Clinical trial NCT03630120
Conditions: Thyroid Cancer Thyroid Cancer, Medullary Differentiated Thyroid Cancer Papillary Thyroid Cancer Follicular Thyroid Cancer Poorly Differentiated Thyroid Gland Carcinoma
Keywords: Thyroid disease Tyrosine kinase inhibitor TKI Medullary thyroid cancer DTC Advanced thyroid cancer Progressive thyroid cancer MTC
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2018-08-06; Completion date: 2019-12-05
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Participants will have been diagnosed with advanced progressive thyroid cancer and are about to start treatment with a tyrosine kinase inhibitor (TKI).

The purpose of this study is to evaluate the efficacy and tolerability of tyrosine kinase inhibitor therapy (Lenvatinib or Sorafenib for differentiated thyroid cancer \[which includes papillary thyroid cancer, follicular thyroid cancer, and poorly differentiated thyroid cancer\]; and Cabozantinib or Vandetanib for medullary thyroid cancer) through adaptive (intermittent) versus conventional (continuous) regimen.

Detailed description:
Population: Patients with advanced progressive 131I-refractory DTC or MTC will be enrolled to this study. Forty-five patients responding to TKI therapy (defined as 50% drop in tumor marker level within the first two months of treatment) will be randomized to receive TKI therapy either through adaptive (intermittent) or conventional (continuous) regimen.

Arms: arm 1: Standard of Care (SOC) TKI Therapy for Differentiated Thyroid Cancer (DTC): Lenvatinib + Sorafenib. arm 2: SOC followed by Adaptive Care TKI Therapy for DTC Participants with \>=50% drop: Lenvatinib + Sorafenib. arm 3: Standard of Care (SOC) TKI Therapy for Medullary Thyroid Cancer: Cabozantinib + Vandetanib. arm 4: SOC followed by Adaptive Care TKI Therapy for MTC Participants with \>=50% drop: Cabozantinib + Vandetanib.
Interventions: intervention 1: Lenvatinib intervention 2: Sorafenib intervention 3: Cabozantinib intervention 4: Vandetanib
Intervention descriptions: intervention 1: Standard of Care: Lenvatinib 24 mg daily. All participants will start receiving standard of care treatment.

Participants in the Adaptive Therapy regimen will receive TKI therapy in cycles: continuous treatment at the indicated dose until the patients' tumor marker (thyroglobulin in DTC or calcitonin in MTC patients) drops by ≥50% from the level at the time of enrollment ("baseline" level). A new cycle of TKI treatment will begin when/if the tumor marker increases to or above the "baseline" level. intervention 2: Standard of Care: Sorafenib 400 mg twice daily. All participants will start receiving standard of care treatment.

Participants in the Adaptive Therapy regimen will receive TKI therapy in cycles: continuous treatment at the indicated dose until the patients' tumor marker (thyroglobulin in DTC or calcitonin in MTC patients) drops by ≥50% from the level at the time of enrollment ("baseline" level). A new cycle of TKI treatment will begin when/if the tumor marker increases to or above the "baseline" level. intervention 3: Standard of Care: Cabozantinib 140 mg daily. All participants will start receiving standard of care treatment.

Participants in the Adaptive Therapy regimen will receive TKI therapy in cycles: continuous treatment at the indicated dose until the patients' tumor marker (thyroglobulin in DTC or calcitonin in MTC patients) drops by ≥50% from the level at the time of enrollment ("baseline" level). A new cycle of TKI treatment will begin when/if the tumor marker increases to or above the "baseline" level. intervention 4: Standard of Care: Vandetanib 300 mg daily. All participants will start receiving standard of care treatment.

Participants in the Adaptive Therapy regimen will receive TKI therapy in cycles: continuous treatment at the indicated dose until the patients' tumor marker (thyroglobulin in DTC or calcitonin in MTC patients) drops by ≥50% from the level at the time of enrollment ("baseline" level). A new cycle of TKI treatment will begin when/if the tumor marker increases to or above the "baseline" level.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Adaptive Tyrosine Kinase Inhibitor Therapy in Patients with Advanced 
Progressive Thyroid Cancer 
NCT03630120 
 
Version 3.0 
January 22, 2019 


 
 
 
 
Adaptive tyrosine kinase 
inhibitor therapy in patients with 
advanced progressive thyroid 
cancer
 
 
Protocol Identifying Number: MCC# 19442 
Principal Investigator: Christine H. Chung, M.D. 
Sponsor: Moffitt Physical Sciences Oncology Center 
Version Number:  3.0 
January 22, 2019 
 
 
 
 
 
 
 


Version 
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Protocol # 19442 
 
 
i 
 
   
 
TABLE OF CONTENTS 
............................................................................................................................................... I 
LIST OF ABBREVIATIONS ....................................................................................................................................... IV 
STATEMENT OF COMPLIANCE 
................................................................................................................................ V 
STUDY SUMMARY 
................................................................................................................................................. VI 
SCHEMATIC OF STUDY DESIGN 
............................................................................................................................ 
VIII 
1. KEY ROLES 
........................................................................................................................................................... 1 
2. INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
..................................................... 1 
2.1 BACKGROUND INFORMATION 
.......................................................................................................... 1 
2.2 RATIONALE ............................................................................................................................................... 2 
2.3 POTENTIAL RISKS AND BENEFITS 
.................................................................................................. 3 
2.3.1 
KNOWN POTENTIAL RISKS 
.......................................................................................................... 3 
2.3.2 
KNOWN POTENTIAL BENEFITS 
.................................................................................................. 3 
3. OBJECTIVES AND PURPOSE ................................................................................................................................. 3 
4. STUDY DESIGN AND ENDPOINTS 
......................................................................................................................... 4 
4.1 DESCRIPTION OF THE STUDY DESIGN 
......................................................................................... 4 
4.2 STUDY ENDPOINTS 
............................................................................................................................... 4 
4.2.1 
PRIMARY ENDPOINT 
..................................................................................................................... 5 
4.2.2 
SECONDARY ENDPOINTS 
........................................................................................................... 5 
4.2.3 
EXPLORATORY ENDPOINTS ...................................................................................................... 5 
5. STUDY ENROLLMENT AND WITHDRAWAL ....................................................................................................... 5 
5.1 
PARTICIPANT INCLUSION
 CRITERIA 
.................................................................................................. 5 
5.2 PARTICIPANT EXCLUSION CRITERIA 
............................................................................................... 7 
5.3 STRATEGIES FOR RECRUITMENT AND RETENTION .............................................................. 8 
5.4 PARTICIPANT WITHDRAWAL OR TERMINATION .......................................................................... 8 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION 
........................................................ 8 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
............................... 8 
5.5 PREMATURE TERMINATION OR SUSPENSION OF STUDY 
....................................................... 8 
6. STUDY AGENT 
..................................................................................................................................................... 9 
6.1 STUDY AGENT(S) AND CONTROL DESCRIPTION 
....................................................................... 9 
6.1.1 
ACQUISITION ................................................................................................................................... 9 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
.................................... 9 
6.1.3 
PRODUCT STORAGE AND STABILITY 
................................................................................... 9 
6.1.4 
PREPARATION 
................................................................................................................................. 9 
6.1.5 
DOSING AND ADMINISTRATION 
............................................................................................ 
10 
6.1.6 
ROUTE OF ADMINISTRATION 
................................................................................................. 
10 
6.1.7 
STARTING DOSE AND DOSE ESCALATION SCHEDULE .......................................... 
10 
6.1.8 
DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
............................................................... 
11 
6.1.9 
DURATION OF THERAPY 
........................................................................................................... 
18 
6.1.10 TRACKING OF DOSE 
.................................................................................................................... 
18 
6.2 STUDY AGENT ACCOUNTABILITY PROCEDURES.................................................................. 
18 
6.2.1 
Drug Accountability 
......................................................................................................................... 
18 
6.2.2 
Treatment Compliance 
................................................................................................................... 
18 
6.2.3 Biological sample accountability 
........................................................................................................... 
18 


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7. STUDY PROCEDURES AND SCHEDULE 
............................................................................................................. 
18 
7.1 STUDY PROCEDURES/EVALUATIONS 
........................................................................................... 
18 
7.1.1 
STUDY-SPECIFIC PROCEDURES 
......................................................................................... 
18 
7.1.2 
STANDARD OF CARE STUDY PROCEDURES 
.................................................................. 18 
 
 
 
 
 
 
 
7.3 STUDY SCHEDULE 
.............................................................................................................................. 
24 
7.3.1 
SCREENING 
.................................................................................................................................... 
24 
7.3.2 
ENROLLMENT/BASELINE............................................................................................................ 
24 
7.3.3 
FOLLOW-UP 
.................................................................................................................................... 
25 
7.3.4 
FINAL STUDY VISIT 
................................................................................................................... 
26 
7.3.5 
EARLY TERMINATION VISIT ................................................................................................. 
26 
7.3.6 
UNSCHEDULED VISIT 
............................................................................................................... 
27 
7.3.7 
SCHEDULE OF EVENTS TABLE 
............................................................................................ 
28 
7.4 CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES 
............................. 
29 
7.5 PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
..................................... 
29 
7.6 PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES .............................. 
30 
7.7 RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES 
............................................ 
30 
7.8 PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE 
.................................... 
30 
8. ASSESSMENT OF SAFETY 
................................................................................................................................. 
30 
8.1 SPECIFICATION OF SAFETY PARAMETERS................................................................................. 
31 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) ........................................................................ 
31 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
.................................................. 
31 
8.1.3 
DEFINITION OF UNANTICIPATED PROBLEMS ................................................................ 
31 
8.2 CLASSIFICATION OF AN ADVERSE EVENT 
............................................................................... 
31 
8.2.1 
SEVERITY OF EVENT 
................................................................................................................. 
31 
8.2.2 
RELATIONSHIP TO STUDY AGENT 
....................................................................................... 
32 
8.2.3 
EXPECTEDNESS 
........................................................................................................................... 
32 
8.3 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
...... 
32 
8.4 REPORTING PROCEDURES 
............................................................................................................... 
32 
8.4.1 
ADVERSE EVENT REPORTING 
............................................................................................. 
32 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING 
........................................................................... 
33 
8.4.3 
UNANTICIPATED PROBLEM REPORTING 
............................................................................. 
33 
8.4.4 
EVENTS OF SPECIAL INTEREST 
.......................................................................................... 
33 
8.4.5 
REPORTING OF PREGNANCY 
............................................................................................... 
33 
8.5 SAFETY OVERSIGHT 
.......................................................................................................................... 
33 
9. CLINICAL MONITORING 
.................................................................................................................................... 
34 
10. STATISTICAL CONSIDERATIONS 
...................................................................................................................... 
34 
10.1 STATISTICAL AND ANALYTICAL PLANS 
..................................................................................... 
34 
10.2 STATISTICAL HYPOTHESES ........................................................................................................... 
34 
10.3 DESCRIPTION OF STATISTICAL METHODS 
............................................................................... 
35 
10.3.1 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
.............................................. 
35 
10.3.2 ANALYSIS OF THE SECONDARY ENDPOINT(S).............................................................. 
35 
10.3.3 EXPLORATORY ANALYSES 
..................................................................................................... 
36 
10.4 SAMPLE SIZE 
........................................................................................................................................ 
36 
10.5 MEASURES TO MINIMIZE BIAS 
........................................................................................................ 
36 


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10.5.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
..................................... 
36 
11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
.................................................... 
36 
12. QUALITY ASSURANCE AND QUALITY CONTROL 
........................................................................................... 
37 
13. ETHICS/PROTECTION OF HUMAN SUBJECTS................................................................................................ 
37 
13.1 ETHICAL STANDARD 
.......................................................................................................................... 
37 
13.2 INSTITUTIONAL
 REVIEW BOARD 
................................................................................................... 
37 
13.3 INFORMED
 CONSENT PROCESS ................................................................................................... 
37 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
................................................................................................................................................ 
37 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
......................................................... 
37 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY 
.............................................................................. 
38 
13.5 FUTURE USE OF STORED SPECIMENS 
..................................................................................... 
38 
14. DATA HANDLING AND RECORD KEEPING 
..................................................................................................... 
38 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ........................................... 
38 
14.2 STUDY RECORDS RETENTION 
........................................................................................................ 
39 
14.3 PROTOCOL DEVIATIONS 
.................................................................................................................... 
39 
14.4 PUBLICATION AND DATA SHARING POLICY 
............................................................................ 
39 
15. STUDY ADMINISTRATION 
.............................................................................................................................. 
39 
15.1 STUDY LEADERSHIP 
........................................................................................................................... 
39 
16. CONFLICT OF INTEREST POLICY 
.................................................................................................................... 
39 
17. LITERATURE REFERENCES 
............................................................................................................................. 
40 
APPENDIX ............................................................................................................................................................. 
42 
APPENDIX 1. THYROID CANCER TUMOR-N
ODE-M
ETASTASIS STAGING SYSTEM (AJCC
 8
TH EDITION STARTING 
JANUARY 2018) 
....................................................................................................................................................... 
42 
APPENDIX 2. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG)
 PERFORMANCE STATUS (20). .................. 
44 
APPENDIX 3. COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (
V4.0). 
................................................ 
45 
APPENDIX 4. RECIST CRITERIA (
VERSION 1.1). 
.................................................................................................... 
46 
 
 
 


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iv 
 
IST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ACT 
Cabozantinib adaptive therapy 
AT 
Adaptive therapy 
ALT 
Adaptive Lenvatinib therapy 
ATT 
Adaptive TKI therapy 
ANCOVA Analysis of Covariance 
CCT 
Conventional Cabozantinib therapy 
CLT 
Conventional Lenvatinib therapy 
CTCAE Common Terminology Criteria for Adverse Events 
CTT 
Conventional TKI therapy 
CMP 
Clinical Monitoring Plan 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Conventional therapy 
DTC  
Differentiated thyroid cancer 
eCRF 
Electronic Case Report Forms 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
MCC 
Moffitt Cancer Center 
MTC 
Medullary thyroid cancer 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
PI 
Principal 
Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
RAIR 
Radioactive Iodine Resistant  
RECIST Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
Tg  
Thyroglobulin 
Tg AB 
Thyroglobulin antibodies 
TKI 
 
Thyrosine kinase inhibitors 
US 
United States 
 
 


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STATEMENT OF COMPLIANCE 
 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on 
the Protection of Human Subjects (45 CFR Part 46), and the Moffitt Physical Sciences Oncology 
Center Terms of  Award. The Principal  Investigator will assure that no deviation from, or 
changes  to the  protocol will  take place  without  prior  agreement  from the  sponsor  and 
documented approval from the Institutional Review Board, except where necessary to eliminate 
an  
immediate  hazard(s) to the  
trial  participants.  All  personnel  
involved  
in the  conduct of this 
study have completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed of 
their obligation to meet the above commitments. 
 
 
Principal Investigator:   Christie H. Chung 
 Print/Type Name 
 
 
Signed:     
 Date: 
 


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vi 
 
STUDY SUMMARY 
 
Title:  
Adaptive tyrosine kinase inhibitor therapy in patients with advanced progressive 
thyroid cancer. 
 
