-top EDTA tube) received at the EET Biobank will be accessioned, 
barcoded, and stored frozen in a -80°C freezer. Note: originally this blood was collected and 
frozen to conduct hPG80 assay, however it was determined that frozen blood is not suitable for 
this assay so these samples will be biobanked for future analysis.  See also notes in Sections 
2.5.2.1, 5.5.3.4 and 11 Study Calenar for details on blood sample collection.  
 
 
5.10.1.2 
Site Performing Correlative Study   
      N/A (as frozen samples are being biobanked).  
 
5.10.1.3 
Contact Information for Notification of Specimen Shipment 
       N/A (as frozen samples are being biobanked).  
 
5.10.2 RNAseq 
 
5.10.2.1 
Specimens Receipt and Processing at the EET Biobank  
 
Archival formalin-fixed paraffin-embedded (FFPE) or pre-treatment formalin-fixed tumor will be 
processed for this assay. Tumor tissue received in formalin will be paraffin-embedded.  All FFPE 
blocks will be sectioned to generate an initial H&E-stained slide for pathology QA review. As 
needed, tumor tissues may be annotated for macrodissection to enrich tumor content. 
 
DNA and RNA will be co-extracted from tumor tissue.  The nucleic acids will be analyzed to 

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determine concentration and quality.  Aliquots of RNA will be shipped to the central sequencing 
laboratory for analysis. 
 
5.10.2.2 
Site Performing Correlative Study 
 
This study will be conducted at the MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) under the supervision of Mickey Williams, Ph.D. (mickey.williams@nih.gov).  
 
5.10.2.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.10.2.4 
Contact Information for Notification of Specimen Shipment 
 
Thomas Forbes (mochasamplereceiving@nih.gov) 
 
5.10.3 ctDNA sequencing 
 
5.10.3.1 
Specimen(s) Receipt and Processing at the EET Biobank  
 
Upon receipt, blood in Streck cfDNA tubes will be processed for plasma and either DNA (at 
C1D1 only) or buffy coat (at Disease Progression) and stored frozen in a -80°C freezer.  Plasma 
will be stored in 1-mL aliquots, and buffy coat will be stored as 1-2 aliquots. 
 
5.10.3.2 
Site(s) Performing Correlative Study   
 
This study will be conducted at the MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) under the supervision of Mickey Williams, Ph.D. (mickey.williams@nih.gov).  
 
5.10.3.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.10.3.4 
Contact Information for Notification of Specimen Shipment 
 
Thomas Forbes (mochasamplereceiving@nih.gov) 

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5.10.4 Single Deoxyribonucleoside Concentrations 
 
5.10.4.1 
Specimen Receipt and Processing at the University of Kentucky  
Frozen plasma aliquots will be received at the University of Kentucky. Upon receipt, plasma will 
be accessioned, barcoded, and stored in a -80°C freezer until distribution for testing.  
5.10.4.2 
Site Performing Correlative Study 
The Kolesar Lab at the University of Kentucky, under the direction of Dr. Jill Kolesar, will conduct 
the proposed studies. The Kolesar lab has more than 20 years of experience in analytical chemistry 
and PK analysis.  
5.10.4.3 
Contact information for notification of specimen shipment 
 
Refer to section 5.7.2.3 and 5.7.2.4. 
 
5.11 
Special Studies 
 
5.11.1 Gallium-68 Dotatate (OR Copper-64 Dotatate)  
 
5.11.1.1 
Outcome Measure 
 
Baseline Gallium-68 Dotatate (or Copper-64 Dotatate) PET/CT prior to therapy is standard of care 
and covered by insurance.  Prior to administration of the novel treatment combination, Gallium-
68 Dotatate (or Copper-64 Dotatate) PET/CT will be performed for all patients to confirm adequate 
somatostatin receptor binding.  Participating sites will send de-identified Dotatate (Gallium-68 or 
Copper-64) scan images/discs of all enrolled study participants to Dr Aman Chauhan at 
amanchauhan@uky.edu, 800 Rose Street, CC 447, Ben Roach Building, Markey Cancer Center, 
40536, Lexington Kentucky.  
 
To confirm receptor expression, Krenning’s score will be applied to Gallium-68 Dotatate (or 
Copper-64 Dotatate) PET/CT images.  Advanced quantitative analysis will be performed as well 
and parameters such as SUVmax, SUVpeak, MTV, and TBI will be obtained per organ and for the 
patient.  Advanced analysis will be performed to determine the optimum quantitative parameter 
that correlates with Objective response measures, PFS, as well as OS. 
 
5.11.1.2 
Assessment 
 
5.11.1.2.1 
Method of Assessment 
 
• Radiopharmaceutical:  Standard dose of Gallium-68 Dotatate will be administered IV 
(0.054 mCi/kg) OR the standard dose for Copper-64 Dotatate. 
• Uptake time:  55-75 minutes 
• CT images of the torso from vertex to mid-thigh will be acquired. 
• PET images will be acquired with the following parameters:  5 minutes/table position. 
 

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See Appendix G for additional details for Dotatate scans (Gallium-68 dotatate, Copper-64 dotatate). 
 
5.11.1.2.2 
Timing of Assessment 
 
Assessment will be performed at baseline unless patients have already had a Gallium-68 Dotatate 
or Copper-64 Dotatate  scan within 6 months of enrollment. 
 
 
5.11.1.3 
Data Recording 
 
5.11.1.3.1 
Method of Recording 
 
• Images will be post-processed using iterative reconstruction method (2 iterations and 8 
subsets), Matrix 
• Image analysis will be performed using MIRADA XD and Syngo Via software. 
 
5.11.1.3.2 
Timing of Recording 
 
Gallium-68 Dotatate (or Copper-64 Dotatate) PET/CT scans will be assessed for inclusion 
determination during the pre-screening period within 2 weeks of patient’s enrollment.  This will 
include review of either newly performed Gallium-68 Dotatate (or Copper-64 Dotatate) PET/CT 
scans or reassessment of previously performed Gallium-68 Dotatate (or Copper-64 Dotatate) 
PET/CT scans within the predetermined acceptable period (within 6 months of enrollment). 
Participating sites with access to Copper-64 Dotatate scans can consider either scan per 
institutional standards.  
 
6. 
TREATMENT PLAN 
 
6.1 
Agent Administration in Dose Escalation Phase  
 
Treatment will be administered on an outpatient or inpatient basis per institutional standard 
operating procedures (SOPs).  Reported adverse events and potential risks are described in Section 
10.  Appropriate dose modifications are described in Section 7.  No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the patient's malignancy. 
 
Oral triapine will be given at the assigned phase 1 dose level.  Patients will be asked to fast (except 
for water) for 2 hours prior to dosing and for 1 hour after ingesting the oral dose (triapine 
complexes strongly with iron ions).  Patients will ingest one dose of triapine within 90 minutes 
after Lutetium Lu 177 Dotatate treatment and once daily after that for 14 days.  Ninety-nine percent 
of Lutetium Lu 177 Dotatate radiation is undetectable by Day 14.  Lutetium Lu 177 Dotatate will 
be administered as IV infusion per FDA label every 2 months at dose of 200 mCi for total of 4 
doses.  All dose cohorts will be treated with same dose of Lutetium Lu 177 Dotatate.   
 
 

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Dose Escalation Schedule 
Dose Level 
Dose * 
Triapine 
Lutetium Lu 177 Dotatate 
Level -2 
50 mg PO QOD, Days 1-14 
200 mCi IV, Day 1 
Level -1 
50 mg PO QD, Days 1-14 
Level 1 # 
100 mg PO QD, Days 1-14 
Level 2 
150 mg PO QD, Days 1-14 
Level 3 
200 mg PO QD, Days 1-14 
* Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. 
# Starting dose. 
 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Triapine 
Fast (except for 
water) for 2 hours 
prior to dosing and 
for 1 hour after 
ingesting the oral 
dose  
As per 
assigned 
dose level 
(See dose 
escalation 
schedule 
above) 
Oral;  
Days 1-14 
of each 
cycle; on 
Day 1, 
within 90 
minutes 
after 
Lutetium 
Lu 177 
Dotatate 
treatment. 
8 weeks 
(56 days) 
Lutetium Lu 177 
Dotatate 
Administer 
antiemetics 30 
minutes before the 
recommended 
amino acid 
solution.  
Administer amino 
acid solution IV 
30 minutes before 
Lutetium Lu 177 
Dotatate. 
200 mCi 
IV; Please refer 
to section 8.2.1 
for details 
regarding 
Lutetium Lu 
177 Dotatate 
route of 
administration.  
 
Day 1 of 
each cycle 
 
The patient will be requested to maintain a medication diary of each dose of triapine (Appendix 
D).  The medication diary will be returned to clinic staff at the end of each course. 

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6.1.1 Triapine 
 
Patients will be instructed to take triapine PO at the assigned dose level.  Triapine will be 
administered on Days 1-14 of every 8 week cycle to overlap with the four administrations of 
Lutetium Lu 177 Dotatate.  On Day 1 of each cycle, patients will ingest one dose of triapine within 
90 minutes after Lutetium Lu 177 Dotatate treatment.  Triapine will be discontinued after the last 
cycle of Lutetium Lu 177 Dotatate administration since triapine does not have anti-tumor activity 
by itself.   
 
