Conditions: Differentiated Thyroid Gland Carcinoma Thyroid Gland Follicular Carcinoma Thyroid Gland Papillary Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
This phase II trial studies how well lenvatinib works when given together with standard of care iodine I-131 in treating patients with radioactive iodine-sensitive differentiated thyroid cancer. Lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the efficacy of lenvatinib pretreatment along with radioactive iodine (RAI) in patients with previously treated RAI sensitive thyroid cancer.

SECONDARY OBJECTIVES:

I. To demonstrate the safety of the combination of lenvatinib and RAI in patients with Iodine sensitive differentiated thyroid carcinoma (DTC).

II. To assess dynamic changes in established serum based biomarkers of DTC (thyroglobulin \[Tg\] and Tg antibody).

III. To explore the utility of protein and genetic biomarkers to predict treatment efficacy.

OUTLINE:

Patients receive lenvatinib orally (PO) once daily (QD) for 8 weeks and up to 12 weeks in the absence of disease progression or unaccepted toxicity. Patients also receive iodine I-131 PO daily as standard of care.

After completion of study treatment, patients are followed up within 6 weeks, every 3 months for 1 year, and then periodically thereafter.

Arms:
arm 1: Patients receive lenvatinib PO QD for 8 weeks and up to 12 weeks in the absence of disease progression or unaccepted toxicity. Patients also receive radioactive iodine (RAI) I-131 orally as standard of care.

Interventions: intervention 1: Lenvatinib
Intervention descriptions: intervention 1: Given orally once daily continuously

Protocol document:
Prot_SAP_000.pdf: 
Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01/04/2021 
1 
A Phase 2 Study of lenvatinib in combination with radioactive iodine therapy in patients 
with progressive RAI-sensitive differentiated thyroid cancer 
Winship Protocol #: 
Winship4271-18 
IRB#: 
IRB00101617 
ClinicalTrials.gov Identifier:  
 NCT03506048 
Eisai Reference #: 
LEN-IIS-M001-1037 
Principal Investigator: 
Taofeek K. Owonikoko, MD, PhD 
Emory University Winship Cancer Institute 
1365 Clifton Road, NE, Room C3080 
Atlanta GA 30322 
Tel/Fax: 404-778-5575/404-778-5575 
Email: towonik@emory.edu 
Co-Investigators 
Medical Oncology: 
Nabil Saba, MD 
Dong M, Shin, MD 
Conor Steuer, MD 
Suresh Ramalingam, MD 
Jennifer Carlisle, MD 
Endocrinology: 
Sabreena Basu, MD 
Priya Dayamani, MD 
Sumathi Srivatsa, MD 
Nuclear Medicine 
Raghuveer Halkar, MD 
David Schuster, MD, PhD 
Erin Grady, MD  
Statistician: 
Zhengjia Chen, PhD 
Study Agents 
Lenvatinib  
Standard Therapies: 
131I Radioactive iodine therapy 
Study Exempt from IND Requirements per 21 CFR 312.2(b).  
Protocol Type / Version # / Version Date: 
[Original/ Version #2 / December 18, 2019] 
Protocol Type / Version # / Version Date: 
[Original/ Version #3 / January 4, 2021] 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
2 
Summary of amendment changes made to protocol version #2: 
1. Page 1: Update study team members 
2. Page 6: Clarify inclusion criteria to include biochemical evidence of disease 
3. Page 14: Clarify inclusion criteria to include biochemical evidence of disease 
4. Page 41: Update study timeline 
 
Summary of amendment changes made to protocol version #3: 
1. Pages 5 & 6: Update inclusion criteria to align with prescribing information for lenvatinib  
2. Page 14: Update to inclusion criteria to align with prescribing information for lenvatinib 
3. Page 29-30: Update to the schedule of activities to correct mistakes regarding lab draws 
and baseline echocardiogram  
 
 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
3 
PROTOCOL SYNOPSIS/SCHEMA  
Background 
Differentiated thyroid cancer consists of papillary and follicular subtypes, which make up 85% 
and 12% of differentiated thyroid cancer respectively. In 2012, there were an estimated 600,000 
people living in the United States with thyroid cancer. The incidence has risen from 4.8 per 
100,000 in 1975 to 14.9 per 100,000 in 2012.1 Perhaps the greatest risk factor for thyroid 
malignancy is prior radiation exposure.2 Papillary and follicular thyroid cancer are primarily 
managed by surgical resection leading to cure in the vast majority of patients. However, patients 
with incompletely resected or residual disease often manifesting as persistent elevation of 
thyroglobulin levels following radioactive iodine (RAI) ablation of thyroid remnant and TSH 
suppression are more likely to recur on long term follow-up.3  
 
Radioactive Iodine in Thyroid Cancer:  
Follicular thyroid epithelial cells possess a membrane sodium-iodide symporter that enables the 
uptake and concertation of iodine in these particular cells.4 This unique ability of thyroid cells 
informed the use of RAI as a therapeutic strategy, which is the mainstay of treatment for 
differentiated thyroid cancer.5 6 Therapy is generally recommended when patients have gross 
extrathyroidal extension, a primary tumor greater than 4 cm or post-operative thyroglobulin 
levels greater than 5 to 10 ng/mL.3 The utility of empiric RAI in patients with identifiable 
disease on imaging that has no iodine uptake on a diagnostic whole body scan remains uncertain. 
One particular study evaluated 27 patients retrospectively, in whom a diagnostic whole body 
scan was negative, and the post-therapy scan showed RAI-avid metastatic lesions at the time of 
RAI remnant ablation.  RAI therapy was given to 12 of 15 patients with progressive disease and 
5 of12 patients with stable lesions. However, this failed to cause any disease regression or even 
stabilize the disease progression. Therefore, patients with persistent progressive disease despite a 
positive post-therapy scan should be considered for treatment interventions other than empiric 
RAI.  7 Studies have shown that RAI sensitive metastatic tumors harbor a different profile of 
genetic mutations compared to RAI refractory disease.  Sabra et al studied tumor samples from 
43 patients with differentiated thyroid cancer who had RAI uptake on their initial ¹³¹I scan. They 
found that RAI sensitive disease was more likely to have a RAS mutation; whereas RAI 
refractory disease harbored a BRAF mutation.8 This distinction in genetic profile can be 
harnessed to guide the use of targeted therapies in RAI sensitive disease.  
 
Rationale for tyrosine kinase inhibitors  
Several signaling pathways are implicated in the development of advanced differentiated thyroid 
cancer, the most common mutations are along the Ras-Raf-MEK-ERK pathways, such as RAS 
and BRAF mutations. Mutations along the PI3K pathway are also common.9, 10 In addition, 
VEGF is important for the growth and proliferation of tumor vasculature, and is mediated by 
tyrosine kinase receptors.11, 12 Therefore inhibition of the receptor tyrosine kinase can inhibit 
multiple pathways of thyroid tumor growth.   
 
RAI Refractory Disease  
With the advent of tyrosine kinase inhibitors (TKIs), the management of metastatic refractory 
thyroid cancer has changed substantially.  Small molecule tyrosine kinase inhibitors such as 
lenvatinib demonstrated clinical efficacy leading to improved PFS compared to placebo in RAI 
refractory thyroid cancer. The pivotal SELECT trial lead to the FDA approval of lenvatinib for 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
4 
advanced RAI-refractory differentiated thyroid cancer. The trial was a 2:1 randomized two-arm 
phase III double-blinded multi-center study in advanced iodine refractory thyroid cancer.13, 14 
Two hundred and sixty-one patients received lenvatinib while 131 patients received placebo. 
PFS was significantly longer in patients who received lenvatinib versus placebo, 18.3 months 
compared to 3.6 months in the placebo.15 Posthoc analysis of the result showed that patients with 
relatively smaller tumor (below the median diameter) derived strong benefit from this agent.16 
 
RAI sensitization using kinase inhibitors  
The Ras-Raf pathways plays an important role in radioiodine resistant thyroid cancer. Activation 
of the RAS, RET and BRAF proteins can lead to MAPK signaling, and downstream inhibition of 
the expression of sodium-iodide symporter. This is in part responsible for iodine uptake in the 
thyroid epithelial cell. Preclinical studies have shown that this is one of the many pathways 
involved in development of radioiodine resistance.17-19 Inhibition of this pathway in mice models 
has shown reversal of iodine resistance.20 Based on this preliminary preclinical evidence, Ho et 
al. studied whether the MEK1/2 inhibitor, selumetinib could resensitize thyroid cancer to 
radioactive iodine. Twenty patients received selumetinib for an average duration of 4 weeks prior 
to retreatment with RAI. Selumetinib increased radioiodine uptake in 12 of the 20 patients.21 
Angiogenic targeting agents was shown to be synergistic with ionizing radiation in preclinical 
cancer models. It is therefore plausible and reasonable to expect that the combination of 
antiangiogenic agent with RAI will also result in improve benefit of RAI in thyroid cancer. 
Lenvatinib, a multireceptor tyrosine kinase inhibitor targeting the kinase activities of vascular 
endothelial growth factor (VEGF) receptors VEGFR1, VEGFR2, and VEGFR3 along with other 
receptor kinases implicated in cancer growth progression including the FGFR1, 2, 3, and 4; 
PDGFR alpha, KIT, and RET may also achieve similar effect. 22 Moreover, post hoc analysis of 
SELECT study data showed that lenvatinib is particularly effective in patients with small volume 
disease. We therefore aim to test whether the addition of lenvatinib to RAI will result in 
improved efficacy of RAI in patients with RAI sensitive differentiated thyroid cancer.  Since 
lenvatinib potently inhibits RET, we aim to conduct a study in patients previously treated with 
RAI, who achieved suboptimal benefit by giving a short course of lenvatinib in order to sensitize 
the tumor both through increased RAI uptake (RET inhibition) and increased cytotoxicity 
(angiogenesis inhibition) to iodine and increase radioactive iodine uptake in the tumor cells post-
treatment. 
 