Précis: 
This is a randomized phase II clinical trial to evaluate the efficacy and tolerability 
of tyrosine  kinase  
inhibitor  (TKI) therapy  through  adaptive  (intermittent)  versus 
conventional  
(continuous)  dosing  schedule  
in  patients with differentiated  
thyroid 
cancer (DTC) or medullary thyroid cancer (MTC). 
 
Objectives: Primary objective: 
• To  evaluate  the efficacy  and  tolerability  of TKI  therapy  (Lenvatinib or 
Sorafenib for  DTC; Cabozantinib  or  Vandetanib for  MTC)  through adaptive 
(intermittent) versus conventional (continuous) regimen.  
 
Secondary objective: 
• To evaluate response and survival of TKI therapy (Lenvatinib or Sorafenib for 
DTC; Cabozantinib  or  Vandetanib  for MTC)  through  adaptive  (intermittent) 
versus conventional (continuous) regimen.  
 
Exploratory objective: 
• To determine  predictive biomarkers of TKI response. 
 
Endpoint: 
Primary endpoint: 
• Time  to  TKI  treatment  discontinuation  due  to progressive  disease, 
intolerability, or disease-related death at 2 years. 
 
Secondary endpoints: 
• Overall response rate   
•  Progression free survival 
•  Overall survival 
 
Exploratory endpoints: 
• Determine  predictive biomarkers of TKI response 
 
Population: Patients with advanced progressive 131I-refractory DTC or MTC will be enrolled 
to this study. Forty-five patients responding to TKI therapy (defined as ≥50% drop 
in tumor marker level within the first two months of treatment) will be randomized 
to  receive  TKI  therapy  either  through  adaptive  (intermittent)  or  conventional 
(continuous) regimen. 
 
Phase: 
Randomized phase II clinical trial 
 
Number of Sites enrolling participants: 1 (Moffitt Cancer Center) 
 
Description of Study Agent:  
 
• All  patients will  start  
receiving  standard  of  care  
treatment: Lenvatinib 24  mg 
daily or Sorafenib 400 mg twice daily with DTC; Cabozantinib 140 mg daily or 
Vandetanib 300 mg daily with MTC. Doses will be adjusted as needed due to 
toxicity or drug tolerance in both arms.  
• Patients in the conventional therapy regimen will receive continuous treatment 
at the indicated dose until disease progression or development of intolerability. 


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vii 
 
• Patients  
in  
the  adaptive  therapy  regimen will  receive TKI  
therapy  
in  cycles: 
continuous  treatment  at  the  
indicated  dose  until  the patients’ tumor  marker 
(thyroglobulin in  DTC patients; calcitonin or  CEA in MTC  patients)  drops  by 
≥50%  
from  
the level at  
the  
time  of  enrollment  (“baseline”  
level). Only  
tumor 
markers that meet inclusion criteria at baseline can be used for randomization 
and adaptive therapy purposes.  A new cycle of TKI treatment will begin: 
•   
o   When/if the tumor marker increases to ≥70% of the “baseline” level.   
OR 
o At  the  discretion of  the  treating  physician  if a patient  develops 
worsening  disease-related  symptoms  with  rising  tumor  marker  
levels 
indicating disease progression.  In the case of resumption for disease-
related  symptoms,  TKI  treatment  will  continue  until  the  symptoms 
improve  at  the  discretion  of  the  treating  physician  and  the  tumor 
markers are again ≤50% from the level at the time of enrollment. 
 
Study Duration: 48 months 
 
Participant Duration: 48 months  
 
 
 


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viii 
 
 
SCHEMATIC OF STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conventional 
therapy 
(N=12) 
Adaptive 
therapy 
(N=24) 
Adult patients with advanced progressive 131I-refractory DTC or MTC to be treated with TKI. 
We expect to enroll 45 patients in 2 years 
Patients with ≥50% drop in tumor marker within first two cycles  
(thyroglobulin in DTC; calcitonin or CEA in MTC)  
Yes (N=36) 
No (N=9) 
Randomize 2:1 
(stratify MTC and DTC) 
Follow-up for 24 months starting Cycle 1 Day 1 of TKI 
Follow up for 24 
months per 
standard of care 


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Protocol # 19442 
 
 
 
1 
 
1. KEY ROLES 
 
PRINICIPAL INVESTIGATOR:    
Christine H. Chung, MD 
Senior Member 
Moffitt Cancer Center  
12902 Magnolia Drive  
Tampa, FL 33612 
Phone: 813-745-5431 
Fax: 813-745-7229 
E-mail: Christine.Chung@Moffitt.Org  
 
 
STATISTICIAN:    
Michael Schell, PhD 
Moffitt Cancer Center  
13131 Magnolia Drive  
Tampa, FL 33612 
Phone: 813-745-6061 
Fax: 813-745-6107 
E-mail: Michael.Schell@moffitt.org 
 
2. INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
2.1 BACKGROUND INFORMATION 
 
Primary  thyroid  cancers  can  be  classified  into  3  groups  according  to  the  cells  of  origin:  1) 
follicular-cell  derived  carcinomas which represent  95%  of  all  thyroid  cancers  and  include 
differentiated thyroid cancers (DTC) such as papillary, follicular and poorly-differentiated thyroid 
carcinomas;  and  undifferentiated  or  anaplastic  thyroid  carcinomas;  2)  parafollicular or  C-cell 
derived carcinomas, termed medullary thyroid carcinomas (MTC) that represent around 4% of 
all  
thyroid  cancers;  and  3)  stromal-cell  derived  carcinomas  
that  represent  <1%  of  all  
thyroid 
cancers  and  
include  
tumors  such  as  
thyroid  
lymphoma,  sarcoma or  
fibrosarcoma. Presently, 
thyroid  cancer  exhibits  
the  most  
rapidly  
increasing  
incidence  of  all  solid  
tumors  
in  
the  United 
States  and  several  other  countries;  and  it  is  already  the  fifth  most  common  cancer  among 
women  in  the  United  States (1-5).  During  2017, it  is  expected  that 56,870 patients  will  be 
diagnosed with  thyroid  cancer (6). Despite  this  rapid  increase  in  incidence,  thyroid  cancer-
specific mortality has remained stable for the last 50 years and most patients with differentiated 
thyroid cancer have an excellent prognosis with an estimated five-year survival rate > 98% (6). 
Nonetheless, the five-year survival rate if distant metastases are present is considerably worse 
(56%), which has also remained unchanged for several decades (6). 
 
In the last decade our understanding of the underlying genetic alterations of thyroid cancer has 
improved significantly, leading to the development of new therapies (7, 8). Since 2011, the FDA 
has  approved four  novel tyrosine  kinase  inhibitors  (TKI) for the treatment  of  progressive 
metastatic thyroid cancer: Lenvatinib and Sorafenib for DTC; and Cabozantinib and Vandetanib 
for MTC).  
 
Lenvatinib is an inhibitor of the vascular endothelial growth factor receptors (VEGFR) 1-3; the 
fibroblast growth factor  
receptors  1-4; the platelet-derived  growth  
factor  
receptor  α; RET; and 
KIT. In a phase III randomized placebo controlled study (SELECT), Lenvatinib was associated 
with  significant  improvements  in  progression-free  survival (18.3  versus  3.6  months) and 
response rate (64.8% versus 1.5%) (9). Sorafenib is an inhibitor of the VEGFR 1-3, RET, RAF 


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2 
 
and platelet-derived growth factor receptor β. In a randomized, double blind, placebo-controlled 
phase  III  trial  (DECISION),  Sorafenib also was  associated  with  a  significant  increase  in 
progression-free survival (10.8 versus 5.4 months) and response rate (54.1% vs. 33.8%) (10). 
Cabozantinib, inhibits  the hepatocyte  growth  factor  receptor  (MET);  the vascular  endothelial 
growth factor receptor 2; and RET. In a phase III randomized placebo controlled study (EXAM), 
Cabozantinib improved the median progression-free  survival from  4.0 to 11.2 months  
(hazard 
ratio,  0.28  [0.19  to  0.40]);  as  well  as  the  response  rate  from  0%  to  28% (11). Finally, 
Vandetanib  selectively  
targets  RET,  VEGFR  and  EGFR  signaling.  
In  a  phase  
III  
randomized, 
double-blind, placebo-controlled study (ZETA), Vandetanib showed to prolong the progression 
free  survival  
from  19.3  months  
in  
the  placebo  group  
to  30.5  months  
in  
the  Vandetanib  group 
(hazard  ratio,  0.46  [0.31-0.69]);  and  to  improve  the  response  rate  (49%  vs  13%)  (12). 
Response to therapy was seen rapidly, at a median of 2 months for radiological response and 
even  earlier  for  tumor  markers  in  the  SELECT  study.(9) Most  patients  on  TKI  therapy, 
however,  develop  resistance  to  the  drug  after  12-18  months  of  treatment,  and  then  tumor 
restarts progression.(9-12)  
 
TKI  therapy  has  proven  to  
increase  the  progression free survival; however,  their  
impact  on 
overall  survival  is  still  unclear,  in  part  due  to  the  rapid  development  of  tumor  resistance. 
Furthermore, TKI  
treatment  
is  associated  
to  significant  
toxicity. Severe  
(grade  3-4)  
treatment 
related adverse events were reported in 76%, 69% and 37% of the patients treated with TKI on 
the SELECT, EXAM and DECISION studies, respectively, compared to 10%, 33% and 26% in 
their  respective placebo-control  groups (9-11).  As  a  consequence  of  the  adverse  events,  a 
dose  reduction  was  necessary  
in  68%  of  
the  study  participants  
treated  with  Lenvatinib,  and 
treatment needed to be interrupted in 82% of patients in the SELECT study (9). Similarly, 64% 
of  the  patients  required  a  dose  reduction  and  66%  treatment  interruption under  Sorafenib 
treatment  in  the  DECISION  trial.(10) In  the  ZETA  study,  a  significantly  higher  proportion  of 
patients required  dose reduction  due to  adverse  events  or QT  prolongation  
in the  Vandetanib 
group  than  in  the  placebo  group  (35%  vs.  3%).(12) TKI  treatment  was permanently 
discontinued in around 15% of the participants in all studies due to adverse events (9-12).  
 
Finding  mechanisms  
that  allow  delaying  
the  selection  of  
resistant  clones and  decreasing  
the 
toxicity profile of TKIs in patients with thyroid cancer might improve the progression free survival 
and could have a positive impact on the overall survival. Adaptive TKI therapy could be one of 
such mechanisms (13).  
 
2.2 RATIONALE 
 
In general, cytotoxic drugs are administered with the assumption that maximum clinical benefit 
is  obtained  by  killing  the  greatest  possible  number  of  cancer  cells.  Consistent  with  this 
premise,  most  systemic  cancer  chemotherapies  are  applied  at  
the  maximum  
tolerated  dose 
density. This model is being theoretically challenged by an alternative model that views cancer 
therapy  as  an  evolutionary  and  ecological  process (13,  14). This  alternative  model  rests  on 
three major assumptions. First, phenotypically or environmentally mediated resistant cells are 
present before treatment. Second, most xenobiotic mechanisms protecting cells from cytotoxic 
agents  do  not  require  mutations,  but  rather  increased  expression  of  molecular  machinery 
already encoded in the genome. Third, cancer populations within a tumor compete with each 
other  
for  space  and  substrate.  Clearly,  
in  
the  presence  of  chemotherapy,  resistant  cells  are 
better  adapted  and,  thus,  fitter  (more  proliferative)  than  wild-type  cells.  However,  in  the 
absence of chemotherapy, this fitness difference is typically reversed because of the metabolic 
cost  of  the  resistance  mechanism  (synthesis,  maintenance,  and  operation  of  membrane 
extrusion  pumps).  In  an  environment  of  limited  substrate,  this  cost  requires  diversion  of 
resources  
from  proliferation  and  
invasion.  In  this  Darwinian  setting,  maximum  dose  density 
therapy  strongly  selects  for  resistant  phenotypes  and,  by  removing  all  competitors,  permits 


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unconstrained  proliferation  of  the  resistant  populations  even  when  no  drug  is  present—a 
phenomenon well recognized in evolutionary dynamics as “competitive release”. 
 
A  recent  study  applied  these  evolutionary  principles  to  prolong  tumor  control  in  preclinical 
models of breast cancer (15). In this study, mice with orthotopic implants of breast cancer cells 
survived  
longer  using  a  
treatment  
regimen  
that  modulated  
the  dose  according  
to  changes  
in 
tumor volume than those receiving standard chemotherapy. One of the limitations to translate 
this  
into  
the  clinical  practice  
is  
that  
tumor  volume  was  evaluated  
twice  a  week  
through  MRI. 
However,  in  thyroid  cancer,  there  are  specific  tumor  markers  (thyroglobulin  for  DTC  and 
calcitonin for MTC) that have a direct correlation with the burden of disease (16, 17). Therefore, 
these  biomarkers  can  be  used as  an  
indirect  reflection  of  
the  response  
to  
therapy to  adjust 
treatment dose. 
 
2.3 POTENTIAL RISKS AND BENEFITS 
 
 
2.3.1 KNOWN POTENTIAL RISKS 
 
Potential  risks  for study  participants  for  both adaptive TKI  therapy  and conventional TKI 
therapy are related to TKI side effects (See section 8 and Appendix 3).  
 
Additionally,  the  efficacy  of  adaptive  TKI  therapy  for  the  treatment  of  advance  progressive 
thyroid cancer is currently unknown. Therefore, there is the potential of disease progression. 
Study  participants  will  be  monitored  closely  with  regular  clinical  examination, tumor  marker 
measurement,  and imaging  studies so  that  progression  is  detected  early if  present.  If  it 
occurs, the treatment will be modified accordingly.  
 
 
2.3.2 
KNOWN POTENTIAL BENEFITS 
 
Lenvatinib  and  Sorafenib  
in  patients  with  advanced  progressive  differentiated  
thyroid  cancer 
and  Cabozantinib,  and  Vandetanib in  patients  with  advanced  progressive  medullary  thyroid 
cancer have proven to increase the progression free survival in phase 3 randomized controlled 
trials (9-12).  
 
3. OBJECTIVES AND PURPOSE 
 
Primary objective: 
• To  evaluate  the  efficacy  and  tolerability  of  TKI  therapy  (Lenvatinib or 
Sorafenib for  DTC; Cabozantinib  or  Vandetanib for  MTC)  
through  adaptive 
(intermittent) versus conventional (continuous) regimen.  
 
Secondary objective: 
• To evaluate response and survival of TKI therapy (Lenvatinib or Sorafenib for 
DTC; Cabozantinib  or  Vandetanib for  MTC)  through  adaptive  (intermittent) 
versus conventional (continuous) regimen.  
 
Exploratory objective: 
• To determine a predictive biomarkers of TKI response. 
 