Patients will be asked to fast (except for water) for 2 hours prior to dosing and for 1 hour after 
ingesting the oral dose.  Capsules should not be opened.  
 
Missed doses for any reason, including vomiting, can be taken up to 6 hours after the scheduled 
dose. If it has been more than 6 hours since the missed dose, this dose should be skipped.  
 
 
6.1.2 Lutetium Lu 177 Dotatate:  
 
Lutetium Lu 177 dotatate and related supportive care drugs will be administered per participating 
institution standard operating procedure per FDA approved label indication, dose and route of 
administration.  Please refer to section 8.2.1 for details regarding Lutetium Lu 177 Dotatate route 
of administration.  
 
Somatostatin Analogs:  If patients were on somatostatin analog long acting release (SSA-LAR) 
depot injections prior to enrollment in the trial, they will continue to be on SSA LAR during the 
trial. Patient will need to discontinue long-acting somatostatin analogs for at least 4 weeks prior to 
initiating Lutetium Lu 177 dotatate unless long-acting somatostatin analog is required for control 
of patients carcinoid syndrome. Patient can receive either long acting octreotide 30 mg every 4 
weeks as deep intramuscular depot injection or lanreotide 120 mg every 4 weeks as deep 
subcutaneous injection, per FDA guidelines. Injections are administered in the superior external 
quadrant of the buttock. 
Patients who need rescue short-acting octreotide to control their functional neuroendocrine 
symptoms per recommendations of their treating physician.  
 
Antiemetic:  Administer antiemetics 30 minutes before the recommended amino acid solution.  
 
Amino Acid Solution:  Initiate an IV amino acid solution containing L-lysine and L-arginine 
(Table 1) 30 minutes before administering Lutetium Lu 177 Dotatate. Use a three-way valve to 
administer amino acids using the same venous access as Lutetium Lu 177 Dotatate or administer 
amino acids through a separate venous access in the patient’s other arm. Continue the infusion 
during, and for at least 3 hours after Lutetium Lu 177 Dotatate infusion. Do not decrease the dose 
of the amino acid solution if the dose of Lutetium Lu 177 Dotatate is reduced. 
Table 1. Amino Acid Solution 
Item 
Specification 
Lysine HCl content 
Between 18 g and 24 g 

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Arginine HCl content 
Between 18 g and 24 g 
Volume 
1.5 L to 2.2 L 
Osmolarity 
< 1050 mOsmol 
 
 
6.2 
Definition of Dose-Limiting Toxicity 
 
DLT will be defined by Grade 3 or greater hematological or non-hematological toxicity per 
CTCAE version 5.0 that is possibly, probably or likely related to study treatment.  The 
following will not be considered DLTs unless determined to be clinically significant and related 
to study treatments by the treating physician:  
• Grade 1-4 lymphopenia  
• Grade 3 nausea, vomiting or diarrhea lasting <72 hours and controlled by optimal 
antiemetic/anti diarrheal therapy;  
DLT will be assessed at the end of Cycle 1.  Patients need to have at least one dose of Lutetium 
Lu 177 Dotatate and at least 80% of the dose cohort-specific triapine during Cycle 1 to be 
evaluable for adverse effects and DLT criteria for dose escalation/de-escalation decisions.  
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 7. 
 
Dose escalation will proceed within each cohort according to the BOIN design described in 
Section 9.1.  Dose-limiting toxicity (DLT) is defined above.   
 
6.3 
Triapine Administration: Dose Expansion Cohort 
 
This study’s dose escalation cohort enrolled 15 patients in order to identify the recommended 
Phase 2 Dose (RP2D) of Triapine. The Recommended Phase II Dose (RP2D) is based on data 
available from 15 patients who were treated with varying doses of Triapine (100mg, 150mg and 
200mg) using BOIN dose escalation design. 
 
6.3.1 Triapine RP2D 
 
After completion of dose escalation on 15 patients, Dose Level 2 was selected as the RP2D for 
the dose expansion cohort. Thus, all patients enrolled in the dose expansion cohort will be 
administered Triapine 150mg orally once a day on Days 1-14 of each Lu-177 dotatate cycle.  
 
An additional 14 patients will be treated at the RP2D dose (i.e., enrolled in the dose expansion 
cohort).  For the expansion cohort, patients will continue to be monitored for occurrence of DLT.   
If 2 of the first 5 patients or if ≥2 of 6 patients experience DLT, the Principal Investigator will 
discuss with all study investigators and with CTEP whether further addition of patients is needed 
to re-assess the RP2DMonitoring of all safety and toxicity data is done by the Principal Investigator 
and the Corresponding Organization on a real-time basis as data are entered into Medidata Rave 
using the Web Reporting Module. All participating sites are expected to notify the Principal 
Investigator when a DLT has occurred. 
 

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6.3.2 Dose Expansion Treatment Regimen 
 
Regimen Description: Dose Expansion Cohort 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
 
Triapine 
 
Fast (except for water) 
for 2 hours prior to 
dosing and for 1 hour 
after ingesting the oral 
dose  
 
RP2D is 
150mg 
once daily 
 
(dose 
expansion 
cohort) 
 
Oral; 
 
Days 1-14 of 
each cycle; on 
Day 1, within 
90 minutes after 
Lutetium Lu 
177 Dotatate 
treatment. 
8 weeks 
(56 days) 
 
Lutetium Lu 
177 Dotatate 
Administer antiemetics 
30 minutes before the 
recommended amino 
acid solution.  
Administer amino acid 
solution IV 30 minutes 
before Lutetium Lu 
177 Dotatate. 
 
 
200 mCi 
 
IV; 
See 8.2.1 
 
 
Day 1 of 
each cycle 
 
The patient will be requested to maintain a medication diary of each dose of triapine (Appendix 
D).  The medication diary will be returned to clinic staff at the end of each course. 
 
 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
 
There are no known drug interactions with triapine.  The non-radioactive form of lutetium is not 
an inhibitor or inducer of cytochrome P450 (CYP) 1A2, 2B6, 2C9, 2C19 or 2D6 in vitro. It is not 
an inhibitor of P-glycoprotein, BCRP, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, or OCT1 in 
vitro.  Because there is a potential for interaction of triapine with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential for drug interactions.  The study team should 
check a frequently-updated medical reference for a list of drugs to avoid or minimize use of.  
Appendix C (Patient Clinical Trial Wallet Card) should be provided to patients if available. 
 
 

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Risk from Radiation Exposure:  Minimize radiation exposure during and after treatment with 
Lutetium Lu 177 Dotatate consistent with institutional good radiation safety practices and patient 
management procedures. 
 
Myelosuppression:  Monitor blood cell counts.  Withhold, reduce dose, or permanently 
discontinue based on severity.  Please refer to section 7 for specific guidance regarding dose 
modification. 
 
Renal Toxicity: Advise patients to urinate frequently during and after administration of Lutetium 
Lu 177 Dotatate.  Monitor serum creatinine and calculated creatinine clearance.  Withhold, 
reduce dose, or permanently discontinue based on severity.  Please refer to section 7 for specific 
guidance regarding dose modification. 
 
Hepatotoxicity:  Monitor transaminases, bilirubin, and albumin.  Withhold, reduce dose, or 
permanently discontinue based on severity. 
 
Neuroendocrine Hormonal Crisis:  Monitor for flushing, diarrhea, hypotension, broncho- 
constriction, or other signs and symptoms. 
 
 
6.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 4 cycles 
or until one of the following criteria applies: 
 
• 
Disease progression (patient will however be monitored for OS) 
 
• 
Intercurrent illness which would, in the judgment of the investigator, a) affect 
assessments of clinical status to a significant degree, b) require discontinuation of drug, 
or c) both a and b 
 
• 
Unacceptable adverse event(s) 
 
• 
Delay in treatment of more than 6 weeks. 
 
• 
Patient decides to withdraw from the study 
 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
• 
Clinical progression 
 
• 
Patient non-compliance 
 
• 
Pregnancy 
 
o All women of child-bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
• 
Termination of the study by sponsor 
 

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• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
In April-May 2022 there was a global shortage of Lutetium 177 dotatate. Study enrollment and 
treatment was held per NCI CTEP’s recommendation. The study was not affected as all patients 
had received cycle 1 of treatment had cleared DLT window. Delay in treatment due to global 
shortage will not trigger protocol deviation and treatment will resume when drug supply is 
restored. Patient will then get back on treatment schedule per protocol.  
 
 
 
6.6 
Duration of Follow-Up 
 
Patients will be followed for 24 months from the time of enrollment or until death, whichever 
occurs first.  Patients removed from study for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. 
 
