Clinical trial NCT04105543
Conditions: Head and Neck Cancer
Sponsor: University of Wisconsin, Madison
Start date: 2019-12-20; Completion date: 2024-02-01
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1 study of the use of an investigational drug that selectively delivers radiation to malignant tumor cells, CLR 131, in combination with external beam radiation therapy (EBRT) in subjects with locoregionally recurrent head and neck cancer. The trial will enroll up to 12 participants who are amenable to retreatment with radiation therapy. Participants who also have distant metastatic disease may be enrolled on this clinical trial, but they must have evaluable disease that will be clinically treated with radiation therapy, as per standard of care. All participants will receive a dosimetry test dose of CLR 131 to establish drug uptake by the tumor and enable Monte Carlo dose estimation based on CLR 131 SPECT/CT imaging evaluation. Participants showing uptake will receive a cumulative tumor dose of 60-70 Gy using personalized dose calculation (via Monte Carlo methods) of CLR 131 combined with external beam radiation.

Detailed description:
Following informed consent, all participants will receive a dosimetry test dose of 15 mCi CLR 131 to establish drug uptake by the tumor and enable Monte Carlo dose estimation based on CLR 131 SPECT/CT imaging evaluation.

Participants who have uptake of the CLR 131 dosimetry test dose at their disease site as determined by the study radiologist will be eligible to participate on the treatment portion of this clinical trial. Participants showing uptake will receive a cumulative tumor dose of 60-70 Gy using personalized dose calculation of CLR 131 (via Monte Carlo) combined with external beam radiation. In this study, we are also studying a subset of up to 6 patients who do not uptake after the CLR 131 test dose, who will still proceed with treatment with CLR 131.

This clinical trial involves two cohorts of subjects: (a) dose escalation and (b) dose expansion. In the dose escalation phase, an mTPI-2 design, an extension of modified toxicity probability interval (mTPI-2), will be used to identify the maximum tolerated dose (MTD) using cohorts of 4 participants and up to 3 dose levels of CLR 131. Participants in the dose escalation phase will receive 2 doses of CLR 131 with the first dose on day 1 followed by the second dose on day 8.

Treatment with CLR 131 on the dose escalation cohort will begin at dose level 1 (15.6 mCi/m2). Participants at dose level 1 will receive an intravenous infusion of CLR 131 at 15.6 mCi/m2 on day 1 followed by a second dose on day 8. Participants at dose level 2 will receive an intravenous infusion of CLR 131 at 18.75 mCi/m2 on day 1 followed by a second dose on day 8.

Once the MTD is determined by the dose escalation phase, participants will be enrolled on the dose expansion cohort. Participants on the dose expansion cohort will receive 2 doses of CLR 131 with the first dose on day 1 followed by the second dose on day 8, with the dose determined by the dose escalation phase.

SPECT/CT imaging will be performed on days 2, 3, 4-6, and 7-8 of the treatment period to visualize and quantitate the biodistribution of CLR 131. Based on these SPECT/CT imaging scans, the Bednarz lab will utilize the Monte Carlo method to predict absorbed dose of CLR 131 to tumors and normal structures.

All participants will start thyroid-protection medication the day prior to the CLR 131 dosimetry test dose and will continue to take thyroid protection medication for 14 days after the last CLR 131 dose.

Based on the calculated absorbed dose of CLR 131 to the specific targeted tissue, the participant will undergo external beam radiation therapy (EBRT) to complete the designated radiation dose outlined in the re-irradiation plan, as per standard of care. Prior to CLR 131 administration and at 3 and 6 months post EBRT, participants will be assessed for changes to swallow function. Prior to CLR 131 administration and at 3, 6 and 12 months post EBRT, quality of life measures and salivary characteristics will be assessed. The investigators anticipate the total study (baseline, CLR 131 administration, EBRT and 3, 6, 12 and 24 month follow up assessments) to take 27 months per participant.

Arms: arm 1: Enrollment will start at dose level 1 (first 4 participants). Participants will receive 2 doses of CLR 131 intravenously with the first dose on day 1 followed by the second dose on day 8.

Dose Level -1 (de-escalation dose, if toxicities warrant) = 12.5 mCi/m\^2 Dose Level 1 (beginning dose) = 15.6 mCi/m\^2 Dose Level 2 (escalation dose) = 18.75 mCi/m\^2

Dose escalation will proceed with no limiting toxicities at each level (maximum of 8 participants at each dose level). With maximum tolerated dose confirmed, an expansion phase will proceed.
Interventions: intervention 1: CLR 131
Intervention descriptions: intervention 1: CLR 131 is a radiopharmaceutical dosed intravenously over a period of approximately 30 minutes, dose will be based on total body surface area calculated from actual body weight and height

Protocol documents:
Prot_SAP_000.pdf: 
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UW19041 Therapeutic Combination of CLR 131 with 
External Beam Radiation in Head and Neck Cancer 
 
Principal Investigators: Justine Yang Bruce, MD 
 
        Paul M. Harari, MD 
IND#: 78434, Division of Oncology Projects 1 
IND Sponsor: Cellectar Biosciences, Inc. 
 
 
 
NCT04105543 
 
 
 


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2 
 
STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Council for Harmonisation 
guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46). All personnel involved in the conduct of this study have 
completed human subjects protection training.


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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
Principal Investigators: 
Signed: 
 
Date:  
 
Justine Yang Bruce, MD 
 
Principal Investigator 


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TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................................... 4 
TABLE OF TABLES ..................................................................................................................................... 7 
LIST OF ABBREVIATIONS.......................................................................................................................... 8 
PROTOCOL SUMMARY ........................................................................................................................... 12 
1 
KEY ROLES AND CONTACT INFORMATION ................................................................................. 16 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................ 20 
2.1 
Background Information ......................................................................................................... 20 
2.1.1 
Head and neck cancer ............................................................................................... 20 
2.1.2 
Locoregional recurrence ............................................................................................ 20 
2.1.3 
CLR 131 ..................................................................................................................... 20 
2.2 
Rationale for a clinical study using CLR 131 in combination with EBRT ................................ 23 
2.2.1 
Hypothesis ................................................................................................................. 24 
2.3 
Potential Risks and Benefits .................................................................................................. 24 
2.3.1 
Potential Risks ........................................................................................................... 24 
2.3.2 
Potential Benefits ....................................................................................................... 27 
3 
OBJECTIVES .................................................................................................................................... 28 
3.1 Study Objectives ......................................................................................................................... 28 
3.1.1 
Primary Objective ....................................................................................................... 28 
3.1.2 
Secondary Objectives ................................................................................................ 28 
3.2 
Study Outcome Measures ..................................................................................................... 28 
3.2.1 
Primary ...................................................................................................................... 28 
3.2.2 
Secondary .................................................................................................................. 28 
4 
STUDY DESIGN ............................................................................................................................... 29 
5 
STUDY ENROLLMENT AND WITHDRAWAL ................................................................................... 31 
5.1 
Number of Subjects ............................................................................................................... 31 
5.2 
Inclusion Criteria .................................................................................................................... 31 
5.3 
Exclusion Criteria ................................................................................................................... 32 
5.4 
Strategies for Recruitment and Retention .............................................................................. 34 
5.4.1 
Subject remuneration ................................................................................................. 34 
5.5 
Treatment Assignment Procedures........................................................................................ 34 
5.5.1 
Evaluable Subject ...................................................................................................... 35 
5.6 
Subject Withdrawal ................................................................................................................ 35 
5.6.1 
Handling of Subject Withdrawals or Subject Discontinuation of Study Intervention .... 35 
5.7 
Premature Termination or Suspension of Study..................................................................... 36 
6 
STUDY INTERVENTION .................................................................................................................. 37 
6.1 
Study Product Description ..................................................................................................... 37 
6.1.1 
Acquisition ................................................................................................................. 38 
6.1.2 
Formulation, Packaging, and Labeling ....................................................................... 38 


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6.1.3 
Product Storage and Stability ..................................................................................... 38 
6.2 
Dosage, Preparation and Administration of Study Product .................................................... 38 
6.3 
Thyroid Protection Medication ............................................................................................... 38 
6.4 
Modification of Study Product Administration for a Subject .................................................... 39 
6.5 
Accountability Procedures for the Study Product ................................................................... 39 
6.6 
Assessment of Subject Compliance with Study Product Administration ................................. 40 
6.7 
SPECT/CT Dosimetry Evaluation .......................................................................................... 40 
6.7.1 
Tumor and Organs at Risk (OAR) Dosimetry ............................................................. 40 
6.8 
External beam radiation therapy (EBRT) ............................................................................... 40 
6.8.1 
Dose specifications and target definition .................................................................... 40 
6.8.2 
Plan evaluation .......................................................................................................... 41 
6.8.3 
Technical factors ........................................................................................................ 41 
6.8.4 
Definition of organs at risk and recommended dose constraints ................................. 41 
6.8.5 
Prioritization for IMRT planning .................................................................................. 42 
6.9 
Concomitant Medications/Treatments .................................................................................... 43 
7 
STUDY SCHEDULE ......................................................................................................................... 44 
7.1 
Screening .............................................................................................................................. 44 
7.1.1 
Dosimetry Test Dose .................................................................................................. 45 
7.2 
Treatment Period ................................................................................................................... 45 
7.2.1 
Treatment Dose ......................................................................................................... 45 
7.3 
Post Treatment Period ........................................................................................................... 46 
7.3.1 
One Month Post CLR 131 Infusion (± 2 weeks) .......................................................... 46 
7.3.2 
3 Months Post EBRT (± 4 weeks) .............................................................................. 46 
7.3.3 
6 months Post EBRT (± 4 weeks) .............................................................................. 47 
7.3.4 
12 months Post EBRT (± 6 weeks) ............................................................................ 47 
7.3.5 
24 months Post EBRT (± 6 weeks)/End of Study Visit ................................................ 48 
7.4 
Withdrawal Visit (+ 30 days) .................................................................................................. 48 
7.5 
Unscheduled Visit .................................................................................................................. 48 
8 
STUDY PROCEDURES /EVALUATIONS ......................................................................................... 50 
8.1 
Study Procedures/Evaluations ............................................................................................... 50 
8.1.1 
Demographics ............................................................................................................ 50 
8.1.2 
Medical History .......................................................................................................... 50 
8.1.3 
Concomitant Medication Review ................................................................................ 50 
8.1.4 
Physical Exam ........................................................................................................... 50 
8.1.5 
Vital Signs .................................................................................................................. 50 
8.1.6 
Height ........................................................................................................................ 51 
8.1.7 
Weight........................................................................................................................ 51 
8.1.8 
ECOG Performance Status ........................................................................................ 51 
8.1.9 
Administration of Thyroid Protection Medication ......................................................... 51 
8.1.10 Administration of CLR 131 ......................................................................................... 51 
8.1.11 Adverse Event Evaluation .......................................................................................... 52 
8.1.12 SPECT/CT Imaging.................................................................................................... 52 


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8.1.13 Electrocardiogram (EKG) ........................................................................................... 52 
8.1.14 Quality of Life Measures ............................................................................................ 52 
8.1.15 Oral Swab and Saliva Collection and Analysis ........................................................... 53 
8.1.16 Oral profile exam (research procedure) ...................................................................... 54 
8.1.17 Modified Barium Swallow Study ................................................................................. 55 
8.1.18 Diagnostic Imaging .................................................................................................... 55 
8.2 
Laboratory Procedures/Evaluations ....................................................................................... 56 
8.2.1 
Clinical Laboratory Evaluations .................................................................................. 56 
9 
CRITERIA FOR DISEASE ASSESSMENT ....................................................................................... 57 
9.1 
Measurable Disease .............................................................................................................. 57 
9.2 
Non-measurable Disease ...................................................................................................... 57 
9.3 
Guidelines for Evaluation of Measurable Disease .................................................................. 57 
10 
RADIATION SAFETY ........................................................................................................................ 59 
10.1 
Radiation Safety Monitoring and Release Criteria .................................................................. 59 
10.2 
Subject Radiation Precautions ............................................................................................... 59 
11 
ASSESSMENT OF SAFETY ............................................................................................................. 61 
11.1 
Specification of Safety Parameters ........................................................................................ 61 
11.1.1 Unanticipated Problems ............................................................................................. 62 
11.1.2 Adverse Events .......................................................................................................... 62 
11.1.3 Serious Adverse Events (SAE) .................................................................................. 62 
11.2 
Time Period and Frequency for Event Assessment and Follow-Up........................................ 62 
11.2.1 Adverse Events .......................................................................................................... 63 
11.2.2 Serious Adverse Events ............................................................................................. 63 
11.2.3 Other Reportable Events ............................................................................................ 63 
11.3 
Characteristics of an Adverse Event ...................................................................................... 65 
11.3.1 Relationship to Study Intervention .............................................................................. 65 
11.3.2 Expectedness ............................................................................................................ 65 
11.3.3 Severity of Event ........................................................................................................ 65 
11.4 
Reporting Procedures ............................................................................................................ 65 
11.4.1 Unanticipated Problem (UP) Reporting to IRB, Cellectar and UWCCC DSMC ........... 65 
11.4.2 Serious Adverse Event Reporting .............................................................................. 66 
11.4.3 Reporting of SAEs and AEs to FDA ........................................................................... 70 
11.4.4 Reporting of Pregnancy ............................................................................................. 70 
11.5 
Halting Rules ......................................................................................................................... 70 
12 
STUDY OVERSIGHT ........................................................................................................................ 71 
Intensive Monitoring .............................................................................................................. 71 
13 
CLINICAL SITE MONITORING ......................................................................................................... 73 
14 
STATISTICAL CONSIDERATIONS .................................................................................................. 74 
14.1 
Study Hypotheses ................................................................................................................. 74 
14.2 
Sample Size Considerations .................................................................................................. 74 
14.3 
Final Analysis Plan ................................................................................................................ 75 
14.3.1 Analysis of Primary Endpoints .................................................................................... 75 


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14.3.2 Analysis of Secondary Endpoints ............................................................................... 75 
15 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 77 
16 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................... 78 
16.1 
Monitoring, Auditing, and Data Quality Control and Assurance Measures ............................. 78 
17 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 79 
17.1 
Ethical Standard .................................................................................................................... 79 
17.2 
Institutional Review Board ..................................................................................................... 79 
17.3 
Informed Consent Process .................................................................................................... 79 
17.4 
Exclusion of Women, Minorities, and Children (Special Populations) ..................................... 79 
17.5 
Subject Confidentiality ........................................................................................................... 80 
17.6 
Future Use of Stored Specimens and Other Identifiable Data ................................................ 80 
18 
DATA HANDLING AND RECORD KEEPING .................................................................................... 81 
18.1 
Data Management Responsibilities........................................................................................ 81 
18.2 
Data Capture Methods ........................................................................................................... 81 
18.3 
Types of Data ........................................................................................................................ 81 
18.4 
Schedule and Content of Reports .......................................................................................... 81 
18.5 
Study Records Retention ....................................................................................................... 82 
18.6 
Protocol Deviations ................................................................................................................ 82 
19 
PUBLICATION/DATA SHARING POLICY ......................................................................................... 83 
20 
LITERATURE REFERENCES........................................................................................................... 84 
APPENDICES ........................................................................................................................................... 90 
APPENDIX A: SCHEDULE OF EVENTS ................................................................................................... 91 
APPENDIX B: ECOG EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS ...... 94 
SUPPLEMENTAL MATERIALS ................................................................................................................. 95 
 
TABLE OF TABLES 
Table 1: 
Other Reportable Events Timeframe .................................................................................. 64 
Table 2: 
FDA Reporting Requirements. ............................................................................................ 67 
Table 3: 
Dose escalation rules .......................................................................................................... 75 
 


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LIST OF ABBREVIATIONS 
 
3D 
Three dimensional 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BUN 
Blood Urea Nitrogen 
BSA 
Body surface area 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CLR 124 
18-(p-[124I]-iodophenyl) octadecyl phosphocholine 
CLR 131 
18-(p-[131I]-iodophenyl) octadecyl phosphocholine 
CLR1404 
18-(p-iodophenyl)octadecyl phosphocholine 
CITI 
Collaborative IRB Training Initiative 
CoC 
Certificate of Confidentiality 
COPD 
Chronic obstructive pulmonary disease 
CRC 
Clinical Regulatory Committee 
CRF 
Case Report Form 
CT 
Computed tomography 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CVA 
Cerebrovascular event 
DHHS 
Department of Health and Human Services 
DIGEST 
Dynamic Imaging Grade of Swallowing Toxicity 
DLT 
Dose Limiting Toxicities 
DOT 
Disease Oriented Team 
DSMC 
Data and Safety Monitoring Committee 
DSMS 
Data and Safety Monitoring System 
EAT-10 
Eating Assessment Test-10 
EBRT 
External beam radiation therapy 
ECOG 
Eastern Oncology Cooperative Group 
eCRF 
Electronic Case Report Form 


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EKG 
Electrocardiogram 
EORTC 
European Organisation for Research and Treatment of Cancer 
FDA 
Food and Drug Administration 
FLC 
Free Light Chain 
FFR 
Federal Financial Report 
FOIS 
Functional Oral Intake Scale 
GCP 
Good Clinical Practice 
GSL 
Glottic/supraglottic larynx 
Gy 
Gray 
HNC 
head and neck cancer 
HNSCC 
head and neck squamous cell carcinoma 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDE 
Investigational Device Exemption 
IMRT 
intensity modulated radiotherapy 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
KeV 
kiloelectron volts 
LINAC 
linear accelerated-based 
mCi 
millicurie 
MDADI 
MD Anderson Dysphagia Inventory 
MEP 
Maximum expiratory pressure(s) 
MM 
Multiple myeloma 
MRI 
magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTPI-2 
modified toxicity probability interval 
N 
Number (typically refers to subjects) 
OAR 
Organs at risk 
OHRP 
Office for Human Research Protections 
ORR 
Overall response rate 
OS 
Overall survival 


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PJP 
Pneumocystis jiroveci pneumonia  
PD 
Prescribed dose 
PET 
positron emission tomography 
PFS 
Progression-free survival 
PLE 
phospholipid ether 
PI 
Principal Investigator 
PRMC 
Protocol Review and Monitoring Committee 
PS 
Performance Status 
PSS 
Performance Status Scale 
PSR 
Protocol Summary Report 
QLQ 
Quality of Life Questionnaire 
QOL 
Quality of Life  
rCTV 
Recurrent clinical tumor volume 
RECIST 
Response evaluation criteria in solid tumors 
rGTV 
Recurrent gross tumor volume 
RMS 
Residual Mucosal Saliva 
rPTV 
Recurrent planning tumor volume 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SCC 
Squamous cell carcinoma 
SF-12 
Medical Outcomes Trust Short Form 12 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
SPECT 
Single photon-emission computed tomography 
SSKI 
Saturated solution of potassium iodide 
TMJ 
Temporal Mandibular Joint 
TSH 
Thyroid-stimulating hormone 
T4 
thyroxine 
ULN 
Upper limit of normal 
UP 
Unanticipated Problem 
US 
United States 
USC 
University of Southern California 
USP 
US Pharmacopeia 
UW 
University of Wisconsin 
UWCCC 
University of Wisconsin Carbone Cancer Center 


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WBC 
White blood cell 
WOCP 
Women of childbearing potential 
XeQoLS 
Xerostomia-related Quality of life score 
 


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PROTOCOL SUMMARY 
Title: 
Therapeutic Combination of CLR 131 with External Beam Radiation in Head and 
Neck Cancer 
Précis: 
This is a Phase 1 study of the use of an investigational drug, CLR 131, in 
combination with external beam radiation therapy (EBRT) in subjects with 
locoregionally recurrent head and neck cancer. The trial will enroll up to 12 
subjects at the Maximum Tolerated Dose (MTD) who are amenable to 
retreatment with radiation therapy. Subjects who also have distant metastatic 
disease may be enrolled on this clinical trial, but subjects must have evaluable 
disease that will be clinically treated with radiation therapy, as per standard of 
care. All subjects will receive a dosimetry test dose of CLR 131 to establish 
drug uptake by the tumor and enable Monte Carlo dose estimation based on 
CLR 131 SPECT/CT imaging evaluation. Subjects showing uptake will receive 
a cumulative tumor dose of 60-70 Gy using personalized dose calculation (via 
Monte Carlo methods) of CLR 131 combined with external beam radiation.  
 