 
 
 


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4. STUDY DESIGN AND ENDPOINTS 
 
 
4.1 DESCRIPTION OF THE STUDY DESIGN 
 
This is a pilot randomized phase 2 clinical trial to evaluate the efficacy and tolerability of TKI 
therapy  
through  adaptive  (intermittent)  versus  conventional  (continuous)  regimen  
in  patients 
with DTC or MTC. Eligible subjects with DTC or MTC will have measurable disease according 
to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and will be randomized 2 to 1 
to  receive  adaptive  (intermittent)  versus  conventional  (continuous)  therapy  when  and if  the 
tumor marker drops 50% or more from the baseline level (before initiating TKI treatment) within 
the  
first  
two  months  of  
treatment.  Randomization  will  be  stratified  by  cancer  
types, DTC vs. 
MTC. Patients  
in  which  the  tumor  marker  does  not  drop  by  50% or  more  within  2  months 
(“non-responders”) will be kept on conventional therapy and used to compare with the patients 
who drop their tumor markers by 50% or more as an exploratory analysis.   
 
All patients will start receiving standard of care treatments: Lenvatinib 24 mg daily or Sorafenib 
400 mg twice daily with DTC; Cabozantinib 140 mg daily or Vandetanib 300 mg daily with MTC. 
Doses will be adjusted as needed due to toxicity or drug tolerance in both arms (See section 
6.1.8).  
 
- Patients  in  the  conventional  therapy  regimen (“responders”  and  non-responders”) will 
receive continuous (daily) treatment at the indicated dose.  
 
- Patients  
in  
the  adaptive  
therapy  regimen  will  receive  TKI  
therapy  
in  cycles:  continuous 
(daily) treatment at the indicated dose until the patients’ tumor marker (thyroglobulin in DTC 
patients; calcitonin or  CEA in  MTC  patients)  drops  by  ≥50%  
from  
the  
level  at  
the  
time  of 
enrollment  (“baseline”  level). ≥70% ofOnly  tumor  markers  that  meet  inclusion  criteria  at 
baseline can be used for randomization and adaptive therapy purposes.  A new cycle of TKI 
treatment will begin: 
 
1.  
When/if the tumor marker increases to ≥70% of the “baseline” level.  
OR 
2. 
At the discretion of the treating physician, if a patient develops worsening disease-
related symptoms with rising tumor marker levels indicating disease progression.  
In  the  case  of  resumption  for  disease-related  symptoms,  TKI  treatment  will 
continue until the symptoms improve at the discretion of the treating physician and 
the tumor markers are again ≤50% from the level at the time of enrollment. 
   
All study participants will be followed for at least 24 months after treatment initiation. Patients 
will  continue  to  receive  treatment until  confirmed  disease  progression, development  of 
unacceptable  toxicity,  withdrawal  of  consent,  or  study  termination  by  investigator.  After 
disease  progression, subjects  will  be  
followed  
for  survival  and  may  be  
treated  according  
to 
standards of care, which includes conventional (continuous) TKI treatment for patients in the 
adaptive therapy arm.  
 
After 24 months, patients  
in  
the  adaptive  
therapy  arm that  
remain  on TKI  
therapy  and  under 
control will be given the choice to continue with adaptive therapy or to convert to conventional 
(continuous) regimen, which is the current standard of care.  
 
4.2 STUDY ENDPOINTS 


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4.2.1 PRIMARY ENDPOINT 
 
The  primary  endpoint  is time  to  TKI  treatment  discontinuation  due  to progressive disease, 
intolerability (Grade 3 and 4 toxicities refractory to best symptom management that are deemed 
probably or definitely related to study treatment only), or disease-related death at 2 years. We 
hypothesize that time  on TKI treatment will be significantly longer for patients on the adaptive 
therapy  arm  than  on the  conventional  therapy arm because we  expect  a  decrease  
in  drug-
associated toxicities and a delay in the selection of resistant clones in the adaptive therapy arm. 
 
 
 
4.2.2 SECONDARY ENDPOINTS 
 
We  will  evaluate  overall  response  rate,  progression  
free  survival and  overall  survival of  
the 
adaptive therapy regimen and of the conventional therapy regimen. 
 
 
4.2.3 EXPLORATORY ENDPOINTS 
 
We will determine predictive biomarkers of TKI response. 
 
 
5. STUDY ENROLLMENT AND WITHDRAWAL 
 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
 
Subjects who meet all inclusion criteria will able to participate in the study.  
 
Inclusion criteria: 
1. All  histologically  or cytologically confirmed  diagnosis  of thyroid  cancer,  other  than 
anaplastic or stromal-cell derived cancers.  
2. Participants with DTC must have negative thyroglobulin antibodies.  
3. Measurable disease meeting the following criteria and confirmed by central radiographic 
review: 
• At least 1 lesion of ≥ 1.0 centimeter (cm) in the longest diameter for a non- lymph 
node  or  ≥  1.5  cm  
in  
the  short-axis  diameter  
for  a  
lymph  node  which  
is  serially 
measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1  using  computerized  tomography/magnetic  resonance  imaging  (CT/MRI).  If 
there is only one target lesion and it is a non-lymph node, it should have a longest 
diameter of ≥ 1.5 cm. 
• Lesions  that  have  had  external  beam  radiotherapy  (EBRT)  or  locoregional 
therapies  such  as  radiofrequency  (RF)  ablation  must  show  evidence  of 
progressive disease (substantial size increase of ≥ 20%) within 12 months to be 
deemed a target lesion. 
4. Participants must show evidence of disease progression comparing (a) scan in screening 
and  (b)  historical  scan  obtained  within  12  months  prior  to  signing  informed  consent, 
according to RECIST 1.1 assessed and confirmed by central radiographic review of CT 
and/or MRI scans. 
5. Participants with  DTC must  not  be  eligible  
for  possible  curative  surgery  and  must  be 
radioiodine (RAI)-refractory / resistant as defined by at least one of the following: 
• One or more measurable  
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radioiodine scan 
• One  or more measurable  
lesions that  has  progressed by  RECIST  1.1  within  12 
months of RAI therapy, despite demonstration of radioiodine avidity at the time of 
that treatment by pre- or post-treatment scanning. 
• Disease progression in a patient that has received a cumulative activity of RAI of 
≥ 550 millicuries (mCi) (22 gigabecquerels), with the last RAI dose administered 
at least 6 months prior to study entry. 
• Otherwise deemed not a candidate for further RAI therapy by a multidisciplinary 
tumor board within 60 days of enrollment 
6. Participants  with  DTC must  be  receiving  thyroxine  suppression  therapy  and  thyroid 
stimulating hormone (TSH) should not be elevated (TSH should be ≤ 0.1 mU/L). 
7. “Measurable” tumor  marker  (non-stimulated thyroglobulin  >10  ng/mL  in  patients  with 
DTC; or serum basal calcitonin >10 pg/mL or CEA > 10 ng/mL in patients with MTC) 
8. Participants may have received prior multi-kinase targeted therapy except the TKI used 
in  this  trial.  For  example,  patients  getting Lenvatinib on  this  study  may  have been 
previously treated with Sorafenib, Vandetanib, Sunitinib, Pazopanib, etc. Each of the TKI 
targeted  agents  will  be  counted  individually,  regardless  of  the  duration  of  its 
administration. 
9. Participants with known brain metastases who have completed whole brain radiotherapy, 
stereotactic  radiosurgery  or  complete  surgical  resection,  will  be  eligible  if  they  have 
remained clinically stable, asymptomatic for 30 days. 
10. All chemotherapy or radiation related toxicities must have resolved to < Grade 2 severity 
per  Common  Terminology  Criteria  
for  Adverse  Events  
(CTCAE  v 5.0),  except  alopecia 
infertility,  anemia  (see  separate  criteria)  and  any  toxicities  deemed  
irreversible  by  
the 
treating physician. 
11. Participants  must  have  an  Eastern  Cooperative  Oncology  Group  
(ECOG)  Performance 
Status of 0 – 2 (See Appendix 2). 
12. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined  as  BP  ≤  150/90 mm  Hg at  screening  and  no  change  in  antihypertensive 
medications within 1 week prior to Cycle 1/Day 1 
13. Adequate renal function defined as calculated creatinine clearance  ≥ 30 mL/min (using 
Cockcroft/Gault formula) 
14. Adequate bone marrow function: 
• Absolute neutrophil count (ANC) ≥ 1500 mm3 (≥ 1.5 × 103/micro liter [μL]) 
• Platelets ≥ 100 × 10^9/ L 
• Hemoglobin ≥ 9.0 g/dL 
• Adequate blood coagulation function as evidenced by an INR≤ 1.5 
15. Adequate liver function: 
• Bilirubin  ≤  1.5  ×  upper  limit  of  normal  (ULN)  except  for  unconjugated 
hyperbilirubinemia or Gilbert
's syndrome who must have a total bilirubin level of < 
3.0 x ULN). 
• Alkaline  phosphatase,  alanine  aminotransferase  (ALT),  and  aspartate 
aminotransferase  (AST)  ≤  3  ×  ULN  (≤  5  ×  ULN  if  participant  has  liver 
metastases). 
16. Males or females age ≥ 18 years at the time of informed consent 
17. Females  must  not  be breastfeeding or  pregnant  at  Screening  or  Baseline  (as 
documented  by  a  negative  human  chorionic  gonadotropin  
[hCG]. A  separate  baseline 
assessment is required if a negative screening pregnancy test was obtained more than 
72 hours before the first dose of study drug. 
All  females  will  be  considered  to  be  of  childbearing  potential  unless  they  are 
postmenopausal (amenorrhea for at least 12 consecutive months, in the appropriate age 
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(ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery 
at least 1 month before dosing). 
18. Females  of  childbearing  potential  must  not  have  had  unprotected  sexual  intercourse 
within  30  days  prior  
to  study  entry  and  must  agree  
to  use  a  highly  effective  method  of 
contraception  (e.g.,  total  abstinence,  an intrauterine  device,  a  double-barrier  method 
[such  as  condom  plus  diaphragm  with  spermicide],  a  contraceptive  implant,  an  oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout 
the  entire  study  period  and  for  30  days  after  study  drug  discontinuation.  If  currently 
abstinent, the participant must agree to use a double-barrier method as described above 
if  she  becomes  sexually  active  during  
the  study  period  or  
for  30  days  after  study  drug 
discontinuation.  Females  who  are using hormonal  contraceptives must have  been  on a 
stable  dose  of  
the  same  hormonal  contraceptive  product  
for  at  
least  4  weeks  prior  
to 
dosing  and  must  continue  
to  use  
the  same  contraceptive  during  
the  study  and  
for  30 
days after study drug discontinuation. 
19. Male participants  must  have  had  a  successful  vasectomy  (confirmed  azoospermia)  or 
they  and  their  female  partners  must  meet  the  criteria  above  (ie,  not  of  childbearing 
potential or practicing highly effective contraception throughout the study period and for 
30 days  after  study  drug  discontinuation).  Those  with  partners  using  hormonal 
contraceptives  must  also  be  using  an  additional  approved  method  of  contraception,  as 
described previously. 
20. Voluntary agreement to provide written informed consent and the willingness and ability 
to comply with all aspects of the protocol 
 
5.2 PARTICIPANT EXCLUSION CRITERIA 
 
Subjects who meet at least one exclusion criteria will not be able to participate in the study.  
Exclusion criteria: 
1. Participants  who  have  received  any  anticancer  treatment  (including  Chinese  herbal 
medicine  specified  for  the  treatment  of  tumor)  within  21  days  or  any  investigational 
agent within 30 days prior to the first dose of study drug. This does not apply to the use 
of TSH-suppressive thyroid hormone therapy. 
2. Major surgery within 21 days prior to the first dose of study drug. 
3. Palliative radiation therapy within 14 days prior to the first dose of study drug. 
4. Participants having > 30 mg/dL urine protein on urine dipstick testing (Participants with 
urine protein < 1 g/24 hour (h) will be eligible). 
5. Gastrointestinal  malabsorption  or  any  other  condition  that  in  the  opinion  of  the 
investigator  might  affect  the  absorption  of Lenvatinib, Sorafenib, Cabozantinib,  or 
Vandetanib.  
6. Significant cardiovascular impairment: history of (a) congestive heart failure greater than 
New  York  Heart  association  (NYHA)  Class  II,  (b)  unstable  angina,  (c)  myocardial 
infarction,  (d)  stroke,  or  (e)  cardiac  arrhythmia  associated  with  impairment  within  6 
months of the first dose of study drug. 
7. Bleeding  or  thrombotic  disorders  (Treatment  with  low  molecular  weight  heparin  is 
allowed). 
8. Radiographic evidence of major blood vessel invasion/infiltration. 
9. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 21 days prior to the 
first dose of study drug. 
10. Active infection (any infection requiring systemic treatment). 
11. Active  malignancy  
(except for  DTC/MTC or  definitively  
treated  basal  or  squamous  cell 
carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within the past 24 
months. 
12. Known intolerance to any of the study drugs (or any of the excipients). 
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participation in a clinical trial. 
14. Females who are pregnant or breastfeeding. 
15. Participants who are taking prohibited medications outlines in section 7.5.  
 
5.3 STRATEGIES FOR RECRUITMENT AND RETENTION 
 
 
Patients with  metastatic  progressive  thyroid  cancer  (DTC  and  MTC) referred  to  medical 
oncologist  clinic  for  systemic  therapy  will  be  screened  based  on  inclusion  and  exclusion 
criteria. Subjects who meet inclusion criteria and are willing to participate in the study will be 
enrolled.  
 
No compensation will be provided for study participation.  
 
5.4 PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
 
Participants are free to withdraw from participation in the study at any time upon request.  
 
An investigator may terminate participation in the study in the following circumstances: 
• If  any treatment-related Grade  4  adverse  events  (AE)  develops  during  TKIs 
therapy.  
• If  any  clinically  adverse  event  (AE),  laboratory  abnormality,  or  other  medical 
condition or situation occurs such that continued participation in the study would not 
be in the best interests of the participant 
• If  the  participant  meets any exclusion  criteria (either  newly  developed  or  not 
previously recognized) that precludes further study participation. 
• Extraordinary medical circumstances: If at any time the constraints of this protocol 
are  detrimental  to  the  patient’s  health,  the  protocol  treatment  should  be 
discontinued. 
• If  patient  develops  progressive  disease,  then  the  patient  will  discontinue  the 
protocol therapy (See Appendix 4). 
• If  patient  develops  unacceptable  toxicity,  then  the  patient  will  discontinue  the 
protocol therapy. 
 
The reason and  date for  patient removal from the  study must be  documented  
in the  Case 
Report Form (CRF). 
 
 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
 
Every  effort  will  be  made  to  undertake  protocol-specified  safety  follow-up  procedures  to 
capture AEs, serious adverse events (SAEs), and unanticipated problems. 
 
Those who discontinue protocol therapy early will be followed for response until progression 
and for survival for 1 year from the date of withdraw or termination.  
 
Patients removed from study for unacceptable adverse events will be followed until resolution 
or stabilization of the adverse event. 
 
5.5 PREMATURE TERMINATION OR SUSPENSION OF STUDY 
 


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This  study  may  be  
temporarily  suspended  or  prematurely  
terminated  by  
the  
investigators.  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants. 
• Demonstration of efficacy that would warrant stopping. 
• Insufficient compliance to protocol requirements. 
• Data that is not sufficiently complete and/or evaluable. 
• Determination of futility. 
 