 
 
 
 

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7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 
Recommended Dose Modifications of Lutetium Lu 177 Dotatate for Adverse 
Reactions  
 
Adverse Reaction 
Severity of Adverse 
Reaction 
Dose Modification  
Thrombocytopenia  Grade 2, 3, or 4  
Withhold dose until complete or partial resolution 
(Grade 0 to 1).  Resume Lutetium Lu 177 Dotatate at 
100 mCi in patients with complete or partial 
resolution.  If reduced dose does not result in Grade 
2, 3 or 4 thrombocytopenia, administer Lutetium Lu 
177 Dotatate at 200 mCi for next dose.  Permanently 
discontinue Lutetium Lu 177 Dotatate for Grade 2 or 
higher thrombocytopenia requiring a treatment delay 
of 16 weeks or longer.  
Recurrent Grade 2, 3, 
or 4  
Permanently discontinue Lutetium Lu 177 Dotatate.  
Anemia and 
Neutropenia  
Grade 3 or 4  
Withhold dose until complete or partial resolution 
(Grade 0, 1, or 2).  Resume Lutetium Lu 177 
Dotatate at 100 mCi in patients with complete or 
partial resolution.  If reduced dose does not result in 
Grade 3 or 4 anemia or neutropenia, administer 
Lutetium Lu 177 Dotatate at 200 mCi for next dose.  
Permanently discontinue Lutetium Lu 177 Dotatate 
for Grade 3 or higher anemia or neutropenia 
requiring a treatment delay of 16 weeks or longer.  
Recurrent Grade 3 or 
4  
Permanently discontinue Lutetium Lu 177 Dotatate.  
Renal Toxicity  
Defined as:  
• Creatinine clearance 
less than 40 mL/min; 
calculate using 
Cockcroft Gault with 
actual body weight, 
or  
• 40% increase in 
baseline serum 
creatinine, or 
• 40% decrease in 
baseline creatinine 
clearance; calculate 
using Cockcroft 
Gault with actual 
body weight.  
Withhold dose until complete resolution.  Resume 
Lutetium Lu 177 Dotatate at 100 mCi in patients 
with complete resolution.  If reduced dose does not 
result in renal toxicity, administer Lutetium Lu 177 
Dotatate at 200 mCi for next dose.  Permanently 
discontinue Lutetium Lu 177 Dotatate for renal 
toxicity requiring a treatment delay of 16 weeks or 
longer.  

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Adverse Reaction 
Severity of Adverse 
Reaction 
Dose Modification  
Recurrent renal 
toxicity  
Permanently discontinue Lutetium Lu 177 Dotatate.  
Hepatotoxicity  
Defined as:  
• Bilirubinemia 
greater than 3 times 
the upper limit of 
normal (Grade 3 or 
4), or  
• Hypoalbuminemia 
less than 30 g/L with 
a decreased 
prothrombin ratio less 
than 70%.  
• Grade 4 AST or 
ALT elevation 
Withhold dose until complete resolution.  Resume 
Lutetium Lu 177 Dotatate at 100 mCi in patients 
with complete resolution.  If reduced Lutetium Lu 
177 Dotatate dose does not result in hepatotoxicity, 
administer Lutetium Lu 177 Dotatate at 200 mCi for 
next dose.  Permanently discontinue Lutetium Lu 
177 Dotatate for hepatotoxicity requiring a treatment 
delay of 16 weeks or longer.  
Recurrent 
hepatotoxicity  
Permanently discontinue Lutetium Lu 177 Dotatate.  
Other Non-
Hematologic 
Toxicity  
Grade 3 or 4  
Withhold dose until complete or partial resolution 
(Grade 0 to 2).  Resume Lutetium Lu 177 Dotatate at 
100 mCi in patients with complete or partial 
resolution.  If reduced dose does not result in Grade 
3 or 4 toxicity, administer Lutetium Lu 177 Dotatate 
at 200 mCi for next dose.  Permanently discontinue 
Lutetium Lu 177 Dotatate for Grade 3 or higher 
toxicity requiring treatment delay of 16 weeks or 
longer.  
Recurrent Grade 3 or 
4  
Permanently discontinue Lutetium Lu 177 Dotatate.  
 
7.2 
Recommended Dose Modifications of Triapine 
 
Dose modification should follow the triapine dose levels in the dose escalation table in Section 
6.1. 
 
Nausea/vomiting 
Management/Next Dose for Triapine 
≤ Grade 2 
No change in dose.  Treat with antiemetics. 
Grade 3 
Holda until ≤ Grade 2.  Resume at one dose level lower, if 
indicated.  Treat with antiemetics. 
Grade 4 
Off protocol therapyc 
aPatients should hold triapine if N/V refractory to anti-emetic therapy. 
bIf appropriate antiemetic treatment does not resolve toxicity down to grade 2 or less within 72 
hours. 
cOff protocol therapy and continue standard of care treatment per treating physician. 

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Diarrhea 
Management/Next Dose for Triapine 
≤ Grade 2 
No change in dose.  Treat with antidiarrheal therapy. 
Grade 3 
Treat with antidiarrheal therapy.  Holda until ≤Grade 2.  
Resume at one dose level lower, if indicated. 
Grade 4 
Off protocol therapyb 
aPatients should hold triapine if diarrhea refractory to anti-diarrheal (Loperamide is 
recommended).  Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
bOff protocol therapy and continue standard of care treatment per treating physician. 
 
 
Neutropenia 
Management/Next Dose for Triapine 
≤ Grade 2 
No change in dose 
Grade 3 
No change in dose 
Grade 4 
Off protocol therapya 
aOff protocol therapy and continue standard of care treatment per treating physician. 
 
 
Thrombocytopenia 
Management/Next Dose for Triapine 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
No change in dose 
Grade 4 
Off protocol therapya 
aOff protocol therapy and continue standard of care treatment per treating physician. 
 
 
Non-hematologic toxicity 
Management/Next Dose for Triapine 
≤ Grade 1 
No change in dose 
Grade 2 
Holda, b until ≤ Grade 1 (See NOTE below) 
Grade 3 
Holdc until < Grade 1 (See NOTE below) 
Grade 4 
Off protocol therapyb 
aPatients requiring a delay of >2 weeks should go off protocol therapy. 
b Grade 2 hypertension unrelated to study drugs in a patient with history of chronic hypertension 
does not warrant holding treatment. 
cOff protocol therapy and continue standard of care treatment per treating physician.  
NOTE: Decision to maintain dose or resume at dose reduction must be reviewed with study PI. 

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7.2.1 Methemoglobinemia 
 
If patient is symptomatic or has hypoxia (<92%) requiring oxygen, obtain “spot” methemoglobin 
level and serial sampling as clinically indicated (based on symptoms such as but not limited to 
skin discoloration, cyanosis, coma, dysrhythmia, levels can be repeated every 6-8 hours until 
levels <20%).  A repeat spot methemoglobin should be obtained prior to the next triapine dose to 
determine whether dose modification or further treatment is indicated.  Supportive care should be 
provided as clinically indicated. 
 
Please note, it is the trend in the O2 saturation that is of importance. Since pulse oximetry is 
known to be unreliable in the presence of significant methemoglobinemia, weight should not be 
given to a single value alone.  In any case where there is significant doubt, serial spot 
methemoglobins should be obtained (as clinically indicated based on symptoms such as but not 
limited to skin discoloration, cyanosis, coma, or dysrhythmia and levels can be repeated every 6-
8 hours until levels <20%) and consultation as needed. 
 
It is expected that all patients will show a transient rise in methemoglobin (up to 10-15%) while 
on study but unless accompanied by hypoxia, or symptoms (e.g., dyspnea), no changes to 
treatment or dose may be required.  However, for patients not fitting this pattern, the following 
guidelines should be followed: 
 
• If methemoglobin is asymptomatic, <20%, and NOT accompanied by hypoxia (oxygen 
saturation <92%):  treat without change in dose. 
 
• IF methemoglobin >15% lasts more than 3 hours OR if methemoglobin >20% OR 
if oxygen saturation <92%, THEN: obtain arterial blood gases (a pO2 <80 should 
result in hospitalization and will be counted as DLT).  If pO2 normalizes within 24 
hours, retreatment at a lower dose level may be considered by the Principal 
Investigator at UPCI. 
 
Treatment options for methemoglobinemia could include methylene blue, 1-2 mg/kg IV over five 
minutes.  However, methylene blue is contraindicated in patients with glucose-6-phosphate 
(G6PD) deficiency, since its pharmacologic action as an electron carrier in the reduction of 
methemoglobin is itself dependent on the generation of NADPH by G6PD through the hexose 
monophosphate shunt. Thus, methylene blue may be at best ineffective in such patients and may 
have the potential to complicate the clinical situation by provoking hemolysis, although this 
association is less clear. In situations where the use of methylene blue may be contraindicated 
(e.g., in those individuals who are in the high-risk group (patients of African, Asian or 
Mediterranean origin/ancestry), who may have had a false negative G6PD deficiency test, the 
successful use of ascorbic acid (1000 mg IV q6h) has been described. 
 
 

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8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 10.1. 
 
 
8.1 
CTEP IND Agent - Triapine 
 
8.1.1 Triapine (NSC # 663249) 
 
Chemical Name:  3-aminopyridine-2-carboxaldehyde thiosemicarbazone 
 
Other Names:  3-AP 
 
Classification:  Triapine, an α-heterocyclic carboxaldehyde thiosemicarbazone (HCT), is a 
ribonucleotide reductase (RNR) inhibitor that acts on the M2 (R2) subunit.  The HCTs are the 
most potent RNR inhibitors, being 65 -5,000 times more potent than hydroxyurea. 
 