 
Objectives: 
Primary:   
• To evaluate the safety and tolerability of CLR 131 in combination with 
external beam radiation therapy in subjects with recurrent cancers of the 
head and neck. Outcome measure: Incidence of adverse events assessed 
using Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0. 
 
 
Secondary:   
• 
To perform dosimetric evaluation of CLR 131 in subjects with recurrent 
cancers of the head and neck. Outcome measure: CLR 131 tumor uptake 
via SPECT/CT imaging and 3D dosimetric evaluations. 
• 
To assess tumor response following treatment with CLR 131 in 
combination with external beam radiation therapy. Outcome measure: 
Overall response rate (ORR) defined as the proportion of subjects who 
experience either a partial response or complete response within 6 
months post completion of EBRT as measured by standard of care 
imaging (e.g. CT, MR, PET-MR). 
• 
To evaluate changes in swallowing function before and after treatment 
with CLR 131 in combination with external beam radiation therapy. 
Outcome measure: Swallow function assessed by Dynamic Imaging 
Grade of Swallowing Toxicity (DIGEST) scale. 
• 
To evaluate changes in quality of life before and after treatment with 
CLR 131 in combination with external beam radiation therapy. Outcome 


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measure: Quality of life assessed by MD Anderson Dysphagia Inventory 
score (MDADI). 
• 
To evaluate salivary flow rate before and after treatment with CLR 131 in 
combination with external beam radiation therapy. Outcome measure: 
stimulated salivary flow. 
 
 
 
Population: 
Up to twelve adult males and females of all races and ethnic groups with 
locoregionally recurrent head and neck cancer who may also have distant 
metastatic disease will be enrolled at the Maximum Tolerated Dose. 
Phase: 
I 
Number of 
Sites: 
1, University of Wisconsin Carbone Cancer Center  
Description of  
Intervention: 
Following informed consent, all subjects will receive a dosimetry test dose of 
15 mCi CLR 131 to establish drug uptake by the tumor and enable Monte 
Carlo dose estimation based on CLR 131 SPECT/CT imaging evaluation.  
Subjects who have uptake of the CLR 131 dosimetry test dose at their disease 
site as determined by the study radiologist will be eligible to participate on the 
treatment portion of this clinical trial. Subjects showing uptake will receive a 
cumulative tumor dose of 60-70 Gy using personalized dose calculation of 
CLR 131 (via Monte Carlo) combined with external beam radiation.  In this 
study, we are also studying a subset of up to 6 patients who do not  uptake 
after the CLR 131 test dose, who will still proceed with treatment with CLR 
131.    
This clinical trial involves two cohorts of subjects: (a) dose escalation and (b) 
dose expansion. In the dose escalation phase, an mTPI-2 design, an 
extension of modified toxicity probability interval (mTPI-2), will be used to 
identify the maximum tolerated dose (MTD) using cohorts of 4 subjects and up 
to 3 dose levels of CLR 131. Subjects in the dose escalation phase will 
receive 2 doses of CLR 131 with the first dose on day 1 followed by the 
second dose on day 8.  
Treatment with CLR 131 on the dose escalation cohort will begin at dose level 
1 (15.6 mCi/m2). Subjects at dose level 1 will receive an intravenous infusion 
of CLR 131 at 15.6 mCi/m2 on day 1 followed by a second dose on day 8. 
Subjects at dose level 2 will receive an intravenous infusion of CLR 131 at 
18.75 mCi/m2 on day 1 followed by a second dose on day 8.  
Once the MTD is determined by the dose escalation phase, participants will 
be enrolled on the dose expansion cohort. Participants on the dose expansion 
cohort will receive 2 doses of CLR 131 with the first dose on day 1 followed by 


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the second dose on day 8, with the dose determined by the dose escalation 
phase. 
SPECT/CT imaging will be performed on days 2, 3, 4-6, and 7-8 of the 
treatment period to visualize and quantitate the biodistribution of CLR 131.  
Based on these SPECT/CT imaging scans, the Bednarz lab will utilize the 
Monte Carlo method to predict absorbed dose of CLR 131 to tumors and 
normal structures.   
All subjects will start thyroid-protection medication the day prior to the 
CLR 131 dosimetry test dose and will continue to take thyroid protection 
medication for 14 days after the last CLR 131 dose. 
Based on the calculated absorbed dose of CLR 131 to the specific targeted 
tissue, the subject will undergo external beam radiation therapy (EBRT) to 
complete the designated radiation dose outlined in the re-irradiation plan, as 
per standard of care. Prior to CLR 131 administration and at 3 and 6 months 
post EBRT, subjects will be assessed for changes to swallow function. Prior to 
CLR 131 administration and at 3, 6 and 12 months post EBRT, quality of life 
measures and salivary characteristics will be assessed.  We anticipate the 
total study (baseline, CLR 131 administration, EBRT and 3, 6, 12 and 24 
month follow up assessments) to take 27 months per participant. 
 
Study 
Duration: 
47 months 
Subject 
Participation 
Duration: 
27 months 
Estimated 
Time to 
Complete 
Enrollment: 
20 months 
Date Accrual 
Goal Met / 
Study Closed 
to Accrual 
April 18, 2022 
Date DLT 
window 
completed by 
last 
participant 
June 16, 2022 


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Schematic of Study Design: 
 
*Approximately 6 safety labs will coincide with SOC EBRT visits, and 6 safety lab visits will fall outside of the SOC EBRT visits. 
The image part with relationship ID rId14 was not found in the file.


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1 KEY ROLES AND CONTACT INFORMATION 
Principal 
Investigators:   
Justine Yang Bruce, MD 
University of Wisconsin Carbone Cancer Center 
WIMR Room 3109 
1111 Highland Avenue 
Madison, WI 53705 
Phone: (608) 262-4961 
jybruce@medicine.wisc.edu 
 
Paul M. Harari, MD 
Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
600 Highland Avenue 
Madison, WI 53792  
Phone: (608) 263-5009 
harari@humonc.wisc.edu 
 
 
Co-Investigators: 
Steve Y. Cho, MD 
Department of Radiology 
University of Wisconsin Carbone Cancer Center 
600 Highland Avenue 
Madison, WI 53792 
Phone: (608) 263-8340 
cho85@wisc.edu 
 
Adam Burr, MD 
Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
K4/B63, 0600 Clinical Science Center 
600 Highland Ave 
Madison, WI 53792  
Phone: (608) 262-4669 
aburr@humonc.wisc.edu 
 
Randall J. Kimple, MD, PhD 
Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
WIMR Room 3107  
1111 Highland Avenue 
Madison, WI 53705 
Phone: (608) 263-3611 


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rkimple@humonc.wisc.edu 
 
Greg K. Hartig, MD 
Department of Surgery 
Division of Otolaryngology-Head & Neck Surgery 
University of Wisconsin School of Medicine and Public Health 
600 Highland Avenue, MC 7375 
Madison, WI 53792 
Phone: (608) 265-8207 
hartig@surgery.wisc.edu 
 
 
Timothy M. McCulloch, MD 
Department of Surgery 
Division of Otolaryngology-Head & Neck Surgery 
University of Wisconsin School of Medicine and Public Health 
600 Highland Avenue, MC 7375 
Madison, WI 53792 
Phone: (608) 263-0192 
mccull@surgery.wisc.edu 
 
Aaron M. Wieland, MD 
Department of Surgery 
Division of Otolaryngology-Head & Neck Surgery 
University of Wisconsin School of Medicine and Public Health 
600 Highland Avenue, MC 7375 
Madison, WI 53792 
Phone: (608) 262-2876 
wieland@surgery.wisc.edu 
 
 
Tiffany Glazer, MD 
Department of Surgery 
Division of Otolaryngology-Head & Neck Surgery 
University of Wisconsin School of Medicine and Public Health 
600 Highland Avenue, MC 7375 
Madison, WI 53792 
Phone: (608) 265-8207 
glazer@surgery.wisc.edu 
 
Bryan P. Bednarz, PhD 
Department of Medical Physics 
University of Wisconsin School of Medicine and Public Health 
1111 Highland Avenue, L5/176  
Madison, WI  53705 
Phone: (608) 262-5225 


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bbednarz2@wisc.edu 
 
 
Susan Thibeault, PhD, CCC-SLP 
Department of Surgery 
Division of Otolaryngology 
University of Wisconsin School of Medicine and Public Health 
1111 Highland Avenue, Room 5107  
Madison, WI  53705 
Phone: (608) 263-6751 
Thibeault@surgery.wisc.edu 
 
Nicole Rogus-Pulia, PhD, CCC-SLP 
Department of Medicine; Division of Geriatrics and Gerontology 
Department of Surgery; Division of Otolaryngology 
University of Wisconsin School of Medicine and Public Health 
Madison GRECC (11G), Room D4240 
2500 Overlook Terrace 
Madison, WI 53705 
(608) 256-1901 ext 11697 
npulia@wisc.edu 
 
Nadine P. Connor, PhD, CCC-SLP 
Department of Communication Sciences & Disorders 
University of Wisconsin College of Letters and Science 
321 Bascom Hill 
500 Lincoln Drive 
Madison, WI 53706 
Phone: (608)262-1044 
nadine.connor@wisc.edu 
 
Institutions: 
University of Wisconsin Carbone Cancer Center 
600 Highland Avenue 
Madison, WI 53792  
 
 
 


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Other Key 
Personnel: 
Biostatisticians:   
Menggang Yu, PhD 
Department of Biostatistics and Medical Informatics 
University of Wisconsin School of Medicine and Public Health 
207c WARF Office Building 
610 Walnut Street 
Madison, WI 53726 
Phone: (608) 261-1988 
meyu@biostat.wisc.edu 
 
Clinical Trials Program Manager: 
Diana Trask 
Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
K4/366 Clinical Science Center 
600 Highland Avenue 
Madison, WI 53792  
Phone: (608) 263-9528 
 


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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
Background Information 
2.1.1 
Head and neck cancer 
In 2018, it is estimated that 64,690 new cases of oral cavity, pharyngeal, and laryngeal cancers 
will occur, which accounts for approximately 3.7 % of new cancer cases in the United States 
(Siegel et al., 2018). Head and neck cancer is a complex heterogeneous disease that arises from 
various sites including the oral cavity, pharynx, larynx, paranasal sinuses and salivary glands. 
Over 90 % of tumors that originate in the oropharyngolaryngeal axis are squamous cell carcinoma 
(SCC). Treatment for head and neck cancer patients includes surgery, radiation and 
chemotherapy in various combinations. Although the majority of patients can be cured from head 
and neck cancers, those patients with locally advanced and/or recurrent head and neck cancer 
have a 5 year overall survival rate of approximately 50-60% (Pulte & Brenner, 2010). Cure rates 
have improved only marginally over the last 30 years (Siegel et al., 2015). 
2.1.2 
Locoregional recurrence 
Approximately 50% of patients with head and neck cancer (HNC) manifest recurrence following 
initial treatment, and the majority of these recurrences are loco-regional (mouth, throat, neck) 
(Cognetti et al., 2008; Forastiere et al., 2001; Forastiere et al., 2008; Peters et al., 2010; Pignon et 
al., 2009; Vokes et al., 1993). Although a proportion of these patients remain potentially curable 
with further local treatment approaches (surgery, radiation, chemoradiation), retreatment is 
technically challenging and accompanied by a significant risk of irreversible damage to normal 
tissues.  
 
Surgery is often limited by tumor adherence to critical structures (base of skull, neurovascular 
bundles), whereas radiation is often limited by normal tissue tolerance (spinal cord, bone, 
cartilage). Although retreatment of head and neck cancer (via surgical re-resection or re-irradiation 
of previously treated sites) is warranted in the attempt to provide disease control, these 
aggressive modalities can result in profound adverse effects on patient health-related quality of life 
(QOL) (A. M. Chen et al., 2011; Dawson et al., 2001; De Crevoisier et al., 1998; Hehr et al., 2005; 
Hoebers et al., 2011; Kasperts et al., 2005; Kramer et al., 2005; Langer et al., 2007; Mendenhall 
et al., 2008; Nag et al., 1998; Salama et al., 2006; S. A. Spencer et al., 2001; Stevens et al., 
1994). There is a compelling need to identify improved treatment approaches for patients with 
locoregionally recurrent head and neck cancer. 
2.1.3 
CLR 131 
CLR 131 [18-(p-[131I]-iodophenyl)octadecyl phosphocholine] is an investigational, radio-iodinated 
cancer therapy that exploits the tumor-targeting properties of phospholipid ethers (PLEs) and PLE 
analogs by malignant cells (Mollinedo et al., 2010; Weichert et al., 2014). To produce CLR 131, 
the core PLE analog 18-(p-iodophenyl)octadecyl phosphocholine (referred to as CLR1404 or 
NM404) is radioiodinated with 131I. 131I was chosen as the radioactive constituent due to its 8-day 
physical half-life and well-established therapeutic capabilities in multiple cancer types such as 


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thyroid cancer, neuroblastoma, non-Hodgkin’s lymphoma, and hepatocellular carcinoma 
(Hackshaw et al., 2007; Macklis & Pohlman, 2006).  
 
CLR 131 selectively delivers radiation to malignant tumor cells, thus minimizing radiation exposure 
to normal tissues; a scenario very difficult to achieve in HNC, even with the use of highly 
conformal radiation techniques. The mechanistic basis for the cancer-cell selective uptake 
involves interaction with lipid raft regions of the plasma membrane (Weichert et al., 2014) In 
preclinical studies, CLR1404 radioiodinated with either 124I for imaging purposes or 131I for 
radiotherapeutic purposes has been evaluated in both xenograft and spontaneous (transgenic) 
tumor models in mice and rats. Imaging studies with CLR 124 [18-(p-[124I]-iodophenyl) octadecyl 
phosphocholine], which is chemically and structurally identical to CLR 131, have demonstrated 
cancer-cell selective uptake and retention in all but 3 of over 60 tumor cell models assessed. 
CLR 131 antitumor activity has been documented in various tumor cell models, including glioma, 
multiple myeloma (MM), breast, prostate, colorectal, ovarian, renal, pancreatic, uterine, and lung 
cancers (Weichert et al., 2014). 
2.1.3.1 
Tumor Selectivity 
The malignant cell selectivity of the alkyl-phospholipids appears to reflect association with lipid 
rafts. The term “lipid rafts” refers to specialized plasma membrane microdomains, rich in 
cholesterol and sphingomyelin that spatially organize signaling pathways regulating cell 
proliferation and survival (Gao et al., 2011; Lingwood & Simons, 2010). 
 
CLR 131 and a variety of structurally related molecules (Mollinedo, 2007; van Blitterswijk & 
Verheij, 2008) use lipid rafts as portals of entry into the cell. There is greater abundance of lipid 
rafts in cancer cells as compared to normal cells (Li et al., 2006), which is believed to be the 
mechanism for selective uptake of CLR 131. Following uptake, CLR1404 displays prolonged 
retention in organelle membranes. Retention of related compounds has been suggested to reflect 
decreased degradation by phospholipases (Barratt et al., 2009).  
 
The selective accumulation and retention of CLR 131 within malignant cells shows strong promise 
in the imaging domain for tumor detection (Deming et al., 2014; Swanson et al., 2015; Weichert et 
al., 2014). In addition, with slow degradation once inside the cell, thereby resulting in prolonged 
tumor exposure, the therapeutic potential of CLR 131 becomes attractive (Morris et al., 2015; 
Weichert et al., 2014). With β-emissions from 131I having a median range of several millimeters, 
radiation from CLR 131 can be sharply deposited within local tumors. 
2.1.3.2 
Preclinical studies using CLR 131 in combination with XRT  
Preclinical studies using CLR 131 in murine model systems of HNC have been exceptionally 
promising. The experimental data confirms strong uptake and retention of CLR 131 in HNC 
xenografts, selective accumulation in tumor versus normal tissues, HNC xenograft growth 
inhibition with CLR 131, and more potent tumor growth inhibition when CLR 131 is combined with 
external beam radiation (Morris et al., 2015). This promising combination will be tested in the 
current Phase 1 clinical trial.  


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2.1.3.3 
Clinical Experience with CLR 131  
To date, 113 subjects with advanced cancer have received CLR 131.  
 
CLR 131 has been investigated in a Phase 1a dosimetry study in 8 subjects with advanced solid 
tumors. This study demonstrated that a single 10 mCi infusion of CLR 131 was exceptionally well 
tolerated. Whole body dosimetric analyses demonstrated that a dose of 20 mCi was predicted to 
deliver 40 cGy to marrow, and this information guided initial dosing in the subsequent therapeutic 
study. 
 
CLR 131 was then examined in a Phase 1b therapy trial in 10 subjects with advanced solid 
tumors. Doses up to 25 mCi/m2 were well tolerated without dose-limiting toxicity. Dose-limiting, but 
reversible, thrombocytopenia and leukopenia were observed at doses of 31.25 mCi/m2 and 
higher. Hematocrit, renal function, and liver function were not significantly affected at doses up to 
37.5 mCi/m2. This study documented selective tumor uptake quantified by single photon-emission 
CT/CT (SPECT/CT) imaging. Stable disease was observed in 4 of 10 subjects, including 2 with 
stable disease for 20 weeks post-infusion. 
 
CLR 131 in combination with dexamethasone is currently under investigation in a Phase 1 trial in 
subjects with relapsed/refractory multiple myeloma (MM) following treatment with both a 
proteasome inhibitor and an immunomodulatory agent. All subjects have been heavily pretreated. 
Seven dose cohorts were examined: 12.5 mCi/m2, 18.75 mCi/m2, 25 mCi/m2, 31.25 mCi/m2, and a 
multiple dose cohorts of 15.625 mCi/m2, 18.75 mCi/m2 and 20 mCi/m2 administered twice, all in 
combination with 40 mg dexamethasone weekly. Thirty-one patients were dosed and the 
independent Data Monitoring Committee confirmed seven dose levels safe and tolerated. The 
overall response rate for patients receiving <60 mCi total body dose was 7% (1/15) and 27% 
(3/11) for patients receiving a >60 mCi total body dose. All evaluable patients achieved a minimum 
of stable disease, with at least one patient at each dose level achieving at least a minor response. 
CLR 131 has been shown to be well tolerated with the majority of adverse events being 
considered mild to moderate. The most common treatment emergent adverse events were 
cytopenias, primarily thrombocytopenia, with very predictable onset, time to nadir and recovery. 
Beyond cytopenias, fatigue was also a frequently reported adverse event. .  
 
