Clinical trial NCT03273712
Conditions: Neuroendocrine Tumors Meningioma Neuroblastoma Medulloblastoma
Sponsor: University of Iowa
Start date: 2017-09-29; Completion date: 2020-05-27
Enrollment: 39 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2 peptide receptor radionuclide therapy trial of 90Y-DOTATOC in patients with somatostatin receptor positive tumors.

Detailed description:
This is a Phase 2 peptide receptor radionuclide therapy trial of 90Y-DOTATOC in patients with somatostatin receptor positive tumors. The somatostatin receptor targeting of the therapeutic will be checked with 68Ga-DOTATOC PET-CT imaging prior to therapy. Treatment consists of 3 cycles, 6-8 weeks apart. Cycle 1 dose is fixed with Cycles 2 and 3 doses to be determined by dosimetry-based calculation of renal doses from previous cycles not to exceed 23 Gy for the total renal dose.

The goals of this project are to

1. Demonstrate the safety and efficacy of dosimetry-guided peptide receptor radiotherapy using 90Y-DOTA-tyr3-Octreotide in patients with neuroendocrine and other somatostatin receptor expressing tumors.
2. Monitor all adverse events associated with peptide receptor radiotherapy using 90Y-DOTATOC.
3. Establish 68Ga-DOTA-tyr3-Octreotide (68Ga-DOTATOC) or 68Ga-DOTATATE PET/CT as an accurate technique for diagnosis, staging, treatment targeting, and monitoring response to 90Y-DOTATOC therapy.

Arms: arm 1: Patients will receive 3 doses of 90YDOTATOC followed by 90Y-DOTATOC PET scans, with 6 -8 weeks between doses. They will be followed for 6-9 months after the last treatment dose. CT or MRI scans will be given at the 3 month and 6-9 month followups plus a 68Ga-DOTATOC or DOTATATE PET scan at the 6-9 month followup. The exact dose of 90YDOTATOC therapy for each patient will be determined by dosimetry.
Interventions: intervention 1: 90Y-DOTA tyr3-Octreotide intervention 2: 68Ga-DOTATOC PET Positron Emission Tomography (PET) whole body scan intervention 3: Amino Acids
Intervention descriptions: intervention 1: 90Y-DOTATOC is a radiopharmaceutical that will be used as a treatment for both children and adults with neuroendrocrine and other somatostatin receptor positive tumors. intervention 2: 68Ga-DOTATOC is a radiopharmaceutical used in PET scans to identify tumors as it can adhere to Somatostatin Receptors. intervention 3: This is a solution of amino acids that will decrease the amount of 90Y-DOTATOC that recirculates through the body after injection, therefore decreasing the radiation dose to the kidneys.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 Phase II,  
Dosimetry-Guided, Peptide Receptor Radiotherapy (PRRT) with  
90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) in Children and Adults  
with Neuroendocrine and other Somatostatin Receptor Expressing Tumors  
 
 
Dosimetry guided PRRT with 90Y-DOTATOC 
 
 
 
Co-Principal Investigators:  Yusuf Menda, MD and M Sue O’Dorisio, MD, PhD 
 
Co-Investigators: 
 
Thomas O’Dorisio, MD 
Joseph Dillon, MD 
Chandrikha Chandrasekharan, MD 
Len Watkins, PhD 
Dijie Liu, PhD 
Kristin Gaimari-Varner, RN 
Kellie Bodeker, MS 
David Bushnell, MD 
Janet Pollock, MD 
Michael Graham, PhD, MD 
Parren McNeely, MD 
John Sunderland, PhD 
Shannon Lehman, BA 
Mark Madsen, PhD 
Gideon Zamba, PhD 
 
Document type: PROTOCOL FOR IND #61,907 
Version number: 5 
IRB# 201708778  
Date: August 19, 2019 
 
 
 


2 
 
Project Goals 
Demonstrate safety and efficacy of dosimetry-guided peptide receptor radiotherapy using 90Y-DOTA-tyr3-
Octreotide in patients with neuroendocrine and other somatostatin receptor expressing tumors. 
 
Monitor all adverse events associated with peptide receptor radiotherapy using 90Y-DOTATOC. 
 
Schema 
 
Phase II,  
Dosimetry-Guided, Peptide Receptor Radiotherapy (PRRT) with  
90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) in Children and Adults  
with Neuroendocrine and other Somatostatin Receptor Expressing Tumors  
 
Screening period Pathology diagnosis of Neuroendocrine Tumor with slides available 
High resolution, contrast enhanced CT or MRI within 120 days of Cycle 1 
68Ga-DOTATATE PET/CT within 6 months of Cycle 1 
No treatment other than Sandostatin or Lanreotide between CT (MRI) and 68Ga-DOTATATE PET and Cycle 1 
Treatment Cycles   
and Followup 
        Imaging and Treatment Schedule 
Initial 
90Y-DOTATOC 
Dose  
Cumulative 
90Y-DOTATOC 
Dose 
Cumulative 
Renal  
Radiation 
Cycle 1 
Week 1  
 
Day 1 
 
Physical exam with height, weight, vitals, labs,         
med list, GFR, pregnancy test; QOL questionnaire 
 
Start 18 hrs IV/PO fluids  
 
 
 
 
Day 2 
90Y-DOTATOC + IV amino acids  
 
Continue IV/PO fluids for 48 hrs                    
50 mCi/m2 
in children; 
120 mCi in 
adults 
120 mCi 
maximum 
 
Day 4 
90Y-DOTATOC PET/CT 
 
 
 
Cycle 2 
Week 
7-9 
Day1 
Physical exam with height, weight, vitals, labs,         
med list, GFR, pregnancy test 
 
Start 18 hrs IV/PO fluids 
 
 
 
Day2 
 90Y-DOTATOC + IV amino acids 
 
Continue IV/PO fluids for 48 hrs                    
Dosimetry  
determined 
270 mCi       
maximum 
  
 
 
 
Day4 
90Y-DOTATOC PET/CT  
 
 
 
Cycle 3 
Week 
13-17 
Day 1 
Physical exam with height, weight, vitals, labs,         
list, GFR, pregnancy test 
 
Start 18 hrs IV/PO fluids 
 
 
 
Days 2-3 90Y-DOTATOC + IV amino acids 
  
Continue IV/PO fluids for 48 hrs   
Dosimetry  
determined 
420 mCi 
maximum 
≤ 23 Gy   
FU 
3 months 
after  
treatment 
Physical exam with height, weight, vitals, labs,         
med list, GFR; QOL questionnaire,                           
CT (MRI) 
 
 
 
6-9 month
after 
treatment 
Physical exam with height, weight, vitals, labs,         
med list, GFR; diagnostic CT (MRI) 
 
68Ga-DOTATOC PET/CT; 
 
 
 


3 
 
 
 
 
 
 
TABLE OF CONTENTS  
 
 
1. 
Background 
  4 
2. 
Project Goals 
  7 
3. 
Hypotheses 
  7 
4. 
Objectives 
  7 
5. 
Eligibility and Exclusion Criteria 
  7  
6. 
Imaging and Treatment Plan including dosimetry measurements 
  9 
7. 
Calendar of Tests and Procedures 
12 
8. 
Duration of Therapy and Stopping Rules 
13 
9. 
Regulatory and Expected Adverse Event reporting 
13 
10. 
Dose Modifications and Delays 
15 
11. 
Response Criteria 
16 
12. 
Statistical Analysis 
17 
13. 
Study Drugs 
18 
14. 
Data Reporting 
22 
15. 
References 
22 
 
 
 
Appendix 1: Amendment—Single Time Point Dosimetry 
 
Appendix 2:  Data Safety Monitoring Plan 
 
 
 
 
 
 
 
Appendix 3:  Data Forms 
 
 
 
 
 
 
 
 
 
Appendix 4:  QoL Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


4 
 
1.0 Background and Rationale 
 
1.1 Somatostatin Receptor Positive Tumors 
Neuroendocrine tumors are solid malignant tumors that arise from dispersed neuroendocrine cells found 
throughout the body. Gastroenteropancreatic neuroendocrine tumors (NETs) can be divided into two groups: 
Carcinoid tumors that may arise from the lungs, stomach, small bowel or colon and pancreatic 
neuroendocrine tumors (also known as pancreatic islet cell tumors). The clinical behavior of NETs is 
extremely variable; some may cause hormone hypersecretion and others may not, the majority of them are 
slow-growing tumors (well-differentiated NETs), whereas some NETs are highly aggressive (poorly 
differentiated NETs). The incidence of NETs is increasing, from 1.1/100,000 per year in 1973 to 5.3/100,000 
per year in 20041. Among NETs, 25% have distant metastases and 25% have regional involvement at the 
time of initial diagnosis1.  Other tumors that express high levels of somatostatin receptors include 
neuroblastoma and medulloblastoma2-4. 
 
The radiological detection and staging of these tumors is challenging and requires a multimodality approach. 
Somatostatin receptor imaging with In-111 Pentetreotide (OctreoScan) and multiphase CT are the most 
commonly used modalities although the use of endoscopic ultrasound and MRI is rapidly increasing. Surgery 
is the only curative option for NETs. However, curative surgery in malignant NET is possible in less than 30% 
of patients with recurrence identified in the majority of patients as late as 15 years after initial surgery. 
Treatment with somatostatin analogs, which include the short acting subcutaneous and long acting release 
(LAR) octreotide as well as long acting lanreotide, are effective in stabilizing NETs and have been recently 
demonstrated to prolong the time to progression of disease5,6. Chemotherapy is generally not effective in low 
grade NETs, but it may be helpful in high grade and pancreatic NETs.  On the other hand, neuroblastoma 
and medulloblastoma are initially responsive to chemotherapy, but relapses are common and salvage 
therapies are not very effective, resulting in <30% overall survival at 5 years7-9. 
 
1.2 Somatostatin Receptor Targeted Imaging  
Tumors that express somatostatin receptors can be targeted with radiolabeled somatostatin analogues for 
imaging and treatment (Figure 1), making theranostics using peptide analogs of somatostatin feasible by 
labeling with one radionuclide for imaging and the same or a different radionuclide for therapy.  
Somatostatin receptor gamma camera imaging with In-111 DTPA-octreotide (OctreoScan) targeting 
somatostatin receptor 2 (SSTR2), is used routinely for imaging of neuroendocrine tumors with a detection 
rate >90% for well-differentiated carcinoid tumors and majority of pancreatic NETs, but only a 50% detection 
rate for insulinomas, which may show a weaker expression of SSTR210.   Over 90% of neuroblastoma tumors 
express somatostatin receptors11; they can be imaged with Octreoscan and they respond to 90Y-DOTATOC 
therapy12,13.  Medulloblastoma has recently been categorized into four genetic categories, each one of which 
includes tumors which express somatostatin receptors, but no category is 100% positive for somatostatin 
receptor expression14-16.  We have also imaged medulloblastoma using Octreoscan12. 
More recently, positron emission tomography (PET) radiopharmaceuticals have been developed that can be 
labeled with Gallium-68 (Ga-68). Gallium-68 is a generator product with a half-life of 68 min (compared to 67 
hours for In-111 in OctreoScan). The parent nuclide of Ga-68 is Germanium-68, which has a half-life of 270.8 
days. Ga-68 decays by 89% through positron emission and 11% by electron capture.  Another advancement 
has been the identification of DOTA as a superior chelator compared to DTPA, increasing the stability and 
receptor targeting of somatostatin analogues17. 
A number of Ga-68 DOTA-conjugated peptides have been introduced, including 68Ga-DOTATOC, Ga-68 
DOTA0-1NaI3-octreotide (68Ga-DOTANOC) and Ga-68 DOTA0-Tyr3-octreotate (68Ga-DOTATATE). All of 
these radiolabeled peptides bind to sstr2, although DOTANOC also binds to sstr3 and sstr5, and DOTATOC 
to sstr518. The primary advantage of Ga-68 based somatostatin receptor PET imaging over OctreoScan 
SPECT is the higher imaging resolution and accurate quantification of uptake due to robust attenuation 
correction. The improved resolution and quantification of uptake obtained with 68Ga-DOTATOC PET should 
provide a more accurate assessment of somatostatin receptor density, which will lead to a more accurate 
prediction of treatment response to somatostatin analogues. A recent study from Europe comparing 68Ga-
DOTATOC with Octreoscan found 68Ga-DOTATOC to be superior in detection of skeletal and pulmonary 
involvement of neuroendocrine tumors19.  We have now published a study of the reproducibility of 68Ga-
DOTATOC PET in our institution. 


5 
 
1.3  68Ga-DOTATOC PET in staging disease for patients with metastatic neuroendocrine tumors. 
Given the clinical efficacy of peptide analogs of somatostatin as a diagnostic agent, studies to test if 
therapeutic radiation could be targeted to tumors in a similar manner was a logical next step. Attempts to 
utilize In-111 DTPA Octreotide as a therapeutic agent have been minimally effective due to the short range of 
auger electrons utilized in this therapy. The efficacy of sstr2 targeted treatment was improved with the 
development of somatostatin analogues labeled with beta emitting radioisotopes.  
 
90Yttrium-DOTA complexes are extremely stable; the dissociation constant for this complex is approximately 
10-25 M. The high stability of the 90Y-DOTA chelated complex is a major advantage.  Additionally, 90Yttrium is 
a high-energy beta minus particle-emitter with a physical half-life of 64.1 h and a mean range of 5 mm in 
tissue, permitting effective treatment of tumors with heterogeneous sstr2 expression due to bystander effects.  
90Yttrium is commercially available in sufficient amounts and in a no-carrier-added form that allows the 
preparation of a radioligand with high specific activity.  
 
There is now a large clinical experience with 90Y-DOTATOC peptide radioreceptor therapy (PRRT) in Europe, 
primarily in adults with neuroendocrine tumors20. An international Phase II clinical trial then followed and 
included several trial sites in the United States, notably the University of Iowa; we entered 40 subjects21. With 
its low toxicity profile, the significant improvement in symptoms and quality of life and the lack of effective 
alternative therapies, PRRT has been suggested as possible first-line therapy in adult patients with 
neuroendocrine tumors. Recent data have also demonstrated a significant survival benefit with PRRT 
compared to historical controls in this population21. We have now conducted a Phase I trial of 90Y-DOTATOC 
in children and young adults at the University of Iowa, which also shows promise of efficacy of this treatment 
in pediatric patient population13.   
 