Mechanism of Action:  Ribonucleotide reductase (RNR) inhibitor  
 
CAS Registry Number:  143621-35-6 
 
Molecular Formula:  C7H9N5S  
 
M.W.: 
195 
 
Approximate Solubility: 
Water = 0.1 mg/mL 
 
 
 
Ethanol = 1.25 mg/mL 
 
 
 
PEG-300 = 15 mg/mL 
 
How Supplied:  Triapine Capsules are supplied by Nanopharmaceutics, LLC and distributed by 
the CTEP, DCTD, NCI.  Each triapine Capsule contains 50 mg of triapine in combination with 
Starch 1500 and Magnesium Stearate in a size 1, hard gelatin, white, opaque capsule.  Each 
bottle contains 30 capsules. 
 
Storage: Store triapine Capsules at room temperature 25ºC, excursions permitted to 15ºC to 
30ºC. 
 
If a storage temperature excursion is identified, promptly return triapine Capsules to between 15 
and 30°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Shelf-life stability studies of triapine Capsules are on-going. 
 
Route of Administration:  Oral administration.  Patients will be asked to fast (except for water) 
for 2 hours prior to dosing and for 1 hour after ingesting the oral dose.  Capsules should not be 
opened. 
Availability 
 
Triapine is an investigational agent supplied to investigators by the Division of Cancer Treatment 
and Diagnosis (DCTD), NCI. 
 

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61 
If the study agent is provided by the NCI under a Collaborative Agreement with the agent 
manufacturer, the text below must be included in the protocol.  Information on the study agent’s 
Collaborative Agreement status will be provided in the approved LOI response letter.  
 
Triapine is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 13.5). 
 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
participating investigator at that institution. 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account status, 
a “current” password, and active person registration status.  For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time.  Refer to the 
PMB’s website for specific policies and guidelines related to agent management.   
 
 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.3 Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.1.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 

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62 
http://ctep.cancer.gov/branches/pmb/agent management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
 
8.2 
Commercial Agent - Lutetium Lu 177 Dotatate (NSC 815530) 
 
Product description:   
 
Lutetium Lu 177 Dotatate injection containing 10 mCi/ml of Lutetium Lu 177 Dotatate is a sterile, 
preservative-free and clear, colorless to slightly yellow solution for IV use supplied in a colorless 
Type I glass 30 mL single-dose vial containing 200 mCi ±10% of Lutetium Lu 177 Dotatate at the 
time of injection.  The solution volume in the vial is adjusted from 20.5 mL to 25 mL to provide a 
total of 200 mCi of radioactivity.  Each single-dose vial contains acetic acid (0.48 mg/mL), sodium 
acetate (0.66 mg/mL), gentisic acid (0.63 mg/mL), sodium hydroxide (0.65 mg/mL), ascorbic acid 
(2.8 mg/mL), diethylene triamine pentaacetic acid (0.05 mg/mL), sodium chloride (6.85 mg/mL), 
and Water for Injection (ad 1 mL).  The pH range of the solution is 4.5 to 6. 
 
Solution preparation:   
 
Lutetium Lu 177 Dotatate is a radiopharmaceutical; handle with appropriate safety measures to 
minimize radiation exposure.  Use waterproof gloves and effective radiation shielding when 
handling Lutetium Lu 177 Dotatate.  Radiopharmaceuticals, including Lutetium Lu 177 Dotatate, 
should be used by or under the control of physicians who are qualified by specific training and 
experience in the safe use and handling of radiopharmaceuticals, and whose experience and 
training have been approved by the appropriate governmental agency authorized to license the use 
of radiopharmaceuticals. 
 
 
• Use aseptic technique and radiation shielding when administering the Lutetium Lu 177 
Dotatate solution.  Use tongs when handling vial to minimize radiation exposure. 
 
• Do not inject Lutetium Lu 177 Dotatate directly into any other IV solution. 
 
• Confirm the amount of radioactivity of Lutetium Lu 177 Dotatate in the 
radiopharmaceutical vial with an appropriate dose calibrator prior to and after Lutetium Lu 
177 Dotatate administration. 
 
• Inspect the product visually for particulate matter and discoloration prior to administration 
under a shielded screen.  Discard vial if particulates or discoloration are present. 

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• Insert a 2.5 cm, 20 gauge needle (short needle) into the Lutetium Lu 177 Dotatate vial and 
connect via a catheter to 500 mL 0.9% sterile sodium chloride solution (used to transport 
Lutetium Lu 177 Dotatate during the infusion).  Ensure that the short needle does not touch 
the Lutetium Lu 177 Dotatate solution in the vial and do not connect this short needle 
directly to the patient.  Do not allow sodium chloride solution to flow into the Lutetium Lu 
177 Dotatate vial prior to the initiation of the Lutetium Lu 177 Dotatate infusion and do 
not inject Lutetium Lu 177 Dotatate directly into the sodium chloride solution.  
 
• Insert a second needle that is 9 cm, 18 gauge (long needle) into the Lutetium Lu 177 
Dotatate vial ensuring that this long needle touches and is secured to the bottom of the 
Lutetium Lu 177 Dotatate vial during the entire infusion.  Connect the long needle to the 
patient by an IV catheter that is prefilled with 0.9% sterile sodium chloride and that is used 
exclusively for the Lutetium Lu 177 Dotatate infusion into the patient.  
 
 
Route of administration:  Lutetium Lu 177 Dotatate is administered IV. 
 
• Use a clamp or pump to regulate the flow of the sodium chloride solution via the short 
needle into the Lutetium Lu 177 Dotatate vial at a rate of 50 mL/hour to 100 mL/hour for 
5 to 10 minutes and then 200 mL/hour to 300 mL/hour for an additional 25 to 30 minutes 
(the sodium chloride solution entering the vial through the short needle will carry the 
Lutetium Lu 177 Dotatate from the vial to the patient via the catheter connected to the long 
needle over a total duration of 30 to 40 minutes). 
• Do not administer Lutetium Lu 177 Dotatate as an IV bolus. 
• During the infusion, ensure that the level of solution in the Lutetium Lu 177 Dotatate vial 
remains constant. 
• Disconnect the vial from the long needle line and clamp the saline line once the level of 
radioactivity is stable for at least five minutes. 
• Follow the infusion with an IV flush of 25 mL of 0.9% sterile sodium chloride. 
• Dispose of any unused medicinal product or waste material in accordance with local and 
federal laws. 
 
Storage:  The product vial is in a lead shielded container placed in a plastic sealed container. 
The product is shipped in a Type A package.  Store below 25 °C (77 °F).  The shelf life is 72 
hours.  Discard appropriately at 72 hours. 
 
 
Agent Ordering:  Lutetium Lu 177 Dotatate is commercially available.  For ordering 
information, please visit: https://hcp.lutathera.com/ordering-lutathera/ 
 
Lutetium Lu 177 Dotatate, accompanying amino acid infusion as well as supportive care 
medication can be administered per treating hospital standard operating procedure per standard 
of care, as approved by FDA.  
 
For additional information, please refer to the package insert. 

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64 
 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
This study is a multicenter phase 1 trial of triapine and Lutetium Lu 177 Dotatate in combination 
for well-differentiated somatostatin receptor-positive GEP-NETs after the failure of at least one 
line of prior systemic cancer treatment.  An expansion cohort with 14 additional patients will be 
enrolled at the RP2D to further assess safety, obtain initial estimates of clinical response outcomes, 
and perform exploratory comparisons of biomarkers.   
 
The primary objective of the phase 1 trial is to determine the MTD and identify the RP2D of 
triapine in combination with Lutetium Lu 177 Dotatate.  The Bayesian optimal interval design 
(BOIN) (Yuan et al., 2016) will be employed to guide dose escalation.  DLT is defined in Section 
6.2 and will be assessed after the first cycle (8 weeks post treatment).  Patients will be enrolled in 
cohorts of 3 beginning at dose level 1.  A target DLT rate of 25% will be assumed with dose 
escalation, λe, and de-escalation boundaries, λd, set at 0.197 and 0.298, respectively.  Based on the 
BOIN design, dose escalation will proceed as shown in the table below until a total of 15 patients 
have been enrolled in the dose escalation part of this phase 1 trial.  MTD and RP2D will be 
estimated using isotonic regression based on toxicity data from all patients.   
 
Dose escalation and de-escalation boundaries Table 
Number of patients 
treated at the current 
dose: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 
Escalate if DLTs  
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
De-escalate if DLTs  1 
1 
1 
2 
2 
2 
3 
3 
3 
3 
4 
4 
4 
5 
5 
 
An expansion cohort with 14 additional patients will be enrolled at the RP2D to further assess 
safety, obtain initial estimates of clinical response outcomes, and perform exploratory comparisons 
of biomarkers.  Assuming that the minimum number of patients enrolled at the RP2D is equal to 
17, the proposed sample size from the phase 1 portion and expansion cohort will produce a two-
sided 95% exact confidence interval with a width equal to 0.44, when the DLT rate is 0.25.   
 