CLR 131 is also under investigation in a Phase 2 study in relapsed or refractory B-Cell 
malignancies (CLOVER-1) where 56 patients have been enrolled to date. Patients received either 
< 60 or ≥ 60 mCi total body dose CLR 131 (25 mCi/m2 single bolus, 31.25 mCi/m2 fractionated or 
37.5mCi/m2 fractionated) either as a bolus dose or fractionated with half on day 1 and half on day 
7 ± 1 day. Patients enrolled in the final dosing group in Part A (Group 4) received an alternate two 
cycle fractionated dose schedule: fractionated 30 mCi/m2 CLR 131 as 15 mCi/m2 on Day 1, Day 
15 (±1 day) for the first cycle, and then repeated Day 57 (± 1 day), and Day 71 (± 1 day) for the 
second cycle (total body dose ≥ 60 mCi). The adverse event profile remains consistent with the 
Phase 1 trial, with the primary treatment emergent adverse events including cytopenias; most 


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commonly thrombocytopenia. The time to onset, nadir, and recovery continue to be predictable 
and the events manageable. Fatigue has also been reported commonly. 
 
CLR 131 is also under investigation in a Phase 1 study of solid tumor and malignant brain tumors 
in children, adolescents, and young adults. This is a dose escalation study with a starting dose of 
15 mCi/m2. To date, ten patients have been enrolled. 
 
Additional information about these trials is available in the CLR 131 Investigator’s Brochure 
(Supplementary Materials). 
2.2 
Rationale for a clinical study using CLR 131 in combination with EBRT 
Locoregional recurrence in HNC represents a significant challenge. Approximately 50 % of HNC 
patients will experience loco-regional disease recurrence following initial therapy that commonly 
includes primary or postoperative radiation. Although some recurrent HNC patients can 
experience long-term tumor control following re-irradiation, this approach must be considered with 
great caution due to the risk of severe injury to normal tissue structures that maintain long-term 
recall from the prior radiation exposure.  
 
Several studies have specifically examined the role of re-irradiation in HNC with general 
conclusions that there is considerable risk for high-grade toxicities (including death), but a defined 
opportunity for long-term survival (2 years) in approximately 10-20% of patients (A. M. Chen et al., 
2011; Dawson et al., 2001; De Crevoisier et al., 1998; Hehr et al., 2005; Hoebers et al., 2011; 
Kasperts et al., 2005; Kramer et al., 2005; Langer et al., 2007; Mendenhall et al., 2008; Nag et al., 
1998; Salama et al., 2006; S. Spencer et al., 2003; S. A. Spencer et al., 2001; Stevens et al., 
1994). 
 
Selection of patients who would most likely benefit from HNC re-irradiation remains an area of 
active investigation.  Efforts to reduce the acute and long-term tissue injury profile by radiation 
with highly conformal techniques are clearly important in the retreatment setting. With the use of 
CLR 131, the dose of external beam radiation therapy can potentially be reduced or more 
precisely targeted, which serves to limit high dose radiation therapy to normal tissues in the head 
and neck.   
 
The aim of this clinical trial is to evaluate the use of the novel radioisotope CLR 131 as a modality 
to provide “internal radiation” to recurrent disease in combination with EBRT. This combination 
regimen would be intended to provide definitive treatment of recurrent head and neck cancer by 
delivering radiation to HNC cells through CLR 131 uptake followed by the more traditional EBRT. 
We hypothesize that CLR 131 will reduce the overall dose of EBRT required for retreatment, and 
minimize the acute and long-term tissue injury that is commonly associated with standard 
reirradiation treatment plans. 
 
Subjects with locoregionally recurrent HNC can be enrolled on this trial. These subjects will have a 
pre-planned radiation treatment dose that is designed based on the consensus opinion of the 
multidisciplinary head and neck oncology tumor board. The standard of care (SOC) radiation dose 


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for this patient population is 60-70 Gy absorbed dose to the recurrent tumor, irrespective of 
radiation delivery technique. Therefore, as long as the SOC radiation dose parameters are met, 
the EBRT described in this study is considered within standard of care.  
 
Prior to treatment with CLR 131, the subject will have a clinical evaluation by a radiation 
oncologist who will design the radiation treatment field. Given the potential for increased toxicities 
both in the acute and long-term setting, these subjects will also be assessed for this clinical trial as 
a means for improving the toxicity profile of EBRT. 
 
Subjects with recurrent and metastatic HNC can be enrolled on this trial provided locoregional 
treatment with EBRT is deemed to be clinically beneficial based on the consensus opinion of the 
multidisciplinary head and neck oncology tumor board. Because of the prior clinical experience of 
CLR 131 in advanced solid malignancies on a prior phase 1 clinical trial, these participants may 
also derive benefit from the systemic treatment of their metastatic disease with CLR 131. Clinical 
response of the metastatic disease will also be assessed during treatment based on RECIST 1.1. 
 
 
2.2.1 
Hypothesis 
The hypothesis of this clinical trial is that reduction of the dose of external beam radiation therapy, 
when given in combination with CLR 131, will be safe and tolerable while maintaining favorable 
tumor response rates and diminishing the adverse impact of radiation treatment on subject 
specific symptoms, such as quality of life, salivary flow and swallowing function.  
 
2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
2.3.1.1 CLR 131 
CLR 131 has demonstrated a favorable safety profile in nonclinical toxicology studies.  
 
In the initial clinical Phase 1a dosimetry study in subjects with advanced solid malignancies, CLR 
131 was well tolerated; adverse events (AEs) included fatigue, constipation, and sialadenitis. 
During the Phase 1b dose escalation study, bone marrow suppression (including 
thrombocytopenia, anemia, decreased white blood cell [WBC] count, and neutropenia), fatigue, 
and an increase in gamma glutamyl transferase were observed. In the ongoing Phase 1 MM 
study, the most frequently reported AEs have been decreases in platelet count, hemoglobin, 
lymphocyte count, neutrophil count, and white blood count; for subjects receiving single or multiple 
dose CLR 131. Of note, subjects receiving multiple dose CLR 131 required fewer transfusions 
(platelet and red blood cell) and growth factor support than subjects receiving a comparable single 
dose (both 25 mCi/m2 and 31.25 mCi/m2) of CLR 131. [ClinicalTrials.gov NCT02952508]   
 


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The multiple dose regimen has been evaluated and found to be tolerable by a data monitoring 
committee of the Phase 1 multiple myeloma trial and has been used as the recommended dosing 
schedule for future trials. Thus, this clinical trial is evaluating the combination of CLR 131 given in 
2 doses with external beam radiation therapy. This study will be the first to explore the 
combination of CLR 131 with EBRT. 
 
CLR 131 is a radiopharmaceutical agent, and subjects should be monitored for signs and 
symptoms of bone marrow suppression, such as fever, fatigue, dyspnea, and bleeding. 
 
Since CLR 131 is a radioactive drug, it is possible that subjects could expose others (like family or 
caregivers) to radiation. Specific instructions about how to minimize this risk will be provided to 
research participants. 
 
Additional information about potential adverse events is available in the CLR 131 Investigator’s 
Brochure (Supplementary Materials). 
2.3.1.1.1 
Thyroid-protection medication 
Side effects of KI (potassium iodide) may include stomach or gastro-intestinal upset, allergic 
reactions, rashes, and inflammation of the salivary glands.  In rare instances, it can cause “Iodism” 
(metallic taste, burning mouth and throat, sore teeth and gums, symptoms of a head cold, and 
sometimes upset stomach and diarrhea) or an allergic reaction can have more serious symptoms. 
These include fever and joint pains; swelling of parts of the body (face, lips, tongue, throat, hands, 
or feet); trouble breathing, speaking, or swallowing; wheezing or shortness of breath. Severe 
shortness of breath requires immediate medical attention. 
2.3.1.1.2 
Dose Limiting Toxicities (DLT) Probably Related to CLR 131 
In this study, expected toxicities include febrile neutropenia, anemia, thrombocytopenia, and 
fatigue including, in some instances, Grade 3 and Grade 4. Per the CLR 131 Investigator 
Brochure, 90% of subjects are anticipated to have blood count recovery approximately 65 days 
after treatment with CLR 131. In this study, a DLT is defined as: 
 
• Grade 4 neutropenia > 4 weeks 
• Grade 4 anemia > 4 weeks 
• Grade 4 thrombocytopenia > 4 weeks 
 
 
• Grade 3 neutropenia > 8 weeks 
• Grade 3 anemia > 8 weeks 
• Grade 3 thrombocytopenia > 8 weeks 
 
 
• Any other Grade 3 or 4 unexpected event at least possibly related to CLR 131 
 


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Growth factor support and blood transfusions are permitted in this study as clinically indicated by 
the treating physician. 
 
Dose escalation will not be confirmed until all subjects in cohort recover to non-DLT levels or meet 
the criteria above. 
2.3.1.2 External beam radiation therapy (EBRT) 
Radiation side-effects in the treatment of head and neck cancer are well known.  Though subjects 
for this trial will be given EBRT as part of standard of care, we are listing the side effects here to 
distinguish from those that are expected as part of CLR 131 administration.   
Common side effects include: mucositis, difficulty swallowing which may necessitate a feeding 
tube, dry mouth, change in taste and smell, reduced saliva production, hoarseness, radiation 
dermatitis, ear pain/infection, hearing loss, fatigue, weight loss, dehydration requiring IV fluids and 
electrolyte replacement, hair loss, tooth decay, decreased thyroid function. Rare and serious side 
effects include: breathing and swallowing issues that require a tracheotomy, nerve damage in the 
head and neck region, radiation necrosis of the jaw, damage to the larynx or nerves, damage to 
the skin, soft tissues or other parts of the head and neck that may require a surgery to correct and 
damage to the spinal cord which may cause permanent weakness. 
2.3.1.3 Modified Barium Swallow (MBS) Studies (standard of care) 
To minimize risk, the procedure has been carefully planned. Radiation dose received during a 
MBS (between 0.2 and 0.85mSv) is lower than doses received from other common fluoroscopic 
and interventional radiology procedures. The risk of developing a fatal cancer from a MBS is 1 in 
39,000. Occasionally, patients may be allergic to the flavoring added to the barium.  There is a 
slight chance that barium could be retained in the gastrointestinal (GI) system, leading to a 
blockage. Women should inform their physician or x-ray technologist if there is any possibility that 
they are pregnant. 
2.3.1.4 Single photon-emission computed tomography (SPECT) /CT  
There is no additional risk associated with SPECT acquisition. However, a low-dose spiral 
computed tomography (CT) scan will accompany every SPECT acquisition for attenuation 
correction, anatomical conformation and dosimetry. The effective radiation dose associated with 
the low-dose spiral CT scan will differ with each individual; however, for the purposes of this study 
population we anticipate radiation exposure from CT scans to be ~1.5 mSv/scan (maximum total 
radiation from 5 scans would be ~7.5 mSv).  For comparison, estimates for natural background 
radiation in the United States (vary based on location) is ~3.1 mSv/year.  
2.3.1.5 Other risks from study-related procedures 
• Blood draws for clinical laboratory testing: bruising, swelling at the injection site, 
dizziness and lightheadedness  


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• Saliva and oral swab collection: dry mouth (expected to resolve within a few minutes 
following collection) 
• Maximum expiratory pressure (MEP) and voluntary cough: subject may feel slightly out 
of breath immediately following the measurement (expected to resolve within a few 
minutes of procedure). 
• Maximum lingual pressure:  subject may experience discomfort or soreness of the 
tongue measurement (expected to resolve within a few minutes of procedure).   
• Questionnaires: risk of loss of confidentiality is possible but not likely with data security 
safeguards in place.  
 
2.3.2 
Potential Benefits 
There is no known benefit to subjects’ participation in this study. While there is hope that a 
subject’s cancer will respond to treatment with CLR 131, there is no proof of that at this stage. 
There is no standard treatment regimen for patients with locoregionally recurrent head and neck 
cancer, and thus re-irradiation with EBRT can be considered for patients in order to provide long 
term disease control. However, patients who undergo re-irradiation for recurrent disease 
experience significant toxicities and side effects. Thus, patients with locally recurrent head and 
neck cancer have an unmet need for treatment options with acceptable side effects and toxicities. 
This study is likely to yield knowledge about the use of CLR 131 in treating head and neck cancer 
when combined with external beam radiation, which could help future patients. 


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3 OBJECTIVES 
3.1 Study Objectives 
3.1.1 
Primary Objective 
• 
To evaluate the safety and tolerability of CLR 131 in combination with EBRT in subjects 
with recurrent cancers of the head and neck 
3.1.2 
Secondary Objectives 
• 
To perform dosimetric evaluation of CLR 131 in subjects with recurrent cancers of the 
head and neck 
• 
To assess tumor response following treatment with CLR 131 in combination with external 
beam radiation therapy 
• 
To evaluate changes in swallowing function before and after treatment with CLR 131 in 
combination with external beam radiation therapy 
• 
To evaluate changes in quality of life before and after treatment with CLR 131 in 
combination with external beam radiation therapy 
• 
To evaluate salivary flow rate before and after treatment with CLR 131 in combination with 
external beam radiation therapy 
3.2 
Study Outcome Measures 
3.2.1 
Primary 
• 
Incidence of adverse events assessed using Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 
3.2.2 
Secondary 
• Median radiation treatment time and median number of dose delays due to toxicity 
• CLR 131 tumor uptake via SPECT/CT imaging and Monte Carlo calculations 
• Overall response rate (ORR) defined as the proportion of subjects who experience either a 
partial response or complete response within 6 months post completion of EBRT as 
measured by standard of care imaging (e.g. CT, MR, PET-MR) 
• Swallow function assessed by Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) 
scale 
• Quality of life (QoL) assessed by MD Anderson Dysphagia Inventory score (MDADI) 
• Salivary flow rate related quality of life assessed by stimulated salivary flow 


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4 STUDY DESIGN 
This is a Phase 1, single center, dose escalation and dose expansion study of subjects with 
locoregionally recurrent head and neck cancer who may also have distant metastatic disease. All 
subjects will receive a dosimetry test dose of CLR 131 (flat dose of 15 mCi) to establish drug 
uptake by the tumor.  
 
Subjects who have tumor uptake of the CLR 131 dosimetry test dose as determined on 
SPECT/CT imaging by the study radiologist will be eligible to participate on the treatment portion 
of this clinical trial.  Any subject who demonstrates tumor uptake of CLR 131 by SPECT/CT 
imaging after the test dose will continue to participate in the treatment portion of the study.  Up to 
six participants who do not demonstrate tumor uptake of CLR 131 by SPECT/CT will also continue 
with the treatment portion of the study.  Based on prior experience of subjects receiving CLR 131, 
75 % of eligible subjects are estimated to demonstrate CLR 131 uptake within their tumors. 
 
Subjects showing uptake will receive a cumulative tumor dose of 60-70 Gy using personalized 
dose calculation of CLR 131 (via Monte Carlo) combined with external beam radiation. If the 
Monte Carlo dose estimate for any subject is greater than 60 Gy for the 2 doses of CLR 131 
(highly unlikely based on preliminary data), then no additional external beam dose will be 
administered. 
 
All subjects will start thyroid-protection medication the day prior to the CLR 131 dosimetry test 
dose and will continue to take thyroid protection medication for 14 days after the last CLR 131 
dose. 
 
Treatment Plan 
Enrollment will start at dose level 1.  Subjects will receive 2 doses of CLR 131 intravenously with 
the first dose on day 1 followed by the second dose on day 8. The dose of CLR 131 will be based 
on the dose escalation schema. 
 
Dose Escalation Schema 
Dose Level 
Doses** of CLR 131 
-1* 
12.5 mCi/m2 
1 
15.6 mCi/m2 
2 
18.75 mCi/m2 
*Dose level -1 is the de-escalation dose. The first four patients will be given Dose 1. Dose -1 will only be 
used if toxicities warrant de-escalation. 
** Dose level listed is administered first on day 1 and again on day 8. 
  
SPECT/CT imaging will be performed on days 2, 3, 4-6, and 7-8 of the treatment period to 
visualize and quantitate the biodistribution of CLR 131. Using the SPECT/CT imaging scans, the 
Bednarz lab will perform the Monte Carlo calculations to predict absorbed dose of CLR 131 to 
tumors and normal structures.  
 


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Based on the calculated absorbed dose of CLR 131 to the specific targeted tissue, the subject will 
undergo EBRT to complete the designated radiation dose outlined in the re-irradiation plan.  
 
At baseline, 3, 6 and 12 months post completion of EBRT, subjects will be assessed for changes 
to head and neck specific subject health-related measures: quality of life and salivary flow rate. 
Swallow function will be assessed at baseline, 3 and 6 months post completion of EBRT (standard 
of care Modified Barium Swallow (MBS) and research-related oral profile exam) see Schematic of 
Study Design). 
 
Enrollment to the study is anticipated to take approximately 20 months. Each subject will 
participate for approximately 27 months, although only about four months will be active 
participation. Details of the study schedule, including lab draws and specific study procedures are 
provided in section 7. 
 
Incomplete dosing of CLR 131 within study timeframe: 
In the event a participant is unable to receive the full study course of CLR 131 within the study 
timeframe such as a delay in drug manufacturing, the study team will evaluate if it is in the best 
interest of the study participant to continue with protocol therapy. If it is deemed appropriate for 
the subject to continue with the CLR 131 administration, their scheduled appointments, labwork 
and SSKI administration will be adjusted appropriately to accommodate the delay. If it is deemed 
in the participant’s best interest to proceed to SOC EBRT, the following scenerios will occur: 
 
• Only test dose (15 mCi) CLR 131 administered:   
o Continue SSKI until 14 days post CLR 131 administration  
o Proceed with EBRT and SOC follow-up. 
 
• If test dose and a single therapeutic dose are administered:  
o Continue with SSKI until14 days post CLR 131 administration 
o Undergo imaging for calculations of EBRT dose de-escalation 
o Proceed to EBRT  
 Modify EBRT dose based on the single therapeutic injection 
o Continue follow-up per protocol. 
 


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5 STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
Number of Subjects 
Up to 12 subjects treated at the MTD are planned for the study. The number of subjects in the 
expansion cohort will depend on the number of subjects treated in the mTPI-2 design (Section 
14.2). Adult men and women of all races and ethnic groups are eligible for this trial. 
 
5.2 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Subject must be informed of the investigational nature of the study and must be able to sign 
a written informed consent. 
2. Subjects with histologically or cytologically confirmed solid malignancy that has recurred in 
the head and neck (above the clavicles) region, e.g., subjects with recurrent cutaneous 
squamous cell carcinoma, salivary gland tumors or esthesioneuroblastoma are eligible for 
this clinical trial. 
3. Subject is 18 years of age or older. 
4. Subjects must have undergone previous curative intent therapy, with radiation as a primary 
or adjuvant therapy. 
5. Subjects may have distant metastatic disease, as long as the locoregional site of 
recurrence is deemed eligible for radiation therapy, and treatment of the loco-regional 
disease is deemed as taking precedence over treatment of the remaining systemic disease. 
6. Subjects must have at least one evaluable (measurable or non-measurable) recurrent 
lesion that is amenable to radiation therapy. 
7. Subjects must demonstrate uptake of CLR 131 via SPECT/CT imaging, as determined by 
the study radiologist, in the specified site of recurrent/metastatic disease that is to be 
treated with radiation therapy.  There is a subset of up to 6 patients who may continue with 
CLR 131 treatment without uptake on the SPECT/CT scan after the test dose. 
8. Subjects must have an ECOG performance status of 0 – 1. 
9. Subjects must have a life expectancy of at least 6 months. 
10. The subject has adequate hematologic function, as evidenced by: 
• an absolute neutrophil count (ANC) ≥ 1500 / µL 
• hemoglobin ≥9 g/dL (5.58 mmol/L) 
• and platelets ≥100,000 / µL 
o If full-dose anticoagulation therapy is used, platelets ≥ 150,000 / µL are required.  