If the study is prematurely terminated or suspended, the PI will promptly inform the IRB and 
will provide the reason for the termination or suspension. 
 
Study  may  resume  once  concerns  about  safety,  protocol  compliance,  data  quality  are 
addressed and satisfy the PI and IRB. 
 
6. STUDY AGENT 
 
6.1 STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 ACQUISITION 
 
Tyrosine  kinase  inhibitors  used  in  this  study, Lenvatinib, Sorafenib, Cabozantinib,  and 
Vandetanib,  are  FDA- approved  and  standard  of  care  for  DTC  and  MTC.  They will  be 
prescribed through specialty pharmacy or conventional pharmacy depending on the availability. 
The study participants will be mailed to home or personally pick up the medication depending 
on the availability. 
 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Lenvatinib is  an  FDA  approved  drug  for  treatment  of  metastatic  progressive  differentiated 
thyroid cancer. Lenvatinib capsules (Lenvima) are produced by Eisai and come in 2 strengths: 
10 mg and 4 mg; capsules are supplied in cartons of 6 blister cards. Each cartoon contains a 
30 day supply of Lenvatinib capsules.  
 
Sorafenib is  an  FDA  approved  drug  for  treatment  of  metastatic  progressive  differentiated 
thyroid cancer. Sorafenib (Nexavar) is produced by Bayer in 200 mg tablets.  
 
Cabozantinib is  an  FDA  approved  drug  for  treatment  of  metastatic  progressive  medullary 
thyroid cancer. Cabozantinib (Cometriq) is produced by Exelixis as 80 mg and 20 mg gelatin 
capsules.  
 
Vandetanib is  an  FDA  approved  drug  for  treatment  of  metastatic  progressive  medullary 
thyroid cancer. Vandetanib (Caprelsa) is produced by Sanofi Genzyme in 2 strengths: 100 mg 
and 300 mg tablets. 
 
 
6.1.3 PRODUCT STORAGE AND STABILITY 
 
Lenvatinib, Sorafenib, Cabozantinib,  and Vandetanib must  be  stored  
in  accordance  with  
the 
instructions on the label at room temperature: 68 F to 77 F (20 C to 25 C). 
 
6.1.4 PREPARATION 
 
No specific preparation of study agent is required.  


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6.1.5 DOSING AND ADMINISTRATION 
 
Study participants with DTC will be taking either:  
 
- Lenvatinib (Lenvima) 24  mg  
in  the  form  of  two  10-mg  capsules  and  one  4-mg  capsule. 
Lenvatinib should  be  
taken  at  
the  same  
time  each  day.  
If  
the  patient  misses  a  dose  and  
it 
cannot be taken within 12 hours, then that dose should be skipped and the next dose should 
be  
taken  at  
the  usual  
time  of  administration.  
  Lenvatinib  may  be  
taken  
in  a  
fasting  state  or 
following a meal. Lenvatinib capsules can be swallowed whole. Alternatively, the capsules can 
be dissolved in one tablespoon of liquid (water or apple juice). Leave the capsule in the liquid 
for  at  least  10  minutes.  Stir  for  at  least  3  minutes.  Drink  the  mixture  and  add  another 
tablespoon  of  
liquid  (water  or  apple  
juice)  to  
the  glass,  swirl  
the  contents  a  
few  
times  and 
swallow the additional liquid. 
Or 
 
-  Sorafenib (Nexavar) 400 mg twice daily in the form of two 200-mg tablets every 12 hours, 
on empty stomach (at least 1 hour before and 2 hours after a meal). If the patient misses a 
dose, the next dose should be taken at the regularly scheduled time, and not double the dose.   
 
Study participants with MTC will be taking either: 
 
- Cabozantinib (Cometriq) 140 mg once daily in the form of one 80-mg capsule and three 20-
mg capsules. Cabozantinib should be taken at the same time each day, on empty stomach (at 
least  1  hour  before and 2  hours  after  meal) with  at  
least  8  ounces  of  water.  
If  
the  patient 
misses a dose and it cannot be taken within 12 hours, then that dose should be skipped and 
the next dose should be taken at the usual time of administration.  
Or 
- Vandetanib (Caprelsa) 300  mg once daily  
in  
the  
form  of one  300-mg tablet. Vandetanib 
should  be  
taken  at  
the  same  
time  each  day.  
If  
the  patient  misses  a  dose  and  
it  cannot  be 
taken within 12 hours, then that dose should be skipped and the next dose should be taken at 
the usual time of administration.  Vandetanib may be taken with or without food. Tablets can 
be dispersed in 2 ounces of water by stirring for approximately 10 minutes (will not dissolve 
completely). Do not use other liquids for dispersion. Swallow immediately after dispersion and 
mix any remaining residue with 4 additional ounces of water and shallow. 
 
 
6.1.6 ROUTE OF ADMINISTRATION 
 
Lenvatinib, Sorafenib, Cabozantinib, and Vandetanib will be taken orally.  
 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
 
The starting dose of Lenvatinib in patients  with DTC is 24 mg/day. This is the maximal dose 
that study participants will receive.   
 
The starting dose of Sorafenib in patients with DTC is 400 mg twice daily. This is the maximal 
dose that study participants will receive.   
 
The  starting  dose  of  Cabozantinib  
in  patients  with  MTC  
is  140  mg/day.  This  
is  
the  maximal 
dose that study participants will receive. Patients with hepatic impairment will start treatment at 
80 mg/day.   
 
The starting dose of Vandetanib in patients with MTC is 300 mg/day. This is the maximal dose 


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that study participants will receive.  
 
 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
 
All patients will start receiving standard of care treatment:  
• DTC: Lenvatinib 24 mg daily or Sorafenib 400 mg twice daily  
• MTC: Cabozantinib 140 mg daily or Vandetanib 300 mg daily.  
 
Dose will be adjusted as needed due to toxicity or drug tolerance in both arms (See below).  
 
- Patients in the conventional therapy regimen (“responders” and non-responders”) will receive 
continuous (daily) treatment at the indicated dose.  
 
- Patients in the adaptive therapy regimen will receive TKI therapy in cycles: continuous (daily) 
treatment at the indicated dose until the patients’ tumor marker (thyroglobulin in DTC patients; 
calcitonin  or CEA in  MTC  patients)  drops  by  ≥50%  
from  
the  
level  at  
the  
time  of  enrollment 
(“baseline” level). Only tumor markers that meet inclusion criteria at baseline can be used for 
randomization and adaptive therapy purposes.  A new cycle of TKI treatment will begin: 
 
1.   When/if the tumor marker increases to ≥70% of the “baseline” level.   
OR 
2. At  
the  discretion  of  
the  
treating  physician  
if  a  patient  develops  worsening  disease-related 
symptoms  with  
rising  
tumor  marker  
levels  
indicating  disease  progression.  
  
In  
the  case of 
resumption  
for  disease-related  symptoms,  TKI  
treatment  will  continue  until  
the  symptoms 
improve at the  discretion  of the treating  physician  and the tumor markers are  again ≤50% 
from the level at the time of enrollment.  
 
All  study  participants  will  continue  
to  receive  
treatment  until  confirmed  disease  progression, 
development  of  unacceptable  toxicity,  withdrawal  of  consent,  or  study  termination  by 
investigator.  
 
After disease progression subjects will be followed for survival and may be treated according 
to standards of care, which includes conventional (continuous) TKI treatment for patients in the 
adaptive therapy arm. 
 
Held doses will be considered missed and will not be made up so that patients will complete 
on-study  
treatment  within  
the  anticipated 24  month  duration.  Treatment  may  be  delayed  
for 
toxicity,  other  palliative  treatments  (i.e.  palliative  radiation,  palliative  surgery,  etc.) for  a 
maximum of 4 weeks. Any treatment beyond the 24 months specified herein will be considered 
off protocol and not subject to the requirements of this protocol. 
 
 
 
6.1.8.1 MANAGEMENT OF MOST COMMON GENERAL SIDE EFFECTS OF TKI 
TREATMENT (NOT AGENT-SPECIFIC) 
 
MANAGEMENT OF HYPERTENSION 
• Insure BP ≤ 150/90 mmHg at the time of study entry.  
• Discuss preventive measurements.  
• Insure that study participants has a BP cuff at home and are willing to measure BP twice a 
day and report if elevated.   


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o Patients will be asked to maintain a diary of these measurements to be reviewed 
with the treating physician or APP during clinic visits 
o If  patient  reports  3  consecutive  at-home  systolic  BP  measurements  of ≥  140 
mmHg and/or diastolic BP measurements of > 90 mmHg, they will be instructed to 
set  up  a  clinic  visit  to  be  assessed  for  further  management.    The  BP 
measurements obtained in clinic will be used to manage hypertension as detailed 
further below. 
• Treat SBP  ≥  140 mmHg and/or  DBP > 90 mmHg  with  antihypertensive  agents 
individualized  to  the  subject’s  clinical  circumstances  based  on  standards  of  clinical 
practice.  
• For  subjects  with  hypertension  and  proteinuria,  treatment  with  an  angiotensin-converting 
enzyme inhibitor or angiotensin-II receptor antagonist is preferred. 
• TKI  should  be  withheld  
in  any  
instances  where  a  subject  
is  at  
imminent  
risk  
to  develop  a 
hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension  (e.g.,  BP  ≥  160/100  mmHg,  significant  risk  factors  for  cardiac  disease, 
intracerebral hemorrhage, or other significant co-morbidities). Once the blood pressure is 
controlled, study drug should be resumed as described below. 
• If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg persists  despite  maximal 
antihypertensive  therapy,  then  study  drug  administration  should  be  interrupted  and 
restarted at a dose of 20 mg once daily when BP ≤ 150/95 mmHg. 
• If  systolic  BP  ≥  160  mmHg  or  diastolic  BP  ≥  100  mmHg  
recurs  on  
the  20-mg  once  daily 
dose  despite  optimal  management  of  hypertension  with  antihypertensive  medications 
(either by dose increase or the addition of a different class of antihypertensive), then study 
drug  administration  should  be  
interrupted  and  restarted  at  a  dose  of  14  mg  once  daily 
when BP ≤ 150/95 mmHg. 
• If  systolic  BP  ≥  160  mmHg  or  diastolic  BP  ≥  100  mmHg  
recurs  on  
the  14-mg  once  daily 
dose  despite  optimal  management  of  hypertension  with  antihypertensive  medications 
(either by dose increase or the addition of a different class of antihypertensive), then study 
drug  administration  should  be  
interrupted  and  restarted  at  a  dose  of  10  mg  once  daily 
when BP ≤ 150/95 mmHg. 
• For Grade 4 hypertension (life- threatening consequences) discontinue study drug. 
• Additional dose reduction should be upon medical judgment of PI. 
 
MANAGEMENT OF PROTEINURIA 
• Regular  assessment  
for  proteinuria  should  be  conducted  as  specified  
in  study  calendar 
(See Table 8). 
• Initial episode of proteinuria: if proteinuria ≥ 2+ is detected on urine dipstick testing study 
drug will be continued and a 24-hour urine collection for total protein will be obtained as 
soon  as  possible  within  72  hours  
to  verify  
the  grade  of  proteinuria.  Withhold  TKI  
for  ≥2 
grams  of  proteinuria/24  hours  and  resume  at  a  reduced  dose  when  proteinuria  is <2 
grams/24 hours.  
• Discontinue TKI for nephrotic syndrome  
 
MANAGEMENT OF DIARRHEA 
• Diarrhea is very common with TKIs. The first step in management of diarrhea, however, is 
to investigate other potential causes including: other medications such as laxatives, stool 
softeners  or  antibiotics;  
lifestyle  
factors  such  as  excessive  dietary  
fiber  or  
lactose;  and 
infectious causes of diarrhea. 
• TKI  related  diarrhea  is  usually  mild  to  moderate  and  early  management  is  essential  to 
prevent dose reduction or discontinuation. Antimotility agents such as loperamide should 
be  
initiated  on  appearance  of mild  diarrhea,  and  patients  should  avoid  
foods  
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minimize the risk of dehydration. 
• If  diarrhea  persists  despite  up  
to  20  mg  
loperamide  per  day,  patients  should  
return  
to  
the 
clinic for further assessment. 
• For patients with persistent grade 2-3 diarrhea, interruption of treatment may be considered 
to allow symptoms to improve. The TKI dose may also be reduced to control diarrhea.  
• If  diarrhea  fails  to  resolve  after  dose  reductions  or  discontinuation,  octreotide  may  be 
considered in some cases.  
• For  patients  with  grade  4  diarrhea  permanently  discontinue  treatment  despite  medical 
management. 
 
MANAGEMENT OF HAND AND FOOT SYNDROME 
• Hand-foot syndrome usually occurs early; and prompt initiation of management can reduce 
its severity and duration. Patients should be informed to keep their skin moisturized and to 
notify their physician of early signs of hand-foot syndrome 
• For  grade  1  (minimal  skin  changes  without  pain),  maintain  TKI  dose  and  keep  skin  well 
hydrated. 
• For  grade  2  (skin  changes  such  as  peeling,  blisters,  bleeding,  edema  or  hyperkeratosis, 
with  pain  
that  
limits  
instrumental  activities  of  daily  
living), TKI  
treatment may  need  
to  be 
interrupted in some cases. Hyperkeratosis should be controlled, the skin kept moisturized 
and discomfort relieved with analgesics.  
• For  grade  3  (skin  changes  such  as  peeling,  blisters,  bleeding, edema  or  hyperkeratosis, 
with  pain  that  limits  self-care  activities  of  daily  living),  TKI  treatment  need  to  be 
interrupted.  Keratosis  on  
the  pressure  points  of  
the  
feet  can  be  shaved  by  a  podiatrist; 
and  may  be  reduced  with  topical  creams  with  salicylic  acid  or  urea.  Other  treatments 
directed  to  reduce  symptoms  and  the  impact  on  patient’s  quality  of  life  are  also 
recommended, including appropriate analgesics.  
   
MANAGEMENT OF MUCOSITIS  
• Before  the  start  of  treatment,  patients  should  have  an  oral  hygiene  check-up.  Patients 
should be advice to brush their teeth and tongue with a soft-bristled brush in addition to 
flossing and rinsing with normal saline. 
• Patients that develop mucositis in the mouth should rinse their mouth out every two to three 
hours. Mouthwash or bicarbonate can be useful for grade 1 mucositis. Additionally: 
• For  grade  1  mucositis  (minor  symptomatic  
inflammation  of  
the  mouth)  maintain  TKI  dose 
and apply triamcinolone in dental paste 2–3 times daily as needed. 
• For  grade  2  mucositis  
(causes  some  pain  but  eating  and  drinking  are  
tolerable)  maintain 
TKI  dose  and  apply  triamcinolone  paste  two  to  three  times  daily  as  needed  AND  oral 
erytrhromycin  250-350mg  daily  OR  minocycline  50  mg  daily.  Mouthwashes  
that  
include 
corticosteroid are very useful for treating mouth ulcers that may develop. 
• For  grade  3  mucositis  (severe  pain  that  prevents  them  eating  or  drinking),  temporarily 
discontinue TKI for 2-4 weeks. Upon improvement to grade 2 or less, reintroduce TKI at a 
reduced dose (see section 6.1.8 for specific details). If toxicities do not worsen, escalate 
the  dose.  
If  no  
improvement,  discontinue.  Apply  clobetasol  ointment  2–3  
times  daily  as 
needed AND oral erythromycin 500 mg daily OR minocycline 100 mg daily. Mouthwashes 
that  
include  corticosteroid  are  very  useful  
for  
treating  mouth  ulcers;  and  analgesics  are 
necessary to treat pain. 
 