 
 
 
 
 
 
 
Figure 2.  Chemical identity of 90Y- DOTATOC and 68Ga-DOTATOC  
Figure 1: Conceptual representation of 
targeted molecular imaging and therapy of 
cancerous tumors. A cell surface receptor is 
identified that is upregulated in cancerous 
tumor cell relative to normal surrounding tissue 
and organs. A peptide vector is developed that 
binds with high affinity and specificity to the 
molecular target. A chelator is added to the 
targeting vector via a molecular linker. The 
chelator can be used to couple a positron 
emitter as the reporter signal for PET, or with a 
beta emitting radionuclide (e.g., 90Y) for 
molecular therapy.  To be effective, the high 
binding affinity of the vector for the target 
antigen and the stable high specific activity 
radiometallation must be maintained after 
placement of the chemical linker.  


6 
 
1.4  Somatostatin Receptor Targeted Therapy 
Known as peptide receptor radionuclide therapy (PRRT), this molecularly targeted internal radiation has been 
utilized in Europe for nearly 20 years.  The two main radiopharmaceutical agents are 90Y-DOTATOC and 
177Lu-DOTATATE, both targeting sstr2.  The response rates are very similar with very few complete 
responses, 20-30% partial responses, and greater than 50% stable disease among patients who have 
progressed on other therapies22,23.  The time to progression following PRRT, for these patients with 
progressive metastatic neuroendocrine tumors has been 36-48 months compared to 5-7 months with 
everolimus or sunitinib24,25.  
 
The normal organ at greatest risk for toxicity with 90Y-DOTATOC is the kidney21,23,26,27.  In our previous Phase 
II trial in adults and our Phase I trial in children, we were able to decrease renal toxicity with amino acid 
infusion and hydration13,21,28.  This trial is designed to utilize dosimetry to maximize radiation dose to tumor 
while minimizing renal toxicity. 
1.5  Study design 
This is a Phase 2 peptide receptor radionuclide therapy trial of 90Y-DOTATOC in patients with somatostatin 
receptor positive tumors. The somatostatin receptor targeting of the therapeutic will be checked with 68Ga-
DOTATOC PET-CT imaging prior to therapy. Treatment consists of 3 cycles, 6-8 weeks apart. Cycle 1 dose 
is fixed with Cycles 2 and 3 doses to be determined by dosimetry-based calculation of renal doses from 
previous cycles not to exceed 23 Gy for the total renal dose.  
 
68Ga-DOTATOC PET imaging and 90Y-DOTATOC peptide receptor radionuclide therapy (PRRT) are readily 
available in Europe, but neither radiopharmaceutical is approved for use in the United States. We are 
presently conducting a safety and efficacy trial of 68Ga-DOTATOC PET in adults and children under IND# 
114,398, that to date has included over 220 subjects with no serious adverse events. We have conducted a 
single institution Phase I trial of 90Y-DOTATOC therapy in children and young adults under IND# 61,907 with 
no serious adverse events13, and we have participated in a Phase II trial of 90Y-DOTATOC PRRT in adults, 
also with no dose limiting toxicities21.  
 
The total radiation dose to kidneys with PRRT using 90Y-DOTATOC is currently limited to ≤ 23 Gy for both 
children and adults.  Several reports, including dosimetry performed on children in our Phase I trial, have 
suggested that this dose limit can safely be raised to as high as 35 Gy to kidneys when performing 
individualized dosimetry measurements to guide therapeutic dosing of 90Y-DOTATOC 26,29,30.  We have 
considerable expertise in the development of theoretical models for dosimetry31, as well as experience in 
performing dosimetry in individual patients13,32.  These studies demonstrated a wide variation in renal dose, 
both between patients and between cycles in any given individual.  In this Phase II therapeutic trial, we 
therefore propose to perform dosimetry for each patient during the first and second cycles of therapy.  The 
method for performing the dosimetry will take advantage of a positron decay component of Yttrium-90 that 
will allow quantification of radiation dose using PET imaging to measure rate of 90Y-DOTATOC into kidneys, 
coupled with semi-quantitative measurement of bremsstrahlung energy using single photon emission 
tomography (SPECT) to follow the body clearance of 90Y-DOTATOC over 72 hrs after injection of the 
therapeutic dose.  
 
We are currently conducting an imaging trial at the request of the FDA, to compare the efficacy of 68Ga-
DOTATOC PET + a low dose CT with 111In-DTPA-tyr3-Octreotide (Octreoscan) SPECT/CT + a high 
resolution, contrast enhanced CT (or MRI).  There are 3 major advantages of 68Ga-DOTATOC PET/CT over 
Octreoscan SPECT/CT: 1) lower dose of radiation using Gallium-68 (T½=68 min) versus Indium-11 (T½=2.8 
day); 2) greater sensitivity of PET compared to SPECT imaging; and 3) 68Ga-DOTATOC PET/CT can be 
completed in a single, 3-hr visit whereas Octreoscan requires 2 visits over a 24 hr period. We now propose to 
utilize 68Ga-DOTATOC (or 68Ga-DOTATATE) and 90Y-DOTATOC in a dosimetry-guided theranostics trial for 
both children and adults with neuroendocrine and other somatostatin receptor positive tumors.   
 
 


7 
 
 
2.0 Project Goals  
 
2.1  Demonstrate safety and efficacy of renal uptake dosimetry-guided peptide receptor radiotherapy 
(PRRT) using 90Y-DOTA-tyr3-Octreotide  (90Y-DOTATOC) in patients with neuroendocrine and other 
somatostatin receptor expressing tumors. 
 
2.2  Monitor all adverse events associated with peptide receptor radiotherapy using 90Y-DOTATOC. 
 
2.3  Establish 68Ga-DOTA-tyr3-Octreotide (68Ga-DOTATOC) or 68Ga-DOTATATE PET/CT as an accurate 
technique for diagnosis, staging, treatment targeting, and monitoring response to 90Y-DOTATOC 
therapy. 
 
3.0 Hypotheses  
 
3.1 Hypotheses: 
1.  We hypothesize that dosimetry-guided, individual dosing of 90Y-DOTATOC will provide excellent tumor 
response. 
 
2. We hypothesize that individual, dosimetry-guided dosing of 90Y-DOTATOC will provide maximum safe 
dose to tumor and minimize renal toxicity while limiting renal radiation dose to ≤ 23 Gy. 
3. We hypothesize that 68Ga-DOTATOC or 68Ga-DOTATATE PET/CT will accurately stage extent of 
disease at study entry and accurately measure response to therapy at six months following last 90Y-
DOTATOC treatment. 
4. We hypothesize that both quantitative PCR and semi-quantitative immunohistochemical analysis of 
somatostatin receptor 2 (sstr2) expression on the first diagnostic biopsy of neuroendocrine tumor will 
positively correlate with standard uptake value (SUV) of that subject’s first 68Ga-DOTATOC or 68Ga-
DOTATATE PET scan at study entry. 
4.0 Objectives 
 
4.1 Primary Objectives 
1. Quantify number of CR, PR, MR, SD and progressions in response to dosimetry-guided PRRT 
utilizing RECIST 1.1 criteria and 68Ga-DOTATOC or 68Ga-DOTATATE PET to evaluate efficacy of 90Y-
DOTATOC therapy in children and adults with neuroendocrine and other somatostatin receptor 
positive tumors.  
2. Monitor renal, hematologic, and clinical toxicities associated with dosimetry-guided 90Y-DOTATOC 
PRRT while maximizing total tumor dose and limiting total renal dose of 90Y-DOTATOC to ≤ 23 Gy.  
4.2 Secondary Objectives   
1. For those subjects who participated in the Comparator study of 68Ga-DOTATOC versus Octreoscan + 
conventional imaging using high-resolution, contrast-enhanced CT or MRI (IRB# 201212736), the 
intent is to determine response to therapy of lesions identified by 68Ga-DOTATOC PET/CT but not 
identified on Octreoscan as a confirmatory measure of true positivity of the Ga-68 DOTATOC avid 
lesion.  
2. Determine if Standard Uptake Value (SUV) on initial 68Ga-DOTATOC/TATE PET imaging correlates 
with SSTR2 expression as measured by quantitative messenger RNA (qPCR) or 
immunohistochemistry (IHC) on the diagnostic biopsy specimen. 
5.0 Eligibility Criteria 
 
5.1 Inclusion Criteria 
1. Disease not amenable to standard treatment (nonresectable or disease present after one or more 
surgeries and/or Sandostatin treatment) or subject has failed existing first line chemotherapy, biologic 
therapy, targeted agent therapy or radiation therapy.  
2. Participation in Iowa Neuroendocrine Tumor Registry.    


8 
 
3. A pathologically confirmed (histology or cytology) malignant neoplasm with at least one target lesion 
that is confirmed by conventional imaging and is determined to express somatostatin receptors by 
68Ga-DOTATOC (TATE) PET within 6 months prior to treatment with 90Y-DOTATOC. 
4. The target lesion is one that either has never received external beam radiation or has been previously 
irradiated and has since demonstrated progression.  Any local irradiation of the target lesion or any 
non-target lesions via external beam, conformal or stereotactic radiation treatments must have 
occurred more than 4 weeks prior to study drug administration.  Any full cranial-spinal radiation, 
whether or not a target lesion is included in the field, must have occurred more than 3 months prior to 
study drug administration.  
5. Life expectancy > 2 months at the time of study drug administration. 
6. Archival tissue from a previous biopsy will be required.   
7. Age ≥ 6 months-90 years at the time of study drug administration.   
8. Performance status as determined by Karnofsky ≥ 60 or Lansky Play Scale ≥ 60% at the time of study 
drug administration.  
9. Completion of Norfolk Quality of Life Questionnaire. 
 
10. Within 7-10 days of study drug administration, patients must have normal organ and marrow function 
as defined below: 
- 
absolute neutrophil count 
>1000/mm3 
- 
Platelets 
>90,000/mm3 
- 
total bilirubin 
<3X ULN for age  
- 
AST(SGOT) & ALT(SGPT) 
<10X institutional upper limit of normal for age 
- 
Urinalysis 
no greater than 1+ hematuria or proteinuria 
- 
Renal function* 
Adults(age18 or >): Serum creatinine ≤ 1.2 
mg/dl; if serum creatinine is >1.2 mg/dL,  
nuclear GFR will be measured. 
GFR will need to be ≥ 80 ml/min/1.73m2 for 
subjects ≤40 years old,  
≥ 70 ml/min/1.73m2 for subjects between 41-50; 
≥ 60 ml/min/1.73m2 for subjects between 51-60;  
≥ 50 ml/min/1.73m2 for subjects > 60 years old. 
 
Children(age <18): nuclear GFR ≥ 80 
mL/min/1.73 m2  
* Renal function criteria based on our previous experience with 90Y-DOTATOC therapy and known 
changes in GFR with age13,21,33-35 
11. The effects of 90Y-DOTA-tyr3-Octreotide on the developing human fetus are unknown. For this reason 
and because Class C agents are known to be teratogenic, women and men of child-bearing potential 
must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study 
entry and for the duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician immediately. 
12. Ability to understand and the willingness to sign a written informed consent document. 
 
5.2 Exclusion Criteria 
1. Pregnant women are excluded from this study because 90Y-DOTATOC is a Class C agent with potential 
teratogenic or abortifacient effects.   
2. Because there is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with 90Y-DOTATOC, breastfeeding should be discontinued until 6 weeks after 
the last administration of study drug. 
3. Surgery within 4 weeks of study drug administration.  
4. External beam radiation to both kidneys (scatter doses of <500 cGy to a single kidney or radiation to < 
50% of a single kidney is acceptable). 


9 
 
5. Prior PRRT with 90Y-DOTATOC (TATE) or 177Lu-DOTATOC (TATE) or 131I-MIBG therapy for this 
malignancy. 
6. Another investigational drug within 4 weeks of study drug administration. 
7. Concurrent, malignant disease for which patient is on active therapy.    
8. Another significant medical, psychiatric, or surgical condition which is currently uncontrolled by treatment 
and which would likely affect the subject's ability to complete this protocol.  
9. Any subject for whom, in the opinion of their physician, a 12-hour discontinuation of somatostatin 
analogue therapy represents a health risk.  Also subjects who have received SandostatinLAR in the past 
28 days or long-acting lanreotide within the past 8 weeks are excluded.  Subjects may be maintained on 
short acting octreotide during the time from last injection of long-acting somatostatin analogue until 12 
hrs prior to injection of study drug. Known antibodies to Octreotide, Lanreotide, or DOTATOC or history 
of allergic reactions attributed to compounds of similar chemical or biologic composition to 90Y-
DOTATOC. 
10. Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) of study 
drug administration or those who have not recovered from adverse events due to agents administered 
more than 4 weeks earlier. 
11. Uncontrolled illness including, but not limited to ongoing or active infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
  12. Subject weighs more than 450 pounds. (Subjects who weigh more than 450 pounds will not be able to fit  
        inside the imaging machines.) 
  13. Inability to lie still for the entire imaging time (due to cough, severe arthritis, etc.) 
 
5.3 Inclusion of Women and Minorities 
 
Both male and female children and adults as well as members of all ethnic groups are eligible for this trial.  
The proposed study population is illustrated in the table below.    
 