Hypothesis 
We hypothesize that short course pretreatment with lenvatinib prior to RAI will result in 
improved efficacy of RAI in patients with iodine sensitive differentiated thyroid cancer  
We also hypothesize that tumors with MAPK pathway alteration will be most vulnerable to this 
therapeutic strategy 
 
Study design and schema –  
Single arm phase II study will enroll patients with advanced differentiated thyroid cancer 
previously treated with RAI and with evidence of anatomic and or biochemical progression 
within 12 months of the last RAI administration. RAI sensitivity requires demonstrable uptake 
on delayed whole body scan following the last RAI treatment prior to enrollment on the current 
study. Consenting and eligible patients will receive lenvatinib at the listed FDA approved dose of 
24mg once daily continuously for 8 weeks. Treatment with lenvatinib may continue for up to 12 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
5 
weeks to accommodate the logistics of RAI treatment and to ensure no break in treatment prior 
to RAI administration. Patients will receive RAI under appropriate preparation with low dose 
iodine diet and recombinant TSH (thyrogen) stimulation. Post RAI, patients will undergo 
delayed whole body scan within 7-10 days of RAI. Subsequent monitoring will include 
biomarker assessment with thyroglobulin and thyroglobulin antibody, TSH and T4 levels.  
 
 
Primary Objectives  
Evaluate the efficacy of lenvatinib pretreatment along with RAI in patients with previously 
treated RAI sensitive thyroid cancer 
 
Secondary Objectives –  
Demonstrate the safety of this approach 
Assess dynamic changes in established serum based biomarkers of DTC activity and putative  
Explore the utility of protein and genetic biomarkers to predict treatment efficacy. 
 
Subjects and Centers –  
Emory University Winship Cancer Institute 
 
Inclusion Criteria  
 
• Prior treatment with therapeutic dose of radioactive iodine (>50mCi) with evidence of 
RAI uptake on delayed scan and with progression (biochemical or anatomic) within 12 
months of RAI  
 
• Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of lenvatinib in patients <18 years of age, children are excluded from this study, but 
will be eligible for future pediatric trials. 
 
• ECOG performance status 0 or 1 (Karnofsky ≥80%, see Appendix A). 
 
• Patients with acceptable organ and marrow function as defined below: 
Progressive 
RAI-sensitive 
WDTC
Lenvatinib
24mg daily x 8 
weeks
RAI therapy per 
SOC but not less 
than the last 
dose of RAI prior 
to progression
Follow-up with TG 
Q3 months and 
imaging 4-6 
months


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
6 
 
− absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− total bilirubin 
≤1.5 × institutional upper limit of normal 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
creatinine within normal institutional limits 
OR 
− creatinine clearance 
≥60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
 
• Confirmed diagnosis of differentiated thyroid cancer (Follicular or papillary thyroid 
cancer and their variants 
 
• Ability and willingness to use appropriate contraception 
 
• The effects of lenvatinib on the developing human fetus are unknown. Also, RAI is 
contraindicated in a pregnant woman. For these reasons and because kinase inhibitor 
agents as well as other therapeutic agents used in this trial may be teratogenic, women of 
child-bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry and for the duration of 
study participation. Should a woman become pregnant or suspect she is pregnant while 
she or her partner is participating in this study, she should inform her treating physician 
immediately. Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and for 2 weeks 
after completion of lenvatinib administration. 
 
• Patients must have biochemical evidence of active disease or measurable disease, defined 
as at least one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm 
(≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical 
exam.  See Section 11 for the evaluation of measurable disease. 
 
• Ability to understand and the willingness to sign a written informed consent document. 
 
Exclusion Criteria 
 
• Patients who have received RAI within 12 weeks of planned retreatment 
 
• Prior receipt of cumulative RAI doses in excess of 1000 mCi. 
 
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., 
have residual toxicities > Grade 1)   
 
• Patients who are receiving any other investigational agents. 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
7 
• Patients with previously untreated and or symptomatic brain metastases are excluded from 
this clinical trial because of the risk of intracranial bleeding with angiogenic agents and 
tumoral swelling from RAI. 
 
• History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to lenvatinib 
 
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
• Patients with uncontrolled hypertension (requirement for more than 2 BP medications or 
grade 2 or higher BP elevation while on adequate doses of not more than 2 antihypertensive 
agents) are excluded from the study because one of the significant adverse events of 
lenvatinib is worsening hypertension 
 
• QTcF interval prolongation  greater than 500 ms 
 
• Recent arterial thromboembolic event within the previous 6 months  
 
• Urine dipstick proteinuria ≥2+ or nephrotic range proteinuria on ≥2gram in 24-hour urine.   
 
• History of gastrointestinal perforation, abscess  or fistula  
 
• History of and or medical condition (e.g. diverticular disease; aneurysm) that predisposes 
to risk of major hemorrhage  
 
• Pregnant women are excluded from this study because lenvatinib is a tyrosine kinase 
inhibitor agent with the potential for teratogenic or abortifacient effects.  Because there is 
an unknown but potential risk for adverse events in nursing infants secondary to treatment 
of the mother with lenvatinib, breastfeeding should be discontinued if the mother is treated 
with lenvatinib. 
 
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with lenvatinib.  
 
Other Therapy 
Recombinant TSH (Thyrogen) 
131I radioactive iodine therapy 
 
Efficacy Measures  
Biochemical response 
Anatomic response 
Time to progression 
Progression free survival (PFS) 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
8 
 
Safety Measures  
Treatment emergent toxicity will be graded using NCI CTCAE v. 4 
 
Correlative Science 
Genomic analysis using TRUsight Illumina platform 
Soluble biomarkers 
cfDNA profile  
 
Statistical Analysis –  
The primary objective of this Phase II trial is to determine the time to progression. We expect 
that the addition of lenvatinib to RAI will significantly improve the duration of benefit measured 
as time to treatment failure (anatomic progression or doubling of TG) in patients treated with 
RAI along with short duration lenvatinib compared to repeat treatment of the same patients with 
RAI alone.  
 
From previous data, we assume that the enrolled patients without the lenvatinib would have 
progressed on prior RAI at a median time of 6 months and that the addition of lenvatinib will 
double the duration of benefit from repeat RAI to a median time of 12 months. We plan the study 
to have power = 0.90 at the significance level of 0.05 to correctly detect that improvement in 
median time to progression from 6 moths to 12 months. Since only an improvement in median 
time-to-progression is of clinical interest, we have a directional hypothesis, and have used a 1-
sided alpha.   Using a one-sample survival study design, with assumed accrual duration of 12 
months and additional follow-up time of 6 months, the minimum sample size requirement is 
N=30 patients. 
 
The time-to-progression (TTP) will be the primary endpoint for study, and will be determined 
using all enrolled patients in accordance with the intention to treat (ITT) principle. The censored 
TTP will be estimated with standard Kaplan-Meier methodology. Both point and 90% 
confidence interval estimates of the median and other statistics (e.g., 3-month rate, 6-month rate, 
etc.) from the censored TTP distribution will be calculated. One interim analysis will be 
conducted after 15 patients have progressed and the trial will stop if the study is significantly 
better than the null hypothesis at the significance level of 0.0013 according to the O’Brien-
Fleming Approach. Otherwise the trial will continue until the targeted sample size is reached. 
 