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• If subject is on full-dose anticoagulation therapy, the anticoagulation therapy 
must be reversible, and reversal of the anticoagulation therapy must not be life-
threatening, as judged by the investigator. 
11. The subject has adequate renal function as defined by: 
• serum creatinine ≤ 1.5 times the upper limit of normal (ULN) or Cockcroft-Gault 
calculated creatinine clearance ≥ 60 ml/min 
12. The subject has adequate hepatic function as defined by: 
• 
total bilirubin ≤ 1.5 mg/dL (25.65 μmol/L) 
• 
aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 times the ULN 
13. Women of childbearing potential (WOCP) have a confirmed negative urine pregnancy test 
within 24 hours prior to test dose of CLR 131. 
14. Subjects must use a medically acceptable method of birth control such as an oral, 
implantable, injectable, or transdermal hormonal contraceptive, an intrauterine device 
(IUD), a double barrier method (condoms, sponge, diaphragm, or vaginal ring with 
spermicidal jellies or cream), or total abstinence during the study participation and for 6 
months after last dose of study drug. Women who are postmenopausal for at least 1 year 
or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) are not 
considered to be WOCP. 
15. Men who are not surgically or medically sterile agree to use an acceptable method of 
contraception. Male subjects with female sexual partners who are pregnant, possibly 
pregnant, or who could become pregnant during the study must abstain from intercourse 
for three weeks after each CLR 131 dose and agree to use condoms at least 6 months 
after the last dose of study drug. Total abstinence for the same study period is an 
acceptable alternative.  
 
5.3 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Recurrent tumor recommended for surgical resection based on multidisciplinary Head and 
Neck Oncology Tumor Board Review  
2. Thyroid cancer 
3. Known hypersensitivity to iodine 
4. Other concurrent severe and/or uncontrolled concomitant medical or psychiatric conditions 
(e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable 
safety risks or compromise compliance with the protocol, per investigator discretion 


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5. Chemotherapy or major surgery within 4 weeks, or radiotherapy within 2 weeks prior to test 
dose of CLR 131.  
6. Subjects with clinically significant adverse events due to agents administered more than 4 
weeks prior to test dose of CLR 131 (alopecia and fatigue excluded). Clinical significance to 
be determined by investigator.  
7. The subject is pregnant, breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit through 6 months after 
the last dose of trial treatment. 
8. Any ongoing or active infection, including active tuberculosis, hepatitis B or C, or known 
infection with the human immunodeficiency virus (HIV) 
9. Concurrent treatment with any other anti-cancer or investigational agents. Subjects cannot 
be receiving concomitant chemotherapy, radiotherapy, experimental therapy or any other 
therapy not otherwise outlined by the trial for the purposes of anti-cancer treatment. 
10. Patient with a history of or concurrent second primary malignancy (stage III or IV) within 5 
years to study enrollment are excluded.  
11. Patients with a history of prior invasive malignancy (except early-stage I or II non-
melanomatous skin cancer, carcinoma in situ of the breast, cervical carcinoma in situ, 
stage I-II papillary thyroid cancer, or low or very low-risk prostate cancer which has been 
completely treated with surgery or radiation) treated within 2 years of study enrollment are 
excluded. 
12. Subjects that have had total body or hemibody irradiation, or have had prior systemic 
radioisotope therapy (except for benign thyroid disease) 
13. Poor venous access and will be unable to receive study drug into a peripheral venous 
catheter.  
14. Significant traumatic injury within 6 weeks prior to enrollment 
15. Extradural tumor in contact with the spinal cord or tumor located where swelling in 
response to therapy may impinge upon the spinal cord 
16. Any history of cerebrovascular accident (CVA) or transient ischemic attack within 12 
months prior to study entry 
17. History of myocardial infarction, ventricular arrhythmia, stable/unstable angina, 
symptomatic congestive heart failure, coronary/peripheral artery bypass graft or stenting or 
other significant cardiac disease within 6 months prior to study entry 
18. QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥480 ms. 
19. Any condition requiring the use of immunosuppression, excluding rheumatologic conditions 
treated with stable doses of corticosteroids (equivalent to ≤ prednisone 10 mg daily) 
20. Ongoing hemodialysis or peritoneal dialysis 
21. Poorly controlled severe COPD 


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22. Uncontrolled hypothyroidism or hyperthyroidism  
23. Any medical condition that predisposes the subject to uncontrolled bleeding such as 
hemophilia, factor deficiencies, severe liver disease, or von Willebrand disease. 
 
5.4 
Strategies for Recruitment and Retention 
The methods used for recruitment of subjects in the study will be devoid of any procedures that 
may be construed as coercive. The recruitment process will not involve any restrictions on socio-
demographic factors, including gender or ethnic characteristics, of the subject population. 
However, the composition of the study patient population will depend on patient sources available 
to the clinical site. 
 
Subjects will be recruited from the treating physicians’ own clinical practice, through clinic 
contacts, and referring physicians. 
 
5.4.1 
Subject remuneration 
Subjects will be eligible to receive remuneration to offset the barriers of additional visits required to 
participate in this study. Subjects are eligible to receive $50 total for completing the SPECT/CT 
scan(s) needed following the test dose and an additional $200 after completing the fourth 
SPECT/CT scan following the first treatment dose of CLR 131. 
 
5.5 
Treatment Assignment Procedures 
Subjects who agree to participate and who provide written informed consent will be enrolled via 
the University of Wisconsin Carbone Cancer Center (UWCCC) Oncore database by the Radiation 
Oncology research team prior to study-specific participation. All subjects must meet eligibility 
criteria as listed above. The research staff will verify eligibility, assign a case number, and register 
the subject in OnCore prior to study-specific participation. The following information will be 
recorded: 
• Protocol number 
• Subject’s name 
• Subject’s medical record number 
• Subject demographic data 
The subject will also be registered with Cellectar Biosciences to ensure drug product availability 
and shipment. Information to be provided to Cellectar Biosciences includes: assigned subject 
identification number, initials, year of birth, body surface area, and dates of planned CLR 131 
administration.  


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5.5.1 
Evaluable Subject 
For evaluation of safety endpoints, any subject that receives any portion of one treatment dose of 
CLR 131 will be included. 
For evaluation of efficacy, subjects must receive all doses of CLR 131 in their entirety and at least 
one post-infusion efficacy assessment.  
 
5.6 
Subject Withdrawal 
Treatment may continue as specified in the above treatment modality sections or until one of the 
following criteria applies: 
• disease progression;  
• intercurrent illness that prevents further administration of treatment;  
• unacceptable adverse event(s) (as determined by the subject, treating physician)  
• subject decides to withdraw consent for participation in the study;  
• subject refuses further treatment (without withdrawing consent for study participation);  
• general or specific changes in the subject's condition render the subject unacceptable for 
further treatment in the judgment of the investigator;  
• new data related to the experimental agent which would suggest that continuing treatment 
on protocol would impose unwarranted potential risks beyond what was known at the time 
of treatment initiation.  
• a female subject becomes pregnant 
 
Subjects will be removed from protocol therapy and the site investigator notified when any of the 
criteria listed above apply. The reason for discontinuation of protocol therapy will be documented 
on the electronic case report form (eCRF). 
5.6.1 
Handling of Subject Withdrawals or Subject Discontinuation of Study Intervention 
If a subject decides to withdraw from the study (and not just from protocol therapy) all efforts 
should be made to complete and report study assessments as thoroughly as possible. The subject 
should be encouraged to complete the withdrawal visit procedures outlined in Section 7.4. A 
member of the research team should contact the subject or a responsible relative by telephone to 
establish as completely as possible the reason for the study withdrawal. A complete final 
evaluation at the time of the subject’s study withdrawal should be made with an explanation of 
why the subject is withdrawing from the study. If the reason for removal of a subject from the study 
is an adverse event, it will be recorded on the eCRF. 
 


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If a subject withdraws from the study prematurely, s(he) must continue taking the thyroid-
protection medication for 14 days after the last CLR 131 infusion to ensure appropriate protection 
of the thyroid. 
5.7 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to the UWCCC DSMC, Cellectar and regulatory authorities. 
If the study is prematurely terminated or suspended, the principal investigator will promptly inform 
the institutional review board (IRB) and will provide the reason(s) for the termination or 
suspension.  
Reasons for early study discontinuation may include, but are not limited to: 
• 
Unacceptable toxicity of study drug 
• 
Request to discontinue the study from a regulatory authority 
• 
Protocol violations 
• 
Poor enrollment 
• 
Company business decision 
• 
Difficulties in manufacturing the investigational product  


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6 STUDY INTERVENTION 
6.1 
Study Product Description 
 
 CLR 131 (also referred to as I-131-CLR1404 or [131I]-CLR1404) is supplied as a ready-for-use 
radiopharmaceutical for IV dosing. Two formulations of CLR 131 are used:  
• For CL1, CLR 131 is provided as a clear, faint yellow to yellow, sterile solution consisting 
of CLR 131 (18-(p-[131I]-iodophenyl) octadecyl phosphocholine) and CLR 1404 (18-(p-
iodophenyl) octadecyl phosphocholine) in sodium chloride injection US Pharmacopeia 
(USP), ethanol USP, polysorbate 20 National Formulary, and sodium ascorbate USP.  
 
• For CL2, CLR 131 is provided as a clear, colorless to yellow, sterile solution consisting of 
CLR 131 (18-(p-[131I]-iodophenyl) octadecyl phosphocholine) and CLR 1404 (18-(p-
iodophenyl) octadecyl phosphocholine) in sodium chloride injection US Pharmacopeia 
(USP), ethanol USP, polysorbate 20 National Formulary, gentisic acid, and sodium 
ascorbate USP.  
 
For both formulations, the study drug is packaged in a single-use vial and must be filtered 
through a 25 mm 0.2 micron sterile filter prior to administration. 
 
CLR 131 is radioactive and should only be prepared, assayed, and administered by personnel 
who are trained to handle radioactive materials. Proper radiation shielding should be used during 
storage, preparation, assay, and administration of CLR 131. The study drug will arrive from 
Cellectar Biosciences in a lead shipping container and should remain in the lead shipping 
container for storage until use.  
CLR 131 Injection is shipped at room temperature (20 – 25 °C; 68 – 77 °F) with excursions during 
shipping of -40 – 70 °C (-40 – 158 °F) allowed. When received at the site, the drug product is to be 
stored as per the lead shield label.  
• For CL1 formulation (identified in lot number as (N-xxxxxxCL1-x), the drug product is to be 
stored refrigerated (2 – 8 °C; 36 – 46 °F). If CLR 131 is refrigerated ≤ 72 hours after 
radiolabeling the shelf-life is 14 days; if the drug product is refrigerated > 72 hours after 
radiolabeling the shelf-life is 11 days.  
• For CL2 formulation (identified in lot number as (N-xxxxxxCL2-x), the drug product is to be 
stored upright at 15 – 25 °C, as directed on the label.  
 
The physical (radioactive) half-life of I-131 is 8.02 days. I-131 decays with beta emissions of 334 
keV (7 %) and 606 keV (90 %) and subsequent gamma emissions of 284 keV (6 %), 364 keV (82 
%), and 637 keV (7 %).  
 
See the CLR 131 Radiopharmacy Manual (Supplementary Materials) for specific handling, 
preparation, administration, and storage requirements. 


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6.1.1 
Acquisition 
CLR 131 will be provided by Cellectar Biosciences’ designated manufacturer and delivered 
directly to the institution in a just-in-time manner. 
6.1.2 
Formulation, Packaging, and Labeling 
CLR 131 Injection: 
• 
Is packaged in single use glass vial(s); 
• 
Must be filtered through a 25 mm 0.2 micron sterile luer-lock syringe filter (or equivalent) 
prior to administration; 
• 
Must be diluted with 0.9 % Sodium Chloride for Injection, USP and thoroughly mixed prior 
to administration via slow IV infusion; 
6.1.3 
Product Storage and Stability 
CLR 131 Injection: 
• 
Should not be subjected to temperatures below -20 degrees centigrade  
(-4 degrees Fahrenheit);  
• Should be stored as per the lead shield label and infused at room temperature; and 
 
• When product is prepared in an appropriate sterile environment as per the instructions in 
the CLR 131 Radiopharmacy and Infusion Manual, the beyond-use date is 48 hours post 
preparation, if kept at room temperature after preparation and the 48 hours falls within the 
expiry of the drug product.  
 
Note: the CLR 131 Radiopharmacy Manual v6.0 and vial and pig labels incorporate 
appropriate language to guide site staff on appropriate storage of CLR 131. 
6.2 
Dosage, Preparation and Administration of Study Product 
Each subject will receive CLR 131 through a freely-running peripheral IV catheter over a period of 
approximately 30 minutes. The dose of CLR 131 will be calculated for each subject based on total 
body surface area (BSA) (not to exceed 2.5 m2) calculated from actual body weight and height. 
The subject will be clinically monitored for adverse reactions during the infusion and for 1 hour 
post-infusion. 
6.3 
Thyroid Protection Medication 
To protect the thyroid from uptake of radioactive iodine, administration of thyroid-protection 
medication is required. Thyroid-protective agents should be administered beginning the day prior 
to the dosimetry test dose of CLR 131 and continue for 14 days after the last dose of CLR 131.  
Thyroid protection medication administration 
CLR 131 dose 
Duration of thyroid protection medication 


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Dosimetry test dose only 
15 days  
Dosimetry test dose +1 Treatment dose 
25-30 days, must take14 days past last dose 
Dosimetry test dose +2 Treatment doses 
32-38 days, must take 14 days past last dose 
 
Potassium iodide tablets 130 mg orally once daily are the preferred thyroid protection medication. 
Acceptable alternatives, per institutional preference, include the following:  
• 
Saturated solution of potassium iodide (SSKI) 2 drops orally twice daily  
• 
Lugol’s 5 % solution 0.8 mL (approximately 16 drops) orally twice daily  
 
Subjects must receive two doses of SSKI, two doses of Lugol’s 5 % solution or one potassium 
iodide tablet (130 mg) prior to CLR 131 infusion. 
 
If a subject withdraws from the study prematurely, they must continue taking thyroid protection 
medications for 14 days after the final CLR 131 infusion to ensure appropriate protection of the 
thyroid.  
6.4 
Modification of Study Product Administration for a Subject 
There are no modifications for dose of CLR 131 or the thyroid protection medication. 
6.5 
Accountability Procedures for the Study Product 
The clinical site staff must maintain a careful inventory of the study drug. Study drug use will be 
recorded on a study drug inventory form. At a minimum, this form will contain the following 
information: 
• 
Subject number and initials for each subject receiving study drug 
• 
Date, quantity and dose (mCi) of study drug received by the clinical site 
• 
Date, quantity and dose (mCi) of study drug dispensed 
• 
Date, quantity and dose (mCi) administered 
 
Periodically, a Cellectar Biosciences’ representative will reconcile the information on the study 
drug inventory form with the actual inventory of study drug used at the clinical site. All used and 
expired radioactive vials of CLR 131 will be stored at the clinical site in long half-life radioactive 
storage per the clinical site’s standard operating procedures (SOPs) until background levels are 
reached (approximately 80 days). Once background levels are reached, the Cellectar Biosciences’ 
representative will return to do a final accountability check of the now-decayed vials. The clinical 
monitor will instruct the site on disposition of the vials either to ship to Cellectar Biosciences for 
disposal or discard per their SOP for waste disposal.  


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6.6 
Assessment of Subject Compliance with Study Product Administration 
Thyroid-protection medication, including instructions for use and a diary, will be provided at 
screening. The subject’s proper use of thyroid protection medication will be confirmed prior to 
every CLR 131 infusion and at appropriate follow-up visits.  
 
It is recommended that the Investigator or his/her designee contact subjects by phone on the day 
prior to the dosimetry test dose to ensure thyroid-protection medication is started and a minimum 
of 2 doses of SSKI, 2 doses of Lugol’s 5 % solution, or 1 potassium iodide tablet (130 mg) are 
taken prior to CLR 131 infusion. 
6.7 
SPECT/CT Dosimetry Evaluation 
6.7.1 
Tumor and Organs at Risk (OAR) Dosimetry 
Subjects will obtain SPECT/CT images of the tumor and organs at risk at sequential imaging time 
points (days 2, 3, 4-6, and 7-8) after administration of the first treatment dose of CLR 131.  
 
SPECT/CT images of tumor and organs at risk will be reconstructed using quantitative SPECT 
reconstruction methods with compensation for attenuation, scatter and the full collimator-detector 
response including septal penetration and scatter. A registered CT image will be used as the 
attenuation map for the SPECT images. Image data will be converted to activity per cubic 
centimeters using a sensitivity measurement made using a point source in air. For studies where 
the count rate is such that greater than 5% count rate losses are expected, deadtime corrections 
will be applied. The time activity curve in each pixel will be computed and fit with a mono-or bi-
exponential function when possible or a piece-wise linear fit when more advanced fitting options 
are not possible. The fits will be integrated and divided by the injected activity to provide a 3D 
residence time image. This will be converted to a dose image using the RAPID Monte Carlo dose 
estimation code (A. Besemer & Bednarz, 2014; A. E. Besemer et al., 2017; A. E. Besemer et al., 
2018). The average dose and 3D dose distribution in each tumor and organs at risk will then be 
computed inside volumes-of-interest defined using CT and SPECT images. 
6.8 
External beam radiation therapy (EBRT) 
External beam radiation therapy will be used in combination with CLR 131 infusions to deliver a 
total dose of 60-70 Gy to the recurrent tumor in subjects determined by study radiologist to exhibit 
uptake of CLR 131.  
The standard of care radiation therapy for this patient population is 60-70 Gy absorbed dose, 
irrespective of radiation delivery. Therefore, as long as the SOC radiation dose parameters are 
met, EBRT described in 6.8 is considered within standard of care. The total dose (60-70 Gy) 
delivered to the recurrent tumor will be at the discretion of the treating Radiation Oncologist. 
6.8.1 
Dose specifications and target definition 
The recurrent gross tumor volume (rGTV), as defined by diagnostic imaging including CLR 131 
uptake imaging and physical exam findings, will receive daily fractions of 2.0-2.5 Gy. The rGTV 


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will undergo a geometric expansion of 3-5 mm to create the recurrent clinical target volume 
(rCTV), which accounts for coverage of areas at high-risk for harboring subclinical disease. The 
rCTV can be modified by the treating Radiation Oncologist to account for areas thought to be free 
of disease (e.g. air space, bone). The rCTV will be expanded by 2-3 mm to create a recurrent 
planning target volume (rPTV). Elective treatment volumes treated to lower dose are generally 
discouraged but permitted at the discretion of the treating physician.  
6.8.2 
Plan evaluation 
Plans will be normalized so that 95 % of the rPTV is covered by the prescription dose (PD). The 
dose to 1cc of the rPTV should not exceed 115 % of the PD. The dose to 0.3 cc of the rPTV 
should not be less than 92 % of the PD. 
6.8.3 
Technical factors 
Participants will undergo CT scan simulation using ≤ 3 mm slices. Subjects will be immobilized 
using an Aquaplast mask. The scan should be performed with IV contrast unless the subject has 
contra-indications (e.g. IV contrast allergy or poor kidney function). Treatment will be delivered via 
linear accelerated-based (LINAC) intensity modulated radiotherapy (IMRT) using high energy 
photon beams. Subjects will be treated with image-guidance radiotherapy. Images will be 
approved prior to the first treatment and following all remaining treatments by a staff Radiation 
Oncologist. Images will be registered either manually or automatically. The region-of-interest for 
image fusion should include the primary tumor and adjacent spinal cord. Following registration, 
translation corrections should be applied to the treatment couch.  
6.8.4 
Definition of organs at risk and recommended dose constraints 
Organs at risk (OARs) in subjects undergoing re-irradiation may have already approached or 
exceeded their respective recommended dose limitation. For example, during the initial treatment 
course, one or both parotid glands may have already exceeded the recommended dose of less 
than 26 Gy. Therefore, in situations such as these, best clinical judgement will be exercised by the 
treating radiation oncologist for dose constraints.  
 