Race and Ethnicity of Children and Adults with Neuroendocrine or other 
Somatostatin Receptor Positive Tumors Referred to UIHC Specialty Clinics 
Year 
2009 
2010 
2011 
2012 
2013 
2014 
 
 
 
 
 
 
 
Solid Tumors 
40 
38 
61 
41 
45 
Pending 
 
 
 
 
 
 
 
Male 
29 
20 
32 
16 
21 
 
Female 
11 
18 
29 
25 
24 
 
 
 
 
 
 
 
 
Hispanic Ethnicity 
2 
1 
3 
4 
3 
 
 
 
 
 
 
 
 
African American 
2 
2 
2 
1 
6 
 
 
 
 
 
 
 
 
American Indian 
0 
0 
0 
0 
0 
 
 
 
 
 
 
 
 
Pacific Islander 
0 
0 
0 
0 
3 
 
 
 
 
 
 
 
 
White 
36 
35 
55 
36 
33 
 
 
 
 
 
 
 
 
Other* 
 
1 
1 
0 
1 
 
 
 
 
 
 
 
 
The 2010 US Census reports the following minorities living in Iowa: 3.2% African-American, 0.1% Native 
Hawaiian/Pacific Islanders, 0.5% American Indian/Alaskan native, 2.0% Asian, and 5.3% Hispanic.  
 
 
6.0 Imaging and Treatment Plan 


10 
 
 
Phase II,  
Dosimetry-Guided, Peptide Receptor Radiotherapy (PRRT) with  
90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) in Children and Adults  
with Neuroendocrine and other Somatostatin Receptor Expressing Tumors  
 
Treatment Cycles      
and Followup 
        Imaging and Treatment Schedule 
Initial 
90Y-DOTATOC 
Dose  
Cumulative 
90Y-DOTATOC 
Dose 
Cumulative 
Renal  
Radiation 
Cycle 1 
Week 1  
 
Day 1 
 
Physical exam with height, weight, vitals, labs,      
list, GFR, pregnancy test; QOL questionnaire 
 
Start 18 hrs IV/PO fluids  
 
 
 
 
Day 2 
90Y-DOTATOC + IV amino acids  
 
Continue IV/PO fluids for 48 hrs                    
50 mCi/m2 
in children; 
120 mCi in 
adults 
120 mCi 
maximum 
 
Day 4 
90Y-DOTATOC PET/CT 
 
 
 
Cycle 2 
Week 
7-9 
Day 1 
Physical exam with height, weight, vitals, labs,      
med list, GFR, pregnancy test 
 
Start 18 hrs IV/PO fluids 
 
 
 
Day 2 
 90Y-DOTATOC + IV amino acids 
 
Continue IV/PO fluids for 48 hrs                    
Dosimetry  
determined 
270 mCi       
maximum 
  
 
 
 
Day 4 
90Y-DOTATOC PET/CT  
 
 
 
Cycle 3 
Week 
13-17 
Day 1 
Physical exam with height, weight, vitals, labs,      
list, GFR, pregnancy test 
 
Start 18 hrs IV/PO fluids 
 
 
 
Days 2-3 
90Y-DOTATOC + IV amino acids 
  
Continue IV/PO fluids for 48 hrs   
Dosimetry  
determined 
420 mCi 
maximum 
≤ 23 Gy   
FU 
3 months  
after  
treatment 3 
Physical exam with height, weight, vitals, labs,      
med list, GFR; QOL questionnaire,                        
diagnostic CT (MRI) 
 
 
 
6-9 months 
after 
treatment 3 
Physical exam with height, weight, vitals, labs,      
med list, GFR; diagnostic CT (MRI) 
 
68Ga-DOTATOC PET/CT; 
 
 
 
 
 
Treatment consists of 3 cycles, 6-8 weeks apart. Cycle 1 dose is fixed.  Cycles 2 and 3 doses will be  
determined by dosimetry-based calculation of renal doses from previous cycles; total renal dose ≤ 23Gy.  
 
6.1 Delivery of Therapeutic Infusion 
 
90Y-DOTA-tyr3-Octreotide and amino acid infusions will be administered on Day 2 of each treatment 
cycle.  A large IV, either 20 gauge peripheral IV or a PICC line, will be inserted to provide free flow of the 
hyperosmolar amino acid solution, thus avoiding local inflammation with risk of blistering.  Amino acid 
infusion will begin 30 min prior to infusion of 90Y-DOTATOC and continue 3.5 hrs after infusion of 
radiotherapeutic drug.   If rate of amino acid infusion is decreased due to nausea, the length of infusion 


11 
 
may be longer than 3.5 hrs. There will be rescue Sandostatin available (subcutaneous bolus of 200 µgm 
(200 µgm/mL)) in case of carcinoid crisis after 90Y-DOTATOC infusion has been completed. 
 
6.2 Methods for Dosimetry Estimates 
Renal dosimetry: Each subject will have renal 90Y-DOTATOC time-of-flight (TOF) PET/CT images taken 
within approximately 48 hours (40-56 hours) after the administration of 90Y-DOTATOC. 
 
Bone Marrow dosimetry: Blood dosimetry will be performed as a surrogate of bone marrow dosimetry. 
Blood samples will be obtained prior to start of Amino Acid infusion, again within 1-4 hours after 
administration of 90Y-DOTATOC and at 48 hrs (40-56 hrs). 
 
6.3 Measurement of Renal Dose 
 
The following information is required to estimate the dose to the kidneys: 
a) An estimate of the radioactivity accumulated in the kidneys, 
b) The kinetics of the radioactivity, and 
c) The size (mass) of the kidneys. 
 
The renal accumulation of the radiopharmaceutical will be measured with Y-90 DOTATOC time-of-flight PET-
CT imaging.  A standard of Y-90 will be also imaged. PET images will be reconstructed with an OSEM 
iterative algorithm that incorporates the time of flight information. The kidney mass will be obtained from CT 
images.  
 
The methods of kinetic analysis of the renal clearance of Y-90 DOTATOC is modified based on our previous 
experience. Our analysis of 47 prior administrations demonstrate that the renal clearance of Y-90 DOTATOC 
follows a biexponential pattern with the majority of the radiation exposure to the kidneys coming from the slow 
(long) component of clearance after the initial fast elimination. The rate constant of the slow component was 
gaussian distributed with a standard deviation less than 30% of the mean. This allows us to use a population 
based rate constant for slow clearance adjusted based on the uptake at 48 hours. The estimated renal 
radiation dose using this approach shows excellent correlation with the measured radiation dose (See 
Appendix 1t: Single Timepoint Dose Estimate for Exponential Clearance) and allows for a clinically feasible 
personalized treatment dosimetry with one follow-up visit after 48 hours of treatment administration. The 
information on renal uptake, renal mass and residence time will be entered into OLINDA software to calculate 
the radiation dose.  
 
The Phase II studies of 90Y-DOTA-tyr3-Octreotide administered to adults suggest that the safe range of <23 
Gy for radiation to kidneys delivered by external beam radiation, is more likely 30-35 Gy when delivered as 
divided doses of targeted internal radiation58.  Furthermore, there were no dose limiting renal toxicity events 
in children or young adults enrolled in the Phase I study.  Nevertheless, because of the young age of 
pediatric subjects described in Aim 1, we limited the total dose to kidneys, including any previous external 
beam radiation to < 23 Gy.  The dose to kidneys measured in Cycles 1 and 2 will be summated for each 
subject.  If this total dose is <23 Gy, the remaining allowable body activity for that subject will be calculated 
according to the following formula:   
1000 x (23 Gy – summed renal dose (Gy))/renal dose per activity (mGy/MBq). 
 
All subjects will receive a concomitant amino acid infusion as renal protectant13.   A parenteral amino acid 
solution which supplies >27 g each of lysine and arginine in 2 liters of normal saline (< 800 mOsm/L) will be 
administered IV at a max of 8.3 mL/kg/hour (max 450 mL/hr) for 4 hours to begin 30 minutes prior to infusion 
of 90Y-DOTATOC. Initial infusion rate should be 300mL/hr or less; if tolerated for initial 30 min, rate may be 
increased to max rate. The total minimum volume which shall be infused is 1600 mL. This will constitute an 
off-label use of these approved amino acid solutions due to the higher than recommended volume infused.  
Any further information regarding dosing should be obtained from the manufacturer's instructions. 
 
Patients will be pre-medicated with EMEND and Lorazepam, and/or another anti-emetic, 30 minutes prior to 
the Amino Acid infusion.    


12 
 
 
 
 
7.0  Calendar of Tests and Procedures 
 
Calendar of Tests and Procedures 
 
Test 
Base 
line6 
C1D17 
 
C1D2 
 
C2 D1 
 
C2D2 
  
C3D1 
 
C3D2  
 
3-4 Month 
Followup8,
11 
 
6–9 
Month 
Followup 
Physical 
Exam 
X 
X 
 
X 
 
X 
 
X 
X 
Medical 
history/treat-
ment history 
 
X 
 
X 
 
 
 
 
 
 
 
Vital signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication 
list 
X 
X 
 
X 
 
X 
 
X 
X 
GFR if 
indicated2 
X 
X 
 
X 
 
X 
 
X12 
X 
Blood Tests3 
X 
X 
X14 
X 
X14 
X 
X14 
X 
X 
QOL 
questionnaire 
X 
X 
 
 
 
 
 
X13 
 
Pregnancy 
Test4 
 
X 
 
X9 
X9 
 
X 
X9 
 
X 
X9 
 
 
68Ga-
DOTATOC 
(TATE) 
PET/CT 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Diagnostic  
CT or MRI 
X 
 
 
 
 
 
 
X 
X 
90Y-DOTATOC 
Therapy (& 
Amino Acids) 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Skin 
assessment15 
 
 
X 
 
X 
 
X 
 
 
Dosimetry 
(blood & 
imaging) 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Adverse 
Event 
Assessment 
X5 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
Fluid diary11 
 
X 
X 
X 
X 
X 
X 
 
 
1. temp, pulse, respirs, b/p, weight. Height at baseline only. Weight at baseline and Day 1 of each cycle. 
2. required for children( <18 years). Required for adults (18 and older) if serum creatinine >1.2mg/dl. If required at baseline for patient, then 
all subsequent time points require nuclear GFR also. 
3. blood tests include: CBC/diff, AST, ALT, creatinine, plus urinalysis at baseline only and T.Bili at baseline only. 
4. required for females of child bearing potential only 
5. Documentation of baseline symptoms 
6. All baseline evaluations within 30 days of first 90Y-DOTATOC dose except blood tests need to be within 10 days and 68Ga-DOTATOC/TATE  
PET/CT needs to be within 6 months of first 90Y-DOTATOC infusion.  The diagnostic scans need to be within 120 days of the first 90Y-
DOTATOC infusion. 
7. events only repeated prior to treatment 1 if they fall outside of the baseline windows noted in footnote 6. 
8. Patients who discontinue dosing of 90 Y-DOTATOC early and who have received at least 1 dose of 90Y-DOTATOC are also required to 
complete follow up appointments per calendar 


13 
 
9. repeat testing can be point of care urine pregnancy test done in Nuclear Medicine. 
10. Patients will be instructed to have fluid intake of 1.5 liters Day 1 and 2 liters/day on Days 3 & 4. 
11. 3-4 month follow up procedures may be performed by patient’s local MD. 
12. If GFR is indicated, patients will be required to return to UIHC. 
13. If patient does not return to UIHC for F/U, QOL may be mailed or e-mailed to patient. 
14.  Electrolytes will be drawn during the last hour of amino acid infusion. 
15.  The skin at the site of the infusion will be assessed by clinic visit or phone at 3-5 days following each infusion of amino acids.  
 
8.0 Duration of Therapy and Stopping Rules 
 
8.1 Stopping Rules for individual subject 
In the absence of treatment delays due to adverse events, treatment may continue for 3 cycles or until 
one of the following criteria applies: 
• 
Cumulative renal radiation dose exceeds 23 Gy. 
• 
Intercurrent illness prevents further administration of treatment. 
• 
Unacceptable adverse event(s) such as irreversible renal or hematopoietic toxicity.    
• 
Initiation of another tumor specific therapy. 
• 
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. 
Other causes of discontinuation from study: 
• 
Termination of study by Sponsor. 
• 
Subject’s condition no longer requires study drug. 
* Note: Disease progression alone does not mandate discontinuation of 90 Y treatment.* 
    
Disease progression per RECIST 1.1 criteria during the follow up period will warrant removal from 
study. 
8.2 Stopping Rules for Trial 
Enrollment will proceed according to a Simon two-stage study design. Thirty-five subjects will be enrolled 
in the first stage; if 5 or fewer patients respond (Stable, PR or CR) as determined by 68Ga-DOTATOC 
PET/CT and diagnostic CT or MRI (RECIST 1.1 criteria), the study will be closed and the treatment ruled 
clinically uninteresting. Otherwise, an additional 29 subjects will be enrolled. If 20 or more responses are 
observed in the total of 64 subjects, then the treatment will be ruled worthy of further study. 
 
9.0  Regulatory and Reporting Requirements 
The Data and Safety Monitoring Committee (DSMC) of the Holden Comprehensive Cancer Center will 
provide data and safety monitoring for this study. “The Data and Safety Monitoring Plan of the Holden 
Comprehensive Cancer Center” provides standard operating procedures to monitor all clinical cancer 
trials at the UIHC. All investigator-initiated trials are automatically monitored by the DSMC. The Data 
Safety and Monitoring Plan for this risk level 4 study is attached as Appendix 1. 
9.1 Adverse Events List and Reporting Requirements 
As with any new drug, this study may involve risks that are currently unforeseeable.  The most frequent 
adverse events observed in adults treated with these drugs are listed below. 
Severity of adverse events will be graded according to NCI Common Terminology Criteria for Adverse 
Events version 4.0 (CTCAE v4.0) which is available at http://ctep.cancer.gov/reporting//ctc.html. 
Adverse events will be collected from time of consent until 30 days post 90Y treatment. Labs will only be 
collected as adverse events if deemed clinically significant by the investigator. Serious Adverse Events 
(SAE’s) that occur >30 days after the last 90Y treatment will only be reported if at least possibly related to 
investigational product. 
 
9.1.1 Routine Adverse Event Reporting Requirements to DSMC 
An adverse event (AE) is defined in the CTEP, NCI Guidelines [2005] as “any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease temporally 
associated with the use of a medical treatment or procedure (attribution of unrelated, unlikely, 
possible, probably or definite).” 