Patients will be given Lenvatinib 24mg daily by mouth for 60 days followed by standard of care 
Radioactive Iodine (RAI) 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
9 
TABLE OF CONTENTS 
 
Protocol synopsis/SCHEMA ...........................................................................................................3 
1. 
OBJECTIVES 11 
1.1 
Primary Objectives.................................................................................................11 
1.2 
Secondary Objectives.............................................................................................11 
2. 
BACKGROUND ...............................................................................................................11 
2.1 
Differentiated Thyroid Cancer ...............................................................................11 
2.2 
Lenvatinib (please refer the FDA prescribing information for full details)...........11 
2.3 
Rationale ................................................................................................................12 
3. 
PATIENT SELECTION ....................................................................................................14 
3.1 
Eligibility Criteria ..................................................................................................14 
3.2 
Exclusion Criteria ..................................................................................................15 
4. 
REGISTRATION PROCEDURES ...................................................................................16 
4.1 
General Guidelines.................................................................................................17 
4.2 
Registration Process ...............................................................................................17 
4.3 
Subject ID Number Assignment ............................................................................17 
5. 
TREATMENT PLAN ........................................................................................................18 
5.1 
Lenvatinib ..............................................................................................................18 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................19 
5.3 
Duration of Therapy ...............................................................................................19 
5.4 
Duration of Follow Up ...........................................................................................20 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................20 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................24 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR).....................24 
7.2 
Serious Adverse Event (SAE) Reporting ...............................................................25 
7.3 
Routine Adverse Event Reporting .........................................................................26 
7.4 
Pregnancy ...............................................................................................................26 
7.5 
Secondary Malignancy...........................................................................................26 
7.6 
Second Malignancy ................................................................................................27 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................27 
8.1 
Study Agents ..........................................................................................................27 
8.2 
Standard of Care Treatment with Radioactive Iodine) ..........................................27 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................28 
9.1 
Exploratory/Ancillary Correlative Studies ............................................................28 
10. 
STUDY CALENDAR .......................................................................................................29 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
10 
11. 
MEASUREMENT OF EFFECT........................................................................................31 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................31 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................38 
12.1 
Institutional Review Board ....................................................................................38 
12.2 
Informed consent ...................................................................................................38 
12.3 
Amendment to the protocol and informed consent form .......................................38 
12.4 
Data Collection and Management ..........................................................................39 
12.5 
Training of study site personnel .............................................................................40 
12.6 
Study oversight and data monitoring .....................................................................40 
12.7 
Study site and timeline ...........................................................................................41 
13. 
STATISTICAL CONSIDERATIONS...............................................................................42 
13.1 
Study Design/Endpoints.........................................................................................42 
13.2 
Sample Size/Accrual Rate ......................................................................................42 
13.3 
Analysis of Secondary Endpoints ..........................................................................42 
13.4 
Reporting and Exclusions ......................................................................................43 
REFERENCES 
45 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................47 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD ...............................................................................................................48 
APPENDIX C 
PILL DIARY and BP Record ....................................................................50 
 
 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
11 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
• Evaluate the efficacy of lenvatinib pretreatment along with RAI in patients with previously 
treated RAI sensitive thyroid cancer 
 
1.2 
Secondary Objectives 
 
• Demonstrate the safety of the combination of lenvatinib and RAI in patients with Iodine 
sensitive DTC 
• Assess dynamic changes in established serum based biomarkers of DTC (Tg and Tg 
antibody)  
• Explore the utility of protein and genetic biomarkers to predict treatment efficacy. 
 
 
2. BACKGROUND 
 
2.1 
Differentiated Thyroid Cancer 
 
Differentiated thyroid cancer consists of two broad subtypes, papillary and follicular carcinomas, 
which make up 85% and 12% of differentiated thyroid cancer respectively.  In 2012, there were 
an estimated 600,000 people living in the United States with thyroid cancer. The incidence has 
risen from 4.8 per 100,000 in 1975 to 14.9 per 100,000 in 2012.1 Perhaps the best established risk 
factor for developing this malignancy is prior radiation exposure.2 Papillary and follicular thyroid 
cancer are treated similarly, and are primarily a surgical disease. Post-operative management is 
determined by residual disease, thyroglobulin levels and radioactive iodine (RAI) uptake, and 
usually consists of ablation of thyroid remnant and TSH suppression.3  
 
 
2.2 
Lenvatinib (please refer the FDA prescribing information for full details) 
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of 
vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and 
VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic 
angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, 
including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth 
factor receptor alpha (PDGFRα), KIT, and RET. The combination of lenvatinib and everolimus 
showed increased antiangiogenic and antitumor activity as demonstrated by decreased human 
endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in 
mouse xenograft models of human renal cell cancer greater than each drug alone. 
 
Absorption:  
After oral administration of LENVIMA, time to peak plasma concentration (Tmax) typically 
occurred from 1 to 4 hours post-dose. Administration with food did not affect the extent of 
absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 
hours. In patients with solid tumors administered single and multiple doses of LENVIMA once 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
12 
daily, the maximum lenvatinib plasma concentration (Cmax) and the area under the concentration-
time curve (AUC) increased proportionally over the dose range of 3.2 to 32 mg with a median 
accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg). 
 
Distribution:  
In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99% (0.3 – 30 μg/mL). 
In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 – 10 
μg/mL). Based on in vitro data, lenvatinib is a substrate of P-gp and BCRP but not a substrate for 
organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, 
OATP1B3, organic cation transporter (OCT) 1, OCT2, or the bile salt export pump (BSEP). 
 
Elimination:  
Plasma concentrations declined bi-exponentially following Cmax. The terminal elimination half-
life of lenvatinib was approximately 28 hours. 
 
Metabolism:  
CYP3A is one of the main metabolic enzymes of lenvatinib. The main metabolic pathways for 
lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-
enzymatic processes. 
 
Excretion:  
Ten days after a single administration of radiolabeled lenvatinib to 6 patients with solid tumors, 
approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively. 
 
Clinical Experience:  
The safety data described below are derived from Study 1 which randomized (2:1) patients with 
radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) to LENVIMA 
(n=261) or placebo (n=131) [see Clinical Studies (14.1)]. The median treatment duration was 16.1 
months for LENVIMA and 3.9 months for placebo. Among 261 patients who received LENVIMA 
in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 
2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity. 
In Study 1, the most common adverse reactions observed in LENVIMA-treated patients (greater 
than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, 
arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, 
proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. 
The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension 
(3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of patients receiving 
LENVIMA and 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 
5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) 
resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased 
appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in 
discontinuation of LENVIMA were hypertension (1%) and asthenia (1%). 
 
 
2.3 
Rationale 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
13 
Radioactive Iodine in Thyroid Cancer  
Thyroid tissue has the unique ability to take up iodine from the blood. Follicular cells have a 
sodium-iodide symporter in the cell membrane that increase the concentration of iodine in these 
particular cells. Because of this symporter, the thyroid cancer cell can take up radioactive iodine 
as well.4 The first published report of using radioactive iodine was in 1946.5 Since then, RAI has 
become of the mainstays of differentiated thyroid cancer treatment and is the primary modality for 
adjuvant control of disease following surgical resection and also for treating patients with 
advanced metastatic disease that is sensitive to iodine.6 Current guideline recommendation 
supports RAI therapy post-surgery in patients with gross extrathyroidal extension, a primary tumor 
greater than 4 cm or post-operative thyroglobulin levels greater than 5 to 10 ng/mL.3 The utility of 
empiric RAI in patients with identifiable disease on imaging that has no iodine uptake on a 
diagnostic whole body scan remains uncertain. One particular study evaluated 27 patients 
retrospectively, in whom a diagnostic whole body scan was negative, and the post-therapy scan 
showed RAI-avid metastatic lesions at the time of RAI remnant ablation. RAI therapy was given 
to 12 of 15 patients with progressive disease and 5 of 12 patients with stable lesions.  However, 
this failed to cause any disease regression or even stabilize the disease progression. Therefore, 
patients with persistent progressive disease despite a positive post-therapy scan should receive 
treatment other than empiric RAI.7 
 
Studies have shown that RAI sensitive metastatic tumors harbor a different profile of genetic 
mutations compared to RAI refractory disease. Sabra et al conducted a retrospective study where 
they identified 43 patients with differentiated thyroid cancer who had RAI uptake on their initial 
¹³¹I scan. The primary tumors were then genotyped for known mutations. They found that RAI 
sensitive disease was more likely to have a RAS mutation; whereas RAI refractory disease 
harbored a BRAF mutation.8 This distinction in genetic profile can perhaps provide benefit to 
using targeted therapies in RAI sensitive disease.  
 
Rationale for tyrosine kinase inhibitors  
As mentioned above, there are several pathways that lead to advanced differentiated thyroid 
cancer, the most common mutations are along the Ras-Raf-MEK-ERK pathways, such as RAS 
and BRAF mutations.  Mutations in the PI-3K pathway are also common.9, 10 In addition, VEGF 
is important for the growth and proliferation of tumor vasculature, and is modulated by receptor 
coupled kinase enzymes.11, 12 Therefore inhibition of the receptor tyrosine kinase can inhibit 
multiple pathways of thyroid tumor growth.   
 