 
Interim Analysis for Phase 1 (Dose escalation) 
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least bi-monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical Officer(s) 
to review accrual, progress, adverse events, and unanticipated problems.  DLT will be assessed as 
defined in Section 6.2 using CTCAE version 5.0 which will be assessed after the first cycle for 
each patient enrolled in the trial.  The dose escalation and cohort sizes are specified in the table 
above.  Automated triggers developed by the Biostatistics and Bioinformatics Shared Resource at 
Markey Cancer Center (MCC) will be run after each patient is enrolled in order to perform real-
time evaluation of DLT to make recommendations to the study team to implement the dose 

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investigators and with CTEP whether further addition of patients is needed to re-assess the RP2D; 
isotonic regression will also be utilized to estimate the DLT rate.  Monitoring of all safety and 
toxicity data is done by the PI and the Corresponding Organization on a real-time basis as data are 
entered into Medidata Rave using the Web Reporting Module.  All participating sites are expected 
to notify the PI when a DLT has occurred. 
 
9.5 
Analysis of Secondary and Correlative Endpoints 
 
ORR will be estimated along with 95% exact binomial confidence interval.  PFS and OS will be 
estimated using the Kaplan-Meier curve and median estimates and confidence intervals will be 
calculated.  Correlative endpoints such as radiographic expression of somatostatin receptors and 
changes from pre to post-treatment will be summarized using descriptive statistics and changes 
from baseline vs. follow-up time points will be assessed using paired test methodologies.  WES 
data will be processed using the data processing and data analysis pipelines from the Biostatistics 
and Bioinformatics shared resource of MCC to identify candidate mutated genes with adjustment 
for false discovery rate.  PK analysis will be performed and PK parameters will be estimated from 
patients enrolled in the dose escalation portion of the phase 1 trial.  PK parameters will be 
compared with historical controls, and exploratorily, we may correlate exposure to toxicity, and 
incorporate data into a population PK model.  Krenning score from the Gallium-68 Dotatate (or 
Copper-64 Dotatate) will be summarized by calculating the proportion of patients in each Krenning 
score category and exploratory assessments for association with clinical response (ORR) will be 
performed using Fisher’s exact test.  Median, interquartile range will be calculated for quantitative 
image measurements from Gallium-68 Dotatate (or Copper-64 Dotatate) and exploratory 
comparison of levels with clinical response (ORR) will be performed using two sample t-test or 
nonparametric analogs.  Mean change in deoxynucleosides between baseline and post treatment 
samples will be assessed by paired t-test or other methods. Deoxynucleoside plasma concentration 
as a predictor of clinical outcomes will explored by linear (progression free survival) and logistic 
regression (response). 
 
Correlative endpoint analyses will be based on patients who received the RP2D from the dose 
escalation portion and expansion cohort. See details in Sections 6.3 and 9.4 for RP2D.  
 
 
 

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Other (hypertonia); Musculoskeletal and connective tissue disorder - Other (leg cramps); Musculoskeletal 
and connective tissue disorder - Other (myoglobin); Musculoskeletal and connective tissue disorder - 
Other (twitching); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Amnesia; Cognitive disturbance; Depressed level of consciousness; 
Dysesthesia; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Nervous system disorders - 
Other (cerebellar toxicity); Nervous system disorders - Other (reflexes decreased); Paresthesia; 
Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delayed orgasm; Delirium; Depression; Insomnia; 
Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Hematuria; Urinary 
frequency; Urinary tract pain; Urine discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Genital edema; Vaginal 
hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Apnea; Epistaxis; Hiccups; Laryngospasm; Pleural effusion; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Erythema multiforme; Hirsutism; 
Hyperhidrosis; Photosensitivity; Pruritus; Skin and subcutaneous tissue disorders - Other (Skin nodule); 
Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hematoma; Phlebitis; Thromboembolic event; Vascular disorders - Other 
(pallor); Vascular disorders - Other (vasodilation) 
 
Note: Triapine in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 
10.1.2 CAEPR for Lutetium Lu 177 dotatate  – Version 2.0, October 22, 2020 
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Lutetium Lu 177 dotatate (NSC 815530) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is 
identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 1326 patients. Below is the CAEPR for 
Lutetium Lu 177 dotatate. 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
 

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syndrome 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment 
related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Ischemia cerebrovascular; Stroke; Transient ischemic attacks 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Hematuria; Nephrotic 
syndrome; Renal and urinary disorders - Other (urethral stenosis); Renal hemorrhage; Urinary frequency; Urinary 
incontinence; Urinary retention; Urinary tract obstruction 
SURGICAL AND MEDICAL PROCEDURES - Surgical and medical procedures - Other (aortic valve 
replacement); Surgical and medical procedures - Other (atherectomy); Surgical and medical procedures - Other 
(atrial septal defect repair); Surgical and medical procedures - Other (bladder catheterization); Surgical and medical 
procedures - Other (cardiac ablation); Surgical and medical procedures - Other (cardiac pacemaker insertion); 
Surgical and medical procedures - Other (cardioversion); Surgical and medical procedures - Other (coronary 
angioplasty); Surgical and medical procedures - Other (coronary arterial stent insertion); Surgical and medical 
procedures - Other (coronary artery bypass); Surgical and medical procedures - Other (dialysis); Surgical and 
medical procedures - Other (heart valve operation); Surgical and medical procedures - Other (hemodialysis); 
Surgical and medical procedures - Other (pulmonary valve replacement); Surgical and medical procedures - Other 
(tricuspid valve repair); Surgical and medical procedures - Other (tricuspid valve replacement)  
VASCULAR DISORDERS - Hypertension; Hypotension; Vascular disorders - Other (atherosclerosis) 
 
 
Note: Lutetium Lu 177 dotatate in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
 
10.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
− 
Adverse events for the agent that are bold and italicized in the CAEPR (i.e., those 
listed in the SPEER column, Section 10.1) should be reported through CTEP-AERS 
only if the grade is above the grade provided in the SPEER. 
 
• Attribution of the adverse event: 
− 
Definite – The adverse event is clearly related to the study treatment. 
− 
Probable – The adverse event is likely related to the study treatment. 
− 
Possible – The adverse event may be related to the study treatment. 
− 
Unlikely – The adverse event is doubtfully related to the study treatment. 
− 
Unrelated – The adverse event is clearly NOT related to the study treatment. 
 
 
 
 

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10.3 
Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting, and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting.    
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event form, 
which is available for entry at each treatment or reporting period, and used to collect AEs that start 
during the period or persist from the previous reporting period.  CRA will enter AEs that occur 
prior to the start of treatment on a baseline form that is not included in the Rave-CTEP-AERS 
integration.  AEs that occur prior to enrollment must begin and end on the baseline Adverse Event 
form and should not be included on the standard Adverse Events form that is available at treatment 
unless there has been an increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-free.  
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs that 
meet reporting requirements.  The CRA completes the report by accessing CTEP-AERS 
via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be made 
to CTEP by telephone at 301-897-7497.  Once internet connectivity is restored, the 24-
hour notification that was phoned in must be entered immediately into CTEP-AERS using 
the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
 

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75 
• Study specific documents:  Protocols > Documents > Education and Promotion, 
and   
• Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU 
Operations Information > User Guides & Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguid
elines.pdf. 
 
10.3.2 Distribution of Adverse Event Reports 
 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial registration 
on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality as long as the death occurred within 30 days after the last administration of the 
investigational agent.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
 
 
 
 
 

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10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  Adverse events reported 
expeditiously through CTEP-AERS must also be reported in routine study data submissions 
in Medidata Rave. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  Adverse events are reported in a routine manner at scheduled 
times during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for 
routine adverse event reporting in Rave. 
 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and submitted 
to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of consent to 90 
days after the last dose of study drug must be reported and then followed for outcome.  Newborn 
infants should be followed until 30 days old.  Please see the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” (at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on how to 
report pregnancy and its outcome to CTEP.  
 
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is 
not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to describe 
the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine adverse 
event reporting unless otherwise specified 

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78 
 
11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 30 days prior to start of protocol therapy.  Scans and x-rays must be done <4 weeks 
prior to the start of therapy.  In the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy.  
 
 
Screening 
Pre-treatment a 
Cycle 1 (8 weeks) 
Cycle 2 (8 weeks) 
Cycle 3 (8 weeks) 
Cycle 4 (8 weeks) 
Disease Progression 
Follow-Up and    
Off-Treatment Visits b,c 
Day 
1c 
Day 
9 
Day 
14 c 
Day 
15 c 
Day 
29 c 
Day 
43 c 
Days 
44-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Triapine 
 
 
A------------------A 
 
 
 
 
A---------A 
 
 
A--------A 
 
 
A--------A 
 
 
 
 
Lutetium Lu 177 
Dotatate 
 
 
B 
 
 
 
 
 
 
B 
 
 
 
B 
 
 
 
B 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
 
X---------------------------------------------------------------------------------------------X 
 
 
Physical exam 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Vital signs 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Performance status d 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
CBC w/diff, plts 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Comprehensive 
Chemistry Panel e 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10388 
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79 
 
Screening 
Pre-treatment a 
Cycle 1 (8 weeks) 
Cycle 2 (8 weeks) 
Cycle 3 (8 weeks) 
Cycle 4 (8 weeks) 
Disease Progression 
Follow-Up and    
Off-Treatment Visits b,c 
Day 
1c 
Day 
9 
Day 
14 c 
Day 
15 c 
Day 
29 c 
Day 
43 c 
Days 
44-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Ga-DOTATATE 
PET/CT Scan f  
(or 64-Cu 
DOTATATE 
PET/CT scan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
 
X---------------------------------------------------------------------------------------------X 
 
X 
Radiologic 
evaluation     
(CT/MRI Scan) g 
Xh  
 
Radiologic measurements should be performed every 8 weeks in the dose escalation cohort. 
Radiologic measurements should be performed every 12 weeks in the dose expansion cohort.  
 