14 
 
Routine adverse events will be reported by submission of an adverse events log to the DSMC at 
the time of DSMC review. 
      9.1.2 Expedited Adverse Event Reporting to DSMC 
Serious adverse events occurring during study procedures with 90Y-DOTATOC will require a 
notification to the DSMC as described in the Data and Safety Monitoring Plan (see appendix 1) 
below regardless of attribution to study intervention. The investigator will continue to follow or 
obtain documentation until the resolution of such an event until it is resolved (with or without 
sequelae) 
9.1.3 Adverse Event Reporting Guidelines –  
Documentation will begin after radiotracer injection and continue through 1 calendar day following 
imaging. This study will use the guidelines developed by the Cancer Therapy Evaluation Program 
(CTEP) for PET and/or SPECT IND agents. For purposes of the below table, it should be noted that the 
radioactive half-life for 90Y is 64.1 hours. Therefore, 10 radioactive half-lives will be 27days for the 
purposes of adverse event reporting. 
 
9.2 Expected Adverse Events Associated with 90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) 
Treatment involves administering a radioactive drug into the bloodstream from where it may attach to 
any cell (cancerous and healthy) that has somatostatin receptors on its surface and normally comes in 
contact with somatostatin.  Therefore, healthy cells may potentially be killed or damaged by this drug.  
Healthy cells that contain somatostatin receptors are present in the pancreas, stomach, duodenum, 
small intestine, large intestine, pituitary, and ovaries.  No damage to these organs has been seen in the 
adults who have taken this drug.  Other healthy organs which do not contain somatostatin receptors but 
which normally come in contact with somatostatin include the bladder.   
 
Kidney exposure is due to the renal clearance of this drug as well as the normal amino acid recirculation 
mechanism that operates to conserve amino acids and small peptides. The kidney contains somatostatin 
receptors and also comes in contact with 90Y-DOTATOC as it is being excreted.  This means the kidney 
usually receives the most radiation of any normal tissue in the body. Adult humans who have received 
90Y-DOTATOC have experienced some damage to the kidney. Some adults have experienced 
permanent decrease in kidney function, but no adults have required dialysis. There is a risk that severe 
kidney damage could occur which may result in the need for permanent dialysis.   Kidney 
damage may occur as a late effect, months after the last dose of 90Y-DOTATOC.  
 
Adults and children have been treated with 90Y-DOTATOC.  Side effects that were observed include:  
bowel obstruction, diarrhea, weight loss, reduced red blood cells (anemia), reduced white blood cells 
(increased chance of infection), and reduced platelets (increased chance of uncontrolled bleeding).  
These effects depended on the dose of 90Y-DOTATOC and occurred at higher doses tested.  Most 
patients recovered from these effects after stopping 90Y-DOTATOC; however, two patients (of a total of 
over 2500 patients treated as of 12/31/13) have developed myelodysplastic syndrome. 
 
An unexpected allergic reaction following the administration of 90Y-DOTATOC or the amino acids may 
consist of shortness of breath, wheezing, lowering of blood pressure, fever, chills, hives, itchiness or 
damage to the blood vessels.  The amino acid solution is hyperosmolar and may cause local 
inflammation or in rare cases, blistering at the infusion site.  A 20 gauge IV line or PICC line is 
recommended to avoid this inflammation.  A phone call will be made to subjects 3-5 days following each 
infusion of amino acids to assess skin changes at the injection site.  The long-term effects of 90Y-
DOTATOC are unknown.  90Y-DOTATOC may cause radiation damage that may not surface until months 
or years later.   
 
Participation in this study may be hazardous to a fetus or a nursing child.  There is not enough 
information to determine whether there are significant risks to a nursing child or a fetus conceived or 


15 
 
carried by a subject who is participating in this study.  Therefore, in order to participate, all females 
capable of becoming pregnant must have a negative pregnancy test within 7 days prior to the first 90Y-
DOTA-tyr3-octreotide treatment.  Female subjects must tell us if they may have become pregnant within 
the previous 14 days because the pregnancy test is unreliable during that time. All subjects capable of 
becoming pregnant must agree to practice a medically acceptable birth control measure (abstinence, 
birth control pills, intrauterine devices, vaginal diaphragm, vaginal sponge, or condom with spermicidal 
jelly) throughout the study and for eight months following the end of the last treatment.  Any females who 
are nursing must refrain from nursing while on study and for three months following the end of the last 
treatment. 
 
 
9.3  Expected Adverse Events Associated with Amino Acid Infusions:  
Generalized flushing, fever, and nausea have been reported during infusions of amino acid 
solutions.  Local reactions consisting of a warm sensation, redness, inflammation of the vein and blood 
clotting at the infusion site have also occurred. Low or high potassium and phosphate levels have been 
observed in some adult patients.  These levels have not been clinically significant and have returned to 
within normal limits after completion of therapy except in one case out of more than 400 individual 
infusions of amino acids.  To avoid this rare electrolyte disturbance, we will check heart rate and 
potassium level 60 min prior to end of amino acid infusion; if >6 meq/L and/or heart rate < 60 bpm, we 
will administer oral or IV NaHCO3 and keep patient sitting or supine until heart rate >65 bpm. 
 
 
9.4  Research radiation dose estimate 
 
9.5  Risks of 90Y-DOTATOC PET/CT Scan Procedure  
 
Risks of Investigational PET/CT: Additional risks include radiation exposure from the investigational low 
dose CT scan and the inconvenience of the investigational PET/CT scan. Children may require sedation 
or anesthesia to remain still during the PET/CT scanning procedure.  The risks of sedation include a 
reaction to the medication used for sedation or anesthesia.  If anesthesia is required, there is a risk of 
injury to the throat or airways from insertion of the breathing tube. 
 
10.0  Dosing Delays/Dose Modifications 
10.1  Dosage Modifications 
Dosimetry will be acquired following treatments1 & 2.  The kidney dose/mCi will be calculated and the 
total target dose that will limit renal dose to ≤ 23 Gy.  The target dose minus 120 mCi will then be divided 
into two equal doses for Cycles 2 and 3 with adjustments based on dosimetry.  Regardless of the total 
dose to kidneys as determined by dosimetry, the maximum dose in Cycle 2 will be 150 mCi; Cycle 3 will 
be limited to ≤ Cycle 2. 
 
Dose of 90Y-DOTATOC will be decreased 25-50% for any subject in whom dosimetry measurement on 
first or second dose indicates probable total renal dose for three cycles will be >23 Gy.  Dose may be 
increased on subsequent cycles so long as summation of dosimetry measurements limits total renal 
dose to < 23 Gy. 
 
Dose of 90Y-DOTATOC will be increased 10-20% for any subject in whom dosimetry measurement on 
first or second dose indicates probable total renal dose for three cycles will be significantly  <23 Gy.   No 
subject will receive > 420 mCi total dose of 90Y-DOTATOC.   
 
Subjects who had a nuclear GFR measured at baseline will be followed for nephrotoxicity by nuclear 
GFR. If they demonstrate a > 30% decrease in GFR as determined by nuclear GFR scan, their dose will 
be reduced by 50% on the next cycle.  Full dose may then be given when GFR returns to 90% of 
baseline.  Patients who experience > 30% decrease in GFR will be placed on an age appropriate dose of 
captopril or other ACE inhibitor.   
Also, patients that experience a rise in serum creatinine above 1.2 (who previously had normal levels) 
will be hydrated and have their serum creatinine repeated. If the creatinine level after hydration remains 


16 
 
elevated above 1.2, then nuclear GFR will be measured. If applicable, dose reductions will be 
implemented as described above. 
 
Nephrotoxicity as demonstrated by > 50% decrease in nuclear scan GFR will be considered a DLT if the 
resulting GFR is below normal for subject’s age, height and weight.  Subjects who experience a DLT are 
eligible to receive subsequent cycles of 90Y-DOTA-tyr3-Octreotide at a reduced dose if the DLT has 
returned to baseline value within 9 weeks of the untolerated 90Y-DOTA-tyr3-Octreotide dose.  The 
subject's subsequent dose must be reduced to 50% of the untolerated dose. 
 
10.2 Dose Delay     
The time elapsed between the end of week 6 of a Cycle Study Period and Day 1 of the next Cycle Study 
Period should be < 3 weeks.  No further interruption between cycles should occur, except delays 
mandated by the protocol itself or regulatory requirements as in periods of enrollment locks or data review 
by health authorities.  If a longer interruption does occur, the subject's continuation will be at the 
discretion of the Principal Investigator; approval will not be unreasonably withheld. 
 
10.3 Concomitant Therapy 
The subject may not receive any other approved or investigational anti-neoplastic therapies for the 
treatment of the refractory somatostatin-receptor positive tumor during the course of the study, excluding 
somatostatin analogues and bisphosphonates.  However, all subjects on somatostatin analogue therapy 
will discontinue therapy from 12 hours prior to a) injection with 68Ga-DOTATOC, and b) infusion with 90Y-
DOTA-tyr3-Octreotide until 12 hours post administration.  Subjects who have been on hormonal therapy 
(other than somatostatin analogues) for > 2 months with SD or PD may continue to receive hormonal 
therapy during this study.  Subjects who initiate another tumor-specific therapy will be discontinued from 
further treatment with 90Y-DOTA-tyr3-Octreotide. Patients may continue long acting Somatostatin 
analogues between cycles of 90Y therapy. It should be administered as standard of care after completion 
of dosimetry imaging for Cycles 1 and 2. Following Cycle 3, it may be given on Day 3 or later.  Patients on 
long acting Lanreotide should have this treatment held until after 90Y treatment Cycle 3. Short acting 
somatostatin analogue can be used at the discretion of the treating physician to bridge the patient.  
 
All subjects who have received at least one dose of 90Y-DOTA-tyr3-Octreotide must continue into the 
Long-Term Follow-up Study Period at the point of treatment discontinuation.  This is necessary to 
determine any long-term effects of treatment with 90Y-DOTA-tyr3-Octreotide.   
 
Subjects may receive, at the discretion of the investigator, appropriate medical treatment for medical 
problems that arise while on study. 
 
11.0 Response Criteria/End of Study Assessments 
11.1 Response criteria according to RECIST 1.1 include:   
  
  
  
Evaluation of Target Lesions 
Complete 
Response 
(CR): 
Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short 
axis to <10 mm. 
  
  
Partial 
Response 
(PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
  
  


17 
 
Progressive 
Disease (PD): 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also considered 
progressions). 
  
  
Stable Disease 
(SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study 
  
  
  
Evaluation of Non-Target Lesions 
Complete 
Response 
(CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis) 
  
  
  
Note:  If tumor markers are initially above the upper normal 
limit, they must normalize for a 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.     
 
 
12.0 Data Analysis and Statistics:  
12.1 Primary Objective 1 
Treatment efficacy, defined as a complete response, partial response or stable disease (CR+PR+SD), is the 
primary endpoint of interest in this dosimetry-guided Phase II trial.  Tumor response will be defined according 
to RECIST1.1 criteria applied on up to five target lesions (primary tumor if not surgically removed, up to two 
liver lesions, up to two nodal metastases, metastatic lesion in other organs, such as ovary, breast) that will be 
quantified and compared between pre-therapy and 3-9 months post-therapy high-resolution, contrast-
enhanced CTs. Osseous metastases may be followed as non-target lesions. 90Y-DOTATOC will be deemed 
worthy of further study if its associated response rate is ≥ 0.60, and clinically uninteresting if its rate is ≤ 0.40. 
Enrollment will proceed according to an optimal Simon two-stage study design. Sixteen (16) subjects will be 
enrolled in the first stage; if 7 or fewer patients respond, the arm will be closed and the treatment ruled 
clinically uninteresting. Otherwise, an additional 30 subjects will be enrolled. If 24 or more responses are 
observed in the total of 46 subjects, then the treatment will be ruled worthy of further study. The study design 
has a probability of early termination equal to 0.72. Power to detect efficacy is 0.80 with a type 1 error rate of 


18 
 
0.05. 
Secondary analysis will focus on time to tumor progression and overall survival. The method of Kaplan- Meier 
will be used to estimate progression and survival rates. Subjects for whom the outcome of interest is not 
observed at the 6 month follow-up will be treated as censored observations in the survival analysis.  
12.2 Primary Objective 2  
Adverse events will be recorded and reported in tabular form by type and grade. If four or more subjects 
experience renal toxicity ≥ Grade 4, the radiopharmaceutical will be declared too toxic and the trial will be 
stopped. If any other irreversible Grade 4 toxicity is observed in four or more subjects, the treatment will be 
declared too toxic and will be stopped. Adverse events will be graded according to the most recent CTE 
guidelines. 
12.3 Secondary Objective 1 
For subjects who participated in the 68Ga-DOTATOC Comparator trial (IRB # 201212736), the number, size, 
and location of discordant lesions between 68Ga-DOTATOC PET/CT and Octreoscan will have been 
tabulated. This analysis will be updated using the results of post- therapy 68Ga-DOTATOC PET/CT for those 
patients who participated in the comparator study, but only received the initial 68Ga-DOTATOC PET/CT due 
to progression on the Octreoscan + high-resolution, contrast-enhanced CT. Lesions that were positive on 
PET, but negative on Octreoscan will be considered true positive if a response to PRRT is documented after 
either Cycle 1 or at 6-9 month followup following last 90Y-DOTATOC infusion. 
For subjects who did not participate in the 68Ga-DOTATOC Comparator trial, all 68Ga-DOTATOC PET/CT 
scans will be acquired as part of this study; number, size, and location of lesions will be analyzed between 
first and subsequent 68Ga-DOTATOC PET/CTs. 
 