RAI Refractory Disease  
With the advent of tyrosine kinase inhibitors (TKIs), the management of metastatic refractory 
thyroid cancer has changed substantially. Small molecule tyrosine kinase inhibitors such as 
sorafenib, lenvatinib and pazopanib have shown clinical efficacy and improved PFS compared to 
placebo in RAI refractory disease. The initial study of sorafenib against placebo in the DECISION 
trial was the first prospectively acquired data in support of angiogenic agents as salvage therapy 
in DTC. The pivotal SELECT trial lead to the FDA approval of lenvatinib for advanced thyroid 
cancer. The trial was a randomized two-arm phase III double-blinded multi-center study for 
patients with advanced iodine refractory disease.13, 14 Two hundred and sixty one patients received 
lenvatinib and 131 patients received placebo. The median PFS was significantly longer in patients 
who received lenvatinib compared to placebo, 18.3 months versus 3.6 months.15 Posthoc subset 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
14 
analysis showed activity of lenvatinib in most patient categories. Particularly relevant to the 
current study is the stronger efficacy of lenvatinib in patients with small volume disease supporting 
the use of this agent earlier in the course of the disease. 
 
Kinase inhibitors as a RAI sensitizer  
The Ras-Raf pathways plays an important role in thyroid cancer. In particular, activation of the 
RAS, RET and BRAF proteins can lead to MAPK signaling, and downstream inhibition of the 
expression of sodium –iodide symporter. This can lead to reduced uptake and limited efficacy of 
RAI in the thyroid cancer cell. Preclinical studies have shown that this is one of the many pathways 
involved in development of radioiodine resistance.17-19 Inhibition of this pathway in mice models 
resulted in the reversal of iodine resistance.20 Building on this preclinical data, Ho et al. conducted 
a study using the MEK1/2 inhibitor selumetinib, as a strategy to resensitize clinically confirmed 
cases of iodine resistant thyroid cancer to RAI. Twenty patients were given a 4-week pretreatment 
with selumetinib followed by standard doses of RAI using lesional dosimetry to further optimize 
the required dose of RAI. Selumetinib increased radioiodine uptake in 12 of the 20 patients. 
Parallel line of investigation in other tumor types such as colorectal cancer and neurorendocrine 
tumors also suggests that anti-angiogenic therapy can potentiate the activity of ionizing radiation 
in part by normalizing the intratumoral blood flow. Indeed, the combination of angiogenic inhibitor 
and internal radiation was found to be synergistic in preclinical models of pancreatic 
neuroendocrine tumors.22 Lenvatinib is a multikinase inhibitor that modulates the angiogenesis 
pathway in addition to its effect on the MAPK pathway. Moreover, post hoc analysis of SELECT 
study data showed that lenvatinib is particularly effective in patients with small volume disease. 
We therefore aim to test whether the addition of lenvatinib to RAI will result in improved efficacy 
of RAI in patients with RAI sensitive differentiated thyroid cancer.  Given the activity of lenvatinib 
as an inhibitor of the MAPK pathway and its direct anti-angiogenic activity coupled with 
established efficacy in RAI resistant tumors, we hypothesize that the combination of lenvatinib and 
RAI will potentiate clinical efficacy of RAI in iodine sensitive DTC. 
We will conduct a phase II efficacy clinical study of the combination of lenvatinib and RAI in 
patients with RAI sensitive disease based on clinical definition but where the duration of benefit 
of RAI was suboptimal. For the purpose of this protocol, suboptimal clinical efficacy of RAI is 
defined as biochemical or anatomical progression of disease within 6 months of receipt of a 
therapeutic dose of RAI (not less than 50mCi) in a patient who was adequately prepared for the 
RAI treatment. Short term administration of lenvatinib for a period of 4-8 weeks will be followed 
immediately by therapeutic dose of RAI as a way to enhance iodine uptake and clinical efficacy 
of RAI.21  
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Prior treatment with therapeutic dose of radioactive iodine (>50mCi) with evidence of RAI 
uptake on delayed scan, with progression within 12 months of RAI  
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
15 
3.1.2 Age ≥18 years. Because no dosing or adverse event data are currently available on the use 
of lenvatinib in patients <18 years of age, children are excluded from this study, but will 
be eligible for future pediatric trials. 
 
3.1.3 ECOG performance status 0 or 1 (Karnofsky ≥80%, see Appendix A). 
 
3.1.4 Patients with acceptable organ and marrow function as defined below: 
 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
≤1.5 × institutional upper limit of normal 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
creatinine 
within normal institutional limits 
OR 
− 
creatinine clearance 
≥60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
 
3.1.5 Confirmed diagnosis of differentiated thyroid cancer (Follicular or papillary thyroid cancer 
and their variants 
 
3.1.6 Ability and willingness to use appropriate contraception 
The effects of lenvatinib on the developing human fetus are unknown. Also, RAI is 
contraindicated in a pregnant woman. For these reasons and because kinase inhibitor agents 
as well as other therapeutic agents used in this trial may be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation. Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately. Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and for 2 weeks 
after completion of lenvatinib administration. 
 
3.1.7 Patients must have biochemical evidence of active disease or measurable disease, defined 
as at least one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm 
(≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical 
exam. See Section 11 for the evaluation of measurable disease. 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have received RAI within 8 weeks 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
16 
3.2.2 Prior receipt of cumulative RAI doses in excess of 1000 mCi. 
  
3.2.3 Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., 
have residual toxicities > Grade 1)   
 
3.2.4 Patients who are receiving any other investigational agents. 
 
3.2.5 Patients with previously untreated and or symptomatic brain metastases are excluded from 
this clinical trial because of the risk of intracranial bleeding with angiogenic agents and 
tumoral swelling from RAI. 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to lenvatinib 
 
3.2.7 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.8 Patients with uncontrolled hypertension (requirement for more than 2 BP medications or 
grade 2 or higher BP elevation while on adequate doses of not more than 2 antihypertensive 
agents) are excluded from the study as one of the adverse events of lenvatinib is worsening 
hypertension 
 
3.2.9 QTc interval prolongation  greater than 500 ms 
 
3.2.10 Recent arterial thromboembolic event within the previous 6 months  
 
3.2.11 Urine dipstick proteinuria ≥2+ or nephrotic range proteinuria on ≥2gram in 24-hour urine.   
 
3.2.12 History of gastrointestinal perforation, abscess  or fistula  
  
3.2.13 History of and or medical condition (e.g. diverticular disease; aneurysm) that predisposes 
to risk of major hemorrhage  
 
3.2.14 Pregnant women are excluded from this study because lenvatinib is a tyrosine kinase 
inhibitor agent with the potential for teratogenic or abortifacient effects.  Because there is 
an unknown but potential risk for adverse events in nursing infants secondary to treatment 
of the mother with lenvatinib, breastfeeding should be discontinued if the mother is treated 
with lenvatinib. 
 
3.2.15 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with lenvatinib.  
 
 
4. REGISTRATION PROCEDURES 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
17 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally at the Winship Cancer Institute at Emory 
Univeristy by the Study Coordinator. Following registration, patients should begin protocol 
treatment within 14 days. Issues that would cause treatment delays should be discussed with the 
Principal Investigator. If a patient does not receive protocol therapy following registration, the 
patient’s registration on the study may be canceled and re-screening may be required at the 
discretion of the study PI. The Study Coordinator should be notified of cancellations as soon as 
possible. 
 
4.2 
Registration Process 
To register a patient, the following documents should be reviewed and verified by the research 
nurse or Study Coordinator and the PI or designee: 
• Copy of required laboratory tests 
• Signed patient consent form and HIPAA authorization form 
• Eligibility Screening Worksheet 
• Register the patient on the study as per Winship Cancer Institute (Winship) standard 
operating procedures for participant registration.  
 
4.3 
Subject ID Number Assignment 
All consented patients regardless of whether they meet study eligibility for treatment initiation 
will be assigned an ID number consisting of an initial “W” indicating Winship and the study 
number (e.g.W1234) followed by the patients’ first and last initials and a 3-digit serial number at 
enrolment starting at 001 e.g. John Doe, the first patient enrolled on study will have a registration 
number W1234JD001. 
 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
18 
5. TREATMENT PLAN 
 
 
5.1 
Lenvatinib 
 
Treatment will be administered on an outpatient basis for lenvatinib and inpatient for RAI unless 
otherwise cleared by the nuclear medicine physician.  Reported adverse events and potential risks 
are described in Section 7. Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy.  
Lenvatinib should be taken at the same time every day, with or without food. Capsules should be 
swallowed whole. Alternatively, the capsules can be dissolved in a small glass of liquid. Measure 
1 tablespoon of water or apple juice and put the capsules into the liquid without breaking or 
crushing them. Leave the capsules in the liquid for at least 10 minutes. Stir for at least 3 minutes. 
Drink the mixture. After drinking, add the same amount (1 tablespoon) of water or apple juice to 
the glass. Swirl the contents a few times and swallow the additional liquid. 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle Length 
Lenvatinib  
None 
 
24 mg tablet 
Oral* 
Once daily  
60 days 
 
 
 
131I 
Thyrogen 0.9mg x 2 
doses  
100-200 mCi 
oral 
Once  
1 day 
 
*The patient will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each course. 
 