 
 
6.1.8.2 MANAGEMENT  OF  MOST  COMMON  SIDE  EFFECTS  SPECIFIC  TO 
EACH TKI AGENT 
 


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Dose Reduction and Interruption 
Instructions for Lenvatinib 
 
Table 1. Adverse Reactions Requiring Dose Modification of Lenvatinib 
 
Adverse Reaction  
CTCAE Grade  Action  
Dose Reduce and Resume  
Lenvatinib 
Hypertension  
 
Grade 31  
Hold  
Resolves to Grade 0, 1, or 2  
Grade 4  
Discontinue  
Do Not Resume  
Cardiac Dysfunction  
 
Grade 3  
Hold  
Resolves  to  Grade  0,  1,  or 
baseline  
Grade 4  
Discontinue  
Do Not Resume  
Arterial Thrombotic Event  Any Grade  
Discontinue  
Do Not Resume  
Hepatotoxicity  
Grade 3 or 4  
Hold  
OR 
Discontinue  
Consider  resuming  
at 
reduced  dose  if  resolves  to 
Grade 0-1 or baseline  
Hepatic Failure  
Grade 3 or 4  
Discontinue  
Do Not Resume  
Proteinuria  
Greater  than  or 
equal  to  2 
gm/24 hours  
Hold  
Resolves  to  less  than  2 
gm/24 hours  
Nephrotic Syndrome  
-------  
Discontinue  
Do Not Resume  
Nausea,  Vomiting,  and 
Diarrhea2  
Grade 3  
Hold  
Resolves  to  Grade  0,  1,  or 
baseline  
Vomiting and Diarrhea2 
Grade 4  
Discontinue  
Do Not Resume  
Renal  
Failure  
or 
Impairment  
Grade 3 or 4  
Hold  
OR 
Discontinue  
Consider  resuming  
at 
reduced  dose  if  resolves  to 
Grade 0-1 or baseline  
GI Perforation  
Any Grade  
Discontinue  
Do Not Resume  
Fistula  
Grade 3 or 4  
Discontinue  
Do Not Resume  
QTc Prolongation  
Greater  than 
500 ms  
Hold  
Resolves  to  less  than  480 
ms or baseline  
Reversible  
Posterior 
Leukoencephalopathy 
syndrome 
Any Grade  
Hold  
OR 
Discontinue  
Consider  resuming  
at 
reduced  dose  if  resolves  to 
Grade 0 to 1  
Hemorrhage  
Grade 3  
Hold  
Resolves to Grade 0 to 1  
Grade 4  
Discontinue  
Do Not Resume  
1: Grade 3 despite optimal anti-hypertensive therapy 
2:    Initiate  prompt  medical  management  for  nausea,  vomiting  or  diarrhea.  Permanently 
discontinue for Grade 4 vomiting and diarrhea despite medical management 
 
Other adverse reactions with Lenvatinib will be managed following the instructions from Table 
2: 
 
Table 2. Dose Modifications for Lenvatinib for treatment-related Persistent and Intolerable 
Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalitiesa  
 
Adverse Reaction  
Modification  
Adjusted Doseb  
First occurrence  
Interrupt until resolved to  
Grade 0-1 or baseline  
20  mg  
(two  10  mg  capsules) 
orally once daily  
Second occurrencec 
Interrupt until resolved to  
Grade 0-1 or baseline  
14  mg  (one  10  mg  capsule 
plus one 4 mg capsule) orally 
once daily  


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Third occurrencec 
Interrupt until resolved to  
Grade 0-1 or baseline  
10  mg  (one  10  mg  capsule) 
orally once daily  
a:  
Initiate  medical  management  
for  nausea,  vomiting,  or  diarrhea  prior  
to  
interruption  or 
dose reduction of Lenvatinib 
b: Reduce dose in succession based on the previous dose level (24 mg, 20 mg, or 14 mg 
per day) 
c: Refers to the same or a different adverse reaction that requires dose modification 
 
Patients  with  confirmed  systolic  BP≥140  mmHg  or  diastolic  BP  ≥90  mmHg  will  be 
administered  antihypertensive  agents  and  monitored  every  1-2  weeks.  In  patients  with 
systolic  BP  ≥160  mmHg  or  diastolic  BP  ≥100  mmHg  despite  optimal  management  the 
treatment dose will be reduced. Patients with confirmed proteinuria Grade ≥2 (1.0–3.4 g/24h) 
will be tested every 2 weeks; and treatment will be interrupted until proteinuria decreases to 
Grade 0–1 or baseline level at which time, a lower dose will be restarted. 
 
For patients with DTC, the recommended dose of Lenvatinib is 14 mg taken orally once 
daily  
in  patients  with  severe  
renal  
impairment  
(creatinine  clearance  
[CLcr]  
less  
than  30 
mL/min calculated by the Cockcroft-Gault equation) or severe hepatic impairment (Child-
Pugh C) 
 
Dose Reduction and Interruption 
Instructions for Sorafenib 
 
Temporary  
interruption  of Sorafenib is  recommended  
in  patients  undergoing  major  surgical 
procedures. 
Temporary  
interruption  or  permanent  discontinuation  of Sorafenib may  be  required  
for  the 
following: 
- Cardiac ischemia or infarction  
- Hemorrhage requiring medical intervention  
- Severe or persistent hypertension despite adequate anti-hypertensive therapy  
- Gastrointestinal perforation  
- QTc prolongation  
- Severe drug-induced liver injury  
 
Table 3. Recommended Doses for Patients with DTC Requiring Sorafenib Dose Reduction 
 
Dose Reduction  
Sorafenib 
Dose  
 
First  
Dose 
Reduction  
600  mg  daily 
dose  
400 mg and 200 mg 12 hours apart (2 tablets and 1 
tablet 12 hours apart – either dose can come first)  
Second  
Dose 
Reduction  
400  mg  daily 
dose  
200 mg twice daily (1 tablet twice daily)  
Third  
Dose 
Reduction  
200  mg  daily 
dose  
200 mg once daily (1 tablet once daily)  
 
When  dose  reduction  
is  necessary  
for  dermatologic  
toxicities,  reduce  
the  Sorafenib  dose  as 
indicated in Table 4 below. 
 
Table  4. Recommended  Sorafenib  Dose  Modifications  for treatment-related Dermatologic 
Toxicities 
 
Dermatologic  
Toxicity 
Grade  
Occurrence  
Sorafenib 
Dose 
Modification  


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Grade  
1:  
Numbness, 
dysesthesia,  
paresthesia, 
tingling,  painless  swelling, 
erythema  or  discomfort  of  
the 
hands  or  
feet  which  does  not 
disrupt  the  patient’s  normal 
activities  
Any occurrence  
Continue treatment  
Grade  2:  Painful  erythema 
and  swelling  of  the  hands  or 
feet  
and/or  
discomfort 
affecting  the  patient’s  normal 
activities  
1st occurrence  
Decrease  dose  to  600  mg 
daily  
If  no  improvement  within  7 
days, see below  
No improvement within 7 days 
at  reduced  dose or 2nd 
occurrence  
Interrupt  until  resolved  or 
improved to grade 1  
If  resumed,  decrease  dose 
(see Table 3)  
3rd occurrence  
Interrupt  until  resolved  or 
improved to grade 1  
If  resumed,  decrease  dose 
(see Table 3)  
4th occurrence  
Discontinue 
Sorafenib 
permanently  
Grade 3:  
Moist  
desquamation, 
ulceration,  blistering,  or 
severe  pain  of  the  hands  or 
feet,  resulting  in  inability  to 
work  or  perform  activities  of 
daily living  
1st occurrence  
Interrupt  until  resolved  or 
improved to grade 1  
If resumed, decrease dose by 
one dose level (see Table 3)  
2nd occurrence  
Interrupt  until  resolved  or 
improved to grade 1  
When  resumed,  decrease 
dose  by  2  dose  levels  (see 
Table 3)  
3rd occurrence  
Discontinue  
Sorafenib 
permanently  
 
Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0–1 after at least 28 days 
of treatment on a reduced dose of Sorafenib, the dose of Sorafenib may be increased one dose 
level  from  the  reduced  dose.  Approximately  50%  of  patients  requiring  a  dose  reduction  for 
dermatologic toxicity are expected to meet these criteria for resumption of the higher dose and 
roughly 50% of patients resuming the previous dose are expected to tolerate the higher dose 
(that  is,  maintain  the  higher  dose  level  without  recurrent  Grade  2  or  higher  dermatologic 
toxicity).  
 
Dose Reduction and Interruption Instructions for Cabozantinib 
 
For Adverse Reactions: 
Withhold  Cabozantinib  for treatment-related NCI  CTCAE  Grade  4  hematologic  adverse 
reactions,  Grade  3  or greater  non-hematologic  adverse  reactions  or  intolerable  Grade  2 
adverse reactions. 
Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to 
Grade 1), reduce the dose as follows: 
 
Table 5. Recommended Doses for Patients with MTC Requiring Cabozantinib Dose Reduction 
 


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Dose Reduction  
Sorafenib Dose  
First Dose Reduction  
100 mg daily dose (one 80-mg and one 20-mg capsule) 
Second Dose Reduction  60 mg daily dose (three 20-mg capsules) 
Third Dose Reduction  
Resume at 60 mg if tolerated, otherwise, discontinue 
 
Permanently discontinue Cabozantinib for any of the following: 
- Development of visceral perforation or fistula formation 
- Severe hemorrhage 
- Serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction) 
- Nephrotic syndrome 
- Malignant  hypertension,  hypertensive  crisis,  persistent  uncontrolled  hypertension  despite 
optimal medical management 
- Osteonecrosis of the jaw 
- Reversible posterior leukoencephalopathy syndrome 
 
In Patients Concurrently Taking a Strong CYP3A4 Inhibitor:  
Reduce  
the  daily  Cabozantinib  dose  by  40 mg (for  example, from  140 mg to  100  mg  daily  or 
from  100  mg  
to  60  mg  daily).  Resume  
the  dose  
that  was  used  prior  
to  
initiating  
the  CYP3A4 
inhibitor 2 to 3 days after discontinuation of the strong inhibitor. 
 
In Patients Concurrently Taking a Strong CYP3A4 Inducer: 
Increase the daily Cabozanib dose by 40 mg (for example, from 140 mg to 180 mg daily or from 
100  mg  
to  140  mg  daily)  as  
tolerated.  Resume  
the  dose that  was  used  prior  
to  
initiating  
the 
CYP3A4  inducer  2  to  3  days  after  discontinuation  of  the  strong  inducer.  The  daily  dose  of 
Cabozantinib should not exceed 180 mg 
 
Dose Reduction and Interruption 
Instructions for Vandetanib  
 
For treatment-related adverse reactions:  
The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets) and then to 100 mg for 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or greater toxicities. 
Interrupt Vandetanib for the following: 
- Corrected  QT  
interval,  Fridericia  (QTcF)  greater  
than  500  ms:  Resume  at  a  reduced  dose 
when the QTcF returns to less than 450 ms. 
- CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or 
improves to CTCAE Grade 1. 
 
For recurrent toxicities:   
Reduce the dose of Vandetanib to 100 mg after resolution or improvement to CTCAE Grade 1 
severity, if continued treatment is warranted. 
Because  of  
the  19-day  half-life,  adverse  
reactions  
including  a  prolonged  QT  
interval  may  not 
resolve quickly. Monitor appropriately. 
 
For patients with renal impairment:  
Reduce the starting dose to 200 mg in patients with moderate (creatinine clearance ³30 to <50 
mL/min) and severe (creatinine clearance <30 mL/min) renal impairment. 
 
For patients with hepatic impairment: 
Vandetanib  is  not  recommended  for  use  in  patients  with  moderate  and  severe  hepatic 
impairment. 
 
 


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6.1.9 DURATION OF THERAPY 
 
TKIs  
therapy  (Lenvatinib,  Sorafenib, Cabozantinib or  Vandetanib)  will  be maintained  until 
radiological disease progression is confirmed or earlier due to toxicity (see section 6.1.8).  
 
6.1.10 TRACKING OF DOSE 
 
Records  of  
treatment  compliance  
for  each  subject  will  be  kept  during  
the  study through  a  pill 
diary which will be checked by the treating physicians or APPs at each visit 
 
6.2 STUDY AGENT ACCOUNTABILITY PROCEDURES 
 
 
6.2.1 Drug Accountability 
 
Lenvatinib is purchased from Esai as a standard of care.  Sorafenib is purchased from Bayer as 
a  standard  of  care.  Vandetinib is  purchased  from  Sanofi  Genzyme  as  standard  of  care.  
Cabozantinib is purchased from Exelixis as standard of care. 
 
6.2.2  Treatment Compliance 
 
Records of study medications used, dosages administered, and intervals between visits will be 
recorded by study personnel.  
 
6.2.3 Biological sample accountability 
 
Record of sample collection and processing will be kept in Moffitt Tissue Core Database and in 
the separate excel sheet. The database will  
include storage information in -800C freezer. The 
tumor, plasma  and PBMC samples  will  be  released  or  further  processed  upon  separate 
instructions from the principal investigator. 
 
 
 
7. STUDY PROCEDURES AND SCHEDULE 
 
 
7.1 STUDY PROCEDURES/EVALUATIONS 
 
7.1.1 STUDY-SPECIFIC PROCEDURES 
 
Study-specific procedures that are not part of standard clinical care include: 
 
• Frequency of thyroglobulin and thyroglobulin antibodies monitoring. 
• Tissue biopsy prior to the initiation of the TKI therapy, at 4 months and at 6 months.  
 
 
7.1.2 STANDARD OF CARE STUDY PROCEDURES 
 
Standard of care procedures obtained during the study: 
• Medical history.  
• Medication history.  
• Physical examination. 
• Radiographic or other imaging assessments. State the specific imaging required and, as 


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appropriate, provide description of what is entailed to perform the specialized imaging. 
Details describing how to perform the imaging in a standard fashion may be described 
in a separate document such as a MOP or SOP. 
•  Laboratory evaluations (Table 6).  
• Assessment of therapy adherence.  
 
7.2 LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS 
 
Table 6. Clinical laboratory tests 
 
Category 
Tests 
Laboratory tests 
CBC  w/differential  (hemoglobin,  hematocrit,  WBC  with 
differential count, platelet count) 
CMP  (Sodium,  potassium,  bicarbonate, chloride,  BUN, 
creatinine, total bilirubin, ALT, AST).  
Magnesium 
INR (only as part of the screening assessment or if clinically 
indicated) 
Amylase, lipase 
Pregnancy test 
Serum or urine β-hCG ( for  women of childbearing potential) 
Thyroid panel  
TSH and free T4 
Thyroglobulin and thyroglobulin antibodies (for DTC only) 
Calcitonin and CEA (for MTC only) 
Urine tests 
Urine dipstick 
ALT= alanine aminotransferase, AST=aspartate aminotransferase, β-hCG = beta-human chorionic 
gonadotropin,  BUN=blood  urea  nitrogen CBC=complete  blood  count,  CMP=comprehensive 
metabolic  panel,  
INR  =  
International  Normalized  Ratio,  TSH=  
thyroid  stimulating  hormone,  T4  = 
thyroxine, WBC=white blood cells.  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 


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 be processed within 2 hours from collection. 
 