The concept of dose forgiveness with regard to the time from prior radiation to re-irradiation, 
especially for critical structures such as the spinal cord, will be taken into account by the treating 
Radiation Oncologist when deciding on final OAR doses. 
 
Recommended dose to OAR may or may not be achievable based upon the prior radiation and 
contribution of CLR 131 to the total dose. 
 
Spinal cord: The spinal cord begins at the cranial-cervical junction (i.e. between the foramen 
magnum and the top of the C1 vertebral body). Superior to this is the brainstem and inferior is the 
spinal cord. The inferior border of the spinal cord is at approximately T3-4 (i.e. 2 cm below the 
lowest slice containing rPTV). The spinal cord will be defined based on the treatment planning CT 
scan. All attempts to limit the combined total dose from the previous and current radiation 
treatment regimen (CLR 131 and EBRT) to less than 60 Gy will be made. Higher point doses can 


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be considered and are at the discretion of the treating physician, however the spinal cord 
maximum point dose including prior radiation course will not exceed 65 Gy.  
  
Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction between 
the foramen magnum and top of the C1 vertebral body. The brainstem will be contoured to the 
level of the posterior clinoid. The brainstem will be defined based on the treatment planning CT 
scan. All attempts to limit the combined total dose from the previous and current radiation 
treatment regimen (CLR 131 and EBRT) to less than 70 Gy will be made. Higher point doses can 
be considered and are at the discretion of the treating physician, however the brainstem maximum 
point dose including prior radiation course will not exceed 72 Gy.  
 
Parotid glands: Parotid glands will be defined based on the treatment planning CT scan. The 
contours will not include the accessory duct (i.e. gland anterior to the masseter muscle). The 
treatment planning goal for the parotid gland that received a lower previous radiotherapy dose 
should be a mean dose of < 26 Gy, but ideally as low as possible given data suggesting a no 
threshold dose response. Depending on the dose received by the parotid gland receiving a higher 
mean dose from the previous treatment, a constraint should be made by the treating physician.  
 
Glottic/Supraglottic larynx (GSL): This will be defined as a volume that begins just inferior to the 
hyoid bone and extends to the cricoid cartilage inferiorly and extends from the anterior 
commissure to include the arytenoids. This includes the infrahyoid and excludes the suprahyoid 
epiglottis. The GSL mean dose from retreatment should be ≤ 35 Gy. 
 
Mandible: This includes the entire boney structure of the mandible from TMJ through the 
symphysis. The recommended maximum dose within the mandible should be < 35 Gy. This 
assumes a maximum dose approaching 60 Gy from the previous radiotherapy treatment plan. 
Therefore, a goal of < 105 Gy should be achievable with contribution from CLR 131. 
 
Pharyngeal constrictors: This includes the structure along the posterior pharyngeal wall from the 
inferior border of the pterygoid plates to the inferior border of the cricoid. A planning goal for a 
mean dose of < 35 Gy from the retreatment should be utilized. 
6.8.5 
Prioritization for IMRT planning 
1. Spinal Cord 
2. Brainstem 
3. rPTV70 
4. Mandible 
5. GSL 
6. Contralateral parotid gland 
7. Ipsilateral parotid gland 
8. Pharyngeal constrictors 


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6.9 
Concomitant Medications/Treatments 
All intercurrent medical conditions will be treated at the discretion of the Investigator according to 
acceptable community standards of medical care. All concomitant medications and treatments will 
be documented appropriately and recorded until 28 days after last EBRT treatment or 85 days 
after first treatment dose of CLR 131, whichever is later. 
 
The following medications are not permitted during the study unless mandated by clinical 
circumstance: 
• Any other investigational treatment 
• Any other systemic antineoplastic therapy including, but not limited to, cytotoxic 
chemotherapy, immunotherapy, monoclonal antibody therapy, systemic radioisotope 
therapy 
• Prophylactic hematopoietic growth factors (note: therapeutic hematopoietic growth factors 
are permitted at the discretion of the treating physician) 
Pneumocystis jiroveci pneumonia (PJP) and viral prophylaxis for subjects with lymphopenia 
should be considered and is at the discretion of individual investigators.  
Initiation of platelet transfusions are suggested for subjects with a platelet count ≤ 20,000 / μL or 
those subjects with symptomatic thrombocytopenia (evidence of bruising or bleeding). 
Cellectar Biosciences advises investigators to refrain from initiating highly myelosuppressive 
therapy in subjects progressing within 85 days of CLR 131 infusion until their blood counts have 
fully recovered to previous baseline. 
There are no known interactions with other medications. 
 
After the recording period only medications used to treat a cancer recurrence will be recorded. 


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7 STUDY SCHEDULE 
7.1 
Screening 
The screening evaluation will occur within 42 days of the test dose of CLR 131. All subjects must 
provide informed consent prior to any procedures being done specifically for the study and must 
satisfy the entry criteria. Procedures and data collection at screening are:  
• 
Signed informed consent form (ICF) 
• 
Demographics (birth date, gender, race, ethnicity) 
• 
Medical history, including comprehensive treatment history for underlying malignancy 
• 
Review of concomitant medications 
• 
Physical examination 
• 
Vital signs 
• 
Height, weight 
• 
ECOG performance status 
• 
Complete blood count (CBC) with differential (within 2 weeks prior to test dose to determine 
eligibility) 
• 
Serum chemistries (within 2 weeks prior to test dose to determine eligibility) 
• 
EKG (within 2 weeks prior to test dose to determine eligibility) 
• 
Urine pregnancy test for WOCP (within 24 hrs prior to the dosimetry test dose) 
• 
Serum thyroid-stimulating hormone (TSH) and free thyroxine (T4) 
• 
Dispense thyroid-protection medication and review instructions with subjects. 
Thyroid-protection medication must be taken within 24 hours before CLR 131 dosing and 
for 14 days after the last CLR 131 dose. 
• 
Adverse event evaluation 
• 
Distribute medication diaries 
• 
Quality of Life surveys 
• 
Saliva and oral swab collection 
• 
Modified barium swallow study 
• 
Oral profile exam 
• 
Diagnostic cross-sectional imaging (any combination of CT, MR, or PET-MR) scans) 
collected from the scans performed as part of standard clinical care. 
• 
Dosimetry Test Dose 
• 
SPECT/CT imaging 


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7.1.1 
Dosimetry Test Dose 
On the day of dosing, prior to infusion, the following tests and procedures will be done: 
• 
Confirm subject is taking thyroid-protection medication as directed 
• 
Urine pregnancy test for WOCP (within 24 hrs prior to the dosimetry test dose) 
• 
Vital signs will be collected prior to and 1 hour post CLR 131 infusion 
 
CLR 131 will be administered through a freely running peripheral IV catheter via a slow infusion of 
approximately 30 minutes duration. For the dosimetry test dose, the dose of CLR 131 will be a flat 
dose of 15 mCi.  
• 
SPECT/CT imaging will be performed approximately three days after infusion to assess 
tumor uptake of CLR 131.  If a subject does not demonstrate CLR 131 uptake on the day 3 
SPECT/CT scan, then a repeat SPECT/CT can be performed 7 days after the CLR 131 test 
dose to reassess for uptake.  
• 
Subjects who demonstrate uptake of CLR 131 on either the day 3 or day 7 SPECT/CT 
scan, along with up to six patients who do not demonstrate uptake of CLR 131 are eligible 
for the treatment doses of CLR 131. 
 
7.2 
Treatment Period 
7.2.1 
Treatment Dose 
The targeted time between the dosimetry test dose and treatment dose will be 7-14 days, but will 
allow for to up to four weeks. Dosing dates for treatment can be scheduled to start -1 or +3 days to 
accommodate clinic scheduling (e.g., holidays, weekends, treating physician schedules, etc.). 
7.2.1.1 
Treatment Dose Administration 
Subjects who have uptake on SPECT/CT imaging scans are eligible for the treatment portion of 
the clinical trial. These subjects will be treated and evaluated as follows: 
• 
Vital signs will be collected prior to and 1 hour post CLR 131 infusion 
• 
On day 1 of the treatment period, CLR 131 will be administered through a freely running 
peripheral IV catheter via a slow infusion of approximately 30 minutes duration. The dose of 
CLR 131 will be calculated for each subject based on total BSA (not to exceed 2.5 m2) 
calculated from actual body weight and height at screening.  
• 
SPECT/CT imaging will be performed on days 2, 3, 4-6, and 7-8. 
• 
A second treatment dose of CLR 131 will be given on day 8. 
• 
CBC with differential and serum chemistries weekly for 12 weeks (beginning at day 1 of first 
treatment dose) 


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• 
Confirm subject is taking thyroid protection medication as directed. 
• 
Adverse event evaluation 
• 
Urine pregnancy test for WOCP (within 24 hrs prior to each CLR 131 dose) 
7.2.1.2 
External beam radiation therapy (EBRT) (approximately 7-14 days after the last CLR 131 
treatment dose) 
Based on the calculated absorbed dose of CLR 131 to the specific targeted tissue, the subject will 
undergo standard of care EBRT to complete the designated radiation dose outlined in the re-
irradiation plan.  
An EKG will be performed on the first day of the SOC EBRT.  During the course of EBRT, 
subjects will be evaluated for any adverse events. 
7.3 
Post Treatment Period 
7.3.1 
One Month Post CLR 131 Infusion (± 2 weeks) 
One month (± 2 weeks) after the first therapeutic CLR 131 dose, the following tests and 
procedures will be done: 
• 
Review of concomitant medications 
• 
Physical examination 
• 
Vital signs 
• 
Weight 
• 
ECOG PS 
• 
CBC with differential  
• 
Serum chemistries  
• 
Confirm subject is taking thyroid-protection medication as directed 
• 
Adverse event evaluation 
7.3.2 
3 Months Post EBRT (± 4 weeks) 
Three months (± 4 weeks) after EBRT is completed, the following tests and procedures will be 
done: 
• 
Review of concomitant medications 
• 
Physical examination 
• 
Vital signs 
• 
Weight 
• 
ECOG PS 


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• 
CBC with differential  
• 
Serum chemistries 
• 
TSH and free T4 
• 
Adverse event evaluation 
• 
Oral profile exam 
• 
Modified barium swallow study 
• 
Quality of Life surveys 
• 
Saliva and oral swab collection 
• 
Diagnostic cross sectional imaging (any combination of CT, MR, or PET-MR scans) 
collected from the scans performed as part of standard clinical care 
7.3.3 
6 months Post EBRT (± 4 weeks) 
Six months (± 4 weeks) after EBRT is completed, the following tests and procedures will be done: 
• 
Review of concomitant medications 
• 
Physical examination 
• 
Vital signs 
• 
Weight 
• 
ECOG PS 
• 
TSH and free T4 
• 
Adverse event evaluation 
• 
Oral profile exam 
• 
Modified barium swallow study 
• 
Quality of Life surveys 
• 
Saliva and oral swab collection 
7.3.4 
12 months Post EBRT (± 6 weeks) 
Twelve months (± 6 weeks) after EBRT is completed, the following tests and procedures will be 
done: 
• 
Review of concomitant medications 
• 
Physical examination 
• 
Vital signs 
• 
Weight 


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• 
ECOG PS 
• 
TSH and free T4 
• 
Adverse event evaluation 
• 
Quality of Life surveys 
• 
Saliva and oral swab collection 
• 
Diagnostic imaging (any combination of CT, MR, or PET-MR scans) collected from the 
scans performed as part of standard clinical care  
7.3.5 
24 months Post EBRT (± 6 weeks)/End of Study Visit 
(Note: this follow-up assessment will not be completed if the subject has initiated a new, anti-
cancer therapy prior to the 24 month visit.) 
Twenty-four months (± 6 weeks) after EBRT is completed, the following tests and procedures will 
be done: 
• 
Physical examination 
• 
TSH and free T4 
• 
Adverse event evaluation 
• 
Diagnostic imaging (any combination of CT, MR, or PET-MR scans) collected from the 
scans performed as part of standard clinical care 
7.4 
Withdrawal Visit (+ 30 days) 
If a subject withdraws or the investigator terminates subject participation prior to 24 months post 
EBRT, the following tests and procedures will be done: 
• 
Review of concomitant medications 
• 
Physical examination 
• 
Vital signs 
• 
Weight 
• 
ECOG PS 
• 
Adverse event evaluation 
7.5 
Unscheduled Visit 
Unscheduled visits with clinically significant tests or procedures will be captured in the OnCore 
database. Subjects who have an urgent or emergent medical condition will be seen by the treating 
physician and/or emergency room and treated as clinically indicated. Medical records will be 
obtained to evaluate for any adverse events, which will be documented in the clinical study 
database. In addition, the principal investigator, in conjunction with the treating physician, will 


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determine the attribution of any adverse events to the medical condition, disease, investigational 
agents, or any other probable causes.  


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8 STUDY PROCEDURES /EVALUATIONS 
8.1 
Study Procedures/Evaluations 
 
8.1.1 
Demographics 
Birth date, gender, race, and ethnicity will be collected at screening (recorded for the study from 
medical records maintained as part of standard clinical care). 
8.1.2 
Medical History 
A thorough review of the subject’s medical history, taking into account all recent and pertinent 
medical conditions including prior cancer treatment, will be performed at screening (within 42 days 
prior to the CLR 131 dosimetry test dose infusion). This will be recorded for the study from 
medical records maintained as part of standard clinical care. 
8.1.3 
Concomitant Medication Review 
All current and recent medications will be reviewed and recorded in the CRF. The medication 
review must be completed within 42 days prior to the dosimetry test dose infusion of 
CLR 131(screening period). A review of concomitant medications will occur at one month post the 
first CLR 131 therapeutic infusion; at 3, 6, and 12 months post EBRT; and at the withdrawal visit. 
This will be recorded for the study from medical records maintained as part of standard clinical 
care for the screening period as well as the 3, 6, and 12 month post EBRT visits. These are 
research-related reviews for the one month post first CLR 131 therapeutic infusion visit and at the 
withdrawal visit (if terminated early). 
8.1.4 
Physical Exam 
A detailed physical exam will be completed at screening; at one month post the first CLR 131 
therapeutic infusion; at 3, 6, and 12 months post EBRT; and at the withdrawal visit. This will be 
recorded for the study from medical records maintained as part of standard clinical care for the 
screening period as well as the 3, 6, and 12 month post EBRT visits. These are research-related 
reviews for the one month post first CLR 131 therapeutic infusion visit and at the withdrawal visit 
(if terminated early).  
8.1.5 
Vital Signs 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be recorded prior to and 
1 hour post each CLR 131 infusion and at the following timepoints: screening; one month post the 
first CLR 131 therapeutic infusion; at 3, 6, and 12 months post EBRT; and at the withdrawal visit. 
This will be recorded for the study from medical records maintained as part of standard clinical 
care for the screening period as well as the 3, 6, and 12 month post EBRT visits. These are 
research-related reviews for the CLR 131 infusion timepoints, as well as one month post first CLR 
131 therapeutic infusion visit and at the withdrawal visit (if terminated early). 


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8.1.6 
Height 
Height will be recorded at screening. This is a standard procedure being done within routine care 
guidelines. 
8.1.7 
Weight 
Weight will be recorded at screening; at one month post the first CLR 131 therapeutic infusion; at 
3, 6, and 12 months post EBRT; and at the withdrawal visit (if applicable). This will be recorded for 
the study from medical records maintained as part of standard clinical care for the screening 
period as well as the 3, 6, and 12 month post EBRT visits. These are research-related measures 
for the one month post first CLR 131 therapeutic infusion visit and at the withdrawal visit (if 
terminated early). 
8.1.8 
ECOG Performance Status 
Determination of the subject’s performance scale (PS) based on the Eastern Cooperative 
Oncology Group (ECOG) rating scale (Appendix B) will be made at screening; at one month post 
the first CLR 131 therapeutic infusion; at 3, 6, and 12 months post EBRT; and at the withdrawal 
visit (if applicable). This will be recorded for the study from medical records maintained as part of 
standard clinical care for the screening period as well as the 3, 6, and 12 month post EBRT visits. 
These are research-related measures for the one month post first CLR 131 therapeutic infusion 
visit and at the withdrawal visit (if terminated early). 
8.1.9 
Administration of Thyroid Protection Medication 
Thyroid-protection medication, including instructions for use and a diary, will be provided at 
screening. The subject’s proper use of thyroid-protection medication will be confirmed at Day 1, 
prior to every CLR 131 infusion, and at applicable follow-up visits to ensure the appropriate use. 
Refer to Section 6.3 for dosing and duration details. 
It is recommended that the Investigator or his/her designee contact subjects by phone on the day 
prior to the dosimetry test dose to ensure thyroid-protection medication is started and a minimum 
of 2 doses of SSKI, 2 doses of Lugol’s 5 % solution, or 1 potassium iodide tablet (130 mg) are 
taken prior to CLR 131 infusion. 
The administration of thyroid-protection medications is a standard clinical procedure being done 
for research-related purposes associated with the administration of the research drug CLR 131.  
8.1.10 Administration of CLR 131 
CLR 131 will be administered through a freely running peripheral IV catheter via a slow infusion of 
approximately 30 minutes duration. The dose of CLR 131 will be calculated for each patient based 
on total BSA (not to exceed 2.5 m2) calculated from actual body weight and height at screening. 
UW Hospital has established guidelines regarding the administration of radioactive material and 
release criteria following such administration. All institutional policies will be followed in this study. 
The institutional policies will be followed in determining whether the CLR 131 administration will be 


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done as an outpatient or inpatient. Suggested guidelines for monitoring for radioactivity and 
criteria to use for discharge are outlined in Section 10.1. 
 
See the CLR 131 Radiopharmacy Manual (Supplementary Materials) for specific administration 
requirements. 
 