Progressive 
RAI-sensitive 
WDTC
Lenvatinib
24mg daily x 8 
weeks
RAI therapy per 
SOC but not less 
than the last 
dose of RAI prior 
to progression
Follow-up with TG 
Q3 months and 
imaging 4-6 
months


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
19 
5.1.1 
131I Radioactive Iodine 
RAI will be administered as a SOC treatment in patients with progressive but RAI-sensitive 
thyroid cancer 
 
5.1.2 Other Agent(s) 
 
Thyrogen is a lyophilized powder containing 1.1 mg of thyrotropin alfa for single use after 
reconstitution with Sterile Water for Injection. A two-injection regimen is recommended: 
THYROGEN 0.9 mg is administered intramuscularly, followed by a second 0.9 mg intramuscular 
injection 24 hours later. Oral radioiodine should be given 24 hours after the second injection of 
THYROGEN in both remnant ablation and diagnostic scanning. The activity of 131I is carefully 
selected at the discretion of the nuclear medicine physician. 
 
Outline of the thyrogen administration protocol. 
 
Low iodine diet for at least two weeks prior to the first thyrogen dose.  
 
Day 1: 
• Baseline TSH, Thyroglobulin, and Thyroglobulin antibodies drawn.  
Labs to be drawn prior to receiving first thyrogen injection. 
• First thyrogen injection (Thyrogen 0.9 mg intramuscularly (IM).  
 
Day 2  
• Second thyrogen injection (Thyrogen 0.9 mg intramuscularly (IM).  
 
Day 3  
• Post thyrogen lab draw for TSH, Thyroglobulin and beta HCG drawn prior to reporting to 
Nuclear Medicine department for radioiodine dosing and scan. 
 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of lenvatinib with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential for drug interactions. [For example, the 
potential targets for drug interaction can involve, but are not limited to CYP450, glucuronidation, 
P-glycoprotein, protein binding, or reduced absorption from proton-pump inhibitors.  Check the 
study agent Investigator’s Brochure for potential sources of drug interactions].  The study team 
should check a frequently-updated medical reference for a list of drugs to avoid or minimize use 
of.  Appendix C (Patient Drug Information Handout and Wallet Card) should be provided to 
patients if available. 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment with lenvatinib will continue 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
20 
for 8 weeks and up to 12 weeks or until one of the following criteria applies: 
 
• 
Intercurrent illness that prevents further administration of RAI 
 
• 
Unacceptable adverse event(s) 
 
• 
Patient decides to withdraw from the study 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
• 
Clinical progression 
 
• 
Patient non-compliance 
 
• 
Pregnancy 
 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation. 
• 
Termination of the study by sponsor 
 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
5.4 
Duration of Follow Up 
 
Patients removed from study for unacceptable adverse event(s) will be followed until resolution 
or stabilization of the adverse event. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
If a dose is missed and cannot be taken within 12 hours, that dose should be skipped and the next 
dose should be taken at the usual time of administration.  
 
For patients with DTC, the recommended dose of LENVIMA 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) 
 
Nausea 
Management/Next Dose for Lenvatinib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
21 
Nausea 
Management/Next Dose for Lenvatinib 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
 
Vomiting 
Management/Next Dose for Lenvatinib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
 
Diarrhea 
Management/Next Dose for Lenvatinib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Neutropenia 
Management/Next Dose for Lenvatinib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Insert any recommended management guidelines, if appropriate. 
 
 
 
Thrombocytopenia 
Management/Next Dose for Lenvatinib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
22 
Thrombocytopenia 
Management/Next Dose for Lenvatinib 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
 
 
Hypertension 
Management/Next 
Dose 
for 
Lenvatinib 
≤ Grade 1* 
No 
dose 
change 
(initiate 
antihypertensive if not previously 
on BP meds) 
Grade 2* 
No 
dose 
change 
(optimize 
antihypertensive regimen) 
Grade 3** 
Hold until ≤ Grade 1. Resume 
treatment with one dose level 
reduction e.g. 20 mg if previously 
on 24 mg.  
Grade 4 
Discontinue.  
* Start anti-hypertensive therapy  
**Despite optimal anti-hypertensive therapy  
 
Cardiac Dysfunction Management/Next 
Dose 
for 
Lenvatinib 
≤ Grade 1* 
No dose change  
Grade 2* 
No dose change  
Grade 3* 
Hold until < Grade 2. Resume at 20 
mg.  
Grade 4 
Discontinue.  
* Start optimal cardiac therapy   
 
Arterial Thrombotic 
Event 
Management/Next 
Dose 
for 
Lenvatinib 
≤ Grade 1 
Discontinue  
Grade 2 
Discontinue 
Grade 3 
Discontinue 
Grade 4 
Discontinue.  
Do not resume.   
 
Hepatotoxicity 
Management/Next 
Dose 
for 
Lenvatinib 
≤ Grade 1 
No dose change 
Grade 2 
No dose change 
Grade 3 
Hold or discontinue. Consider 
resuming 
with 
1 
level 
dose 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
23 
Hepatotoxicity 
Management/Next 
Dose 
for 
Lenvatinib 
reduction if resolves to ≤ Grade 1 or 
baseline.  
Grade 4 
Discontinue.  
For hepatic failure- discontinue and do not resume.  
 
Proteinuria 
Management/Next 
Dose 
for 
Lenvatinib 
Greater than or equal 
to 2 gm/24 hours  
Hold until resolves, then reduce by 
1 dose level 
For nephrotic syndrome, discontinue permanently.  
 
 
Renal Failure 
Management/Next 
Dose 
for 
Lenvatinib 
≤ Grade 1 
No dose change 
Grade 2 
No dose change 
Grade 3 
Hold or discontinue. Consider 
resuming 1 dose level reduction if 
resolves to ≤ Grade 1 or baseline.  
Grade 4 
Hold or discontinue. Consider 
resuming at 1 dose level reduction 
if resolves to ≤ Grade 1 or baseline. 
 
GI perforation 
Management/Next 
Dose 
for 
Lenvatinib 
Any grade   
Discontinue 
Immediate medical attention necessary.  
 
Fistula 
Management/Next 
Dose 
for 
Lenvatinib 
Grade 3 or 4   
Discontinue 
Immediate medical attention necessary.  
 
QT prolongation 
Management/Next 
Dose 
for 
Lenvatinib 
Greater than 500 ms    Hold until resolves to less than 480 
ms then dose reduce to 20 mg 
Immediate medical attention necessary.  
 
Reversible 
Posterior 
Leukoencephalopathy 
Syndrome 
Management/Next 
Dose 
for 
Lenvatinib 
Any grade    
Hold, consider resuming at 20 mg 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
24 
Reversible 
Posterior 
Leukoencephalopathy 
Syndrome 
Management/Next 
Dose 
for 
Lenvatinib 
if resolves to Grade 0 or 1 
Immediate medical attention necessary.  
 
Hemorrhage 
Management/Next 
Dose 
for 
Lenvatinib 
Grade 3    
Hold, consider resuming at 20 mg if 
resolves to Grade 0 or 1 
Grade 4 
Discontinue 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The type of 
AEs and the characteristics of an observed AE will determine whether the event requires expedited 
reporting to the IRB and Eisai Inc. in addition to routine reporting. 
 
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
Please refer PI for lenvatinib and 131I 
 
7.1.1 CAEPR for Lenvatinib 
In DTC, the most common adverse reactions (incidence greater than or equal to 30%) for lenvatinib 
are hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, 
nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, 
abdominal pain, and dysphonia.  
Please refer to the package insert for a complete list of adverse events.  
 
7.1.2 CAEPR for RAI (adapted from Tala and Turtle; Clinical Oncology Volume 22, Issue 6, 
August 2010, Pages 419-429) 
 
Second malignancies: 
• Leukemia 
RR: 2.5 (95% CI: 1.3–5.53) / Dose related: 0.8 extra cases/GBq/10.000 
person-years. 
• Solid tumors RR: 1.19 (95% CI: 1.04–1.36) / Dose related: 14.4 extra cases/GBq/10.000 
person-years. Effects appear after cumulative dose of 200 mCi for soft tissue and bone 
cancer. 
Salivary glands damage: 
• Transitory (Occur in about 39%; dose dependent). 
Taste alteration that could last some months. 
Salivary glands swelling/tenderness that could last some months. 
 
• Permanent (occur in < 5%; dose dependent). 
Persistent salivary gland swelling and pain. 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
25 
Dry mouth (difficulty swallowing). 
Persistent taste alterations. 
Gum disease and dental cavities 
 
• Nasolacrimal duct obstruction (occurs in approximately 2.5% with doses >100 mCi) 
 
Reproductive problems 
• Women – 
Temporary Amenorrhea/oligomenorrhea (occurs in 20–27%) 
No established long-term effect on infertility, miscarriage, and fetal malformation. 
 