  
 
 
 


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7.3 STUDY SCHEDULE 
 
7.3.1 SCREENING 
 
Screening Visit (Day -28 to -0) 
Before performing  any  procedures  or  assessments,  
the  nature  of  
the  study  and  
the  potential 
risks  associated  with  
the  
trial  will  be  explained  
to  all  subject  candidates  and  written  
informed 
consent  will  be  obtained.  Once  
informed  consent  has  been  obtained  (within 8  weeks  of  
first 
dose of study drug), the following procedures and evaluations will be performed: 
 
• Verify inclusion/exclusion criteria (See Sections 5.1-5.2)  
• Record demographic data. 
• Evaluate ECOG performance status  (Appendix 2).  
• Establish pTNM staging and diagnosis (Appendix 1). 
• Record medical and surgical history. 
• Obtain  vital  signs  
(systolic  and  diastolic  BP,  HR,  RR,  and  body  
temperature),  weight,  and 
height. BP, HR, and RR will be obtained after subjects have been resting for 5 minutes. For 
subjects with  an  elevated  BP  (≥  140/90  mmHg),  confirmation  should  be  obtained  by 
performing  2  assessments  1  hour  apart.  Systolic  BP  ≥  160  mmHg  or  diastolic  BP  ≥  100 
mmHg should be confirmed by repeat measurements after an hour. 
• Perform a comprehensive physical examination (including a neurological evaluation). 
• Collect blood samples for laboratory testing and thyroid panel and pregnancy test if indicated 
(See Table 6 for the tests to be performed).  
• Collect urine sample for dipstick testing (See Table 6 for the tests to be performed). 
• Collect urine sample for β-hCG pregnancy testing from all women of childbearing potential. 
• Perform  targeted  radiologic  imaging  studies,  CT/MRI  of head/neck/chest/abdomen/pelvis 
and other areas of known disease at screening plus any areas of newly suspected disease. 
• Record  all  prior  and  concomitant  medication  use  (prescription  and  nonprescription 
medications as well as transfusions). 
• Plan for obtaining tumor tissue.  
 
The screening form must be completed for all subjects screened, providing reasons for screen 
failure when applicable. 
 
7.3.2 ENROLLMENT/BASELINE 
 


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Enrollment/Baseline: Cycle  0  Day -2 to Cycle  1  Day  1 (cycles  are  considered  to  
last  28 
days) 
 
The baseline assessment can be performed on Cycle 1 Day 1 (C1D1), prior to treatment.  
 
Clinical  and  laboratory  assessments  are  valid  if  obtained  within  72  hours  of  baseline 
assessment.  
• Obtain  informed consent or  verify  previously  obtained  during  screening  signed informed 
consent form. 
• Verify inclusion and exclusion criteria. 
• Obtain laboratory tests; urinary dipstick; and thyroid panel. 
• Confirm negative urine/serum pregnancy test. 
• Obtain demographic information, medical history, medication and social history. 
• Evaluate ECOG performance status.  
• Obtain vital signs. 
• Record all concomitant medication use.  
• Perform a comprehensive physical examination.  
• Establish  new  baseline  tumor  assessments  (selection  of  target  and  non-target  lesions) 
based  upon  scans taken (CT  and/or  MRI)  
that showed  evidence  of  disease  progression 
(unless performed within 4 weeks). 
• Verify that study participant received Lenvatinib/Sorafenib/Cabozantinib/Vandetanib through 
special pharmacy.  
• Educate about potential AEs and SAEs. Encourage early recognition and reporting.  
• Obtain tumor tissue (should be done prior to initiation of therapy).  
 
 
7.3.3 FOLLOW-UP 
 
Follow-up Visits 
Study participants will be seen weekly for the first cycle (Cycle 1 Days 8, 15 and 22), every 
two weeks for the second cycle (Cycle 2 Days 1, 15), every four weeks until cycle 12 (Day 1 
of Cycles 3-12); and every 2 cycles thereafter until end of study (Day 1 of cycles 14, 16, 18, 
20  and 24). However,  when  
the  patient  
is  off  
the  TKI  with  observation  only  
in  
the  adaptive 
arm, the patient needs to follow up every 28 days (+/- 7 days) for determination of starting a 
new cycle.  
 
In each scheduled visit we will: 
• Obtain vital signs. 
• Record all concomitant medication use.  
• Perform a comprehensive physical examination.   
• Evaluate ECOG performance status.  
• Obtain laboratory tests and urinary dipstick.  
• Assess for AEs and SAEs.  
• Assess compliance with the medication.  
• Assess survival.  
 
Thyroid panel evaluation 
Thyroid panel will be assessed every 2 weeks during the first two cycles (Cycle 1 Day 15, Cycle 
2  Day  1,  Cycle  2  Day 15,  and  Cycle  3  Day  1). If  the  tumor  marker  (thyroglobulin  in  DTC 
patients; calcitonin or  CEA in  MTC patients)  drops  by ≥50% from  baseline  (Cycle  1  Day  1) 
during the first two cycles (analysis of Cycle 3 Day 1 included), the patient will be randomized to 
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the standard therapy arm will then get Thyroid panel checked every 3 cycles (Day 1 of Cycle 6, 
9, 12). Patients randomized to the adaptive therapy arm will get Thyroid panel checked every 
cycle  (Day  1) during  the  first  two  years.  After  24  months,  patients  in  the  adaptive  therapy 
regimen  who  remain  on  TKI  therapy  will  be  given  the  choice  to  continue  with  the  adaptive 
therapy  
regimen  and  monitoring  of  
the  
thyroid  panel  
in  every  cycle;  or to convert  
to  standard 
(continuous) regimen in which case thyroid panel evaluation will be checked every 3 cycles. In 
either case, all patients that continue to receive TKI therapy beyond 24 months will be treated 
off trial. Patients in which the tumor marker does not drop ≥50% within the first two months of 
TKI therapy will be managed by the standard of care.  
 
Diagnostic imaging 
Diagnostic  
imaging  of  affected  and  suspected  sites  
(CT  and/or  MRI)  will  be  done  at  Day  1  of 
cycles 3, 6, 9, 12, 16, 20, 24 in all patients. Diagnostic imaging will continue to be done every 4 
months thereafter while the patient remains on TKI therapy or as clinically indicated otherwise. 
 
 
 
7.3.4 FINAL STUDY VISIT 
 
Final Study Visit  
 
At  the  end  of  the  study  (at  least  24  months  after  TKI  initiation)  the  following  data  will  be 
collected: 
• Obtain vital signs. 
• Record all concomitant medication use.  
• Perform a comprehensive physical examination.   
• Evaluate ECOG performance status.  
• Obtain laboratory tests and urinary dipstick.  
• Obtain thyroid panel (if not done within previous 3 weeks) 
• Assess for AEs and SAEs.  
• Assess compliance with the medication.  
• Diagnostic imaging of affected and suspected sites (CT and/or MRI). 
• Assess survival.  
 
 
 
 
 
7.3.5 EARLY TERMINATION VISIT 
 
An End of Treatment (EOT) visit will be performed for all subjects who do not complete the 24 
month  treatment  period  for  any  reason  (e.g.  disease  progression,  unacceptable  toxicity, 
withdraw  consent,  etc.).  At  
the  end  of treatment  (30 days after last TKI dose,  or  any  
time 
within 30 days of being removed from treatment for patients in the adaptive therapy arm) the 
following data will be collected: 
• Obtain vital signs. 
• Record all concomitant medication use.  
• Perform a comprehensive physical examination.   
• Evaluate ECOG performance status.  
• Obtain laboratory tests and urinary dipstick.  
• Assess for AEs and SAEs.  
• Assess compliance with the medication.  


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• Assess survival.  
 
 
 
7.3.6 UNSCHEDULED VISIT 
 
Unscheduled visits may be related but not limited to development of TKI toxicities. In that case 
the  Grade  of  toxicity  will  be  documented  and  the  medication  dose  will  be  adjusted  as  per 
protocol (See section 6.1.8, and Appendix 3). All unscheduled visit will be documented in the 
patients chart.  
 
 




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a: Patients in adaptive therapy arm will continue to follow the schedule with TKI withheld as long as their markers 
continue to be below 70% of the ‘baseline’ level.  Upon resumption of TKI therapy the Cycle number will match that 
which would be expected based on duration on treatment (ie TKI therapy is omitted, not held). 
b: Efforts should be made to conduct study visits on the day scheduled during the first month (± 3 days) and there 
after  ±  5  days.  Clinical  
laboratory  assessments  may  be  conducted  anytime  within  72  hours  prior  
to  
the  scheduled 
visit, unless otherwise specified in the Schedule of Visits and Procedures. 
c: Informed consent may be taken up to 8 weeks prior to C1D1. 
d:  The  baseline  assessment  can  be  performed  on  Cycle  1  Day  
(C1D1),  prior  
to  
treatment.  Clinical  and  
laboratory 
assessments are valid if obtained within 72 hours of baseline assessment.  
e: For pTNM Staging see Appendix 1 
f: For ECOG assessments see Appendix 2. 
g: Assessments will include vital signs (resting BP, HR, RR, and body temperature, weight, and height. Height will be 
measured  at  
the  Screening  Visit  only.  Elevated BP  (Systolic BP ≥  140 mmHg and/or  elevated  Diastolic  BP ≥ 90 
mmHg)  should  be  confirmed  by 2  assessments  1  hour  apart.  
If  systolic  BP  
is  ≥  160  mmHg  or  diastolic  BP  ≥100 
mmHg, BP should be confirmed by repeat measurements after an hour. 
h: Laboratory tests include: CBC  w/differential, CMP, ALT,  AST, magnesium, amylase, lipase, urine dipstick and if 
clinically indicated INR (see Table 6).   
i: Thyroid panel includes: TSH, free T4, and for patients with DTC thyroglobulin and thyroglobulin antibodies; and for 
patients with MTC calcitonin and CEA (see Table 6). Thyroid panel results may be collected up to 7 days prior to the 
first dose on Cycle 1 Day 1.  These lab tests should be performed while the patient is in a fasting state. 
j: Serum or urine, in women of childbearing potential only. 
k: Baseline imagine to include CT/MRI of head /neck/chest/abdomen/pelvis and other areas of known disease.  On 
treatment imagine will include only areas of known disease plus any areas of newly suspected disease. 
l: AEs/SAEs will be assessed during each visit clinically and based on laboratory data. Patients will be encouraged to 
report AEs/SAEs at the earliest recognition via the phone between the visits.  
m: Includes the analysis on Cycle 3, day 1.  Only a decrease in tumor markers that met inclusion criteria at baseline 
may be used for randomization purposes. 
n: End of Treatment visit is to occur 30 days after the last dose of TKI therapy (or within 30 days of being removed 
from treatment in the case of adaptive therapy patients) ±7 days.  The optional research biopsy may be taken up to 
30 days after this visit as scheduling may require.  If the subject is unable or unwilling to return to clinic this visit can 
be conducted via a telephone call.  
 
 
7.4 CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
All concomitant prescription medications,  over-the-counter medications, and non-prescription 
medications taken during study participation will be recorded on the case report forms (CRFs).  
All additional local therapies for metastatic lesions (including, but not limited to EBRT, surgery, 
embolization, ethanol injections, etc.) will be recorded on CRFs.  
 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Due  
to  
its  common  use  and  
interference  with  many  
thyroid  hormone  and  biomarker  assays 
including thyroglobulin, patients will not be allowed to take supplemental biotin in any form. 
 
For  patients  treated  with Lenvatinib, Sorafenib, Cabozantinib,  or Vandetanib treatment,  the 
following concomitant medications will not be permitted unless discussed with, and approved 
by the clinical instigators.  
Lenvatinib: No medications are contraindicated.  
- No  dose  adjustment  of  LENVIMA  
is  recommended  when  co-administered  with  CYP3A, P-
glycoprotein  
(P-gp),  and  breast  cancer  
resistance  protein  
(BCRP)  
inhibitors  and  CYP3A  and 
P-gp inducers. 
 
Sorafenib: Sorafenib  
in  combination  with carboplatin/paclitaxel is  contraindicated  
in  patients 
with  squamous  cell  lung  cancer.  In  combination  with gemcitabine/cisplatin is  not 
recommended in patients with squamous cell lung cancer 
- Avoid  concomitant  use  of  strong  CYP3A4  inducers (such  as,  carbamazepine, 
dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort), when possible, 
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Cabozantinib: No medications are contraindicated.  
 - Avoid  taking  a  strong  CYP3A4  inhibitor (e.g.,  ketoconazole,  itraconazole,  clarithromycin, 
atazanavir,  
indinavir,  nefazodone,  nelfinavir,  
ritonavir,  saquinavir,  
telithromycin,  voriconazole) 
while taking Cabozantinib or reduce the dosage of Cabozantinib if concomitant use with strong 
CYP3A4 inhibitors cannot be avoided (see section 6.1.8).  
- Avoid ingestion of foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are 
known to inhibit cytochrome P450 while taking Cabozantinib.  
- Avoid chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, 
rifampin,  rifabutin,  
rifapentine,  phenobarbital,  St.  John’s  Wort)  with  Cabozantinib  or  
increase 
the  dosage  of  Cabozantinib  if  concomitant  use  with  strong  CYP3A4  inducers  cannot  be 
avoided. 
- Concomitant  administration  of  MRP2  
inhibitors  may  
increase  
the  exposure  
to  cabozantinib. 
Monitor patients for increased toxicity when MRP2 inhibitors (e.g., abacavir, adefovir, cidofovir, 
furosemide,  lamivudine,  nevirapine,  ritonavir,  probenecid,  saquinavir,  and  tenofovir)  are 
coadministered with Cabozantinib. 
 
Vandetanib: No medications are contraindicated. 
- Avoid administration of Vandetanib with anti-arrhythmic drugs (including but not limited to 
amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may 
prolong the QT interval (including but not limited to chloroquine, clarithromycin, dolasetron, 
granisetron, haloperidol, methadone, moxifloxacin, and pimozide). 
- Avoid concomitant use of known strong CYP3A4 inducers during Vandetanib therapy. Avoid 
concomitant  use  of  St.  John’s  Wort  because  it  can  decrease Vandetanib  exposure 
unpredictably. 
- Use caution and closely monitor for toxicities when administering Vandetanib with drugs that 
are transported by OCT2 like metformin. 
- Use caution and closely monitor for toxicities when administering CAPRELSA with digoxin 
 
 
7.6 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Most  common  adverse events  of Lenvatinib, Sorafenib, Cabozantinib,  or Vandetanib  
therapy 
will  be  discussed  in  detail  with  the  study  participant  on  enrollment/baseline  visit.  Early 
recognition  and  early  management  of  adverse  events  will  be  emphasized.  The  study 
participant will be provided with the information on the preventive strategies for most common 
adverse events of TKI therapy.  
 