X 
Pregnancy test i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-Hour Urine 
5HIAA  j 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X j 
 
Xj 
 
blood collection 
(EDTA) for 1.3.3 – 
frozen blood will be 
biobanked for future 
analysis in lieu of 
hPG80 assay 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ctDNA blood 
collection (Streck) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X k 
 
Deoxyribonucleosid
es blood collection  
(EDTA) l 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tumor tissue 
collection m 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood    
collection n 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10388 
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80 
 
Screening 
Pre-treatment a 
Cycle 1 (8 weeks) 
Cycle 2 (8 weeks) 
Cycle 3 (8 weeks) 
Cycle 4 (8 weeks) 
Disease Progression 
Follow-Up and    
Off-Treatment Visits b,c 
Day 
1c 
Day 
9 
Day 
14 c 
Day 
15 c 
Day 
29 c 
Day 
43 c 
Days 
44-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Methemoglobin 
Level by peripheral 
venous blood o 
 
 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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81 
 
STUDY CALENDAR NOTES:  
 
A: 
Triapine: Dose as assigned on Days 1-14 of each cycle.  Cycle length = 8 weeks 
                                 The recommended Phase 2 Dose of Triapine was determined to be: 150mg once a day on Days 1-14 of each cycle. Cycle length = 8 weeks  
        
B: 
Lutetium Lu 177 Dotatate:  200 mCi IV, Day 1 of each cycle for a total of 4 doses.  Cycle length = 8 weeks. 
 
 
 
 
a: 
Pre-treatment collections should be preferably collected on a separate day from screening, but may be collected on the same day at the discretion of the site. 
 
b: 
Follow-up checks and surveillance CT/MRI scans to be conducted every 3-months for 24 months from the time of enrollment or until death, whichever occurs first.  Patients removed from 
study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.  Additional scan not needed at the end-of-study visit.  
 
c:    Cycles 1-4 visit windows: Days 9,14 +/- 2 days. All other visits +/- 3 days.   
                Visit windows for Follow-up (Q3-mos visits):   3 weeks visit windows.  
                The following exception applies to visit windows: Dosing of Lu-177 dotatate cannot be given prior to scheduled date. It can be delayed per visit windows in appropriate situations.  
 
d:     Performance status evaluations should be evaluated every 4 weeks. 
 
e: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
 
f: 
To be performed if NETSPOT, DETECTNET (64Cu dotatate scan) or Octreoscan has not been performed within 6 months. 
 
g:    7 days +/- window is allowed for scans to accommodate logistical issues in obtaining timely scans for unforeseeable circumstances.  
 
h:  
To confirm progression within the last 3 years. 
 
i:  
Pregnancy test for women of childbearing potential. 
 
 
j:      24-Hour Urine 5HIAA should be collected prior to dosing Lutetium Lu-177 dotatate. 24 Hr Urine 5HIAA should be collected unless in exceptional circumstances that patient cannot collect or 
        deliver a 24-Hr sample, alternative 5HIAA assessment per institutional standard can be allowed.  
        5HIAA will also be collected at the end of PRRT treatment (clinic visit for Cycle 4 Day 29) or at disease progression, whichever happens first.  If patient does not receive all 4 doses of PRRT  
        then 24 Hr Urine 5HIAA can be collected at the end-of-treatment visit for that particular patient.    
 
 
k:  
Optional collection. 
 
 
 
l:      Two 8mL K2 EDTA white top tubes will be collected at three timepoints for all participants on C1D1 (pre-treatment), on C2D1 (pre-treatment), and at disease progression.   
 
 
 
m:  If archival tissue within the last 6 months is not available, a fresh biopsy will be mandatory. 
 
 

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82 
 
Screening 
Pre-treatment a 
Cycle 1 (8 weeks) 
Cycle 2 (8 weeks) 
Cycle 3 (8 weeks) 
Cycle 4 (8 weeks) 
Disease Progression 
Follow-Up and    
Off-Treatment Visits b,c 
Day 
1c 
Day 
9 
Day 
14 c 
Day 
15 c 
Day 
29 c 
Day 
43 c 
Days 
44-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
Day 
1 c 
Day 
14 c 
Day 
29 c 
Days 
30-56 
 
n:  
PKs: To be collected in the dose-escalation cohort only. 
 
PK time points on Cycle 1, Day 9 (+/- 1 day) include: Pre, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours.  
PK WINDOWS:   
Pre dose: within 30 minutes  
30 minutes: +/- 5 minutes 
60 minutes: +/- 5 minutes    
1 hour 30 minutes: +/- 5 minutes 
2 hours: +/-  5 minutes 
3 hours: +/-  10 minutes 
4 hours: +/-  10 minutes 
6 hours: +/- 10 minutes 
8 hours: +/- 10 minutes 
 
o: Methemoglobin: to be collected in dose-escalation cohort only, on Cycle 1 Day 1 and Cycle 1 Day 9.  
              Methemoglobin timepoint on Cycle 1 Day 1 is pre-treatment.  
              Methemoglobin timepoints on Cycle 1 Day 9 (+/- 1 day) include: Pre, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours, i.e., blood is to be drawn at each of the PK blood draws.  
                              Methemoglobin Windows for C1D9 are:  
 Pre dose: within 30 minutes  
30 minutes: +/- 5 minutes 
60 minutes: +/- 5 minutes    
1 hour 30 minutes: +/- 5 minutes 
2 hours: +/-  5 minutes 
3 hours: +/-  10 minutes 
4 hours: +/-  10 minutes 
6 hours: +/- 10 minutes 
  8 hours: +/- 10 minutes 
 
 

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83 
 
12. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of these drugs has not yet been established, the intent of offering this 
treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability.  Patients 
with measurable disease will be assessed by standard criteria.  For the purposes of this study, 
patients should be re-evaluated every 8 weeks.  In addition to a baseline scan, confirmatory scans 
(CT or MRI) will also be obtained 8 weeks (+/- 7 days), following initial documentation of an 
objective response. 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 8 weeks following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with study treatment. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least three cycle of therapy, and have had their disease re-evaluated post-
baseline will be considered evaluable for response.  These patients will have their response 
classified according to the definitions stated below.  Patients who exhibit objective disease 
progression prior to the end of Cycle 1 will also be considered evaluable.  
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
24-Month Progression-Free Survival:  24-month PFS is defined as the percentage of patients alive 
with no evidence of radiological progression per RECIST 1.1 at 24 months from the time of 
enrollment.  
 
 Overall survival:  OS is defined as the time from date of enrollment to the date of death due to 
any cause.  

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84 
 
12.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might not be considered 
measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in follow-up, only the short 
axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] short 
axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  

NCI Protocol #: 10388 
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85 
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice thickness 
greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation is not 

NCI Protocol #: 10388 
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86 
advised.  However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET.  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that 
site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring.  
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication.  However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
 
 

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87 
12.1.4 Response Criteria 
 
12.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
 
12.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 

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88 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 

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89 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from registration to time of progressive disease as defined 
by RECIST 1.1 criteria or death from any cause, whichever occurs first. 
 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for adverse event reporting can be found in 
Section 10 (Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious 
adverse events; reporting of expedited adverse events; and accumulation of reported adverse 
events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, or 
more frequently, conference calls with the Study Investigators and the CTEP Medical Officer(s) 
to review accrual, progress, and adverse events and unanticipated problems.  
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.   
Requirements to access Rave via iMedidata: 

NCI Protocol #: 10388 
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90 
 
• 
A valid account, and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.   
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an 
Associate Plus (AP) registration type, 
o Rave Investigator role, must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 
o Rave Read Only role, site staff must have at a minimum an Associates (A) 
registration type. 
• 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from iMedidata 
to activate their account.  Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.  
 
13.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 

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approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm)  and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will be 
included when appropriate to meet unique study requirements.  The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by the 
CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly basis.  
The trial’s lead institution is responsible for timely submission to CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm). 

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13.3 Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics.  
 
The DQP is located on the CTSU members’ website under Data Management.  The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries.  DQP 
Queries, DQP Delinquent Forms, and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, and timeliness reports.  Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website.  Staff that have Rave study access can access the Rave study data using a direct link on 
the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, and DQP Delinquent Forms modules. 
 
Note:  Some Rave protocols may not have delinquent form details or reports specified on the 
DQP.  A protocol must have the Calendar functionality implemented in Rave by the Lead Protocol 
Organization (LPO) for delinquent form details and reports to be available on the DQP.  Site staff 
should contact the LPO Data Manager for their protocol regarding questions about Rave 
Calendaring functionality.  
 