12.4 Secondary Objective 2 
Compare SUVmax between primary tumor, liver lesions, and extra-hepatic lesions with expression levels of 
sst2 using qRT-PCR and/or receptor IHC from fresh frozen or paraffin-embedded samples where available. 
Compare maximum SUVs of primary tumor, liver lesions, and extra-hepatic lesions with expression level of 
sst2 RNA and IHC on fresh frozen tissue, or paraffin embedded samples (block(s) or 10 unstained slides) to 
determine whether or not any correlation exists between SUVmax, sst2 expression, or sst2 protein and 
response to PRRT. The study is expected to delineate whether measurement of sst2 expression by either 
qRT-PCT or immunohistochemistry at diagnosis can predict response to 90Y-DOTATOC. We will construct a 
table tabulating SUVmax, level of RNA expression, and IHC level for all lesions biopsied. With 64 subjects 
the correlation between SUV max, RNA expression and IHC will be determined. Analysis of SUVmax 
compared with sst2 RNA and receptor protein expression on primary tumor and metastatic lesions will be 
considered worthy of further study if > 50% of lesions demonstrate a positive correlation. Tissue will be sent 
to 3080 Med Lab in University of Iowa Hospital and Clinics for analysis. 
13.0 Study Drug 
 
13.1  90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC); IND# 61,907 
 13.1.1 Chemistry, Manufacturing and Control  
Peptide Receptor Radionuclide Therapy (PRRT) requires a peptide conjugate that consists of the peptide 
receptor ligand as the targeting moiety and a chelator to bind the radionuclide as shown in Figures 1 and 2. 
[90Y]Yttrium-DOTA-tyr3-Octreotide (90Y-DOTATOC) consists of the targeting peptide tyr3-octreotide which is 
conjugated to the chelating moiety (DOTA) to bind the radionuclide ([90Y]Yttrium).  [90Y]Yttrium-DOTA 
complexes are extremely stable36.  
 
The manufacture of 90Y-DOTATOC will be conducted in the University of Iowa Nuclear Medicine 
Radiotherapeutics Laboratory. At least two technical personnel, one of whom has a postgraduate degree 


19 
 
(MS, PharmD, MD, or PhD) will be present during manufacture and quality control procedures to confirm 
adherence to standard operating procedures and release criteria. Reagents and supplies used for the 
preparation of 90Y-DOTATOC are received and inspected per specification sheets and accepted or rejected.  
Accepted reagents and supplies are labeled with appropriate expiration dates, initialed, assigned 
identification numbers and then stored in specified locations in the Radiotherapeutics Laboratory.  
 
Manufacture: 
The starting material, DOTA-tyr3-Octreotide (DOTATOC), is manufactured under GMP conditions and is 
obtained commercially with appropriate certificate of analysis documentation.  Manufacturing of 90Y-
DOTATOC will be performed using a synthesis unit specifically designed for this purpose ModularLab 
PharmTracer from Eckert & Zeigler, Berlin, Germany.  The system utilizes a purpose-built, disposable, GMP-
certified (sterile, pyrogen-free) cassette that is snapped into place on the synthesis unit.  Computer control 
manages the flow of reagents for radiolabeling, purification, and transfer of the product to the final product 
vial via a hydrophilic PVDF sterilizing 0.22 μm filter. A new cassette is used for each preparation and 
preparations are usually used for a single patient study. 
 
The final product collection vial is labelled with the batch number and other relevant information (see section 
13.1.2 Labeling). The vial is weighed, then prefilled under aseptic conditions with sterile isotonic saline for 
injection containing ascorbic acid. This solution acts as a diluent and the ascorbic acid as an agent to aid in 
prevention of radiolysis of the final product.  Ascorbic acid 10-50 mg, typically 50 mg for the high radioactivity 
runs, is dissolved in 1 mL ultrapure water and this is added to a 100 mL bag of sterile isotonic saline.  After 
thoroughly mixing, 84 mL is removed with a sterile syringe and passed through the sterilizing filter into the 
final product collection vial.  When the reaction product is added later in the process (~ 16 mL solution) the 
solution will be close to 100 mL. This volume, in this vial, gives a finely defined geometry for accurate 
radioactivity dose measurement.     
 
GMP grade [90Y]Yttrium chloride, measured against a NIST standard, is purchased commercially (e.g., 
Perkin-Elmer) for each manufacturing procedure37.  The received [90Y]Yttrium chloride radioactivity (typically, 
50 – 250 mCi) is calibrated to expected time of start of synthesis.  Prior to synthesis the amount of received 
radioactivity is confirmed with the dose calibrator in the Radiotherapeutics Laboratory. The PharmTracer 
system transfers the [90Y]Yttrium chloride using the ascorbate buffer (typically, 50 mg ascorbic acid in 1.5 mL 
ultrapure water) directly to a reaction vessel. The ascorbic acid serves not only as a buffer but also as an aid 
in prevention of radiolysis. The reaction vessel contains DOTATOC precursor dissolved in ultrapure water.  
To achieve maximum radiolabeling and high specific activity, the amount of precursor is restricted to the 
range 50-200 micrograms, typically 115 µg. The reaction mixture is heated to 95 °C for 25±5 minutes.   
The product is purified by passing the diluted solution (approximately 2-3 mL) through a solid phase 
extraction (SPE) C-18 cartridge, which retains the 90Y-DOTATOC while allowing any remaining free 
[90Y]Yttrium to pass through the column into the waste vial. The C-18 cartridge is rinsed with isotonic saline 
for injection to remove any residual free [90Y]Yttrium, followed by elution of 90Y-DOTATOC with 47.5% ethanol 
in water (2 mL), followed by isotonic saline (14 mL), directly through a sterile 0.22 micron membrane filter into 
the final product collection vial. The final product collection vial, containing ~100 mL of solution, is then 
agitated to give a homogenous solution of product suitable for quality control sampling and final release 
measurements.   
 
Small aliquots (total 1.5 – 2 mL) are then taken for quality control testing and the product line and vent filter 
are removed. The final product collection vial is weighed and the contained radioactivity measured and 
recorded on the master batch sheet that then translates to the final product label. Radiochemical yields of 
>90% (uncorrected for decay) are routinely achieved. The final sterilization filter is retained for a QC pressure 
test to ensure filter integrity. The production process requires approximately 3 hours to complete. 
 
Quality Control: 
The QC process takes approximately 1.5 hours to complete.  The quality control tests are performed and 
compared to release criteria prior to release of the final product as shown in Table 1 below. 
 
Table 1.  Analytical Specifications for 90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) 


20 
 
Test 
Release Criteria 
Appearance 
Clear and no visible impurities 
Filter Test 
>1 bar from 2 bar overpressure at 1 minute 
pH 
3.0 – 7.0 
Radiochemical Purity 
>90% 
Endotoxin 
Pass gel clot tests (sample & positive 
control)  
 
 
Appearance: Any visible cloudiness or precipitate will disqualify the product for human use. 
 
Filter Test: A filter pressure test is conducted by applying pressure to the sterilizing filter at 2 bar inert gas 
(nitrogen or argon) and monitoring the leak rate for 1 minute to ensure the integrity of the filter used for final 
product sterilization. The system pressure should be greater than 1 bar (100 kPa, 15 psi) above atmospheric 
pressure after 1 minute of terminating gas supply overpressure.  In the unlikely event that the filter pressure 
test fails, the product may be re-filtered with a fresh sterile filter under aseptic conditions with all the quality 
control tests being conducted on samples of the newly filtered material.  
 
pH: The pH of the final product is measured by spotting pH paper. 
 
Radiochemical Purity: The radiochemical purity of the final product is determined on a reverse phase high 
pressure liquid chromatography (HPLC) system equipped with a radiation detector, using a C18 reverse 
phase column and mobile phase of 0.1% TFA in water (mobile phase A) and acetonitrile (mobile phase B).  
Using this column and mobile phase system, free Y-90 will elute with the void volume of the column while 
90Y-DOTATOC will be retained for a significant time on the column and the two species can be differentiated 
by their differences in retention time.  Radiochemical purity is determined by integration of the 90Y-
DOTATOC peak at a known retention time (7.8±0.5 min) and comparison to any peaks of trace free Y-90 and 
degradation peptides that may be present.  This determination will be conducted by senior technical 
personnel. 
 
Bacterial Endotoxins: Samples of final product will be tested using the limulus amebocyte lysate (LAL) gel-
clot test.  If either the positive control or product fails in the LAL gel-clot test, the entire test will be repeated in 
triplicate. Failure of any one of the triplicate gel clot tests will disqualify the product for human use. 
 
Sterility: Tryptic Soy Broth (TSB) and Fluid Thioglycollate Media (FTM) are inoculated with a 0.25 mL 
sample each of final product, incubated (TSB at room temp, FTM at 32° C) and checked for growth during the 
following 14 days. At the completion of the sterility test, the batch record is completed and filed.  This test will 
not be complete at the time of administration of the product.  If any product fails this test after administration 
of the product to a patient, that patient will be contacted to ask about any symptoms and treated if clinically 
indicated. An investigation of the source of contamination will be conducted and further patient studies 
terminated until the source identified and rectified. 
 
Expiration date:  The product expires in 48 hrs.  If product will be used later than 24 hours after production, 
a second small sample with be obtained from the product vial and re-examined by HPLC. If radiochemical 
purity is <90%, the product will be declared expired and will not be administered to any patient. 
 
Table 2 demonstrates the Quality Control testing on three successive productions of 90Y-DOTATOC at the 
University of Iowa.  Each production was performed according to the standard operating procedure described 
herein using 115 μg DOTATOC and 200±10 mCi Y-90.  Detailed batch records and HPLC chromatograms 
are attached in a separate Chemistry, Manufacturing and Control document. 
 
Table 2.  Quality Control Measurements on Three Successive 
Production Runs for 90Y-DOTATOC Manufactured at University of Iowa 


21 
 
 
1/13/2015 
1/15/2015 
1/21/2015 
Yield 
180.8 mCi 
192.8 mCi 
205.0 mCi 
Radiochemical 
Purity 
97%@time zero 
96%@time zero 
100%@time zero 
Appearance 
Clear 
Clear 
Clear 
pH 
5.0 
5.0 
5.0 
Sterility 
Pass@14 days 
Pass@14 days 
Pass@14 days 
Endotoxin 
Pass 
Pass 
Pass 
Expiration Date 
Pass all release 
criteria @ 48 hrs 
Pass all release 
criteria @ 48 hrs 
Pass all release 
criteria @ 48 hrs  
 
13.1.2 Labeling 
Abiding by ALARA (as low as reasonably achievable) principles for handling radioactivity the actual final 
product vial (FPV) will not contain all the desired information.  The FPV label will have the batch number, 
product name, and other limited information: for example 
 
  
 
 
The shielded container of the FPV will be labeled with all relevant information: for example 
 
 
 
The values on these labels, including the batch number, are generated automatically from the master batch 
file.  Each label is inspected for correctness prior to affixing to the appropriate container. 
 
13.1.3 Environmental Assessment 
We request a categorical exclusion for the Environmental Impact Statement requirement in section 21 CFR 
part 25 because this radiopharmaceutical meets the conditions stipulated in Section 25.24(c)(4). This material 


22 
 
is intended for in-house human clinical research only and any material not consumed for patient use will be 
treated and contained as low level radioactive waste.  This waste is managed by the University of Iowa 
Radioactivity Protection Office / Environmental Protection Office. All waste generated during manufacture and 
dispensing is held for decay of radioactivity. Yttrium-90 decays to stable Zirconium-90. All waste is 
incinerated when activity levels are below acceptable limits.  We anticipate doing 100 or less manufactures 
per year.  We further expect to use 115 µg or less per run of precursor peptide, DOTATOC, which amounts to 
less than 10 mg total of peptide for the 100 runs per year. For comparison the unlabeled Octreotide is used 
therapeutically at 300 μg/dose subcutaneously 3 times daily up to 60 mg intramuscular (long-acting) 
Sandostatin LAR every 4 weeks. 
 
 
13.3 Previous Human Experience with 90Y-DOTATOC 
90Y-DOTATOC PRRT was also pioneered in Europe where it has been demonstrated to be the most effective 
therapy to date for patients with neuroendocrine tumors, with a mean time to disease progression is greater 
than 4 years23,38. University of Iowa investigators participated in an international Phase II study of 90Y-
DOTATOC PRRT and enrolled over 40 subjects.  This clinical trial also demonstrated safety and efficacy of 
PRRT in humans when care is taken to protect the kidneys with concomitant amino acid infusion21.  
University of Iowa investigators also hold the only IND (#61,907) in the United States for this 
radiopharmaceutical and have completed the only Phase I trial of 90Y-DOTATOC PRRT in children.  
University of Iowa investigators have treated 18 children and young adults as well as 40 older adults with 90Y-
DOTATOC PRRT; no irreversible renal toxicity has been experienced in these patients, primarily due to 
rigorous hydration prior to and after administration of the therapy as well as providing the total dose in 3 
moderately sized doses rather than 2 higher doses.  The major goal of this present study will be to determine 
if individualized, dosimetry-guided dosing of 90Y-DOTATOC can successfully optimize dose to tumor while 
limiting renal toxicity for every patient. 
 
13.4 Pharmacology and Toxicology Information 
The above summary of human experience provides strong evidence that the amount of investigational drug 
(DOTATOC) in mass quantity and the amount of radiation (as also provided via our measured radiation 
dosimetry) are acceptable in terms of risk. The NOAEL level of DOTATOC has never been established in 
humans, despite studies reporting much larger mass quantity use than we propose, with some using multiple 
large doses5.  The radiation toxicity from the investigational radioisotope is also, accordingly, within the 
acceptable range for patients with life-threatening malignancies whose treatment we believe will benefit from 
the use of the proposed investigational imaging procedure.  Accordingly, we believe the risk/benefit of our 
proposed investigation to be justified. 
 
13.5 Other Agents:  Amino Acid Solution 
The amino acid solution will be prepared in the University of Iowa Pharmacy. The solution used for these 
studies will contain a minimum of 27g each of arginine and lysine in a volume of 2 liters when diluted to < 800 
mOsm/liter will be administered at 8.3 mL/kg/hr with a maximum rate of 450 mL/hr to be administered starting 
30 min prior to infusion of 90Y-DOTATOC.  
 
13.6 Agent Accountability 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of the 
inventory and disposition of all agents received from DCTD using the NCI Drug Accountability Record Form.  
 