• Men 
Temporary reduction in sperm counts and rise in levels. 
No fertility, miscarriage or congenital abnormalities if RAI <200 mCi 
Persistent increase of FSH if cumulative activities >500 mCi. 
 
Bone Marrow Dose related side effects 
At low doses of approximately 100 mCi, associated with a significant but mild decline in 
white blood cells and platelet counts that persists for at least 1 year after ablation 
 
7.2 
Serious Adverse Event (SAE) Reporting 
All SAE's that are considered as possibly related to Lenvatinib will be reported to Eisai, 
without any exceptions.  Please send report of SAE to ESI Safety 
Eisai Product Safety  
100 Tice Blvd.  
Woodcliff Lake, NJ 07677  
Tel: 1-888-274-2378  
Fax: -1-732-791-1111  
Email: ESI_Safety@eisai.com 
 
Timing of Report to Emory IRB of Protocol Deviations, Serious Adverse events, 
Deaths and Non Compliance*  
Type of Events 
Reporting requirement 
Protocol 
Deviations 
Promptly**: if substantive deviation from protocol and affects 
rights, safety or welfare of subjects, their willingness to continue in 
study or the integrity of the research data. 
•Never: if they do not affect any of the above. 
Serious Adverse 
Events 
•Promptly **: if unanticipated, related and involving risk to 
participant or others or if happening at increased frequency, 
duration or intensity than previously anticipated. 
•Periodically ***: if related to study participation. 
•Never: If not related to study participation. 
Internal Deaths 
•Promptly**: if related to study participation. 
•Periodically ***: If not related to study participation. 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
26 
Non Compliance 
Promptly**: The IRB compliance review (CoRe) team will assess 
if event is possibly serious and/or continuing; if so, Full Board 
(Committee Q) will review. 
(*) This applies to internal events, and external events from sites of Emory sponsor-investigator studies.  
(**) Promptly: 10 business days from the date the PI first learned about the event  
(***)Periodically: at continuing review 
 
7.2.1 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting but must be 
reported through the routine reporting mechanism (Section 7.4): 
 
CTCAE SOC 
Adverse Event 
Grade 
≥24h 
Hospitalizationa 
Vascular Disorders 
Hypertension 
1 or 2 
No 
Cardiac Disorders  
Cardiac Dysfunction 
1 or 2 
No 
Gastrointestinal Disorders  
Nausea 
1 or 2 
No 
Gastrointestinal Disorders  
Vomiting 
1 or 2 
No 
 
 
 
 
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of hospitalization 
by ≥24 hours of a patient. 
 
 
7.3 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. AEs reported 
expeditiously must also be reported in routine study data submissions. 
 
7.4 
Pregnancy 
 
Pregnancy as well as its outcome must be documented. Any reported pregnancy occurring in a 
patient or patient’s partner from the time of consent to 90 days after the last dose of study drug 
must be reported and then followed for outcome.  Newborn infants should be followed until 30 
days old. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is 
not considered a metastasis of the initial neoplasm. 
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
27 
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE reporting 
unless otherwise specified. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
Study Agents 
 
 
8.1.1 Lenvatinib 
 
 
Availability 
 
Lenvatinib is the investigational agent employed in this study. It is supplied to investigators 
by Eisai Inc.  
 
 
8.1.2 Agent Ordering and Agent Accountability 
 
 
8.1.2.1 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all study agents. 
 
8.2 
Standard of Care Treatment with Radioactive Iodine) 
 
Product description: RAI to be administered per standard protocol in the Nuclear Medicine 
Division of Emory University. 
 
Solution preparation: Standard preparation with low iodine diet for at least 2 weeks along with 
thyrogen stimulation or withdrawal as applicable 
 
Route of administration: Orally administered. 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
28 
Agent Ordering: Per standard nuclear medicine ordering process from commercial vendor.   
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Genomic analysis using TRUsight Illumina platform using archival tumor samples 
Soluble biomarkers of angiogenesis using LUMINEX platform 
 
 
9.1 
Exploratory/Ancillary Correlative Studies 
 
9.1.1 Genomic analysis using TRUsight Illumina platform using archival tumor samples 
9.1.1.1 
Collect archival samples from the Emory or outside facility pathology department 
9.1.1.2 
Site(s) Performing Correlative Study: Emory Integrated Genomics Core 
 
9.1.2 Soluble biomarkers of angiogenesis and immune modulation  using LUMINEX platform 
9.1.2.1 
Collect peripheral blood sample in heparinized tube for plasma separation and storage 
9.1.2.2 
Handling of Specimens(s) -  Store at -80o 
9.1.2.3 
Site(s) Performing Correlative Study  - Stanford Immune Monitoring Lab 
 
 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
29 
10. STUDY CALENDAR 
 
Schedules shown in the Study Calendar below are provided as an example and should be 
modified as appropriate. 
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy. In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy otherwise, baseline samples obtained within 7 days of starting 
treatment do not need to be repeated.  
Unless otherwise specified, events may occur within a window of ±2 days, ±1 week or a ±1 month 
as applicable. 
 
 
Baselin
e 
Cycle 1 
Cycle 2 
Cycle 3i 
 
 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3h 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Follow-upj 
Off Studyc 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Physical exam 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Performance status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
CBC 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Serum chemistrya 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
TG, TG Ab, TSH, Free T4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Stimulated TG/Tg Ab 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Xd 
 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
Xb 
 
 
 
 
Xb 
 
 
 
Xb 
 
 
 
 
 
Thyrogen Administration 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Xd 
 
Archival tissue sample  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram* 
X 
 
Peripheral blood for biomarker 
analysis 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Xk 
 
Lenvatinib 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pill Diary 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Quality of Life Questionnaire 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Nuclear Medicine Consult  
Xf 
 
 
Radioactive Iodine Therapy 
 
 
 
 
 
 
 
 
 
X 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
X 
Response Assessments 
X 
Tumor measurements are done at 3 and 6 months post RAI and then Q3-6 months X 
X 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
30 
thereafter as clinically indicated.   
Radiologic evaluation 
X 
Radiologic measurements include a post-therapy scan 7-10 days after RAI and CT scans, (without 
contrast) MRI or neck ultrasound as clinically indicated for patients with measurable disease every 3 
months after completion of RAI for up to 1 year then Q 4-6 months thereafter as clinically necessary. 
X 
Biochemical Responseg 
 
Xg 
Xg 
 
 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium. 
b: 
Serum or urine pregnancy test (for women of childbearing potential). 
c: 
Off-study evaluation. 
d.      Stimulated TG to be obtained at baseline (not required if obtained within 3 months of enrolment), with RAI treatment and at 6 months and 
12 months post RAI 
e.      Paired plasma sample to be collected in heparinized tubes at baseline and at the end of treatment with lenvatinib  
f.       Referral to nuclear medicine for consultation and scheduling of RAI treatment should occur no later than 4 weeks prior to planned RAI 
treatment  
g.   Biochemical response will be assessed using suppressed and stimulated thyroglobulin, thyroglobulin antibody. Thyroglobulin and 
thyroglobulin antibody will be checked at baseline and post RAI every 3 months for 12 months and every 4-6 months thereafter as clinically 
indicated. Stimulated thyroglobulin obtained at baseline, prior to RAI, at 3 months, 6 months and 12 months post RAI will be used to define 
biochemical response. Unstimualte Tg levels may be used if unable to obtain stimulated Tg 
h.      May be conducted by phone if necessary due to logistical reasons 
i.      Required only if lenvatinib extends beyond 8 weeks due to logistical needs for RAI treatment 
j.      Regular follow-up within 6 weeks post RAI treatment and every 3 months for 1 year and thereafter per standard of care 
k.     Optional sample collection 
*      As clinically indicated 
 
 
 
 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
31 
11. MEASUREMENT OF EFFECT 
 
 
11.1 
Antitumor Effect – Solid Tumors 
 
Biochemical Response: Biochemical response will be assessed using suppressed and stimulated 
thyroglobulin, thyroglobulin antibody. Thyroglobulin and thyroglobulin antibody will be checked 
at baseline and post RAI every 3 months for 12 months and every 4-6 months thereafter as 
clinically indicated. Stimulated thyroglobulin obtained at baseline, prior to RAI, at 3 months, 6 
months and 12 months post RAI will be used to define biochemical response.  
Response will be classified as previously defined23 using the stimulated TG/TG Ab levels at 
baseline as reference point: 
 
• Excellent response: no clinical, biochemical, or structural evidence of disease 
• Biochemical incomplete response: abnormal thyroglobulin (Tg) or rising anti-
thyroglobulin antibody levels in the absence of localizable disease 
• Structural incomplete response: persistent or newly identified locoregional or distant 
metastases 
• Indeterminate response: non-specific biochemical or structural findings which cannot be 
confidently classified as either benign or malignant. 
 