The administration of CLR 131 is a research-related procedure. 
8.1.11 Adverse Event Evaluation 
Adverse event assessment will be performed at screening (standard of clinical care); at Day 1 
prior to each CLR 131 infusion (research-related); weekly during EBRT (research related); at 3, 6, 
and 12 months post EBRT (standard of clinical care); and at the withdrawal visit (research-related 
if applicable). Adverse events will be assessed as described in Section 11, Assessment of Safety. 
8.1.12 SPECT/CT Imaging 
SPECT/CT imaging will be completed at two potential timepoints after the CLR 131 dosimetry test 
dose to evaluate for tumor uptake:  (a) approximately three days and (b) approximately 7 days 
after the CLR 131 test dose. The SPECT/CT scan on day 7-8will be completed only if CLR 131 
uptake by the tumor is not demonstrated on the day 3 scan. Uptake in the specified site of 
recurrent/metastatic disease that is to be treated with radiation therapy will be determined by the 
study radiologist.  
Subjects with demonstrated uptake on either SPECT/CT scan (day 3 or day 7) after the test dose 
and up to six subjects who do not demonstrate uptake of CLR 131 will receive treatment doses of 
CLR 131.  These subjects will have additional SPECT/CT imaging completed in order to visualize 
and quantitate the biodistribution of the CLR 131 treatment dose. Based on these SPECT/CT 
imaging scans, the Bednarz lab will utilize the Monte Carlo method to predict absorbed dose of 
CLR 131 to tumors and normal structures. 
SPECT/CT imaging, which is a research-related procedure, will be performed on days 2, 3, 4-6, 
and 7-8 following the first CLR 131 treatment dose. 
8.1.13 Electrocardiogram (EKG) 
An EKG will be performed at the baseline/screening visit, as well as on the first day of treatment 
for EBRT.  This is a research-related procedure. 
8.1.14 Quality of Life Measures 
Quality of life (QoL) surveys will be collected at screening and at 3, 6, and 12 months post EBRT. 
The surveys are anticipated to take ~ 20 minutes to complete. 
• 
SF-12  
• 
EORTC QLQ-C30 
• 
EORTC QLQ-H&N35 
• 
MDADI 


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• 
EAT-10 
• 
XeQoLS 
 
The completion of QOL surveys is a research procedure. 
 
Validated health outcome surveys will be used to assess subject perception of mental and 
physical health, QOL, cancer-related H&N functioning, swallowing-related QOL and xerostomia 
before and after re-irradiation (Connor et al., 2006). 
 
Each subject will serve as their own control with complete QOL evaluation prior to and following 
treatment. This will take into account various baseline dysfunctions that may be present from prior 
HNC therapy.  
 
Perception of general health and QOL will be evaluated using the Medical Outcomes Trust Short 
Form 12 (SF-12) (Ware et al., 1995) and the European Organization for Research and Treatment 
of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) (Hammerlid et al., 2001; 
Hjermstad et al., 1995; Kemmler et al., 1999). The SF-12 is a shorter version of the widely-used 
SF-36 and was chosen for its well-established acceptance as a valid and reliable measure of 
perception of physical and mental health across a large range of disease entities, including HNC 
(Gandek et al., 1998; Terrell et al., 1997; Terrell et al., 2004). The EORTC QLQ-C30 was chosen 
for its sensitivity to cancer-related QOL and symptomatology, such as nausea/vomiting, fatigue 
and pain, and because it was identified previously as being well-developed, reliable, valid, and 
responsive (Ringash & Bezjak, 2001). 
 
Specific cancer-related H&N functioning will be assessed with the EORTC QOL Questionnaire 
H&N35 (EORTC QLQ-H&N35) (Bjordal et al., 1999; Sherman et al., 2000). This validated 
instrument incorporates items related to swallowing, eating, dry mouth, and saliva production and 
is sensitive to cancer site and stage (Bjordal et al., 1999). The EORTC QLQ-C30 and QLQ-
H&N35 will be administered together and will yield a global health status score.  
 
The MD Anderson Dysphagia Inventory (MDADI) and Eating Assessment Tool (EAT-10) will be 
used to investigate swallow-related QOL (P. H. Chen et al., 2009; Rosenthal et al., 2007; 
Rosenthal et al., 2008) and the Xerostomia-related QOL scale (XeQoLS) will be used to measure 
subject-perceived dry mouth and its implications for QOL (Henson et al., 2001; Rogers et al., 
2010). 
8.1.15 Oral Swab and Saliva Collection and Analysis 
Oral swab and saliva collection and analysis will occur at screening, and at 3, 6 and 12 months 
post EBRT. This is a research procedure which will take ~10-20 minutes. 
Participants will be asked to refrain from all intake of food and drink, smoking, and use of 
toothpaste for one hour prior to collection. Samples from the buccal mucosa and tongue dorsum 
will be obtained using a cotton tip collection swab. 


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Saliva (unstimulated and stimulated) and saliva flow rates will be collected. Guidelines for 
collecting unstimulated and stimulated saliva developed by the University of Southern California 
(USC) School of Dentistry (Navazesh & Kumar, 2008) will be adapted and used in this project. 
Unstimulated whole saliva production will be collected first for each subject, followed by collection 
of saliva during unflavored gum base chewing to obtain a sample of stimulated saliva (Dawes, 
1987; Logemann et al., 2001). Salivary compositional analyses will focus on qualitative aspects of 
saliva previously found to change following radiation treatment: salivary viscosity (Sim et al., 2018; 
Tolentino Ede et al., 2011), pH (Chitra & Shyamala Devi, 2008; Sim et al., 2018), total protein 
concentration (mg/mL) (Richards et al., 2017; Valdez et al., 1993), amylase (mU/mL) (Almstahl et 
al., 2001; Chitra & Shyamala Devi, 2008), mucin (MUC5B, mU/mL) (Almstahl et al., 2001; Dijkema 
et al., 2012) and alpha and beta microbiota diversity (Hu et al., 2013). 
At the same time as saliva collection, a mucositis grade will be determined by the study team 
using the World Health Organization (WHO) Oral Mucositis Assessment Scale. Also, the study 
team will grade oral health using the Kayser-Jones Brief Oral Health Status Examination 
(BOHSE), a valid and reliable scoring instrument developed for use with older adults by non-
dental health care providers (Kayser-Jones et al., 1995).  
8.1.16 Oral profile exam (research procedure) 
Subjects will participate in an oral exam which will involve the following measurements: residual 
mucosal saliva (RMS), resting swallow frequency, maximum expiratory pressure, peak airflow 
during voluntary cough, and maximum lingual pressures. Oral exams will occur during the 
screening and at the 3 and 6 month post EBRT visits. This is a research procedure which is 
estimated to take a total of 15-20 minutes per visit.  
8.1.16.1 Residual Mucosal Saliva (RMS) 
RMS, which correlates with hyposalivation and dryness perception, will be collected from the 
anterior hard palate (AHP), buccal (BUC), anterior tongue (AT), and lower labial (LL) surfaces 
using SialoPaper strips (Oraflow Inc., Smithtown, NY, USA). These strips will be applied for 10 
seconds and measured using Periotron device (Oraflow Inc.). 
8.1.16.2 Resting swallow frequency 
Resting swallow frequency will be measured with combined methods: respiratory bellows around 
the diaphram, motion sensor around neck, and visual observation by research staff.  
8.1.16.3 Maximum Expiratory Pressures (MEP)   
Digital manometers will measure MEPs (cm H2O) as a measure of expiratory force generation in 
all patients enrolled. The MEP will be calculated as the best of three trials within 10 % variance.  
8.1.16.4 Peak airflow during voluntary cough (PCF)  
Peak airflow during voluntary cough (PCF) will be measured using a peak airflow meter (Mini 
Wright Peak Flow Meter). Participants will be asked to inhale to total lung capacity (TLC) and to 


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“cough hard like there is something stuck in the throat” while standing. The PCF will be calculated 
as the best of three trials within 10 % variance.  
8.1.16.5 Maximum Lingual Pressures (MLP) 
Participants will have maximum lingual pressures measured using an Iowa Oral Performance 
Instrument (IOPI).  Participants will press as hard as they can with their tongue against a pressure 
bulb positioned between the tongue and hard palate.  
8.1.17 Modified Barium Swallow Study 
Modified barium swallow (MBS) studies will be performed at screening, 3 and 6 months post 
EBRT. This is a standard clinical procedure being done within routine care guidelines. The 
procedures below are detailed for the purposes of this study to control for consistent treatment 
within this study group.  
All subjects will be examined using videofluoroscopy (Supplemental Materials). Each subject will 
be seated in the lateral plane while radiographic images of bolus swallows are captured in 
continuous acquisition mode keeping the entire oral cavity and pharynx in view.  
 
Subjects will swallow pre-measured mL boluses of thin liquid barium. Other consistencies 
assessed will include nectar and honey thick barium liquids, puree (pudding) thick barium, 
mechanical soft and regular solids, including a pill (barium capsule) and a shortbread cookie 
coated with pudding-thick barium.  
 
Evaluation measures were chosen because similar measurements have been shown to be 
sensitive to hyposalivation (Rogus-Pulia & Logemann, 2011).  
 
Our ability to assess and measure parameters related to swallowing is demonstrated by our prior 
work (List et al., 1996a; List et al., 1990; List et al., 1996b). In addition to the videofluoroscopic 
swallowing assessments, diet will be rated using the Performance Status Scale (PSS) Normalcy 
of Diet Rating and the Functional Oral Intake Scale (FOIS).  
 
To perform the rated measures, such as oral residue and Dynamic Imaging Grade of Swallowing 
Toxicity (DIGEST) scores, video recordings for all subjects at all timepoints will be presented in 
random order to two trained raters, who will be speech-language pathologists who specialize in 
swallowing and were not involved in the data collection. Ten percent of samples will be included 
twice to measure intra-rater reliability. To encourage adequate inter-rater reliability, raters will view 
a training sequence that does not include test items and provides anchors for each parameter until 
90 % agreement is reached. Any occurrences of penetration or aspiration will be noted and rated 
using the Penetration Aspiration Scale (Robbins et al., 1999; Rosenbek et al., 1996). 
8.1.18 Diagnostic Imaging 
Diagnostic imaging will be performed at screening, 3 months post EBRT, and 12 months post 
EBRT. Imaging studies can be obtained at any time if clinically indicated by the treating physician. 


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Imaging studies may consist of any combination of CT, MR, or PET-MR scans, as clinically 
indicated. If cross sectional imaging is unable to be obtained, other imaging modalities may be 
used (see section 9.3). The imaging study performed at screening should be repeated at 
subsequent assessments.  
 
Imaging studies are standard clinical care procedures being done within routine care guidelines. 
8.2 
Laboratory Procedures/Evaluations 
Laboratory testing will be completed by CLIA-certified labs.  
8.2.1 
Clinical Laboratory Evaluations 
8.2.1.1 
Complete Blood Count with Differential 
Blood will be drawn for CBC with differential at screening (standard of clinical care); weekly for 12 
weeks beginning with day 1 treatment dose (research-related procedure); and at 3 months post 
EBRT (standard of clinical care).  
The CBC will include red blood cell count, hemoglobin, hematocrit, WBC count with differential 
including % neutrophils, lymphocytes, monocytes, eosinophils and basophils, absolute neutrophil 
count, and platelet count. 
8.2.1.2 
Serum Chemistries 
Blood will be drawn for serum chemistries at screening, weekly for 12 weeks starting with first 
treatment dose of CLR 131 and at 3 months post EBRT. This is a standard procedure being done 
for research-related purposes of radiotherapeutic administration. 
 
The serum chemistries will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase, total bilirubin, calcium, protein, albumin, and phosphorus. 
8.2.1.3 
Pregnancy Test 
A urine pregnancy test will be completed within 7 days prior to the CLR 131 dosimetry test dose in 
women of childbearing potential. Women who are postmenopausal for at least 1 year or surgically 
sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) are not considered to be 
of childbearing potential.  
 
Pregnancy testing is being done as part of standard clinical care. 
8.2.1.4 
Thyroid Function Tests 
Blood will be drawn for serum analysis of TSH and free T4 at screening; 3, 6, and 12 months post 
EBRT. This is a research procedure for the screening, 3 and 6 month post EBRT visits.  This is a 
standard clinical procedure performed within routine guidelines for the 12 month post EBRT visit. 


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9 CRITERIA FOR DISEASE ASSESSMENT 
For the purposes of this study, subjects will be evaluated for evidence of response and 
progression at 3 and 12 months post-completion of the EBRT portion of the protocol – see study 
calendar. Only those subjects who receive a treatment dose of study drug will be assessed for 
response and/or progression. Those with inadequate uptake after the dosimetry test dose will only 
be followed for safety measures. 
  
Response and progression will be evaluated in two distinct fashions. For those without evidence 
of metastatic disease at the time of study enrollment, response and progression will be evaluated 
using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 Committee (Eisenhauer et al., 2009).  
 
For those with metastatic disease at the time of study enrollment, study lesions will be defined 
within the locoregional recurrence field that will be receiving EBRT. Those lesions will be 
assessed for response and progression using RECIST 1.1 criteria. Lesions outside of the radiation 
field can be assessed for response to CLR 131 alone. Once palliative systemic therapy is initiated 
for systemic disease burden, subjects will be censored as having disease progression, regardless 
of the status of the locoregional target lesions. 
Note: Lesions are either measurable or non-measurable using the criteria provided below.  
9.1 
Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as > 20 mm with conventional techniques (CT, MRI, 
x-ray) or as > 10 mm with spiral CT scan. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan. 
9.2 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter  
< 20 mm with conventional techniques or < 10 mm using spiral CT scan or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions 
are all non-measurable. 
9.3 
Guidelines for Evaluation of Measurable Disease 
Measurements will be recorded for the study from standard of care scans in the medical records 
maintained as part of standard clinical care. All measurements should be taken and recorded in 
metric notation using a ruler or calipers. All baseline evaluations should be performed as closely 
as possible to the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 


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Note:  Tumor lesions that are situated in a previously irradiated area can be considered 
measurable only if there is documented growth of the lesion, and at least 8 weeks have elapsed 
since completion of radiation treatments. 
When possible, the same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been used 
to assess the antitumor effect of a treatment.  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter (e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: These techniques should be performed with cuts of 10 mm or less in 
slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and 
neck tumors and those of extremities usually require specific protocols. 
Ultrasound: When the primary endpoint of the study is objective response evaluation, US should 
not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules. 
Ultrasound might also be useful to confirm the complete disappearance of superficial lesions 
usually assessed by clinical examination. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation has 
not yet been fully and widely validated. Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers. Therefore, the 
utilization of such techniques for objective tumor response should be restricted to validation 
purposes in reference centers. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained. 
 


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10 RADIATION SAFETY 
10.1 
Radiation Safety Monitoring and Release Criteria 
UW Hospital has established guidelines/policy regarding the release criteria following 
administration of radioactive material. All institutional policies will be followed in this study. The 
guidelines below are recommendations only, and the regulations of the institution will take 
precedence. 
  
Prior to the initiation of this trial, the Radiation Safety Officer will be contacted to determine the 
release criteria to be followed for subjects participating in the trial. The institution’s Radiation 
Safety Officer will conduct all appropriate training of research staff. 
 
Sponsor suggested guidelines for monitoring for radioactivity and criteria to use for discharge are: 
 
• 
Starting one day after the CLR 131 infusion, medical physics/radiation oncology personnel will 
monitor subject radiation levels at 1 meter from umbilicus. 
• 
Subjects will be discharged from the hospital when their radiation level is < 7 mrem/hr and the 
discharge is cleared by radiation safety personnel. 
10.2 
Subject Radiation Precautions 
Prior to the initiation of this trial, the Radiation Safety Officer will be contacted to determine all 
required precautions to be followed by subjects participating in the trial. The Radiation Safety 
Officer will perform all appropriate training of research staff. 
 
Written instructions, approved by the institution’s Radiation Safety Officer, describing methods to 
limit radiation dose to others must be given to the subject prior to CLR 131 infusion. The following 
precautions, conservatively derived from recommendations of the Society of Nuclear Medicine 
and Molecular Imaging (Silberstein et al., 2012) and the American Thyroid Association Taskforce 
on Radioiodine Safety, 2011, are suggested for subjects following the administration of CLR 131 
to lessen the risk to others:  
For three weeks after each dose of CLR 131: 
• Sleep alone and abstain from intercourse  
• Do not sleep with infants, small children or pregnant women for three weeks after 
CLR 131 infusion 
For one week after each dose of CLR 131:  
• Avoid participating in feeding, clothes changing and similar care of infants and small 
children  
• Limit time with and maintain a distance of approximately 3-6 feet from pregnant 
women and children  
• Do not prepare food for others that requires prolonged handling with bare hands  


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• Do not share dishes, utensils, towels or face cloths with others prior to washing  
• Do not share razors, toothbrushes, food or drinks with others  
• Flush toilet twice after use and wash hands for 20 seconds afterwards. Men should 
urinate sitting down.  
• Rinse the sink and wash hands thoroughly after brushing teeth  
• Do not stay in a location other than a private residence (such as a hotel)  
• Limit the time spent in public places to 1-2 hours if you can maintain 3 feet distance 
from others and avoid places such as theaters, sports arenas or stadiums, and so 
forth, where the option of getting a seat farther away from others may not always be 
possible  
• Bathe/shower daily for at least three days after CLR 131 infusion  
• Avoid prolonged use of public transportation the first day after CLR 131 infusion  


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11 ASSESSMENT OF SAFETY 
11.1 
Specification of Safety Parameters 
The Investigator should elicit information regarding the occurrence of AEs through open-ended 
questioning of the subject, physical examination, and review of laboratory results. Adverse event 
data collection and reporting, which are required as part of every clinical trial, are done to ensure 
the safety of subjects enrolled in the studies as well as those who will enroll in future studies using 
similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. 
Additionally, certain adverse events must be reported in an expedited manner to allow for optimal 
monitoring of patient safety and care. The first step is to identify the event using the Common 
Terminology Criteria for Adverse Events (CTCAE). The CTCAE document provides descriptive 
terminology for adverse event reporting. A grading (severity) scale is provided for each adverse 
event term. 
 