7.7 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Acute toxicities will be managed as described above in the “dose adjustments / modifications/ 
delays” section of this protocol. 
 
7.8 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE 
 
Lenvatinib and Sorafenib, and Cabozantinib  and Vandetanib are  FDA  approved  drugs  for 
treatment of progressive metastatic RAI refractory differentiated thyroid cancer and medullary 
thyroid  cancer,  
respectively.  Study  participant  will  
receive  
the  medication  as  per  standard  of 
care if indicated upon study closure.  
 
 
8. ASSESSMENT OF SAFETY 
 


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8.1 SPECIFICATION OF SAFETY PARAMETERS 
 
Study participants will be monitored closely based on clinical, laboratory and imaging studies 
as outlined in study calendar (Table 8).  Lenvatinib, Sorafenib, Cabozantinib and Vandetanib 
AEs and  SAEs have  been  well  described  
in  
literature (9-12).  Patients  will  be  educated  and 
encouraged to report any AEs and SAEs promptly. Our primary endpoints include evaluation 
of safety and toxicity of adaptive TKI therapy and its comparison to conventional TKI therapy by 
measuring  incidence  of AEs and  SAEs and  time  to  its  developments  in  adaptive  and 
conventional therapy arms.  
 
All  AEs  and  SAEs  will  be  graded  according  to CTCAE  v5.0 (Appendix  3)  and  recorded  
in 
patient’s charts and CRFs.  
 
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
An  adverse  event  (AE)  is  defined  as  any  untoward  medical  occurrence,  including  an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical  product.  The  event  does  not  necessarily  have  
to  have  a  causal  
relation  with 
this treatment. 
 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
 
A serious adverse event (SAE) is defined as any AE that results in death, is immediately life-
threatening, results in persistent or significant disability/incapacity, requires or prolongs patient 
hospitalization, is a congenital anomaly/birth defect, or is to be deemed serious for any other 
reason if it is an important medical event when based on appropriate medical judgement that 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definitions. 
Patients  may  be  hospitalized  
for  administrative  or  social  
reasons  during  
the  study  
(e.g.  
long 
distance from home to site). These and other hospitalizations planned at the beginning of the 
study do not need to be reported as an SAE in case they have been reported at screening visit 
in the source data and have been performed as planned. 
 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS 
 
Unanticipated adverse therapy effect, any serious adverse effect on health or safety, or any 
life-threatening problem or death caused by, or associated with, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence or any other 
unanticipated serious problem associated with the therapy that relates to the rights, safety, or 
welfare of subjects.   
 
8.2 CLASSIFICATION OF AN ADVERSE EVENT 
 
 
 
8.2.1 SEVERITY OF EVENT 
 
All AEs will be graded using the CTCAE 5.0 criteria (Appendix 3).  
For AEs not included in the protocol-defined grading system, the following guidelines will be 
used to describe severity. 
 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
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Moderate  – Events result in a low level of  inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
Severe – Events interrupt  a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually  potentially life-threatening  or 
incapacitating. 
 
 
8.2.2 RELATIONSHIP TO STUDY AGENT 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. 
 
Related – The AE is known to occur with the study agent, there is a reasonable possibility that 
the study agent caused the AE, or there is a temporal relationship between the study agent and 
event. Reasonable possibility means that there is evidence to suggest  a causal relationship 
between the study agent and the AE. 
Not Related – There is not a reasonable possibility that the administration of the study agent 
caused the event, there is no temporal relationship between the study agent and event onset, 
or an alternate etiology has been established. 
 
8.2.3 EXPECTEDNESS 
 
The PI will be responsible for determining whether an AE is expected or unexpected. An AE 
will be  considered  unexpected if  the nature, severity, or frequency of the  event  is  not 
consistent with the risk information previously described for the study agent. 
 
8.3 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
The study participants will be monitored closely throughout the study for occurrence of AE or 
SAE.  The  patients  will  be  educated  regarding  most  comment  AEs  and  SAEs and  will  be 
encouraged to report promptly.  
 
If AEs and SAEs occur, information to be collected includes event description, time of onset, 
clinician’s assessment of severity,  relationship  to study  product,  and time of 
resolution/stabilization  of event. All  AEs  occurring during  the study will be  documented 
appropriately, regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition  
that is present at the time that the participant is screened will be 
considered as baseline and  not reported as  an  AE. However, if the study participant’s 
condition deteriorates at any time during  the study, it will  be recorded as an  AE. 
Unanticipated  problems will be recorded in the data collection  system throughout the 
study. 
 
Events will be followed for outcome information until resolution or stabilization is achieved. 
 
8.4 REPORTING PROCEDURES 
 
 
8.4.1 ADVERSE EVENT REPORTING 
 
All AEs occurring prior to initiation of TKI therapy do not need to be reported. 
 




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The data and safety plan will define criteria for stopping the trial according to rules set forth 
by this protocol. This trial will be continuously monitored by the PI and the research team 
and  
reviewed  at  weekly  Head  and  neck-Endocrine  Oncology Research  Group  meetings. 
Safety  and  monitoring  reports  will  be  submitted  to  the  PMC  after  completing the  
first 2 
cycles after  the  randomization  of  initial  5  patients  in  each  arm or  more  frequently  if 
requested by the PMC. A final safety and monitoring report including all 45 patients will be 
submitted  to  the  PMC  within  three  months  of  completing  the  study  enrollment.  This 
protocol will be subject to periodic internal audits based on risk or as recommended by the 
PMC. 
 
9. CLINICAL MONITORING 
 
Data  will  be  captured  in  OnCore,  Moffitt’s  electronic  Clinical  Trials  Database.  For  each 
participant enrolled,  
the electronic  CRF  must  be  completed  by  
the  assigned  data  manager  or 
other  authorized  study  staff.  Any  paper  
forms  should  be  
typed  or  
filled  out  
indelible  
ink  and 
must be legible. Errors should be crossed out but not obliterated, the correction inserted, and 
the  change  initialed  and  dated  by  the  investigator  or  his/her  authorized  delegate.  This  also 
applies to records for those patients who fail to complete the study. If a patient stops dosing or 
terminates  from  the  study,  the  dates  and  reasons  must  be  noted  on  the  CRF.  If  a patient 
terminates  from  the  study  because  of toxicity,  thorough  efforts  should  be  made  to  clearly 
document  the  outcome. Regulatory  documents  and  case  report  forms  will  be  monitored 
internally according to Moffitt Cancer Center Monitoring Policies. Monitoring will be performed 
regularly  by  the  MCC  Clinical  Monitoring  Core  for  accuracy,  completeness,  and  source 
verification of data entry, validation of appropriate informed consent process, reporting of SAEs, 
and  adherence  to  the  protocol,  Good  Clinical  Practice  (GCP)  guidelines,  and  applicable 
regulatory requirements. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported to the Protocol Monitoring Committee. 
 
10. STATISTICAL CONSIDERATIONS 
 
 
10.1 STATISTICAL AND ANALYTICAL PLANS 
 
This is a randomized phase II clinical trial  with 2:1 randomization to adaptive therapy versus 
conventional  therapy.    The  primary  endpoint  is  time-to-discontinuation  (TTD)  of  treatment, 
which is a “surv
ival analysis”-type statistical comparison.  We plan to enroll 24 patients on the 
adaptive  
therapy  and  12  on  
the  conventional  
therapy  arm.  
  Assuming  uniform  enrollment  of 
patients for 2 years, w
ith a minimum follow-up of 2 years, and a one-sided α = 0.20, we  will 
have 82% power to detect a hazard ratio of 0.50, assuming 12 and 24 month median TTD for 
the conventional and adaptive therapy groups.  If the median TTD of the adaptive group is 20 
months (HR=0.6), the power is 67%. 
 
We anticipate that 20% of the patients w
ill not have the ≥50% drop in tumor markers needed 
for study randomization arm of the study.  Thus, we anticipate recruiting ~45 patients to have 
36 patients for randomization. 
 
The  ~9  patients  enrolled  to  the  trial  not  candidates  for  the  randomization  will  be  given 
conventional therapy as standard of care. As an exploratory analysis, and realizing that the 
sample  sizes  are  small,  we  will  compare  their  PFS  rates  with  the  12  patients  from  the 
randomized portion of the trial who receive conventional therapy using the log-rank test. 
 
 
10.2 STATISTICAL HYPOTHESES 


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We  hypothesize  that  we  will  prolong  time  to  treatment  discontinuation  with  the adaptive 
therapy regimen (experimental group) compared to the continuous therapy regimen (control 
group).    Literature  suggests  that  the  median  time  to  discontinuation  with standard 
(continuous) therapy is 12 months. We hypothesize that the median time to discontinuation will 
increase  
to  24 months  
(Hazard  
ratio  0.50)  with  
the  adaptive  
therapy  
regimen.  The  power of 
the study to detect this difference is 82% for an alpha of 0.20.  
 
 
10.3 DESCRIPTION OF STATISTICAL METHODS 
 
 
10.3.1 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary endpoint is the time-to-discontinuation of treatment. 
 
• The measurement endpoint is the status of a patient 12 months following the start 
of TKI.   
• This  
is  a  binary  metric.  
  1  =  
the  patients  
is  still  
receiving  TKI  at  12  months;  0  = 
patient is no longer on TKI due to cancer progression and/or toxicity. 
• The  
results  will  be  described  as  %  patients  
that remain  on  TKI  at  12  months  by 
experimental and control groups.  
• The  
test  statistic  will  a  Fisher’s  Exact  
test  on  a  
two  by  
two  contingency  
table  of 
patient  counts  based  on  all  four  combinations  of  whether  a  patient  remains  or 
does  not  remain  on  TKI  (0  or  1)  by  treatment  group  (adaptive  therapy  or 
continuous therapy) 
• We will begin by comparing the historical control patients with the control patients 
of the trial.  If these two groups do not differ (using a Type I error rate of p > 0.1) 
then  
they  shall  be  combined  
to  provide  
the  patient  counts  
for  
the  Fisher’s  Exact 
Test comparison of the control group to the experimental group of the trial. 
• If the historical control patients differ from the control patients of the trial (using a 
Type  I  error  rate  of  p  <  0.1)  then  they  will  be  compared  separately  to  the 
experimental  group  using  Fisher  Exact  test’s  with  a  Bonferroni  adjusted  Type  
I 
error rate of p < 0.05.  
 
 
10.3.2 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
• To estimate overall response rate. 
The  
response  
rate  will  be  estimated  using  binomial  
theory  with  Wilson’s  method  
for  
the  95% 
confidence interval. 
 
• To estimate progression-free survival. 
The median progression-free survival rates will be estimated from the Kaplan-Meier curve with 
the 95% confidence interval obtained from Greenwood’s formula. 
 
• To estimate overall survival.  
The median overall survival rates will be estimated from the Kaplan-Meier curve with the 95% 
confidence interval obtained from Greenwood’s formula. 


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10.3.3 EXPLORATORY ANALYSES 
 
• To determine a predictive biomarkers of TKI response 
 
Exploratory  analysis  
to  assess  
the  association  of  potential  biomarkers  with  disease  
response 
will be made using logistic regression. 
 
10.4 SAMPLE SIZE 
 
 
The  planned study  
is  a  
randomized  clinical  
trial,  with  2:1  
randomization  
to  adaptive  
therapy 
versus  conventional  therapy.  The  primary  endpoint  is  time-to-discontinuation (TTD) of 
treatment,  which  is  a  “surv
ival  analysis”-type  statistical  comparison.  We  plan  to enroll  24 
patients on the adaptive therapy and 12 on the conventional therapy arm. Assuming uniform 
enrollment of patients for 2 years, with a minimum follow-up of 2 years, and a one-sided α = 
0.20,  we  will  have  82%  power  
to  detect  a  hazard  
ratio  of  0.50, assuming  12  and  24  month 
median  TTD  for  the  conventional  and  adaptive  therapy  groups.  If  the  median  TTD  of  the 
adaptive group is 20 months (HR=0.6), the power is 67%. 
 
We anticipate that 20% of the patients w
ill not have the ≥50% drop in tumor markers needed 
for study randomization arm of the study.  Thus, we anticipate recruiting ~45 patients to have 
36 patients for randomization. 
 
Objective  time-to-discontinuation  criteria  are  described  in  Section 4.2.1. Patients  may 
electively withdraw from treatment at any time and w
ill be counted as a discontinuation event.   
All randomized patients will be included in the primary analysis. A sensitivity analysis will also 
be conducted, where the patients who choose to withdraw are considered as censored (non-
events) at the time of w
ithdrawal.  
 
 
10.5 MEASURES TO MINIMIZE BIAS 
 
10.5.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
 
In order to encourage enrollment of study participants, who may prefer the adaptive therapy 
arm, patients will  be  randomized 2:1  ratio  to  receive  TKIs  adaptive  therapy  vs  TKIs 
conventional therapy. All randomized patients w
ill be included in the primary analysis. 
 
The  
randomization  assignments  will  be  made  by  
the  Moffitt  Biostatistics  Core  and  placed 
into  a  web-accessed  SRAR  system.  Researchers  consenting  the  patients  will  become 
unblinded upon treatment assignment. The use of variable block sizes makes it more difficult 
for consenters to guess the treatment randomization assignments in advance of the consent 
process. Blocking also helps ensure ongoing balance in treatment allocation. 
 
  
 
11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
 
Medical and research records for this trial including  but not limited to, hospital records, 
clinical and office charts, laboratory notes, will be maintained in compliance with regulatory 
and MCC institutional requirements for the protection of  confidentiality of participants. 


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Investigators of the study will have access to records. 
 
12. QUALITY ASSURANCE AND QUALITY CONTROL 
 
 
Quality control procedures will be implemented beginning with the data entry system and data 
quality control checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated for clarification/resolution. 
 
13. ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
 
13.1 ETHICAL STANDARD 
 
The investigators will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human  Subjects of  Research. The investigators  agree to  adhere  to  the 
instructions  and  procedures  described  
in  
it  and  
thereby  
to  adhere  
to  
the  principles  of  Good 
Clinical Practice. 
 
13.2 INSTITUTIONAL REVIEW BOARD 
 
The protocol, informed consent form, recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of  both the protocol and the consent 
form will  be  obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a  determination will be made regarding 
whether previously consented participants need to be re-consented. 
 
Information  regarding  study  conduct  and  progress  will  be  reported  to  the  IRB  per  Moffitt 
institutional standards. 
 