For the purposes of this study, patients should be evaluated for response with a post-therapy scan 
5-10 days after RAI and with cross sectional imaging at 3 and 6 months and Q4 months through 1 
year post RAI. Thereafter, imaging will be obtained per standard clinical requirements 
approximately, every 4-6 months as indicated.   
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria. 
 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with lenvatinib.  
 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
32 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
33 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have 
slice thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for 
body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
34 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that 
the PET portion of the CT introduces additional data which may bias an investigator if it 
is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement.  Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  In addition, thyroglobulin and thyroglobulin anti-body 
should be checked simultaneously.  
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
35 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 
cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm (0.5 cm).  (Note:  the appearance 
of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 
cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
36 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
11.1.5 Biochemical Response:  
Thyroglobulin and thyroglobulin antibody will be checked at 6 weeks, 3 months, 6 
months after RAI and every 3-6 months thereafter as clinically indicated. Biochemical 
response will be assessed using suppressed and stimulated thyroglobulin, thyroglobulin 
antibody. Response will be classified as previously defined using the stimulated TG/TG 
Ab levels at baseline as reference point.23 
 
• Excellent response: no clinical, biochemical, or structural evidence of disease 
• Major Biochemical Response: a reduction in TG levels of  ≥50% over baseline 
• Minor Biochemical Response: a reduction in TG levels of  < 50% over baseline 
• Biochemical incomplete response: abnormal thyroglobulin (Tg) or rising anti-
thyroglobulin antibody levels in the absence of localizable disease 
• Structural incomplete response: persistent or newly identified locoregional or distant 
metastases 
• Indeterminate response: non-specific biochemical or structural findings which cannot 
be confidently classified as either benign or malignant. 
 
 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
37 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.1.6 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
38 
11.1.7 Time to Progression 
 
Treatment failure leading to disease progression will be defined according to RECIST 1.1 
criteria for anatomically defined lesions.  
Biochemical progression will be defined as a 50% increase in thyroglobulin levels (either 
stimulated or unstimulated) over baseline or nadir, whichever is lower; or a minimum of 
10% increase in thyroglobulin levels on each of three consecutive measurements if each 
measurement is obtained at least 12 weeks apart. 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Institutional Review Board 
The study will be performed in accordance with ethical principles as enshrined in the Declaration 
of Helsinki and consistent with ICH/Good Clinical Practice as adopted by the FDA in the Federal 
regulations, and applicable regulatory requirements for subject data protection. Copies of the 
Declaration of Helsinki and amendments will be provided upon request or can be accessed via the 
website of the World Medical Association at http://www.wma.net/e/policy/17-c_e.html. 
The Emory University Institutional Review Board (IRB) will have oversight responsibility and 
must approve the final study protocol, including the final version of the ICF and any other written 
information and/or materials to be provided to the patients. The protocol will be re-approved by 
the IRB annually or at any other interval deemed appropriate by the IRB.  
The study sponsor will provide Regulatory Authorities, IRBs and Investigators with safety updates 
or reports according to local requirements. Eisai will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements. 
 
12.2 
Informed consent 
Each subject (or legally authorized representative) must receive adequate information regarding 
the nature of the study, its purpose, the procedures involved, the expected duration, the potential 
risks and benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect subsequent medical treatment or relationship with 
the treating physician. 
The informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should have adequate amount of time to read and consider the 
consent document before signing and should be given a copy of the signed document. No patient 
can enter the study before his/her informed consent has been obtained. 
 
12.3 
Amendment to the protocol and informed consent form 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by Eisai before implementation. Amendments significantly 
affecting the safety of subjects, the scope of the investigation or the scientific quality of the study 
require additional approval by the IRB.   
Examples of amendments requiring such approval are: 
• Increases in drug dose or duration of exposure of subjects, 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
39 
• Significant changes in the study design (e.g. addition or deletion of a control group) 
• Increases in the number of invasive procedures 
• Addition or deletions of a test procedure required for monitoring of safety. 
 
These requirements for approval should in no way prevent any immediate action from being taken 
by the investigator in the interests of preserving the safety of all patients included in the trial.  If 
an immediate change to the protocol is felt to be necessary by the investigator and is implemented 
for safety reasons Eisai will be notified and the IRB must be informed immediately. Amendments 
affecting only administrative aspects of the study do not require formal protocol amendments or 
IRB approval but the IRB must be kept informed of such administrative changes.  
Examples of administrative changes not requiring formal protocol amendments and IRB approval 
include: 
• Changes in the staff used to monitor trials  
• Minor changes in the packaging or labeling of study drug. 
 
12.4 
Data Collection and Management 
Data will be collected using an institutional electronic data recording system, Oncore. Electronic 
case report forms and study calendar will be generated prior to study activation. Investigator 
responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and in the US 
Code of Federal Regulations. The Investigator will permit study-related audits by Eisai or its 
representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, EMEA), providing direct 
access to the facilities where the study took place, to source documents, to CRFs, and to all other 
study documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during audits to review data and resolve any queries and to allow direct access to the subject’s 
records (e.g., medical records, office charts, hospital charts, and study related charts) for source 
data verification. The data collection must be completed prior to each visit and be made available 
so that the accuracy and completeness may be checked. 
 
12.4.1 Disclosure and confidentiality 
The investigator will keep all information provided by Eisai in strict confidence and will request 
similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents provided by 
Eisai (investigators' brochures and other material) will be stored appropriately to ensure their 
confidentiality. The information provided to the investigator may not be disclosed to others 
without direct written authorization from Eisai, except to the extent necessary to obtain informed 
consent from patients who wish to participate in the trial. 
All study participant information will be kept in a confidential manner by the assigning of a unique 
random number to each study participant. All data will be kept confidential as per institutional 
guidelines and policies. Any breach of confidentiality is a serious matter and conflicts with 
institutional policies and will be reported to the IRB.  
 
 
12.4.2 Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of the study 
and the distribution of the protocol therapy, that is copies of CRFs and source documents (original 
documents, data, and records [e.g., hospital records; clinical and office charts; laboratory notes; 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
40 
memoranda; subject’s diaries or evaluation checklists; SAE reports, pharmacy dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives, microfilm, or magnetic media; x-rays; 
subject files; and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical study; documents regarding subject treatment and drug 
accountability; original signed informed consents, etc.]) be retained by the Investigator for as long 
as needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval). 
 
12.5 
Training of study site personnel 
The study PI (sponsor-investigator) will provide training as appropriate to the delegated 
responsibility to all staffs involved in the conduct of the study. Before the first patient is enrolled 
in the study, study staff and co-investigators will review and discuss the requirements of the 
clinical study protocol and related documents including getting trained in any study-specific 
procedures and electronic data capture systems to be utilized. 
The Sponsor-Investigator will ensure that appropriate training relevant to the study is given to all 
of these staff and any new information relevant to the performance of this study is forwarded to 
the staff involved. The Principal Investigator will maintain a record of all individuals involved in 
the study (medical, nursing, and other staff). 
 
12.6 
Study oversight and data monitoring 
 
12.6.1 Source data and documents 
In accord with section 1.51 of the ICH E6 document all information in original records and 
certified copies of original records or clinical findings, observations, or other activities necessary 
for the reconstruction and evaluation of the trial is considered source data. Source data are 
contained in source documents, which can be original records or certified copies of hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects' diaries of evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial.  
Case Report Forms (CRFs): Source data may be collected in the source documents or entered 
directly onto the case report forms. 
 
12.6.2 Data and Safety Monitoring Committee 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will provide 
oversight for the conduct of this study.  The DSMC functions independently within Winship 
Cancer Institute to conduct internal monitoring functions to ensure that research being conducted 
by Winship Cancer Institute Investigators produces high-quality scientific data in a manner 
consistent with good clinical practice (GCP) and appropriate regulations that govern clinical 
research. Depending on the risk level of the protocol, the DSMC review may occur every 6 months 
or annually.  For studies deemed High Risk, initial study monitoring will occur within 6 months 
from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed.  For studies 
deemed Moderate Risk, initial study monitoring will occur within 1 year from the date of the first 
subject accrued, with 2 of the first 5 subjects being reviewed.  Subsequent monitoring will occur 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
41 
in routine intervals per the Winship Data and Safety Monitoring Plan (DSMP).  
 
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with the 
protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute Internal 
Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, accuracy and 
availability of source documents, AEs/SAEs, and essential regulatory documents.  Following the 
monitoring review, monitors will provide a preliminary report of monitoring findings to the PI and 
other pertinent individuals involved in the conduct of the study.  The PI is required to address and 
respond to all the deficiencies noted in the preliminary report.  Prior to the completion of the final 
summary report, monitors will discuss the preliminary report responses with the PI and other team 
members (when appropriate).  A final monitoring summary report will then be prepared by the 
monitor.  Final DSMC review will include the final monitoring summary report with 
corresponding PI response, submitted CAPA (when applicable), PI Summary statement, and 
available aggregate toxicity and safety data.   
 