13.4 
CTEP Multicenter Guidelines 
 
N/A 
 
 
13.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of the 

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NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement.  A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  

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Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings.  Press releases and 
other media presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 
 
 
 

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Boons G, Vandamme T, Peeters M, et al.  (2018).  Cell-free DNA from metastatic pancreatic 
neuroendocrine tumor patients contains tumor-specific mutations and copy number variations.  
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receptor (sst1-sst5) expression in normal human tissue: Correlation of sst2 mRNA and SUVmax.  
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and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and 
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Caplin ME, Pavel M, Cwikla JB, et al.  (2014).  Lanreotide in metastatic enteropancreatic 
neuroendocrine tumors.  N Engl J Med.  371(3):224-33. PMID: 25014687 
 
Chao J, Synold TW, Morgan RJ, et al.  (2012).  A phase I and pharmacokinetic study of oral 3-
aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of 
advanced-stage solid cancers: A California Cancer Consortium Study.  Cancer Chemother 
Pharmacol.  69(3):835-43. PMID: 22105720 
 
Chauhan A, Yu Q, Ray N, et al.  (2018).  Global burden of neuroendocrine tumors and changing 
incidence in Kentucky.  Oncotarget.  9(27):19245-54. PMID: 29721198 
 
Chauhan A, Prieur A, Kolesar J, Arnold A, Payen L, Mahi Y, Vire B, Sands M, Evers B.M., 
Joubert D, Anthony L. hPG80 (Circulating Prograstin), a Novel Blood-Based Biomarker for 
Detection of Poorly Differentiated Neuroendocrine Carcinoma and Well Differentiated 
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Cremonesi M, Ferrari M, Grana CM, et al.  (2007).  High-dose radioimmunotherapy with 90Y-
ibritumomab tiuxetan: Comparative dosimetric study for tailored treatment.  J Nucl Med.  
48(11):1871-79. PMID: 17978355 
 
Dasari A, Shen C, Halperin D, et al.  (2017).  Trends in the incidence, prevalence, and survival 
outcomes in patients with neuroendocrine tumors in the United States.  JAMA Oncol.  
3(10):1335-42. PMID: 28448665 
 
Drug, Lutathera. Package Insert.  (2018).  LUTATHERA.  Advanced Accelerator Applications 

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USA, Inc. 
 
Drug, Triapine. Investigator’s Brochure.  (2018).  Triapine® Oral Capsules (3-Aminopyridine-2-
Carboxaldehyde Thiosemicarbazone or 3-AP).  Version 22 October 2018.  Nanopharmaceutics, 
LLC.  Rensselaer, NY. 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al.  (2009).  New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1).  Eur J Cancer.  45(2):228-47.  
PMID: 19097774 
 
Green RC, Berg JS, Grody WW, et al. (2013). American College of Medical Genetics and 
Genomics recommendations for reporting of incidental findings in clinical exome and genome 
sequencing.  Genet Med.  15(7):565-74. PMID: 23788249 
 
Kalia SS, Adelman K, Bale SJ, et al.  (2016).  Recommendations for reporting of secondary 
findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy 
statement of the American College of Medical Genetics and Genomics.  Genet Med.  19(2):249-
55. PMID: 27854360 
 
Kunos CA, Andrews SJ, Moore KN, et al. (2019). Randomized Phase II Trial of Triapine-
Cisplatin-Radiotherapy for Locally Advanced Stage Uterine Cervix or Vaginal Cancers. 
Frontiers in oncology. 9:1067. PMCID: PMC6803528 
 
Kunos CA, Chiu SM, Pink J, et al.  (2009).  Modulating radiation resistance by inhibiting 
ribonucleotide reductase in cancers with virally or mutationally silenced p53 protein.  Radiat 
Res.  172(6):666-76. PMID: 19929413 
 
Kunos CA, Colussi VC,  Pink J, et al. (2011a). Radiosensitization of human cervical cancer cells 
by inhibiting ribonucleotide reductase: Enhanced radiation response at low-dose rates. 
International journal of radiation oncology, biology, physics. 80(4): 1198-204. PMID: 21470790 
 
Kunos CA, Ferris G, Pyatka N, et al. (2011b). Deoxynucleoside salvage facilitates DNA repair 
during ribonucleotide reductase blockade in human cervical cancers. Radiation research. 176(4): 
425-33. PMID: 21756082 
 
Kunos CA, Ivy SP. (2018). Triapine radiochemotherapy in advanced stage cervical cancer. 
Frontiers in oncology. 8:149.  PMID: 29868473 
 
Kunos CA, Radivoyevitch T, Pink, J, et al. (2010). Ribonucleotide reductase inhibition enhances 
chemoradiosensitivity of human cervical cancers. Radiation research. 174(5): 574-81.  
PMID: 20954859 
 
Kunos CA, Radivoyevitch T, Waggoner S, et al.  (2013).  Radiochemotherapy plus 3-
aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage 
cervical and vaginal cancers.  Gynecol Oncol.  130(1):75-80. PMID: 23603372 
 
Kunos CA, Waggoner S, von Gruenigen V, et al.  (2010).  Phase I trial of pelvic radiation, 

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weekly cisplatin, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC 
#663249) for locally advanced cervical cancer. Clin Cancer Res. 16(4):1298-1306.  
PMID: 20145183 
 
Kvols, LK, Moertel CG, O'Connell MJ, et al.  (1986).  Treatment of the malignant carcinoid 
syndrome: Evaluation of a long-acting somatostatin analogue.  N Engl J Med.  315(11):663-66. 
PMID: 2427948 
 
Kwekkeboom DJ, de Herder WW, Kam BL, et al.  (2008).  Treatment with the radiolabeled 
somatostatin analog [177Lu-DOTA0,Tyr3] octreotate: toxicity, efficacy, and survival.  J Clin 
Oncol.  26(13):2124-30. PMID: 18445841 
 
Matsumoto J, Kiesel BF, Parise RA, et al.  (2017).  LC-MS/MS assay for the quantitation of the 
ribonucleotide reductase inhibitor triapine in human plasma.  J Pharm Biomed Anal.  146:154-
60. PMID: 28881312 
 
Modlin IM, Kidd M, Bodei L, et al.  (2015).  The clinical utility of a novel blood-based multi-
transcriptome assay for the diagnosis of neuroendocrine tumors of the gastrointestinal tract.  Am 
J Gastroenterol.  110(8):1223-32.  PMID: 26032155 
 
Panarelli N, Tyryshkin K, Wong JJM, et al.  (2019).  Evaluating gastroenteropancreatic 
neuroendocrine tumors through microRNA sequencing.  Endocr Relat Cancer.  26(1):47-57.  
PMID: 30021866 
 
Pavel M, Jann H, Prasad V, et al.  (2017).  NET blood transcript analysis defines the crossing of 
the clinical rubicon: When stable disease becomes progressive.  Neuroendocrinology.  
104(2):170-82. PMID: 27078712 
 
Rinke A, Muller HH, Schade-Brittinger C, et al.  (2009).  Placebo-controlled, double-blind, 
prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in 
patients with metastatic neuroendocrine midgut tumors: A report from the PROMID Study 
Group.  J Clin Oncol.  27(28):4656-63. PMID: 19704057 
 
Starr J, Mody K, Roberts A, Kasi P.  (2019).  Circulating tumor DNA analysis of neuroendocrine 
tumors.  J Clin Oncol.  37(15 supplement):e15698.  
 
Strosberg J, El-Haddad G, Wolin E, et al.  (2017).  Phase 3 trial of 177Lu-Dotatate for midgut 
neuroendocrine tumors.  N Engl J Med.  376(2):125-35.  PMID: 28076709 
 
van der Zwan WA, Bodei L, Mueller-Brand J, et al.  (2015).  GEPNETs update: Radionuclide 
therapy in neuroendocrine tumors.  Eur J Endocrinol.  172(1):R1-8. PMID: 25117465 
 
 
 
van der Zwan WA, Brabander T, Kam BLR, et al.  (2019).  Salvage peptide receptor 
radionuclide therapy with [177Lu-DOTA,Tyr3]octreotate in patients with bronchial and 

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gastroenteropancreatic neuroendocrine tumours.  Eur J Nucl Med Mol Imaging.  46(3)704-17. 
PMID: 30267116 
 
Walter D, Harter PN, Battke F, et al.  (2018).  Genetic heterogeneity of primary lesion and 
metastasis in small intestine neuroendocrine tumors.  Sci Rep.  8(1):3811. PMID: 29491456 
 
Yao JC, Fazio, Singh S, et al.  (2016).  Everolimus for the treatment of advanced, non-functional 
neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): A randomised, 
placebo-controlled phase 3 study.  Lancet.  387(10022):968-77. PMID: 26703889 
 
Yao JC, Garg A, Chen D, et al.  (2019).  Genomic profiling of NETs: a comprehensive analysis 
of the RADIANT trials.  Endocr Relat Cancer.  26(4):391-403. PMID: 30667365 
 
Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR.  (2016).  Bayesian optimal interval design: A 
simple and well-performing design for phase I oncology trials.  Clin Cancer Res.  22(17):4291-
301. PMID: 27407096 
 
 
 

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

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APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING SERUM 
CREATININE 
 
Formula to estimate renal function using serum creatinine provided by the NCI’s Investigational Drug 
Steering Committee (IDSC) Pharmacological Task Force in table below. 
 