14.0 Data Reporting 
 
Data for this study will be secured by entry into OnCore and EPIC.  Both of these electronic medical record 
systems are maintained behind a firewall under the control of University of Iowa Hospitals and Clinics IT 
Department.  Both systems are password protected and all computers on which data can be entered are 
secured in locked rooms when unattended.  Any hard copies of data are secured in the Clinical Trials Support 
Services Office located at 11510 FPF. 
 
 


23 
 
The agent, DOTA-tyr3-Octreotide utilized in the manufacture of 90Y-DOTA-tyr3-Octreotide for this study is 
provided to the investigators under a Clinical Trials Agreement (CTA) between Isotope Technologies 
Garching GmbH, Lichtenbergstr. 1, 85748 Garching, Germany (ITG) and the University of Iowa.  Therefore, 
the following guidelines apply to the use of 90Y-DOTA-tyr3-Octreotide in this study: 
 
1. 90Y-DOTA-tyr3-Octreotide may not be used for any purpose outside the scope of this protocol, nor can 
90Y-DOTA-tyr3-Octreotide be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for 90Y-DOTA-tyr3-Octreotide are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. 
2. Clinical Trial Data and Results and Raw Data developed under a Clinical Trials Agreement (CTA) or 
Cooperative Research and Development Agreement (CRADA) will be made available exclusively to 
the University of Iowa investigators, the NCI, and the FDA, as appropriate. 
 
15.0  References 
 
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prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. Journal of 
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2. 
O'Dorisio MS, Khanna G, Bushnell D. Combining anatomic and molecularly targeted imaging in 
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Fruhwald MC, O'Dorisio MS, Pietsch T, Reubi JC. High expression of somatostatin receptor 
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Juweid ME, Menda Y, O'Dorisio MS, et al. 111In-pentetreotide versus bone scintigraphy in the 
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5. 
Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, 
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metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 
2009;27(28):4656-4663. 
6. 
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perspectives. JEndocrinolInvest. 2005;28(5 Suppl):14-18. 
7. 
DuBois SG, Messina J, Maris JM, et al. Hematologic toxicity of high-dose iodine-131-
metaiodobenzylguanidine therapy for advanced neuroblastoma. J Clin Oncol. 2004;22(12):2452-
2460. 
8. 
Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal 
tumour outcome based on gene expression. Nature. 2002;415(6870):436-442. 
9. 
Thacker MM, Temple HT, Scully SP. Current treatment for Ewing's sarcoma. ExpertRevAnticancer 
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10. 
Kwekkeboom DJ, de Herder WW, van Eijck CH, et al. Peptide receptor radionuclide therapy in 
patients with gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med.40(2):78-88. 
11. 
Schilling FH, Bihl H, Jacobsson H, et al. Combined (111)In-pentetreotide scintigraphy and (123)I-
mIBG scintigraphy in neuroblastoma provides prognostic information. Med PediatrOncol. 
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12. 
Khanna G, Bushnell D, O'Dorisio MS. Utility of radiolabeled somatostatin receptor analogues for 
staging/restaging and treatment of somatostatin receptor-positive pediatric tumors. Oncologist. 
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13. 
Menda Y ODM, Kao S, Khanna G, Michael S, Connolly M, Babich J, O’Dorisio T, Bushnell D, Madsen M.  . Phase I Trial 
of 90Y-DOTA-tyr3-Octreotide Therapy in Children and Young Adults with Refractory Solid Tumors That Express 
Somatostatin Receptors. J Nuc Med. 2010;51(10):1524-1531. 


24 
 
14. 
Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: the 
current consensus. Acta neuropathologica. 2012;123(4):465-472. 
15. 
Remke M, Hering E, Gerber NU, et al. Somatostatin receptor subtype 2 (sst(2)) is a potential 
prognostic marker and a therapeutic target in medulloblastoma. Childs Nerv Syst. 
2013;29(8):1253-1262. 
16. 
Whittier KL, Boese EA, Gibson-Corley KN, et al. G-protein coupled receptor expression patterns 
delineate medulloblastoma subgroups. Acta neuropathologica communications. 2013;1(1):66. 
17. 
Kwekkeboom DJ, Bakker WH, Kooij PP, et al. [177Lu-DOTAOTyr3]octreotate: comparison with 
[111In-DTPAo]octreotide in patients. EurJNuclMed. 2001;28(9):1319-1325. 
18. 
Wild D, Macke HR, Waser B, et al. 68Ga-DOTANOC: a first compound for PET imaging with high 
affinity for somatostatin receptor subtypes 2 and 5. EurJNuclMedMolImaging. 2005;32(6):724. 
19. 
Buchmann I, Henze M, Engelbrecht S, et al. Comparison of 68Ga-DOTATOC PET and 111In-
DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. 
EurJNuclMedMolImaging. 2007;34(10):1617-1626. 
20. 
Forrer F, Waldherr C, Maecke HR, Mueller-Brand J. Targeted radionuclide therapy with 90Y-
DOTATOC in patients with neuroendocrine tumors. Anticancer Res. 2006;26(1B):703-707. 
21. 
Bushnell DL, Jr., O'Dorisio TM, O'Dorisio MS, et al. 90Y-edotreotide for metastatic carcinoid 
refractory to octreotide. J Clin Oncol. 2010;28(10):1652-1659. 
22. 
Kwekkeboom DJ, de Herder WW, Krenning EP. Somatostatin receptor-targeted radionuclide 
therapy in patients with gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin 
North Am. 2011;40(1):173-185, ix. 
23. 
Imhof A, Brunner P, Marincek N, et al. Response, Survival, and Long-Term Toxicity After Therapy 
With the Radiolabeled Somatostatin Analogue [90Y-DOTA]-TOC in Metastasized Neuroendocrine 
Cancers. J Clin Oncol. 2011;29(17):2416-2423. 
24. 
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic 
neuroendocrine tumors. N Engl J Med. 2011;364(6):501-513. 
25. 
Yao JC, Lagunes DR, Kulke MH. Targeted therapies in neuroendocrine tumors (NET): clinical trial 
challenges and lessons learned. Oncologist. 2013;18(5):525-532. 
26. 
Barone R, Borson-Chazot F, Valkema R, et al. Patient-specific dosimetry in predicting renal 
toxicity with (90)Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose-effect 
relationship. J NuclMed. 2005;46 Suppl 1:99S-106S. 
27. 
Bodei L, Cremonesi M, Ferrari M, et al. Long-term evaluation of renal toxicity after peptide 
receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated 
risk factors. EurJNuclMedMolImaging. 2008;35(10):1847-1856. 
28. 
Bushnell D, Menda Y, O'Dorisio T, et al. Effects of intravenous amino acid administration with Y-
90 DOTA-Phe1-Tyr3-Octreotide (SMT487[OctreoTher) treatment. Cancer BiotherRadiopharm. 
2004;19(1):35-41. 
29. 
Anderson CJ, Schwarz SW, Connett JM, et al. Preparation, biodistribution and dosimetry of 
copper-64-labeled anti-colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')2. 
JNuclMed. 1995;36(5):850-858. 
30. 
Walrand S, Jamar F, van Elmbt L, Lhommel R, Bekonde EB, Pauwels S. 4-Step renal dosimetry 
dependent on cortex geometry applied to 90Y peptide receptor radiotherapy: evaluation using a 
fillable kidney phantom imaged by 90Y PET. J Nucl Med. 2010;51(12):1969-1973. 
31. 
Madsen MT, Bushnell DL, Juweid ME, et al. Potential increased tumor-dose delivery with 
combined 131I-MIBG and 90Y-DOTATOC treatment in neuroendocrine tumors: a theoretic 
model. JNuclMed. 2006;47(4):660-667. 


25 
 
32. 
Bushnell DL, Madsen MT, O'Cdorisio T, et al. Feasibility and advantage of adding (131)I-MIBG to 
(90)Y-DOTATOC for treatment of patients with advanced stage neuroendocrine tumors. EJNMMI 
research. 2014;4(1):38. 
33. 
Delanaye P, Schaeffner E, Ebert N, et al. Normal reference values for glomerular filtration rate: 
what do we really know? Nephrol Dial Transplant. 2012;27(7):2664-2672. 
34. 
Delanaye P, Ebert N. Assessment of kidney function: Estimating GFR in children. Nature reviews 
Nephrology. 2012;8(9):503-504. 
35. 
Schaeffner ES, Ebert N, Delanaye P, et al. Two novel equations to estimate kidney function in 
persons aged 70 years or older. Ann Intern Med. 2012;157(7):471-481. 
36. 
Jurkin D, Gildehaus FJ, Wierczinski B. Kinetic stability studies on yttrium(III)-1,4,7,10- 
tetraazacyclododecane-1,4,7,10-tetraacetic acid by free-ion selective radiotracer extraction. Anal 
Chem. 2007;79(24):9420-9426. 
37. 
Schultz MK, Cessna JT, Anderson TL, et al. A performance evaluation of 90Y dose-calibrator 
measurements in nuclear pharmacies and clinics in the United States. Appl Radiat Isot. 
2008;66(2):252-260. 
38. 
Bodei L, Cremonesi M, Grana C, et al. Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3-
octreotide (90Y-DOTATOC) in neuroendocrine tumours. EurJNuclMedMolImaging. 
2004;31(7):1038-1046. 
 
 
 
 
Appendix I 
Single Timepoint Dose Estimate for Exponential Clearance 
Introduction:  Personalized dosimetry is highly desirable for many radionuclide therapy protocols in 
order to deliver the maximum tumor dose while sparing the critical organs. The determination of the 
total integrated activity (Ã) for radiation dose estimates generally requires measurements of tissue 
activity at multiple time points with a minimum of at least 2 time samples for each exponential 
component.  This can add many additional days to the procedure creating a burden for both the patient 
and the clinic.   
The aim of this paper is to demonstrate that in certain situations where the clearance of the radiotracer 
is described by a mono- or bi-exponential model and quantitative information about the long 
component is approximately known, it may be possible to obtain a useful estimate of Ã from a single 
time point measurement (Ã*).  This approach may prove to be accurate and simple enough to allow 
personalized dosimetry to more effectively manage radionuclide cancer treatments and thereby making 
personalized dosimetry feasible. 
Single exponential derivation:  We first derive the single point estimation approach for a single 
component exponential:   
 
 
 
A(t) = A0 exp(-kt)   Eq. 1 
Where A0 is the activity at t = 0 and k is the effective clearance rate constant. 
The total number of decays associated with Eq. 1 is:    
Ã = A0/k                    Eq.  2  
If k is known and a quantitative activity measurement is made at time T, then   is determined from: 
  
 
 
 
 
 
 
Ã = A(T) exp(kT)/k Eq. 3     
Suppose we can accurately measure A(T) but only a population mean value is known for k (indicated by 
k*).   We hypothesize that Ã can be estimated from:        
 
 
 
 
 
 
 
Ã* = A(T) exp(k*T)/k*   
Eq. 4 
In Eq. 4, A(T) and T are measured and k* is known from either previous population measurements of 
from theoretical pharmacokinetic considerations.   


26 
 
Optimal sampling time:  The time T where  Ã* is exactly equal to Ã for all values of k can be 
determined by setting Eq. 2 equal to Eq. 3:   A0/k = A(T) exp(k*T)/k* =  A0 exp(-kT) exp(k*T)/k*  .  
Solving this for T yields:  
T = ln(k*/k)/(k*- k)  = (1/k*) ln(k*/k)/(1 – k/k*) =  τ* ln(k*/k)/(1 – k/k*), 
Eq. 5 
where τ* is the mean life of the estimated clearance rate. A plot of Eq 5 as a function of is shown in 
Figure 1 
 
 
 
 
 
 
 
 
 
 
 
Figure 1.  
Plot of 
optimal 
sampling 
time as a 
function of 
k*/k.  There 
is a 
singularity 
when k*/k 
= 1 
since all 
sampling 
points are 
equally 
valid.   
For the situation in 
which k* is the expectation 
value for the random variable k, the best sample time is therefore T =  τ*. 
Validation of single exponential case:  We hypothesize that Eq. 4 can be used to estimate the actual 
total number of decays without precisely knowing the actual clearance rate k if we know the 
expectation value k*for a population of samples.  As noted above, k* may have been determined from 
previous studies where sufficient samples were acquired to accurately determine individual k values or 
in some cases from prior knowledge about the tracer pharmacokinetics.  To evaluate this hypothesis, a 
simulation using Excel was performed where values of k are randomly sampled for a set of initial 
activity levels (A0).  Without any loss of generality, k* is assumed to equal 1/time (with arbitrary time 
units) and the values of k are selected from a random number generator with a gaussian distribution 
with a mean of 1 and a standard deviation of 0.18.  In the 500 samples that were taken, k ranged from 
0.42 to 1.58.  The actual total number of decays Ã determined from Eq. 2 was compared against the 
estimated total number of decays Ã* determined from Eq. 4 as a function of sampling time T.  Linear 
regressions were performed on the plots of Ã as a function of Ã* to determine the slope, intercept, 
correlation coefficient and the standard error of estimate.   


27 
 
Results of Single Exponential Simulation:  The simulation result for the optimal sample time is shown 
in Figure 2, while the linear regression parameters as a function of sample time are given in Table 1. 
 
Figure 2.  Single exponential simulation comparing actual decays with the single point time estimation. 
 
Table 1  Linear Regression Results for Ã Comparison to Ã*as a function of Sample Time 
Sample 
Time T (τ)
Slope
Intercept
r2
SEE
0.2
            
1.07
                  
(43.7)
                
0.89
                  
266.8
               
0.6
            
1.08
                  
(60.7)
                
0.96
                  
160.1
               
1.0
            
1.04
                  
(23.3)
                
0.99
                  
67.1
                  
1.4
            
0.96
                  
57.2
                  
0.99
                  
80.2
                  
1.8
            
0.86
                  
165.3
               
0.96
                  
163.8
               
 
 
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
0
1,000
2,000
3,000
4,000
Actual Total Decays (Ã)
Estimated Total Decays (Ã*)


28 
 
The plot of the simulation data shows an excellent correspondence between the estimated total decays 
calculated from a single time point sample and the actual total decays.  Table 1 demonstrates that ideal 
sample time occurs at the mean life associated with k* as expected from the results given by Eq 5 and 
the plot shown in Figure 1. 
 