All AEs, whether serious or not, will be described in the source documents and the AE page of the 
Case Report Form (CRF). All new events, as well as those that worsen in intensity or frequency 
relative to baseline, that occur after administration of study drug through the period of protocol-
specified follow-up must be captured. 
Specific anticipated adverse events are described in section 2.3. 
Information to be reported in the description of each AE includes but is not limited to: 
• 
Medical diagnosis of the event. (If a medical diagnosis cannot be determined, a description 
of each sign or symptom characterizing the event should be recorded.)  
• 
The date of onset of the event  
• 
The date of resolution of the event 
• 
Whether the event is serious or not 
• 
Action taken 
• 
Outcome 
• 
Relatedness to the study drug (see below) 
• 
Subject’s condition is intermittent or continuing 
• 
The grade of the event based on the CTCAE v5.0 
 
 


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11.1.1 Unanticipated Problems 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to subjects or others to include, in general, any incident, experience, or outcome that meets 
all of the following criteria: 
• unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
• related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
11.1.2 Adverse Events 
An adverse event is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research. 
11.1.3 Serious Adverse Events (SAE) 
A serious adverse event is defined as any adverse event that meets one of the following criteria: 
• Results in death; OR 
• Is life-threatening; OR 
• Requires hospitalization or prolongs existing hospitalization; OR 
• Results in significant or persistent disability or incapacity; OR 
• Results in a congenital anomaly/birth defect 
Planned hospitalizations for disease-related surgery, routine procedures, non–disease-related 
procedures, and inpatient hospitalization for radiation protection/exposure levels are not 
considered SAEs. 
11.2 Time Period and Frequency for Event Assessment and Follow-Up 
Unanticipated problems will be recorded in the data collection system throughout the study.  
The PI will record all adverse events with start dates occurring any time after informed consent is 
obtained until 28 days after the last EBRT treatment or 85 days after first treatment dose of 
CLR 131, whichever is later. At each study visit, the investigator will inquire about the occurrence 


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of AE/SAEs since the last visit. Events will be followed for outcome information until resolution or 
stabilization. 
11.2.1 Adverse Events 
• AEs will be recorded from time of informed consent until 28 days after last EBRT treatment or 
85 days after first treatment dose of CLR 131, whichever is later. 
• AEs will be recorded per the reporting time above regardless of whether or not they are 
considered related to the study drug(s). 
• AEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within OnCore. 
• All AEs considered related to study drug(s) will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever occurs first. If the subject begins a new anticancer therapy, the AE reporting period 
for non-serious AEs ends at the time the new treatment is started. 
• Only clinically significant laboratory abnormalities will be captured as adverse events on the 
appropriate study specific eCRF form within OnCore. 
11.2.2 Serious Adverse Events 
• SAEs, both related or unrelated to the study, will be recorded from time of informed consent 
until 28 days after last EBRT treatment or 85 days after first treatment dose of CLR 131, 
whichever is later. 
• Any SAEs experienced after this period will only be reported if the investigator suspects a 
causal relationship of possibly, probably or definitely related to the study treatment. 
• SAEs will be reported on the SAE Submission Form and entered in SAE tab in OnCore within 
the timeframe listed in Table 2.  
• SAEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within OnCore. 
• All SAEs, regardless of relation to study drug, will be followed until resolution to ≤ Grade 1 or 
baseline and/or deemed clinically insignificant and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
• Recurrent episodes, complications, or progression of the initial SAE will be reported as follow-
up to the original episode within 24 hours of the investigator receiving the follow-up 
information. 
Reporting and submission requirements are described in Section 11.4. 
11.2.3 Other Reportable Events 
Reporting timeframes begin when PI learns of the occurrence of the event.  
 


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Table 1: 
Other Reportable Events Timeframe 
Event 
Definition 
Reporting  
Breach of 
confidentiality 
The exposure of any study information or 
communications directly related to a study subject to 
anyone not named as study staff or the release of a 
study subject’s identifiable information to study staff who 
were not specified to receive such information in the 
protocol or IRB application.  
Within 14 business days 
of knowledge of event 
Protocol 
deviation 
A deviation is an incident involving a departure from the 
IRB-approved protocol in the actual conduct of the study. 
Deviations may result from the action of the participant, 
investigator, or staff. 
See details below 
Major deviations 
Deviations are considered major when the unapproved 
change(s) in previously approved research activities, 
implemented without IRB approval, may potentially 
adversely affect subjects’ rights, safety, welfare, or 
willingness to continue participation, or affect the 
scientific design of the study and/or the integrity of the 
resultant data. 
Within 14 business days 
of knowledge of event  
Minor deviations  Deviations are considered minor when the unapproved 
change(s) in previously approved research activities, 
implemented without IRB approval, do not adversely 
affect subjects or the integrity of the study data. 
Cumulative minor 
deviations are reported at 
the time of continuing 
review.  
Protocol 
violation 
An incident involving an intentional deviation from the 
IRB-approved protocol that was not implemented in 
response to an emergency situation and that may impact 
a subject’s rights, safety, and/or welfare, makes a 
substantial alteration to risks to subjects, or affects the 
scientific design of the study and/or the integrity of the 
resultant data. Violations may also be repeated 
deviations (major or minor) of the same nature. 
Violations can represent serious or continuing non-
compliance with the federal regulations and guidelines 
for ethical conduct of human subject research. 
Within 14 business days 
of knowledge of event  
Protocol 
Exceptions 
A protocol exception is an IRB-approved deviation for a 
single subject or a small group of subjects but is not a 
permanent revision to the research protocol. 
Protocol exceptions must 
be approved by local IRB 
prior to implementation. 


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11.3 Characteristics of an Adverse Event 
11.3.1 Relationship to Study Intervention 
The PI will determine the relationship of adverse events to the research intervention using the 
following scale: 
• Definite = AE is definitely related to the study procedures 
• Probable = AE is likely related to the study procedures 
• Possible = AE is possibly related to the study procedures 
• Unlikely = AE is doubtfully related to the study procedures 
• Unrelated = AE is definitely not related to the study procedures 
11.3.2 Expectedness  
The Study PI will be responsible for determining whether an adverse event is expected or 
unexpected. An adverse event will be considered unexpected if the nature, severity, or frequency 
of the event is not consistent with the risk information previously described for the intervention. 
There are expected significant toxicities and adverse events associated with CLR 131 treatment. 
The most significant toxicities associated with CLR 131 involve myelosuppression such as 
neutropenia, anemia, and thrombocytopenia, which in some cases are Grade 3 or 4. These 
adverse events are expected to occur within 4 weeks from the first CLR 131 dose and are 
expected to be resolved by approximately 65 days after the last treatment dose of CLR 131. Thus, 
the DLT period has been defined to account for the expected toxicities of CLR 131 in section 
2.3.1.1.1 
There are expected significant toxicities and adverse events associated with SOC EBRT. These 
toxicities include Grade 3 radiation mucositis and Grade 3 radiation dermatitis.   
11.3.3 Severity of Event 
Adverse events will be documented and recorded at each visit using NCI CTCAE version 5.0.  
11.4 
Reporting Procedures 
11.4.1 Unanticipated Problem (UP) Reporting to IRB, Cellectar and UWCCC DSMC 
Incidents or events that meet the OHRP criteria for unanticipated problems require the creation 
and completion of an unanticipated problem report form. OHRP recommends that investigators 
include the following information when reporting an adverse event, or any other incident, 
experience, or outcome as an unanticipated problem to the IRB: 
• appropriate identifying information for the research protocol, such as the title, investigator’s 
name, and the IRB project number; 
• a detailed description of the adverse event, incident, experience, or outcome;  


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• an explanation of the basis for determining that the adverse event, incident, experience, or 
outcome represents an unanticipated problem;  
• a description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the unanticipated problem. 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported using the 
following timeline:   
• Unanticipated problems that are serious adverse events will be reported to the IRB, 
Cellectar Biosciences (clinical@cellectar.com) and to the UWCCC DSMC per Table 2 
timeline. 
• Any other unanticipated problem will be reported to the IRB, Cellectar Biosciences 
(clinical@cellectar.com) and the UWCCC DSMC per Table 1 timeline.  
• All unanticipated problems should be reported to appropriate institutional officials (as 
required by an institution’s written reporting procedures), the supporting agency head (or 
designee), and OHRP within one month of the IRB’s receipt of the report of the problem 
from the investigator. 
11.4.2 Serious Adverse Event Reporting 
Depending on the nature, severity, and attribution of the serious adverse event an SAE report will 
be phoned in, submitted in writing, or both according to Table 2 below. All serious adverse events 
must also be reported to the UWCCC DSMC. All serious adverse events must also be reported to 
the UW IRB (if applicable), and any sponsor/funding agency not already included in the list. 
 
SAEs experienced by a subject after the active reporting period has ended should be reported to 
Cellectar Biosciences if the PI becomes aware of them; at a minimum, all SAEs that the PI 
believes have at least a reasonable possibility of being related to investigational product are to be 
reported to Cellectar Biosciences. 
 
Determine the reporting time line for the SAE in question by using the following table.  


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Table 2: 
FDA Reporting Requirements.  
FDA Reporting Requirements for Serious Adverse Events (21 CRF Part 312) 
NOTE: Investigators MUST immediately report to the UWCCC DSMC, Cellectar Biosciences, and 
the IRB (if applicable) and any other parties outlined in the protocol ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64). 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death. 
2) A life-threatening adverse event (the subject was at risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it were more severe). 
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. * 
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 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). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to 
Cellectar and UWCCC DSMC within the timeframes detailed in the table below: 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
hospitalization ≥ 
24 hrs 
10 Calendar Days 
24 Hour; 5 Calendar Days 
Not resulting in 
Hospitalization ≥ 
24 hrs 
Not required 


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*Planned hospitalizations for disease-related surgery, routine procedures (such as G-
tube placement), non–disease-related procedures, and inpatient hospitalization for 
radiation protection/exposure levels are not considered SAEs. A hematologic adverse 
event grade 1-4 will not be defined as an SAE if it can be managed with blood product 
transfusions, unless it exceeds the window for a dose limiting toxicity. 
 
Expedited AE reporting timelines are defined as: 
• 
24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
• 
10 Calendar Days – A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
Serious adverse events that occur more than 28 days after last EBRT treatment or 85 days after 
first treatment dose of CLR 131, whichever is later and have an attribution of possible, probable, 
or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
11.4.2.1 Reported within 24 Hours 
Serious Adverse Events requiring reporting within 24 hours (as described above) must also be 
reported to the UWCCC DSMC within one business day. See 11.4.2.1.1.1. SAEs will also be 
reported to Cellectar Biosciences within 24 hours of discovery of the event. The OnCore SAE 
Details Report must be submitted along with other report materials as appropriate (FDA Medwatch 
Form #3500 and/or any other documentation available at that time of initial reporting). Within 10 
working days, all available subsequent SAE documentation must be submitted electronically along 
with a 24 hour follow-up SAE Details Report and a completed UWCCC SAE Routing Form to 
saenotify@uwcarbone.wisc.edu. All follow up SAE documentation will also be submitted to 
Cellectar Biosciences (clinical@cellectar.com). All information is entered and tracked in the 
UWCCC database. 
 
The Principal Investigator notifies all investigators involved with the study at the UWCCC, the IRB, 
and Cellectar Biosciences. 
11.4.2.1.1 Report to the UWCCC, and Cellectar Biosciences: 
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting Workflow for 
DOTs on the UWCCC website (http://kb.wisc.edu/uwccc) for specific instructions on how and what 
to report to the UWCCC for [24] hour initial and follow-up reports. A follow-up report is required 
to be submitted within 10 days of the initial [24] hour report. 


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For this protocol, the following entities are required to be notified: 
a. saenotify@uwcarbone.wisc.edu 
b. UWCCC PIs: Justine Yang Bruce, MD and Paul Harari, MD 
c. UWCCC PM: Diana Trask 
d. Cellectar Biosciences (clinical@cellectar.com) 
e. Medpace: medpace-safetynotification@medpace.com 
f. Any other appropriate parties listed on the SAE Routing Form (for follow-up reports only) 
11.4.2.1.2 Report to the IRB 
Consult the UW-IRB website for reporting guidelines.  
11.4.2.2 Reported within 10 Calendar Days 
Serious Adverse Events requiring reporting within 10 calendar days (as described above) must 
also be reported to the Data and Safety Monitoring Board (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu. SAEs will also be reported to Cellectar Biosciences. The OnCore 
SAE Details Report must be submitted along with other report materials as appropriate (FDA 
Medwatch Form #3500 and/or any other documentation available at the time of initial reporting). 
The UWCCC DSMC Chair will review the information and determine if further action is required. 
All information is entered and tracked in the UWCCC database. 
The Principal Investigator notifies all investigators involved with the study at the UWCCC, the IRB, 
and Cellectar Biosciences.  
11.4.2.2.1 Report to the UWCCC and  Cellectar Biosciences: 
Reference the SAE SOP and the SAE Reporting Workflow for DOTs on the UWCCC website 
(http://kb.wisc.edu/uwccc) for specific instructions on how and what to report to the UWCCC for 
[10] day reports.  
 
For this protocol, the following entities are required to be notified: 
a. saenotify@uwcarbone.wisc.edu 
b. UWCCC PIs: Justine Yang Bruce, MD and Paul M. Harari, MD 
c. UWCCC PM: Diana Trask 
d. Cellectar Biosciences (clinical@cellectar.com) 
e. Medpace: medpace-safetynotification@medpace.com 
f. Any other appropriate parties listed on the SAE Routing Form (for follow-up reports only) 


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11.4.2.2.2 Report to the IRB: 
Consult the UW-IRB website for reporting guidelines. 
11.4.3 Reporting of SAEs and AEs to FDA 
As Cellectar Biosciences holds the IND for CLR 131, they assume responsibility for reporting all 
events in accordance with FDA 21 CFR 312.32. Cellectar has contracted with a CRO, Medpace 
for SAE management for the IND. 
Medpace clinical Safety Contact information: 
US:  Phone: 1-513-579-9911, dial 3 
Or      1-800-730-5779, dial 3 
FAX:  1-513-570-5196 
  Or    1--866-336-5320 
 
Email: Medpace-safetynotification@medpace.com 
 
11.4.4 Reporting of Pregnancy 
• Pregnancy will be reported from time of first study drug until 85 days after discontinuation of 
CLR 131. 
• Pregnancy will be reported to UW within 1 business day of discovery of the event. 
To ensure subject safety, each pregnancy in a subject on study treatment will be reported to UW 
within 1 business day of learning of its occurrence. The pregnancy will be followed to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
11.5 
Halting Rules 
During the conduct of this study, adverse events and serious adverse events that are categorized 
as probably related to CLR 131 will be evaluated and analyzed weekly by the principal 
investigators.  If >25 % of subjects have serious adverse events that are probably related to 
CLR 131 treatment, then enrollment for the study will be suspended for further analysis. 
Subsequent review of serious, unexpected, and related AEs will be evaluated by the DSMC, IRB, 
Cellectar Biosciences. Cellectar Biosciences and local regulatory authorities retain the authority to 
suspend additional enrollment and administration of CLR 131 for the entire study, as applicable. 
 


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12 STUDY OVERSIGHT 
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for the regular 
review and monitoring of ongoing clinical research in the UWCCC.  A summary of DSMC 
activities are as follows: 
• Review clinical trials conducted at the UWCCC for subject safety, protocol compliance, and 
data integrity. 
• Review Serious Adverse Events (SAE) requiring expedited reporting, as defined in the 
protocol, for clinical trials conducted at the UWCCC, and studies conducted at external 
sites for which the UWCCC acts as an oversight body. 
• Review reports generated through the UWCCC DSMS elements (Internal Audits, Quality 
Assurance Reviews, Response Reviews, Compliance Reviews, and Protocol Summary 
Reports). 
• Notify the protocol Principal Investigator of DSMC decisions and, if applicable, any 
requirements for corrective action related to data or safety issues. 
• Work in conjunction with the UW Health Sciences IRB in the review of relevant safety 
information as well as protocol deviations, non-compliance, and unanticipated problems 
reported by the UWCCC research staff, when appropriate.  
• Ensure notification of SAEs which require expedited reporting are provided to external sites 
participating in multi-institutional clinical trials coordinated by the UWCCC. 
Monitoring and Reporting Guidelines 
UWCCC quality assurance and monitoring activities are determined by study sponsorship and risk 
level of the protocol as determined by the PRMC. All protocols (including Intervention Trials, Non-
Intervention Trials, Behavioral and Nutritional Studies, and trials conducted under a Training 
Grant) are evaluated by the PRMC at the time of committee review. UWCCC monitoring 
requirements for trials without an acceptable external DSMB are as follows: 
Intensive Monitoring 
Protocols subject to intensive monitoring generally include UW Institutional Phase I. These 
protocols undergo review of subject safety at regularly scheduled DOT meetings where the results 
of each subject’s treatment are discussed, and the discussion is documented in the DOT meeting 
minutes. The discussion includes the number of subjects enrolled, significant toxicities, dose 
adjustments, and responses observed. Protocol Summary Reports are submitted on a quarterly 
basis by the study team for review by UWCCC DSMC. All reports from the UWCCC DSMC will be 
provided to Cellectar Biosciences.  


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Review and Oversight Requirements 
 
• Study Progress Review  
o Protocol Summary Reports (PSR) are required to be submitted to UWCCC DSMC 
quarterly. The PSR provides a cumulative report of SAEs, as well as instances of 
noncompliance, protocol deviations, and unanticipated problems, toxicities and 
responses that have occurred on the protocol in the timeframe specified. PSRs for 
those protocols scheduled for review are reviewed at each DSMC meeting.  
o Protocol Summary Reports enable DSMC committee members to assess whether 
significant benefits or risks are occurring that would warrant study suspension or 
closure. This information is evaluated by the DSMC in conjunction with other reports of 
quality assurance activities (e.g., reports from Internal Audits, Quality Assurance 
Reviews, etc.) occurring since the prior review of the protocol by the DSMC.  
o In the event that there is significant risk warranting study suspension or closure, the  
UWCCC DSMC will notify the PI of the findings and ensure the appropriate action is 
taken for the protocol (e.g., suspension or closure). The DSMC ensures that the PI 
reports any temporary or permanent suspension of a clinical trial to the appropriate 
agencies. Any UWCCC DSMC findings and requirements for follow-up action are 
submitted to the UWCCC CRC.  
 


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13 CLINICAL SITE MONITORING 
Cellectar Biosciences or their designee may periodically monitor the data for the study. A clinical 
monitor will make regularly scheduled trips to the clinical sites to review the progress of the study. 
The actual frequency of monitoring trips will depend on the enrollment rate and performance at the 
site. At each visit, the monitor will review various aspects of the study including, but not limited to, 
screening and enrollment logs, compliance with the protocol and with the principles of ICH GCP, 
completion of CRFs, source data verification, and study drug accountability and storage. 
In addition to the above, a representative from Cellectar Biosciences’ auditing staff or government 
inspectors may review the conduct/results of the study at the clinical site. The Investigator must 
promptly notify Cellectar Biosciences of any audit requests by regulatory authorities. 
 
 


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14 STATISTICAL CONSIDERATIONS 
14.1 
Study Hypotheses 
Reducing the dose of external beam radiation therapy, when given in combination with CLR 131, 
will be safe and tolerable while maintaining favorable tumor response rates and diminishing the 
adverse impact of radiation treatment on subject specific symptoms, such as quality of life, 
salivary flow and swallowing function.  
14.2 
Sample Size Considerations 
An mTPI-2 design, an extension of modified toxicity probability interval (mTPI-2), will be used to 
identify the MTD using cohorts of 4 subjects and up to 3 dose levels of CLR 131(Ji et al., 2007; Ji 
& Wang, 2013). The first 4 subjects will be treated at Dose Level 1. The maximum number of 
subjects treated at a dose level will be 8, with one exception: if 1 out of 8 subjects experiences a 
DLT at Dose Level 1, the study team will consider the possibility of treating 2 additional subjects at 
Dose Level 1. The trial can be monitored using columns 4 and 8 of Table 3 below, which contains 
the dose-escalation rules. Dose escalation will not be confirmed until all subjects in cohort recover 
to non-DLT levels or meet the criteria above. If 0 out of 4 subjects experiences a DLT at Dose 
Level 2, the study will move directly to the expansion phase. 
 
 
Dose Level 
Doses* of CLR 131 
-1 
12.5 mCi/m2 
    1** 
15.6 mCi/m2 
2 
18.75 mCi/m2 
*Dose level listed is administered on first on day 1 and again on day 8. 
**The first 4 subjects will be treated at dose level 1.  Dose level -1 will be used as a de-escalation dose. 
 