13.3 INFORMED CONSENT PROCESS 
 
13.3.1 CONSENT/ASSENT  AND  OTHER  INFORMATIONAL  DOCUMENTS 
PROVIDED TO PARTICIPANTS  
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to initiation therapy 
with TKIs (Lenvatinib, Sorafenib, Cabozantinib, and Vandetanib) starting study product.  
 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
An investigator will explain to each participant the nature of the study, its purpose, procedures 
involved, expected duration, and potential risks and benefits. All patients will be informed that 
participation in the study is voluntary and that they may withdraw from the study at any time, 
and  that  withdrawal  of  consent  will  not  affect  their  subsequent  medical  treatment.  This 
informed consent will be given by means of a standard written statement and will be submitted 
for IRB approval prior to use. No patient will enter the study before informed consent has been 
obtained. In accordance with the Health Information Portability and Accountability Act (HIPAA), 
the  written  
informed  consent  document  (or  a  separate  document  
to  be  given  
in  conjunction 
with the consent document) will include a subject authorization to release medical information 
to  the  study  sponsor  and  supporting  agencies  and/or  allow  these  bodies,  a  regulatory 
authority,  or  Institutional  Review  Board  access  to  the  patient’s  medical  information,  which 


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includes all hospital records relevant to the study, including the patient’s medical history. 
 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY 
 
 
The study participant’s contact information will be securely stored at Moffitt during the study. At 
the end of  the study, all records will continue to be kept in a secure location  
for as long a 
period as dictated by Moffitt IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at  Moffitt. This will  not include the participants’ 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems will be secured and password protected. At the end of the study, all study databases 
will be de-identified and archived at the Moffitt. 
 
All unpublished information that the Coordinating Center gives to the investigator shall be kept 
confidential and shall not be published or disclosed to. 
 
The  contents  of  
this  protocol  and  any  amendments  and  
results  obtained  during  
the  course  of 
this study will be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC 
and will not be disclosed in whole or in part to a third party without the prior written consent of 
the PI (or her designee).   
 
No data collected as part of this study will be utilized in any written work, including publications, 
without the written consent of the PI. All persons assisting in the performance of this study must 
be bound by the obligations of confidentiality.  
 
13.5 FUTURE USE OF STORED SPECIMENS 
 
 
Data  collected  
for this study will  be analyzed and stored  at  
the  OnCore  
research  database. 
After the study is completed, the de-identified, archived data will be transmitted to and stored 
at OnCore under the supervision of the PI. With the participant’s approval and as approved by 
local IRBs, de-identified biological samples will be stored at the MCC. These samples could 
be used for future research.  
 
During the conduct of the study, an individual participant can choose to withdraw consent to 
have biological specimens stored for future research. However, withdrawal of  consent with 
regard to biosample storage will not be possible after the study is completed. 
 
14. DATA HANDLING AND RECORD KEEPING 
 
 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Data collection will be collected by investigators/clinical stuff under supervision of the PI. The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and 
maintained for recording data for each participant enrolled in the study.   
 


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Clinical data (including AEs and concomitant medications) and clinical laboratory data will be 
entered  into Power  Chart,  a CFR Part 11-compliant data capture system provided by the 
Cerner. The data system  
includes password protection  and internal quality  checks, such as 
automatic range checks, to identify data that appear  
inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 
 
14.2 STUDY RECORDS RETENTION 
 
Following closure of the study, MCC will maintain a copy of all site study records in a safe and 
secure location for a minimum of 10 years after completion of the study.  
 
14.3 PROTOCOL DEVIATIONS 
 
 
The study  protocol  will  be followed  as  written. If  
investigators  
identify  any  deviations from  
the 
protocol, they will report them in writing to the PI within 1 week or discuss it in the weekly Head 
and  Neck  Cancer  Clinical  Research  Meetings.  Any  change  
to  
the  protocol  
requires  a  written 
protocol amendment or administrative change will be submitted to IRB. This requirement should 
in no way prevent any immediate action from being taken by the investigators in the interest of 
preserving the safety of all subjects included in the study.  
 
14.4 PUBLICATION AND DATA SHARING POLICY 
 
 Clinical trial will be registered at ClinicalTrials.gov.  
 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by primary investigator.  
 
The  detailed  obligations  regarding  the  publication  of  any  data,  material  results  or  other 
information,  generated  or  created  
in  relation  to  the  study  shall  be  set  out  
in  the  agreement 
between all investigators.  
 
15. STUDY ADMINISTRATION 
 
 
15.1 STUDY LEADERSHIP 
 
The Principal Investigator is responsible for performing the following tasks: 
 
• Coordinating, developing, submitting, and obtaining approval for the protocol as well as 
its subsequent amendments. 
• Taking responsibility for the overall conduct of the study and for monitoring the progress 
of the study. 
• Reviewing and ensuring reporting of Serious Adverse Events (SAE). 
• Principal Investigator has the authority to stop the study. 
 
16. CONFLICT OF INTEREST POLICY 
 
None of the participating investigators have conflicts of interests related to the study.  
 
New  conflicts  of  interests  developed  during  the  clinical  trial  will  be  reported  to  the  PI  and 


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addressed accordingly to the institutional policies.  
 
 
17. LITERATURE REFERENCES 
 
1. 
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Impact of Diagnostic Changes on the Rise in Thyroid Cancer Incidence: A Population-
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2. 
Vaccarella S, Franceschi S, Bray F, Wild CP, Plummer M, Dal Maso L 2016 Worldwide 
Thyroid-Cancer Epidemic? The Increasing Impact of Overdiagnosis. The New England 
journal of medicine 375:614-617. 
3. 
Davies L, Morris LG, Haymart M, Chen AY, Goldenberg D, Morris J, Ogilvie JB, Terris 
DJ,  Netterville  J,  Wong  RJ,  Randolph  G  2015  AMERICAN  ASSOCIATION  OF 
CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY 
DISEASE  STATE  CLINICAL  REVIEW:  THE  
INCREASING  
INCIDENCE  OF  THYROID 
CANCER. Endocrine practice : official journal of the American College of Endocrinology 
and the American Association of Clinical Endocrinologists 21:686-696. 
4. 
La  Vecchia  C,  Malvezzi  M,  Bosetti  C,  Garavello  W, Bertuccio  P,  Levi  F,  Negri  E  2015 
Thyroid  cancer  mortality  and  incidence:  a  global  overview.  International  journal  of 
cancer 136:2187-2195. 
5. 
Siegel  RL,  Miller  KD,  Jemal  A  2016  Cancer  statistics,  2016.  CA:  a  cancer  
journal  
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clinicians 66:7-30. 
6. 
Howlader  N,  Noone  AM,  Krapcho  M,  Miller  D,  Bishop  K,  Kosary  CL,  Yu  M,  Ruhl  J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, (eds). CK 2017 SEER Cancer 
Statistics Review, 1975-2014, National Cancer Institute. . 
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2014 Integrated genomic characterization of papillary thyroid carcinoma. Cell 159:676-
690. 
8. 
Fagin JA, Wells SA, Jr. 2016 Biologic and Clinical Perspectives on Thyroid Cancer. The 
New England journal of medicine 375:2307. 
9. 
Schlumberger  M,  Tahara  M,  Wirth  LJ,  Robinson  B,  Brose  MS,  Elisei  R,  Habra  MA, 
Newbold  K,  Shah  MH,  Hoff  AO,  Gianoukakis  AG,  Kiyota  N,  Taylor  MH,  Kim  SB, 
Krzyzanowska  MK,  Dutcus  CE,  de  
las  Heras  B,  Zhu  J,  Sherman  SI  2015  Lenvatinib 
versus  placebo  in  radioiodine-refractory  thyroid  cancer.  The  New  England  journal  of 
medicine 372:621-630. 
10. 
Brose MS, Nutting CM,  Jarzab B, Elisei R, Siena S, Bastholt L, de la Fouchardiere C, 
Pacini F, Paschke R, Shong YK, Sherman SI, Smit JW, Chung J, Kappeler C, Pena C, 
Molnar  I,  Schlumberger  MJ  2014  Sorafenib  in  radioactive  iodine-refractory,  locally 
advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 
3 trial. Lancet (London, England) 384:319-328. 
11. 
Elisei  R,  Schlumberger  MJ,  Muller  SP,  Schoffski  P,  Brose  MS,  Shah  MH,  Licitra  L, 
Jarzab B,  Medvedev V,  Kreissl  MC, Niederle B,  Cohen EE, Wirth LJ, Ali H, Hessel  C, 
Yaron  Y,  Ball  D,  Nelkin  B,  Sherman  SI  2013  Cabozantinib  in  progressive  medullary 
thyroid  cancer.  Journal  of  clinical  oncology  
:  official  
journal  of  
the  American  Society  of 
Clinical Oncology 31:3639-3646. 
12. 
Wells SA, Jr., Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei 
R,  Jarzab  B,  Vasselli  JR,  Read  J,  Langmuir  P,  Ryan  AJ,  Schlumberger  MJ  2012 
Vandetanib  
in  patients with  
locally  advanced  or  metastatic medullary  
thyroid  cancer:  a 
randomized,  double-blind  phase  
III  
trial.  Journal  of  clinical  oncology  
:  official  
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the American Society of Clinical Oncology 30:134-141. 
13. 
Gatenby RA, Silva AS, Gillies RJ, Frieden BR 2009 Adaptive therapy. Cancer research 
69:4894-4903. 
14. 
Gatenby RA 2009 A change of strategy in the war on cancer. Nature 459:508-509. 
15. 
Enriquez-Navas PM, Kam Y, Das T, Hassan S, Silva A, Foroutan P, Ruiz E, Martinez G, 


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Minton  S,  Gillies  RJ,  Gatenby  RA  2016  Exploiting  evolutionary  principles  to  prolong 
tumor  control  in  preclinical  models  of  breast  cancer.  Science  translational  medicine 
8:327ra324. 
16. 
Bachelot A, Cailleux AF, Klain M, Baudin E, Ricard M, Bellon N, Caillou B, Travagli JP, 
Schlumberger  M  2002  Relationship  between  tumor  burden  and  serum  thyroglobulin 
level in patients with papillary and follicular thyroid carcinoma. Thyroid : official journal of 
the American Thyroid Association 12:707-711. 
17. 
Machens  A,  Dralle  H  2010  Biomarker-based  
risk  stratification  
for  previously  untreated 
medullary  thyroid  cancer.  The  Journal  of  clinical  endocrinology  and  metabolism 
95:2655-2663. 
18. 
Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, 
Luber  B,  Alani  RM,  Antonarakis  ES,  Azad  NS,  Bardelli  A,  Brem  H,  Cameron  JL,  Lee 
CC,  Fecher  LA,  Gallia  GL,  Gibbs  P,  Le  D,  Giuntoli  RL,  Goggins  M,  Hogarty MD, 
Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, 
Lim  M,  Lipson  EJ,  Marie  SK,  Netto  GJ,  Oliner  KS,  Olivi  A,  Olsson  L,  Riggins  GJ, 
Sartore-Bianchi A, Schmidt K, Shih l M, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, 
Harkins  TT,  Veronese  S,  Wang  TL,  Weingart  JD,  Wolfgang  CL,  Wood  LD,  Xing  D, 
Hruban  RH,  Wu  J,  Allen  PJ,  Schmidt  CM,  Choti  MA,  Velculescu  VE,  Kinzler  KW, 
Vogelstein B, Papadopoulos N, Diaz LA, Jr. 2014 Detection of circulating tumor DNA in 
early- and late-stage human malignancies. Sci Transl Med 6:224ra224. 
19. 
Amin  MB,  Edge  S,  Greene  F,  Byrd  DR,  R.K.  B,  Washington  MK,  Gershenwald  JE, 
Compton  CC,  Hess  KR,  Sullivan  DC,  Jessup  JM,  Brierly  JD,  Gaspar  LE,  Schilsky  RL, 
Balch  CM,  Winchester  DP,  Asare  EA,  Madera  M,  Gress  DM,  Meyer  LR  2017  AJCC 
Cancer Staging Manual. Eighth edition. Springer, New York. 
20. 
Oken  MM,  Creech  RH,  Tormey  DC,  Horton  J,  Davis  TE,  McFadden  ET,  Carbone  PP 
1982  Toxicity  and  response  criteria  of  the  Eastern  Cooperative  Oncology  Group. 
American journal of clinical oncology 5:649-655. 
21. 
Eisenhauer  EA,  Therasse  P,  Bogaerts  J,  Schwartz  LH,  Sargent  D,  Ford  R,  Dancey  J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe 
D,  Verweij  J  2009  New  
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247. 
 
 
 








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Appendix 3. Common Terminology Criteria for Adverse Events (v4.0).  
The  National  Cancer  Institute’s  Common  Terminology  Criteria  
for  Adverse  Events  (CTCAE 
v5.0  published  27  Nov  2017)  provides  descriptive  
terminology  
to  be  used  
for  adverse  event 
reporting in clinical trials. A brief definition is provided to clarify the meaning of each AE term. 
To increase the accuracy of AE reporting, all adverse event terms in CTCAE version 5.0 have 
been correlated with single-concept, Medical Dictionary for Regulatory Activities (MedDRA®) 
terms. 
 
CTCAE v5.0 grading refers to the severity of the AE. CTCAE grades 1 through 5, with unique 
clinical descriptions of severity for each AE, are based on this general guideline: 
 
Grade CTCAE Status 
1 
Mild; asymptomatic  or  mild  symptoms;  clinical  or  diagnostic  observations  only; 
ntervention not indicated. 
2 
Moderate; minimal,  local,  or  noninvasive  intervention  indicated;  limiting  age- 
appropriate instrumental activities of daily living (ADL).a 
3 
Severe  or  medically  significant  but  not  immediately  life-threatening; hospitalization  or 
prolongation of hospitalization indicated; disabling, limiting self-care ADL.b 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to adverse event. 
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b: Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
Adapted  from  the  Cancer  Therapy  Evaluation  Program,  NCI.  CTCAE v5.0.  Available  from 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/CTCAE v5 Quick Refer
ence 8.5x11.pdf  
 
 
 


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Appendix 4. RECIST criteria (version 1.1).  
Tumor  
response  assessments  
in  
this  clinical  
trial  will  utilize  Response  Evaluation  Criteria  
in 
Solid  Tumors  (RECIST  1.1)  based  on  the  2009  article  by  Eisenhauer  et  al  entitled,  New 
Response Evaluation Criteria in Solid Tumors:  revised RECIST guideline (version 1.1) (21). 
As required by RECIST 1.1, the protocol states that the minimum duration of stable disease is 
7 weeks following the date of first dose of study drug. 
 
Evaluation of target lesions 
Complete Response: 
Disappearance of all target lesions 
Partial Response : 
At least a 30% decrease in the sum of the longest diameter of target 
lesions, taking as reference the baseline sum LD 
Progressive Disease: 
At least a 20% increase in the sum of the LD of target lesions, taking 
as  reference  the  smallest  sum  LD  recorded  since  the  treatment 
started or the appearance of one or more new lesions 
Stable Disease: 
Neither  sufficient  shrinkage  to  qualify  for  partial response  nor 
sufficient  increase  to  qualify  for  progressive  disease,  taking  as 
reference the smallest sum LD since the treatment started 
Evaluation of non-target lesions 
Complete Response: 
Disappearance of all non-target lesions and normalization of tumor 
marker level 
Incomplete  Response/          
Stable Disease: 
Persistence  of  one  or  more  non-target  lesion(s)  or/and 
maintenance of tumor marker level above the normal limits 
Progressive Disease: 
Appearance  of  one  or  more  new  lesions  and/or  unequivocal 
progression of existing non-target lesions (1)