1. Estimated creatinine clearance (ClCr) by the Cockcroft-Gault (C-G) equation (Cockcroft and 
Gault, 1976). 
 
 
Followed by conversion to a value normalized to 1.73 m2 with the patient’s body surface area 
(BSA). 
 
References 
1. Cockcroft, D.W. and M.H. Gault.  (1976).  Prediction of creatinine clearance from serum 
creatinine.  Nephron.  16:31-41. 
 

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APPENDIX D 
PATIENT’S MEDICATION DIARY – ONCE DAILY (QD) 
 
 
 
PATIENT’S MEDICATION DIARY 
 
     Today’s date _______________________________ 
Agent _______Triapine_______________ 
     Patient Name_________________________ (initials acceptable) Patient Study ID _____________________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle.  Each cycle is 8 weeks. 
2. 
You will take your dose of triapine every day for the first 14 days of the cycle.  You will take ____ 50 mg capsules every day 
for the first 14 days of the cycle.  You need to fast (except for water) for 2 hours prior to dosing and for 1 hour after ingesting 
the oral dose.  You should swallow the capsule whole.  Do not open the capsules or take capsules until the bottle is empty. 
3. 
Record the date, the number of capsules you took, and when you took them.   
4. If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please return the forms to your physician when you go for your next appointment. 
 
Day 
 
Date 
What time was 
dose taken? 
# of capsules taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
Do not take triapine after Day 14 of each cycle 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment____________________________________________________________________ 
2. 
Date patient was removed from study_____________________________________________________________________ 
3. 
Patient’s planned total daily dose________________________________________________________________________ 
4. 
Total number of pills taken this month (each size)___________________________________________________________ 
5. 
Physician/Nurse/Data Manager’s Signature and Date_________________________________________________________ 
 
    Patient’s 
signature:____________________________________________________________________________________ 
 
CTEP-assigned Protocol # 10388 
 
Local Protocol # ___________________ 

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APPENDIX E 
PRE-BIOPSY ASSESSMENT 
 
A pre-biopsy lesion assessment can increase trial safety and efficiency.  By agreement between all 
investigators, an attempt at biopsy will be made if the clinical trial team determines that a biopsy 
poses minimal relative risk, provides potential clinical gain to the participant, and will likely yield 
sufficient tissue for analysis.   
 
Pre-biopsy assessments will be reported and tracked through a trial-specific CRF within the CTEP 
Medidata Rave system.  Additional information can be found in the Investigational Radiology SOP 
available at:   
https://ctep.cancer.gov/initiativesPrograms/docs/ETCTN IR Research Biopsy SOP.pdf.  
 
Individual Patient Pre-Biopsy Assessment.  IR co-investigators are encouraged to apply this pre-
biopsy scoring and correlation system to assist in the determination of biopsy appropriateness. 
 
• IR co-investigators assign a subjective score of 1-3 based on likelihood of success due to 
lesion characteristics.  
 
1.  Biopsy should not be done  
A. Due to safety concerns 
B. Due to lack of suitable lesion for biopsy 
 
2.  Uncertainty about success  
A. Due to access path to lesion 
B. Due to lesion characteristics  
 
3.  Likely successful  
 
• Lesion characteristics to be considered 
• Size (small) (<2 cm) 
• Location/path to lesion 
• Morphologic features (necrosis, sub-solid, sclerosis, ill-defined/infiltrative) 
• PET (+/-), avidity  
• Organ/site (sclerotic bone is low yield; fine needle aspiration to be used) 
 
 

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APPENDIX G 
IMAGE ACQUISITION AND ANALYSIS 
 
Image Acquisition: 
Contrast Computed Tomography:  All pretreatment and post treatment imaging will include CT scans 
with the following parameters: 
Liver protocol triple phase spiral CT studies including arterial, portal venous and 3 minutes delayed 
phases with image of the abdomen and pelvis acquired from base of lungs, above diaphragm, and includes 
the entire liver to iliac crest + a single phase from above diaphragm to symphysis pubis  (shown in figure 
1). Scan parameters detailed in Table 1.  Images will be reconstructed with thick (3-5 mm) and thin (1-1.5 
mm) slice thickness. 
 
Table 1: CT acquisition parameters 
 
Contrast CT 
Non-contrast CT*  
Contrast 
Omnipaque 350 
None 
Ref kV* 
120 
120 
Ref. mAs 
150-200 
88 
Care kV 
On 
On 
Pitch 
0.6-1 
1.5 
FOV 
400 
500 
* Part of the PET/CT acquisition; kV= KiloVolt; mAs=Milli-Ampere second; 
FOV=Field of View 
 
Positron Emission Tomography PET/CT: All patients will undergo at least 
one 68Ga-DOTATATE PET/CT scan (or one 64-Cu Dotatate scan). 
No specific patient preparations were required. Our study protocol was 
developed according to the SNMMI guidelines. Sixty minutes after the 
intravenous administration of a weight-based 68Ga-DOTATATE activity (0.054 
mCi/kg; or after administration of a 64-Cu Dotatate per FDA approved dosing), 
both PET and CT images of the torso from vertex to mid-thigh (Figure 1) will be 
acquired with the patient in supine position and arms placed above head. Patients 
will be asked to evacuate the bladder prior to scan acquisition. 
CT images will be acquired without iodinated contrast administration with 
parameters illustrated in Table 1. Images with 5 mm slice thickness will be 
reconstructed using a standard soft tissue reconstruction kernel (standard filtered 
back projection B30s). 
Following CT image acquisition, List-mode 3-dimensional PET images will be acquired with the 
following parameters; acquisition time of 4 minutes per table position, 168 x168 matrix and 50 x 50 cm 
FOV. CT-based attenuation correction was performed. After decay and scatter correction, PET data were 
reconstructed using ordered-subsets expectation maximization (OSEM) with 2 iterations and 8 subsets 
using the algorithm. 
 
 
 
 
Figure 3: 
Illustration of CT 
scan coverage. 
Green lines 
represent CT 
coverages and red 
lines represent 
PET/CT coverage. 

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Measurability of Tumor at Baseline 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as follows: 
• 
Measurable tumor lesions: Must be accurately measured in at least one dimension (longest  
• 
diameter in the plane of measurement is to be recorded) on CT scan (CT scan slice thickness no 
greater than 5 mm) with a minimum size of 
• 
Lesions: 10 mm longest diameter. 
• 
Lymph nodes: 15 mm in short axis. 
• 
Non-measurable lesions: Non-measurable are all other lesions, including small lesions (longest 
diameter <10mm or pathological lymph nodes with ≥10 to <15mm short axis) as well as truly 
non-measurable lesions.  
▪ 
Leptomeningeal disease 
▪ 
Ascites 
▪ 
Pleural or pericardial effusion 
▪ 
Inflammatory breast disease 
▪ 
Lymphangitic involvement of skin or lung 
▪ 
Abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
Specifications by Methods of Measurements 
Measurement of Lesions: All measurements should be recorded in metric notation, using calipers if 
clinically assessed.  
 
Method of Assessment: The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
 
 
Tumor Response Evaluation 
• 
Assessment of Overall Tumor Burden and Measurable Disease: To assess objective response 
or future progression, it is necessary to estimate the overall tumor burden at baseline and use this 
as a comparator for subsequent measurements. Only patients with measurable disease at baseline 
should be included in protocols where objective tumor response can be assessed. Measurable 
disease is defined by the presence of at least one measurable lesion.  
• 
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions: When more than one 
measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a 
maximum of two lesions per organ) representative of all involved organs should be identified as 
target lesions and will be recorded and measured at baseline (this means in instances where 
patients have only one or two organ sites involved a maximum of two and four lesions 
respectively will be recorded). Target lesions should be selected on basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. 
 
 
 
 

NCI Protocol #: 10388 
Version Date: 17.May.2023 
109 
 
APPENDIX H 
TISSUE BIOPSY VERIFICATION 
 
 
A copy of the diagnostic pathology report must be shipped with all tissue specimens sent to the 
EET Biobank. 
 
If the corresponding pathology report is not available for the biopsy, then a copy of the 
radiology report or operative report from the biopsy procedure and the diagnostic 
pathology report must be sent to the EET Biobank. A completed copy of this appendix (i.e., 
Tissue Biopsy Verification) must also be submitted to the EET Biobank. 
 
Note: If this information is not provided with the biopsy specimen, then it will not be accepted by 
the EET Biobank. 
 
 
Please have the Clinician* responsible for signing out this patient’s case complete the following: 
 
ETCTN Universal Patient ID:  
 
 
ETCTN Patient Study ID:   
 
 
Date of Procedure (mm/dd/yyyy):   
 
 
Tissue Type (circle one): 
Primary 
Metastatic 
 
Time point (circle one):  Baseline 
 
Site Tissue Taken From:   
 
 
Diagnosis:   
 
 
I agree that this tissue may be released for research purposes only and that the release of this 
tissue will not have any impact on the patient’s care. 
 
 
 
Clinician Signature 
Date 
 
 
 
Clinician Printed Name 
 
*Note: For the purposes of this form, Clinician could include the Nurse Practitioner, Registered Nurse, Pathologist, 
Radiologist, Interventional Radiologist, Surgeon, Oncologist, Internist, or other medical professional responsible for 
the patient’s care.  
 
Version: 1 
Effective Date: 9/2019