 
 


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Table 3: 
Dose escalation rules 
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
D 
D 
S 
S 
S 
S 
S 
S 
E 
2 
  
DU 
DU 
D 
D 
D 
S 
S 
S 
S 
3 
  
  
DU 
DU 
DU 
DU 
D 
D 
D 
D 
4 
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
D 
5 
  
  
  
  
DU 
DU 
DU 
DU 
DU 
DU 
6 
  
  
  
  
  
DU 
DU 
DU 
DU 
DU 
7 
  
  
  
  
  
  
DU 
DU 
DU 
DU 
8 
  
  
  
  
  
  
  
DU 
DU 
DU 
9 
  
  
  
  
  
  
  
  
DU 
DU 
10 
  
  
  
  
  
  
  
  
  
DU 
 
Column indicates the number of subjects treated. Row indicates the number of subjects with DLTs. E: Escalate to the 
next higher dose; S: Stay at the same dose; D: De-escalate to the previous lower dose; DU: De-escalate to the 
previous lower dose and the current dose will never be used again in the trial; sample size = 10, target toxicity 
probability = 0.2, epsilon 1 =0.1, epsilon 2 =0.1. 
 
The number of participants treated in the expansion cohort is dependent on the number of 
participants treated at the MTD in the dose escalation phase using the the mTPI-2 design. Up to 
12 subjects will be treated at the MTD. Statistical analysis for outcomes is based on participants 
treated at the MTD, including dose escalation patients treated at the MTD. 
 
In recent years, the head and neck oncology program at UW has evaluated approximately 75-100 
patients per year with recurrent HNC. We estimate that approximately half of these patients would 
be potential candidates for this trial. Assuming enrollment of 50 % of eligible patients, and 
CLR 131 uptake in 75 % of subjects administered a dosimetry test dose, we anticipate no 
problems to accrue the necessary subjects over 24 months.  
 
14.3 
Final Analysis Plan 
14.3.1 Analysis of Primary Endpoints 
Adverse events will be reported using frequency tables. Confidence intervals will be constructed 
using exact statistical methods (such as exact binomial confidence interval) due to small sample 
size. 
14.3.2 Analysis of Secondary Endpoints 
Median radiation treatment time and median number of dose delays due to toxicity will be 
reported. CLR 131 tumor uptake via SPECT/CT imaging and Monte Carlo calculations will be 
reported. Quality of life measures (including swallow function assessed by DIGEST scale and 


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QOL assessed by MDADI score) will be analyzed using frequency tables and confidence intervals 
constructed using exact statistical methods (such as exact binomial confidence interval) or 
summary statistics. Comparison of continuous and categorical QOL measures before and after 
treatment will be described using summary statistics and analyzed using the Wilcoxon signed rank 
test and McNemar’s test, respectively. ORR will be reported as a proportion with an exact 
confidence interval. Stimulated salivary flow will be reported before and after treatment using 
summary statistics. 


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15 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Study staff will maintain appropriate medical and research records for this study, in compliance 
with ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. Study staff will permit authorized representatives of Cellectar 
Biosciences, and regulatory agencies to examine (and when required by applicable law, to copy) 
research records for the purposes of quality assurance reviews, audits, and evaluation of the 
study safety, progress and data validity.  
Source documents will include all records within the HealthLink Electronic Medical Records 
system such as hospital records, clinical and office charts, laboratory notes, memoranda, 
pharmacy dispensing records, copies or transcriptions certified after verification as being accurate 
and complete, photographs or digital photo files, x-rays, and subject files and records kept at the 
pharmacy, at the laboratories, and medico-technical departments involved in the clinical trial. In 
addition, protocol specific forms will be designed which require treating physician signature to 
serve as source documents.  This may include forms such as toxicity forms with grading and 
attribution and tumor measurement forms. 


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16 QUALITY CONTROL AND QUALITY ASSURANCE 
16.1 
Monitoring, Auditing, and Data Quality Control and Assurance Measures  
All personnel involved in FDA regulated clinical trial activities are required to complete the Human 
Subjects Training and Good Clinical Practice (GCP) via CITI every 3 years. Training is monitored 
at each IRB continuing review and with the submission of protocol amendments. 
At the protocol level, the Principal Investigators will assign and document protocol responsibilities 
based on study roles. Training on all IRB approved protocols (initial version and subsequent 
amendments) are documented for each person listed as key personnel on the University of 
Wisconsin Health Sciences IRB application. These documents are retained with the study 
regulatory files, and collection is coordinated by Human Oncology regulatory staff. 
Eligibility checklists are signed by the study coordinator and the treating physician prior to 
enrollment. Adverse event grading and attributions are assigned by physicians at clinic visits and 
will be signed by the physician at that time. 
Other relevant UWCCC SOPs include: 
• Adverse Event Assessment and Documentation_SOP 
• CTRP and ClinicalTrials.gov Reporting_SOP 
• Delegation of Authority Log_SOP 
• Informed Consent Process_SOP 
• Maintaining a Regulatory File_SOP 
• OnCore Data Quality Assurance_SOP 
• Protocol Deviation_Guidance 
• Reportable Events_SOP 
• Reporting of Serious Adverse Events (SAEs) at UWCCC, 1SP, JC, And Affiliate 
Sites_SOP 
• Source Documentation_SOP 
• Study Close Out_SOP 


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17 ETHICS/PROTECTION OF HUMAN SUBJECTS 
17.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, as drafted by the US National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 
and/or the ICH E6.  
17.2 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form 
must be obtained before any subject is enrolled. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented in the study. 
17.3 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout study participation. Extensive discussion of risks and possible 
benefits of study participation will be provided to subjects and their families, if applicable. A 
consent form describing in detail the study procedures and risks will be given to the subject. 
Persons who are not fluent in English and persons with impaired decision-making capacities will 
not be eligible for enrollment in this study.  
 
Consent forms will be IRB-approved, and the subject is required to read and review the document 
or have the document read to him or her. The investigator or designee will explain the research 
study to the subject and answer any questions that may arise. The subject will sign the informed 
consent document prior to any study-related assessments or procedures. Subjects will be given 
the opportunity to discuss the study with their surrogates or think about it prior to agreeing to 
participate. They may withdraw consent at any time throughout the course of the study. A copy of 
the signed informed consent document will be given to subjects for their records. The rights and 
welfare of the subjects will be protected by emphasizing to them that the quality of their clinical 
care will not be adversely affected if they decline to participate in this study. 
 
The consent process will be documented in the clinical or research record. 
17.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
Children are excluded from this study because insufficient data are available in adults to judge 
potential risks in children. 
Adults of any gender or racial/ethnic group may participate in this study. 


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17.5 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) 
and their agents. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to any study information relating to subjects. 
All members of the study team will be listed on the IRB application and are required to undergo 
annual HIPAA training to ensure responsible conduct regarding protected health information (PHI) 
in research. In addition, Human Subjects Training and Good Clinical Practice trainings are 
required every three years for members of the study team. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  All PHI is stored securely on password 
protected servers. 
The study monitor or other authorized representatives of the sponsor may inspect all study 
documents and records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) for the study subjects. The clinical study site will permit 
access to such records. 
To further protect the privacy of study participants, the study team has applied for and received  a 
Certificate of Confidentiality (CoC) for this study from the FDA. A Certificate of Confidentiality 
prohibits study team members from disclosing information or biospecimens that may identify study 
participants in legal proceedings or in response to a legal request without their consent. 
17.6 
Future Use of Stored Specimens and Other Identifiable Data 
All specimens for this study will be exhausted for use in this study. No study-related specimens 
will be banked after the study has ended. 


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18 DATA HANDLING AND RECORD KEEPING 
This study will report clinical data using the UWCCC data management system utilizing study 
specific case report forms. Key study personnel are trained on the use of case report forms and 
will comply with protocol specific instructions for data collection.  
 
Subject demographics, subject-specific study treatment calendars, adverse events and other 
information will be maintained with the UWCCC data management system.  
 
Participant data will be collected using protocol specific case report forms (CRFs). The CRFs will 
be approved by the study’s Principal Investigator and the study biostatistician prior to release for 
use. The Study Coordinator or designee will be responsible for registering the subject into the 
UWCCC data management system at time of study entry, completing CRFs based on the subject 
specific calendar, and updating the subject record until subject death or end of required study 
participation.  
18.1 
Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the investigator. All source documents and laboratory reports must be reviewed by 
the study team and data entry staff, who will ensure that they are accurate and complete. 
Unanticipated problems and adverse events must be reviewed by the investigator or designee. 
 
UWCCC Radiotherapy will serve as the Clinical Research Office for this trial.  
18.2 
Data Capture Methods 
Data will be collected through the web-based clinical research platform, OnCore (Forte Research), 
a system compliant with Good Clinical Practices and Federal Rules and Regulations. UWCCC 
personnel will coordinate and manage data for quality control assurance and integrity. All data will 
be collected and entered into OnCore by study site personnel. We will also utilize REDCap for 
Biospecimen tracking purposes. The data in REDCap will be coded, and no subject identifiers will 
be stored in the Biospecimen REDCap Database. 
18.3 
Types of Data 
Subject demographics, subject medical history, subject specific study treatment calendars, 
adverse events, laboratory/pathology reports obtained during the course of treatment and 
afterwards, e.g., blood tests, biopsy results), findings from physical exams, and imaging scan 
reports/outcomes will be maintained within the UWCCC data management system. 
18.4 
Schedule and Content of Reports 
The UWCCC Protocol Review and Monitoring Committee (PRMC) determines the level of risk, 
thus the appropriate timelines for review of study documents, conduct and accrual.  Protocol 
Safety Reports are run, reviewed and signed off by the study PI per the determined schedule. 
PSRs are then sent for review to the Data Safety Monitoring Committee (DSMC).   


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Protocol Safety Reports include information such as accrual, adverse events, serious adverse 
events, and unanticipated problems. Annual review by the UW Health Sciences IRB will review 
accrual, reportable events, and study progress.  
18.5 
Study Records Retention 
Shadow research charts with original consent forms and documents specifically created for this 
study will be maintained in the Department of Human Oncology until the study is terminated.  The 
records will then be sent to Wisconsin State Records Archiving facility for long term storage (10 
years) and re-archived as needed. Study records will be maintained for at least three years from 
the date that the grant federal financial report (FFR) is submitted to the NIH. 
18.6 
Protocol Deviations 
Except in the case of a medical emergency, no protocol deviation is authorized. Changes to the 
protocol will be established by amendments by the Principal Investigator approved by the UW HS 
IRB. Protocol deviations may affect the conduct of the study from legal and ethical points of view 
and may influence the statistical analysis and pertinence of the study. Medical emergencies have 
to be handled in the subjects’ best interest. The investigator has to contact the IND Sponsor to 
clarify if a subject may continue in the study when a protocol violation out of medical reasons has 
occurred. Protocol deviations that are not identifiable from the eCRF have to be recorded in a 
protocol deviation form. Protocol deviations will be evaluated at the data review meeting before 
database lock and will be described in the statistical analysis plan.  
All deviations must be addressed in study source documents and reported to the UW HS IRB per 
their policies using Table 1 as a guideline. The Principal Investigator is responsible for knowing 
and adhering to the reviewing IRB requirements. 
 
 


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19 PUBLICATION/DATA SHARING POLICY 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
The clinical trial will be registered on ClinicalTrials.gov, which is sponsored by the National Library 
of Medicine. 
The study investigators will have sole right to determine the content of the presented and 
published data. As PIs, Drs. Bruce and Harari will retain a spot as both first and last author on all 
manuscripts, unless either elects to forgo this. Co-Is will have input into all remaining authorship 
spots.  


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20 LITERATURE REFERENCES 
 
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De Crevoisier, R, Bourhis, J, Domenge, C, Wibault, P, Koscielny, S, Lusinchi, A, Mamelle, G, 
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APPENDICES 
 
Appendix A: 
SCHEDULE OF EVENTS 
Appendix B: 
ECOG EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS 


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APPENDIX A: SCHEDULE OF EVENTS 
Assessment 
Screening Period 
Treatment Period 
Post Treatment 
With-
drawal 
D-42 
to  
D-1 
Dosimetry 
Test Dose 
Treatment 
dose 1 
Treatment 
dose 2 
EBRT 
Safety 
Monitoring 
Visits12 
1 mo post 
CLR 131 
Infusion 
(± 2 wks) 
3 mo post 
EBRT 
(± 4 wks) 
6 mo post 
EBRT 
(± 4 wks) 
12 mo post 
EBRT 
(± 6 wks) 
24 mo post 
EBRT 
(± 6 wks)17 
With-
drawal
14 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
review17 
X 
 
 
 
 
 
X 
X 
X 
X 
 
X 
Physical exam 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Vital signs1 
X 
X15 
X15 
X15 
 
 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
X 
X 
X 
X 
 
X 
ECOG 
Performance 
Status 
X 
 
 
 
 
 
X 
X 
X 
X 
 
X 
CBC with diff2 
X11 
 
X12 
X12 
X12 
X12 
X12 
X 
 
 
 
 
Serum 
chemistries3 
X11 
 
X12 
X12 
X12 
X12 
X12 
X 
 
 
 
 
Pregnancy test for 
WOCP4 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Electrocardiogram 
X16 
 
 
 
X16 
 
 
 
 
 
 
 
Serum TSH, free 
T4 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
Administration of 
thyroid-protection 
X 
X 
X 
X 
 
 
X13 
 
 
 
 
 


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92 
Assessment 
Screening Period 
Treatment Period 
Post Treatment 
With-
drawal 
D-42 
to  
D-1 
Dosimetry 
Test Dose 
Treatment 
dose 1 
Treatment 
dose 2 
EBRT 
Safety 
Monitoring 
Visits12 
1 mo post 
CLR 131 
Infusion 
(± 2 wks) 
3 mo post 
EBRT 
(± 4 wks) 
6 mo post 
EBRT 
(± 4 wks) 
12 mo post 
EBRT 
(± 6 wks) 
24 mo post 
EBRT 
(± 6 wks)17 
With-
drawal
14 
medication (start 
D-1)5 
Adverse event 
evaluation6 
X 
 
X 
X 
weekl
y 
X 
X 
X 
X 
X 
X 
X 
QOL Surveys 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
Oral swab and 
saliva collection 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
Research oral 
profile exam and 
SOC Modified 
barium swallow 
study 
X 
 
 
 
 
 
 
X 
X 
 
 
 
SPECT/CT 
Imaging 
 
X7 
X8 
X 
 
 
 
 
 
 
 
 
Disease Assessment 
SOC Diagnostic 
imaging9 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
Treatment 
Administration of 
CLR 13110 
 
X15 
X15 
X15 
 
 
 
 
 
 
 
 
SOC EBRT 
 
 
 
 
X 
 
 
 
 
 
 
 
Notes 
1. 
Vital signs include blood pressure, pulse, respiratory rate, and temperature. 
2. 
CBC to include red blood cell count, hemoglobin, hematocrit, white blood cell count with differential including % neutrophils, lymphocytes, monocytes, eosinophils and 
basophils, absolute neutrophil count, and platelet count. 
3. 
Serum chemistries to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, AST, ALT, alkaline phosphatase, total bilirubin, calcium, protein, 
albumin, and phosphorus. 


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93 
 
Assessment 
Screening Period 
Treatment Period 
Post Treatment 
With-
drawal 
D-42 
to  
D-1 
Dosimetry 
Test Dose 
Treatment 
dose 1 
Treatment 
dose 2 
EBRT 
Safety 
Monitoring 
Visits12 
1 mo post 
CLR 131 
Infusion 
(± 2 wks) 
3 mo post 
EBRT 
(± 4 wks) 
6 mo post 
EBRT 
(± 4 wks) 
12 mo post 
EBRT 
(± 6 wks) 
24 mo post 
EBRT 
(± 6 wks)17 
With-
drawal
14 
4. 
A negative urine pregnancy test is required within 24 hours prior to each CLR 131 dose. 
5. 
Thyroid protection medication to begin 1 day prior to dosimetry test dose and continue until 14 days post last treatment dose of CLR 131. 
6. 
For subjects with unresolved treatment-related toxicity, follow as medically appropriate until resolution or stabilization.  AEs will be recorded from time of informed 
consent until 28 days after last EBRT treatment or 85 days after first treatment dose of CLR 131, whichever is later.  
7. 
SPECT/CT imaging will be performed approximately approximately 3 days after CLR 131 dosimetry test dose to confirm tumor uptake. If uptake is not seen at that 
timepoint, an additional SPECT/CT scan will be performed 7 days post CLR 131 test dose. Uptake in the specified site of recurrent/metastatic disease that is to be 
treated with radiation therapy will be determined by the study radiologist. 
8. 
SPECT/CT imaging will be performed on days 2, 3, 4-6, and 7-8 of the treatment period to visualize and quantitate the biodistribution of CLR 131. 
9. 
Imaging may consist of any combination of CT, MR or PET-MR scans as clinically indicated. 
10. Time between dosimetry test dose and first treatment dose: approximately 14 days, but can be permitted up to 4 weeks. Dosing dates for treatment can be scheduled 
to start -1 or +3 days to accommodate clinic scheduling (for example: holidays, weekends, treating physician schedules, etc.). 
11. Screening laboratory tests are to be collected within two weeks of dosimetry test dose to determine eligibility  
12. CBC with differential and serum chemistries to be done weekly beginning with D1 treatment dose and continue for 12 weeks. Approximately 6 visits will coincide with 
CLR 131 administration and/or SOC EBRT visits, and ~6 visits may fall outside of SOC EBRT visits. 
13. Duration of thyroid protection medication: 32-38 days; must take for 14 days post last CLR 131 dose. 
14. If a subject withdraws or the investigator terminates subject participation prior to the 12 month post EBRT visit, the withdrawal visit procedures will be completed. 
15. Vital signs are to be collected prior to and 1 hr post infusion of CLR 131. 
16. Electrocardiograms will be performed at the baseline visit and the first day of treatment with external beam radiation therapy. 
17. Follow-up assessment will not be completed if the subject has initiated a new, anti-cancer therapy prior to the 24 month visit.  
18. All concomitant medications and treatments will be documented appropriately and recorded until 28 days after last EBRT treatment or 85 days after first treatment 
dose of CLR 131, whichever is later.  Anti-cancer therapy drugs will be continue to be captured at all study timepoints 


Cellectar                                                                                  04Oct 2022  
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APPENDIX B: ECOG EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS 
 
Grade Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50 % of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50 % of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
As published: 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5(6):649-655.  
http://www.ecog-acrin.org [homepage on the Internet]. Eastern Cooperative Oncology Group and American 
College of Radiology Imaging Network, Robert Comis MD and Mitchell Schnall, MD PhD, Group Co-Chairs. 
[cited 2016 September 12]. Available from: http://www.ecog-acrin.org/resources/ecog-performance-status 
 
 
 


Cellectar                                                                                  04Oct 2022  
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SUPPLEMENTAL MATERIALS 
These documents are relevant to the protocol, but they are not considered part of the protocol.  They 
are stored and modified separately. As such, modifications to these documents do not require 
protocol amendments. 
• Videofluoroscopy Study Manual 
• CLR 131 Radiopharmaceutical Manual 
• CLR 131 Investigational Brochure 
• CLR 131 Patient Pamphlet