Single exponential derivation:  The derivation for bi-exponential clearance is similar to the mono-
exponential derivation:  
 
 
A(t) = A1 exp(-k1t) + A2 exp(-k2t)        
 
Eq 6    
The total decays are equal to:   Ã = A1/k1 + A2/k2              Eq 7 
In most radionuclide therapy cases, the major portion of the radiation dose comes from the longer 
component (k2).  Hence, Eqs 6 & 7 are rewritten in terms of A2 and k2.  
 
Define A1 /A2 = c;    k1/k2 = a , then                    
  
 
 
A(t) = cA2 exp(-ak2t) + A2 exp(-k2t)   
Eq 8  
  
and  
 
 Ã = A2/k2 (c/a + 1)                       
Eq 9  
The activity at time t = T is:  A(T) = cA2 exp(-ak2T) + A2 exp(-k2T)  
  
Solving for A2,  A2  = A(T)/(c exp(-ak2T) + exp(-k2T)), thus:    
 
  Ã   =                         A(T) x    (c/a + 1)                       
Eq 10                 
                     [(c exp(-ak2T) + exp(-k2T)) x k2] 
Using a similar approach as with the single exponential case, the equation for the estimated total decays 
is written as: 
  Ã* =                  A(T) x    (c*/a* + 1)               
 
Eq  11  
              [(c* exp(-a*k2*T) + exp(-k2*T)) x k2*] 
As with the single exponential case, k2* is the effective clearance rate constant for the long component, 
but now there are 2 additional parameters that need to be included, c* and a*. At first glance, having 
this many parameters might seem to make the approach challenging and in the general case that is true.  
However, in instances that will be useful for radionuclide therapy, it will often be the case that a* > 10 
and c* will be less than 2.  When that is true, then: 
(c*/a* + 1)  ≈ 1 and   [(c* exp(-a*k2*T) + exp(-k2*T)) x k2*] ≈ exp(-k2*T)) x k2*, 
Thus,   Ã*  ≈    A(T) exp(k2*T)) /k2*  which is an approximation of the result obtained for the single 
exponential case in Eq 4. 
 
 


29 
 
Validation of the biexponential case:  Using a similar approach as with the single exponential case, we 
hypothesize that Eq. 11 can be used to estimate the actual total number of decays without precisely 
knowing the actual biexponential parameters c, a, and k2 as long as we know their expectation values 
(c*, a*, k2*) for a population of samples. To evaluate this hypothesis, a simulation using Excel was 
performed where values of c, a and k2 are randomly sampled for a set of initial activity levels (A2).  For 
this simulation, the values of c*, a* and k2* were determined from an actual clinical protocol that 
focused on the radiation dose to kidneys from Y-90 DOTATOC treatments. The parameters used in the 
simulation are given in Table 2.  Note that while the standard deviation associated with k2* is relatively 
small, the standard deviations associated with c* and a* are large. 
Table 2.  Biexponential Simulation Parameters 
c* 
a* 
k2* 
mean 
     1.6  
 12.1  
   0.020  
standard deviation 
 
1.04 
 
3.90 
 
0.0036 
maximum 
4.2 
19.0 
0.034 
minimum 
0.03 
5.4 
0.009 
 
The individual values of k2 are selected from a random number generator with a gaussian distribution 
while the distribution for c was triangular and the distribution for a was uniform.  The maximum and 
minimum values for each of the parameters in the 500 samples that were generated show the large 
range over which c and a varied.  The actual total number of decays Ã determined from Eq. 9 was 
compared against the estimated total number of decays Ã* determined from Eq. 11 as a function of 
sampling time T.  Linear regressions were performed on the plots of Ã as a function of Ã* to determine 
the slope, intercept, correlation coefficient and the standard error of estimate.   
Results of the biexponential simulation:  The simulation result for the optimal sample time is shown 
in Figure 3, while the linear regression parameters as a function of sample time are given in Table 3.  
Although the correlation and standard error of estimate associated with the bi-exponential simulation 
are not as good as those obtained for the single exponential experiment, there still is a very strong 
correlation between the estimated and actual total decays.  Table 3 shows the linear regression results 
as a function of the single sample time T, which is expressed in terms of the mean time associated with 
k2* (τ2). 
Table 3.  Biexponential simulation linear regression results as a function of sample time T 
Sample 
Time T (τ2) 
 
Slope 
 
Intercept 
 
r2 
 
SEE 
0.2 
0.93 
41 
0.91 
134 
0.6 
1.05 
-21 
0.96 
90 
1 
1.03 
4 
0.96 
86 
1.4 
0.96 
46 
0.95 
102 
1.8 
0.88 
99 
0.92 
132 
As with the single exponential simulation results, the best sampling time in terms of the correlation and 
particularly the standard error of estimate is at T = τ2. 
 
 


30 
 
 
Figure 3.  Biexponential simulation comparing actual decays with the single point time estimation. 
Retrospective analysis of clinical study:  There has been an ongoing clinical trial at the University of 
Iowa in which three cycles of Y-90 DOTATOC is used to treat patients with neuroendocrine cancer.  The 
radiation dose to the kidneys from the first 2 cycles was determined using the following procedure.  
After administration of Y-90 DOTATOC and amino acids (~ 5 h), subjects were imaged with PET/CT to 
quantify kidney activity and then immediately imaged with bremsstrahlung SPECT/CT.   Additional 
SPECT/CT was acquired at 24, 48 and 72 hours.  Kidney dose was determined from the SPECT/CT 
clearance scaled by the PET/CT activity measurement.    
The single time point approach was applied retrospectively to this data and used to calculate the kidney 
dose as a function of sampling time using the population means obtained for c*, a* and k2 from the 47 
patient studies which are given in Table 4.  Figure 5 shows a plot of a comparison of the actual kidney 
dose and the estimated kidney dose at the best sampling time from our protocol (t = 48 hours).  This is 
fairly close to the ideal sample time of 1/k2* = 50 hours. 
Table 4.  Mean values of c*, a*, and k2* from 47 patient samples. 
c* 
a* 
k2* 
mean 
     1.11  
 12.3  
   0.020  
standard deviation 
 
1.06 
 
7.3 
 
0.005 
 
Table 5.  Retrospective analysis of clinical Y-90 DOTATOC data as a function of sample time. 
Sample 
Time T (h) 
 
Slope 
 
Intercept 
 
r2 
 
SEE 
5 
 0.83  
 115.4  
 0.83  
 108.1  
24 
 0.86  
 63.8  
 0.94  
 66.8  
48 
 0.94  
 43.6  
 0.95  
 60.9  
 -
 500
 1,000
 1,500
 2,000
 2,500
0
500
1,000
1,500
2,000
2,500
Actual Total Decays (Ã) 
Estimated Total Decays (Ã*) 


31 
 
72 
 0.94  
 62.3  
 0.92  
 75.4  
 
Figure 4.  Comparison of actual and estimated kidney dose. 
 
 
 
 -
 300
 600
 900
 1,200
 1,500
 -
 300
 600
 900
 1,200
 1,500
Actual Kidny Dose (cGy)
Estimated Kidney Dose (cGy)


32 
 
Discussion and conclusions:  In this paper we have demonstrated that under conditions where there is 
exponential clearance of a radiotracer and some prior knowledge about the tracer kinetics is available, 
it is possible to accurately estimate the total numbers of decays (and thereby radiation dose) from a 
single time point measurement of activity.  The simulations from both the single exponential and 
biexponential cases show excellent results for the estimations when the appropriate sample time is 
used.  We have demonstrated that the best sample time is equal to the mean time associated with the 
rate constant k for a single exponential and k2 for the biexponential case.  The simulations support this 
result since the minimum standard error of estimate is found when T = τ.  More importantly, the actual 
clinical results obtained by retrospectively applying the single time dose approach shows the same 
behavior.  These results support the contention that the management of administered activity to 
patients undergoing radionuclide therapy can be determined with sufficient accuracy with a single time 
point activity measurement if information exists about population averages for the tracer kinetic 
parameters.  The most favorable condition will be obtained when the rate constant of the long 
component (k2) is gaussian distributed with a standard deviation that is less than 30% of the mean.   
This does appear to be the case for Y-90 DOTATOC in the kidneys and is likely to be the case for other 
similar agents such as Lu-177 DOTATOC.   
There is a straight forward way to predict whether this approach will work for a specific 
radiotherapeutic agent for which dosimetry data exists.  One only needs to plot the actual total number 
of decays against one of the activity samples that was used to calculate the dose.  If there is a strong 
linear relationship, then subsequent treatments could rely on the single time point method given in this 
paper.  There is reason to believe that the application of this approach will substantially reduce the 
burden of both patients and the clinic through the reduction of imaging procedures over many days 
while still providing sufficient radiation dose information to guide the treatment of these patients.   
 
 
 
 
 
 
Appendix II 
 
HCCC Clinical Trial Data and Safety Monitoring Plan (DSMP) 
 
 
Type of Clinical Trial: 
 
 Investigator-initiated (UI/HCCC) 
 
Investigator-initiated, participating site 
 Pilot study 
 
Phase I 
 Phase I/II 
 
Phase II 
 Phase III 
 
Compassionate-use drug protocol 
 
Interventional Treatment 
 
Interventional Non-Treatment 
 
Interventional Treatment 
 
 
 


33 
 
 
Study risk-level:  
 Level 1—low risk of morbidity or death, * <1% of death or any adverse event  
 Level 2—risk of death* <1% or any adverse event 1% – 5%  
 Level 3—risk of death* 1% – 5% or grade 4 – 5 SAE 1% – 5%                                                               
  Level 4—risk of death* >5% or grade 4 – 5 SAE >5%  
 Drugs being used on a “compassionate” basis  
* Risk of death” refers specifically to 100-day treatment-related mortality 
___________________________ 
 
Reporting and Monitoring Requirements:  
All institutional investigator initiated trials (IITs), regardless of assigned risk level are subject to routine 
DSMC monitoring activities which may include but are not limited to review of signed consent documents, 
eligibility and adverse event reporting.  
 
All institutional IITs have the following reporting requirements as part of their DSMP: 
• Provide an annual progress report to the DSMC and PRMC 
• Register subjects in HCCC’s Clinical Trial Management System, OnCore 
• Document Adverse Events  
• Document protocol deviations  
 
Selected monitoring strategy based on risk-level: 
 
Risk Level 4 
Interventional treatment trials involving investigational agents or devices with a risk of death* (>5% or grade 
4 – 5 SAE >5%), e.g. all investigator initiated INDs, most Phase I/II trials, gene therapy, gene manipulation or 
viral vector systems high-risk clinical procedures if performed solely for research purposes.  The use of a new 
chemical or drug for which there is limited or no available safety data in humans. 
 
Study Safety Review 
An independent study monitor and/or the DSMC Chair (or designee), will review study data (provided by the 
PI/available in OnCore) and communicate with the PI at least biannually.  A copy of this communication will 
be forwarded to the DSMC and PRMC Chairs.   
 
Additional Reporting Requirements:  
- A scanned copy of the completed eligibility checklist, with screening information and signature from 
evaluating study team member, will be attached in OnCore for ongoing review by DSMC staff.  
- Serious adverse events will be entered directly into an OnCore SAE report by the research team.  OnCore 
will send an automatic notification to the DSMC Chair/acting Chair and staff for review.  


34 
 
- The DSMC utilizes a risk-based monitoring approach.  The trial's research records will be monitored at 
minimum twice per year.  Monitoring may be done more frequently depending on the protocol, risks to 
subjects, reported serious/adverse events, patient population and accrual rate.   Records for a minimum of 
25% of subjects will be monitored for the entire study.    
Monitoring will involve the following: 
• review eligibility of patients accrued to the study, 
• check for the presence of a signed informed consent, 
• determine compliance with protocol’s study plan, 
• determine whether SAEs are being appropriately reported to internal and external regulatory 
agencies,  
• compare accuracy of data in the research record with the primary source documents, 
• review investigational drug processing and documentation, 
• assess cumulative AE/SAE reports for trends and compare to study stopping rules. 
 
 
Routine Adverse Event Reporting 
 
For non-serious Adverse Events, documentation will begin after radiotracer injection and continue through 1 
calendar day following imaging. For studies using PET or SPECT IND agents, the AE reporting period is 
limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  [90Y is 64.1 hours. Therefore, 10 radioactive half-lives will be 27days]. 
 
Collected information should be recorded in the electronic/Case Report Forms (eCRF/CRF) for that subject. A 
description of the event, its severity or toxicity grade, onset and resolved dates (if applicable), and the 
relationship to the study drug (if a grade 3 or higher) should be included. Documentation should occur in real 
time. 
 
Serious Adverse Event Reporting 
 
For any experience or condition that meets the definition of a serious adverse event (SAE), recording of the 
event will begin after radiotracer injection and continue through 1 calendar day following imaging.  For 
studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  [90Y is 64.1 hours. 
Therefore, 10 radioactive half-lives will be 27days] 
Investigators must report to the DSMC any serious adverse events (SAE), whether or not they are considered 
related to the investigational agent(s)/intervention (21 CFR 312.64). SAEs must be reported via an OnCore 
SAE Report within 1 business of learning of the event.  
 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
 
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization OR prolongation of existing hospitalization 
for ≥ 24 hours  


35 
 
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
 
Data Monitoring and Management  
All studies that undergo PRMC review and/or utilize HCCC Clinical Research Services (CRS) resources are 
required to register subjects in OnCore. Subject registration includes the following: 
• Consent date and the IRB approved consent used  
• Date of eligibility and eligibility status (eligible, not eligible) 
• On study date and subject’s disease site (and histology if applicable) 
• On treatment date (if applicable)  
 
If/when eCRFs are developed for this study, the following data monitoring strategy will be used: 
 
 
Subject Data 
 
In addition to the subject registration and subject status data entered in OnCore for all HCCC trials, research 
staff also enter the subject study data into electronic case report forms (eCRFs) for HCCC investigator 
initiated studies. eCRFs are approved by the PI and statistician prior to study activation to ensure the most 
effective data acquisition. All information on eCRFs will be traceable to the source documents which are 
generally maintained in the subject’s file. eCRF data are expected to be entered into OnCore within 30 
calendar days after a subject’s study visit.  
 
Forms Monitoring 
 
OnCore eCRF data are monitored on a routine basis (dependent on accrual) to ensure all mandatory fields are 
entered completely, accurately and within time requirements. The assigned DSMC monitor manages the 
logistics associated with the data monitoring review. Once the clinical trial is identified for monitoring, the 
monitor arranges for a selection of cases to review from among the subjects registered in OnCore.  As part of 
the forms monitoring process, the assigned monitor will issue queries within the eCRF to resolve missing, 
incomplete and/or incorrect information. A member of the research team is expected to respond to monitoring 
queries within 14 business days.  
 
This process can often identify a misunderstanding or deficiency in protocol requirements early in the study 
and can improve data quality.  
 
Final Reports 
 
A summary of each subject’s data record is continually available to the PI, research staff, and DSMC from 
OnCore’s Biostat Console. The availability of this information is a valuable tool for the preparation of final 
reports and manuscripts as well as ongoing deficiency reports. 
 


36 
 
Appendix III – Data forms 
 
IRB# 201708778 
 
 
 
 
 
 Inclusion 
 Exclusion 
 Physical exam 
 Data collection for 90Y-DOTATOC PET/CT 
 Karnofsky performance scale 
 Lansky play scale 
 QOL questionnaire 
 Patient Home Going Instructions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
University of Iowa Hospital and Clinics 
Inclusion / Exclusion 90Y-DOTATOC Theranostics  
Patient:_______________________  


37 
 
Inclusion 
Criteria 
 
 
 
1 
Y / N 
Disease not amenable to standard treatment (nonresectable or disease present after one or more surgeries and/or 
Sandostatin treatment) or subject has failed existing first line chemotherapy, biologic therapy, targeted agent therapy or 
radiation therapy.  
2 
Y / N 
Participation in Iowa Neuroendocrine Tumor Registry (IRB 199911057) 
3 
Y / N 
A pathologically confirmed (histology or cytology) malignant neoplasm with at least one target lesion that is confirmed 
by conventional imaging and is determined to express somatostatin receptors by 68Ga-DOTATOC (TATE) PET within 6 
months prior to treatment with 90Y-DOTATOC. 
Date of PET: 
Date of Conventional Imaging:                                                                         
4 
Y / N 
The target lesion is one that either has never received external beam radiation irradiated or has been previously 
irradiated and has since demonstrated progression.  Any local irradiation of the target lesion or any non-target lesions 
via external beam, conformal or stereotactic radiation treatments must have occurred more than 4 weeks prior to study 
drug administration.  Any full craniospinal radiation, whether or not a target lesion is included in the field, must have 
occurred more than 3 months prior to study drug administration.  
External Beam: N/A // Date:_________________//Progression Y / N 
Craniospinal radiation: N/A // Date_______________ 
5 
Y / N 
 Life expectancy > 2 months at the time of study drug administration. 
6 
Y / N 
 Archival tissue from a previous biopsy will be required.   
7 
Y / N 
Age ≥ 6 months-90 years at the time of study drug administration.       Age______________ 
 
 
8 
Y / N 
Performance status as determined by Karnofsky ≥  60% or Lansky Play Scale ≥ 60% at the time of study drug 
administration.  
9 
Y / N 
Completion of Norfolk Quality of Life Questionnaire. 
 
10 
Y / N 
Within 7-10 days of study drug administration, patients must have normal organ and marrow function as defined below: 
absolute neutrophil count 
>1000/mm3 
Platelets 
>90,000/mm3 
total bilirubin 
<3X ULN for age  
AST(SGOT) & ALT(SGPT) 
<10X institutional upper limit of normal for age 
Urinalysis 
no greater than 1+ hematuria or proteinuria 
Renal function 
Adults(age 18 or >): Serum creatinine ≤ 1.2 mg/dl; if serum 
creatinine is >1.2 mg/dL,  
GFR will need to be ≥ 80 ml/min/1.73m2 for subjects ≤40 years 
old,  
≥ 70 ml/min/1.73m2 for subjects between 41-50;  
≥ 60 ml/min/1.73m2 for subjects between 51-60;   
≥ 50 ml/min/1.73m2 for subjects > 60 years old. 
 
Children(age <18): creatinine and nuclear GFR ≥ 80 
mL/min/1.73 m2  
11 
Y / N 
Negative pregnancy test.  The effects of 90Y-DOTA-tyr3-Octreotide on the developing human fetus are unknown. For this 
reason and because Class C agents are known to be teratogenic, women and men of child-bearing potential must agree 
to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of 
study participation.  Should a woman become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 


38 
 
12 
Y / N 
Ability to understand and the willingness to sign a written informed consent document. 
Exclusion 
Criteria 
1 
Y / N 
 Pregnant women.     
Pregnancy status: male // female: premenarchal / >60y.o. / negative serum pregnancy / post menopausal x 12 M / ultrasound 
negative 
2 
Y / N 
Breastfeeding women.   
3 
Y / N 
Surgery within 4 weeks of study drug administration.  
 
 
4 
Y / N 
External beam radiation to both kidneys (scatter doses of <500 cGy to a single kidney or radiation to < 50% of a single 
kidney is acceptable). 
 
 
5 
Y / N 
Prior PRRT with 90Y-DOTATOC (TATE) or 177Lu-DOTATOC (TATE) or 131I-MIBG therapy for this malignancy. 
6 
Y / N 
Another investigational drug within 4 weeks of study drug administration. 
7 
Y / N 
 Concurrent, malignant disease for which patient is on active therapy.    
8 
Y / N 
Another significant medical, psychiatric, or surgical condition which is currently uncontrolled by treatment and which 
would likely affect the subject's ability to complete this protocol.  
 
 
9 
Y / N 
Any subject for whom, in the opinion of their physician, a 12-hour discontinuation of somatostatin analogue therapy 
represents a health risk.  Also subjects who have received long-acting somatostatin analogue in the past 28 days or 
long-acting lanreotide within the past 16 weeks are excluded.  Subjects may be maintained on short acting octreotide 
during the time from last injection of long-acting somatostatin analogue until 12 hrs prior to injection of study drug. 
Known antibodies to Octreotide, Lanreotide, or DOTATOC or history of allergic reactions attributed to compounds of 
similar chemical or biologic composition to 90Y-DOTATOC. 
Last somatostatin therapy:  long acting date and type:____________________________ 
                                                         short acting usage:________________________ 
10 
Y / N 
Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) of study drug 
administration or those who have not recovered from adverse events due to agents administered more than 4 weeks 
earlier. 
Date of last chemotherapy:_________________________ 
11 
Y / N 
Uncontrolled illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.      
12 
Y / N 
Subject weighs more than 450 pounds. (Subjects who weigh more than 450 pounds will not be able to fit inside the 
imaging machines.) 
13 
Y / N 
Inability to lie still for the entire imaging time (due to cough, severe arthritis, etc.) 
 
Signature of Investigator: ______________________________ 
 
Date:____________________ 
 
 


39 
 
University of Iowa Hospital   
Patient:_______________________  
 
Physical exam for 90Y-DOTATOC 
Subject Data 
1) Limited Physical Exam:  
a) HEENT (Circle or fill in blank): 
 NORMAL OR____________________________ 
b) Chest (Circle or fill in blank):   
NORMAL OR____________________________ 
c) Cardiovascular (Circle or fill in blank): NORMAL OR____________________________ 
d) Abdomen (Circle or fill in blank):  
NORMAL OR____________________________ 
e) Integument (Circle or fill in blank): 
 NORMAL OR____________________________ 
f) Musculoskeletal (Circle or fill in blank): NORMAL OR____________________________ 
g) Neurological (Circle or fill in blank): NORMAL OR____________________________ 
 
 
 
Investigator (Signature)____________________________  (Date) ___________ 
 
 


40 
 
University of Iowa Hospital   
Patient:_______________________  
  
 
Data Collection for 90Y-DOTATOC PET/CT 
 
This page will be completed in the PET Center:  Date______________________ 
 
 
1) Pregnancy test (urine) required? Y / N Results_________________  
 
2) 90Y-DOTATOC Dose:_________mCi @ Injection Time_____:_____  
3)PET Scan Uptake period __________min. 
4) Vital Signs (supine) at PET Completion: P _____, BP ______/______, RR________ Temp _________ °C 
5) Were any adverse events reported or observed since the 90Y-DOTATOC injection? 
 
□ No □ Yes 
If yes, provide a narrative of what the patient reported and/or what was observed. 
________________________________________________________________ 
________________________________________________________________ 
________________________________________________________________ 
________________________________________________________________ 
________________________________________________________________ 
________________________________________________________________ 
Signature of PET staff: __________________________________ Date / Time:  __________________  


41 
 
 
University of Iowa Hospital   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient:_______________________  
 
 
 
Karnofsky Performance Scale 
 
 
 
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA 
 
Able to carry on normal activity and to work; no 
special care needed 
100 Normal no complaints; no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
Unable to work; able to live at home and care for 
most personal needs; varying amount of assistance 
needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Required occasional assistance, but 
is able to care for most of his 
personal needs. 
50 
Required considerable assistance 
and frequent medical care. 
Unable to care for self; required equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; required special care and 
assistance. 
30 
Severely disabled; hospital 
admission is indicated although 
death not imminent. 
20 
Very sick; hospital admission 
necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes 
progressing rapidly. 
0 
Dead 
  
  
 
 
 
 
Signature:___________________________ Date:________________ Time:____________ 
 
 


42 
 
University of Iowa Hospital    
 
 
 
 
 
 
 
Patient:_______________________  
 
 
 
Lansky Play Scale 
 
LANSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA 
 
Able to carry on normal activity and to work; no 
special care needed 
100 Fully active. 
90 
Minor restriction in physically 
strenuous play. 
80 
Restricted in strenuous play, tires 
more easily, otherwise active. 
Mild to moderate restriction. 
70 
Both greater restrictions of, and less 
time spent in active play. 
60 
Ambulatory up to 50% of time, limited 
active play with 
assistance/supervision. 
50 
Considerable assistance required for 
any active play, fully able to engage 
in quiet play. 
Moderate to severe restriction. 
40 
Able to initiate quiet activities. 
30 
Needs considerable assistance for 
quiet activity. 
20 
Limited to very passive activity 
initiated by others (e.g., TV). 
10 
Completely disabled, not even 
passive play. 
0 
Dead 
  
  
 
 
 
 
Signature:___________________________ Date:________________ Time:____________ 
 
 


43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
University of Iowa Hospital
Patient Diary 
Patient name_________________________
Treatment # _________
Track the # of cups (8 oz each) of water you drink 
1
2
3
4
5
Date:______________
6
7
8
9
10
11
12
13
14
15
1
2
3
4
5
Date:______________
6
7
8
9
10
11
12
13
14
15
1
2
3
4
5
Date:________________
6
7
8
9
10
11
12
13
14
15
Signature________________________
Date________________
Adult (≥18):  38 ml/kg=__________ml ÷ 1000=__________Liters x 4 =___________cups (8 oz each)
Pediatrics (< 18): 
 11-20 kg :  (1000 ml + 50ml/kg for each kg over 10) x 1.5 = ___________ml ÷ 1000 =_________Liters x 4 = ___________cups (8 oz each)
 > 20 kg : (1500ml + 20 ml/kg for each kg over 20) x 1.5 = ___________ml ÷ 1000 = _________Liters x 4 = __________cups (8 oz each)
Day prior to treatment (18 hrs)  ______ glasses x .75 = 
________glasses
1st day after treatment drink ______ glasses
2nd day after treatment drink _______ glasses
Pediatrics (<18):


44 
 
 
 
 
UNIVERSITY OF IOWA HOSPITALS AND CLINICS 
DEPARTMENT OF RADIOLOGY 
DIVISION OF NUCLEAR MEDICINE 
 
 
RADIATION PROTECTION PRECAUTIONS AFTER Y-90 DOTATOC THERAPY 
 
Radiation from Y-90 DOTATOC does not penetrate outside the body, but a small amount of radiation may be 
present for about a week following treatment in body fluids, such as blood and urine.  Certain precautions are 
suggested for one week after treatment to limit any potential radiation exposure to others.  You should wash 
your hands thoroughly after urination and use a condom during sexual intercourse.  In general, it is not 
necessary to avoid contact with friends or family during this time, and isolation is not required.  You can 
usually return to work and your usual activities following treatment.  Please follow the following instructions 
after treatment with Y-90 DOTATOC: 
 
1. For 1 week after each treatment, clean up spilled urine and dispose of any body fluid-contaminated 
material to prevent it being handled (e.g., flush it down toilet or place it in plastic bag in household trash); 
Wash hands thoroughly after using toilet). 
 
2.  For 1 week after each therapy, use condoms for sexual relations. 
 
3. There may be potential risks to the fetus from Y-90 DOTATOC radiation therapy. You should follow 
effective means of contraception throughout the therapy duration and for 1 year after the completion of the 
last cycle of treatment. 
 
4.  To further protect your kidneys, drink extra water or juice for the next 2 days after discharge.  Please, for 
the sake of your kidneys, keep the fluid diary you have been given.  This diary will help us determine if you 
need extra IV fluid. 
 
 
If you have concerns after you leave the hospital, please contact Dr. Sue O’Dorisio at 319-356-3595 or 
Dr. Yusuf Menda at 319-356-2000.  
 
I have read this explanation or had it read to me and understand it. 
 
 
 
________________________ 
_________________________________________ 
Date  
 
 
 
Signature 
 
 

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