The DSMC will render a recommendation and rating based on the overall trial conduct.  The PI is 
responsible for ensuring that instances of egregious data insufficiencies are reported to the IRB.  
Continuing Review submissions will include the DSMC recommendation letter.  Should any 
revisions be made to the protocol-specific monitoring plan after initial DSMC approval, the PI will 
be responsible for notifying the DSMC of such changes.  The Committee reserves the right to 
conduct additional audits if necessary. 
 
 
12.7 
Study site and timeline 
12.7.1 Number of patients & centers 
The maximum number of patients enrolled depends on the overall toxicity and DLT experience on 
study. We project a minimum of 15 patients and maximum of 30 patients depending on whether o 
not the study was stopped after the planned interim analysis or proceed to full accrual. This is a 
single center study to be conducted at the Emory University Winship Cancer Institute, an NCI-
designated comprehensive cancer center. 
 
12.7.2 Population 
Patients with advanced differentiated thyroid cancer who have been previously treated with 
therapeutic doses of RAI and who are candidates for further RAI treatment will be enrolled to the 
study.  
 
12.7.3 Study duration/timelines:  
Total accrual duration: 36 months 
Study start (FPFV): 04/01/2018 
Recruitment end (LPFV):  03/31/2021  
End of Study (LPLV): 09/30/2021 
Completion of study report (CSR) - 03/31/2022 
Publication date -06/30/2022 
 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
42 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
The primary objective of this Phase II trial is to determine the time to treatment failure. We expect 
that the addition of lenvatinib to RAI will significantly improve the duration of benefit measured 
as time to treatment failure (anatomic progression or doubling of TG) in patients treated with RAI 
along with short duration lenvatinib compared to repeat treatment of the same patients with RAI 
alone.  
 
From previous data, we assume that the enrolled patients without the lenvatinib would have 
progressed on prior RAI at a median time of 6 months and that the addition of lenvatinib will 
double the duration of benefit from repeat RAI to a median time of 12 months. We wish to have 
power = 0.90 at the significance level of 0.05 to correctly detect that improvement in median time 
to progression from 6 moths to 12 months. Since only an improvement in median time to 
progression is of clinical interest, we have a directional hypothesis, and have used a 1-sided alpha. 
Using a one-sample survival study design, with assumed accrual duration of 12 months and 
additional follow-up time of 6 months, the minimum sample size requirement is N=30 patients. 
 
The time-to-progression will be the primary endpoint for study, and will be determined using all 
enrolled patients in accordance with the intention to treat (ITT) principle. The censored time-to-
treatment failure will be estimated with standard Kaplan-Meier methodology. Both point and 90% 
confidence interval estimates of the median and other statistics (e.g., 3-month rate, 6-month rate, 
etc.) from the censored time-to-treatment failure distribution will be calculated. One interim 
analysis will be conducted after 15 patients have treatment failure and the trial will stop if the study 
is significantly better than the null hypothesis at the significance level of 0.0013 according to the 
O’Brien-Fleming Approach. Otherwise the trial will continue until the targeted sample size of 30 
patients is reached. 
 
 
13.2 
Sample Size/Accrual Rate 
Patient sample size is 30. Accrual rate is 2-3 per month.  
 
13.3 
Analysis of Secondary Endpoints 
Demographic and other baseline data will be summarized descriptively. Categorical data will be 
presented as frequencies and percentages. For continuous data, summary statistics will be 
presented (i.e., mean, median, standard deviation, minimum, maximum).  
in the expansion phase for each arm of the study. 
 
13.3.1 Analysis of Response Endpoints 
Efficacy evaluable population - Response will be analyzed in the following patient groups: 
• All patients who received any amount of the investigational agent 
• Patients who completed at least 2 cycles of therapy and have a baseline and restaging scans 
performed  
• All patients enrolled in the expansion cohort treated at the RP2D.  
 
Summaries of the number of patients with best objective response in each of the following 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
43 
categories will be provided:  
• Complete Response (CR) 
• Partial Response (PR) 
• Stable Disease (SD) 
• Progressive Disease (PD)  
• Non-Evaluable (NE) 
• Disease Control (DC = CR+PR+SD) 
Objective response rate and disease control rate will be summarized. For the expansion cohorts, 
objective response rate will be presented along with 95% exact confidence intervals.  
Demonstrate the safety of this approach 
Assess dynamic changes in established serum based biomarkers of DTC activity and putative  
Explore the utility of protein and genetic biomarkers to predict treatment efficacy. 
 
13.4 
Reporting and Exclusions 
 
13.4.1 Evaluation of Toxicity 
All patients who received any amount of the investigational agent will be evaluable for toxicity 
assessment.  
 
13.4.2 Evaluation of Response 
All patients included in the study will be assessed for anatomic response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one 
of the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
In addition, biochemical response will be assessed as follows:23 
 
• Excellent response: no clinical, biochemical, or structural evidence of disease 
• Biochemical incomplete response: abnormal thyroglobulin (Tg) or rising anti-
thyroglobulin antibody levels in the absence of localizable disease 
• Structural incomplete response: persistent or newly identified locoregional or distant 
metastases 
• Indeterminate response: non-specific biochemical or structural findings which cannot 
be confidently classified as either benign or malignant. 
 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be 
protocol specific.  


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
44 
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.). However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported. The 95% confidence intervals should also be provided.  
 
 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
45 
REFERENCES 
 
1. SEER Stat Fact Sheet: Thyroid Cancer Available from URL: 
http://seer.cancer.gov/statfacts/html/thyro.html [accessed October 20, 2016]. 
2. Schneider AB, Sarne DH. Long-term risks for thyroid cancer and other neoplasms after 
exposure to radiation. Nat Clin Pract Endocrinol Metab. 2005;1: 82-91. 
3. Haddad R, et al. . NCCN Guidelines Thyroid Carcinoma. National Comprehensive Cancer 
Network. 2016;Version 1.2016. 
4. Spitzweg C, Harrington KJ, Pinke LA, Vile RG, Morris JC. Clinical review 132: The sodium 
iodide symporter and its potential role in cancer therapy. J Clin Endocrinol Metab. 2001;86: 
3327-3335. 
5. Seidlin SM, Marinelli LD, Oshry E. Radioactive iodine therapy; effect on functioning 
metastases of adenocarcinoma of the thyroid. J Am Med Assoc. 1946;132: 838-847. 
6. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association 
Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid 
Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and 
Differentiated Thyroid Cancer. Thyroid. 2016;26: 1-133. 
7. Sabra MM, Grewal RK, Tala H, Larson SM, Tuttle RM. Clinical outcomes following empiric 
radioiodine therapy in patients with structurally identifiable metastatic follicular cell-derived 
thyroid carcinoma with negative diagnostic but positive post-therapy 131I whole-body scans. 
Thyroid. 2012;22: 877-883. 
8. Sabra MM, Dominguez JM, Grewal RK, et al. Clinical outcomes and molecular profile of 
differentiated thyroid cancers with radioiodine-avid distant metastases. J Clin Endocrinol Metab. 
2013;98: E829-836. 
9. Haugen BR, Sherman SI. Evolving approaches to patients with advanced differentiated 
thyroid cancer. Endocr Rev. 2013;34: 439-455. 
10. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159: 676-690. 
11. Zeng H, Dvorak HF, Mukhopadhyay D. Vascular permeability factor (VPF)/vascular 
endothelial growth factor (VEGF) peceptor-1 down-modulates VPF/VEGF receptor-2-mediated 
endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent 
pathways. J Biol Chem. 2001;276: 26969-26979. 
12. Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor 
signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2002;62: 
4645-4655. 
13. Mitsutake N, Knauf JA, Mitsutake S, Mesa C, Jr., Zhang L, Fagin JA. Conditional 
BRAFV600E expression induces DNA synthesis, apoptosis, dedifferentiation, and chromosomal 
instability in thyroid PCCL3 cells. Cancer Res. 2005;65: 2465-2473. 
14. Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA, Nistal M, Santisteban P. 
The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated 
papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. Endocr 
Relat Cancer. 2006;13: 257-269. 
15. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-
refractory thyroid cancer. N Engl J Med. 2015;372: 621-630. 
16. Robinson B, Schlumberger M, Wirth LJ, et al. Characterization of Tumor Size Changes Over 
Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer. J Clin Endocrinol Metab. 
2016;101: 4103-4109. 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
46 
17. Durante C, Puxeddu E, Ferretti E, et al. BRAF mutations in papillary thyroid carcinomas 
inhibit genes involved in iodine metabolism. J Clin Endocrinol Metab. 2007;92: 2840-2843. 
18. Knauf JA, Kuroda H, Basu S, Fagin JA. RET/PTC-induced dedifferentiation of thyroid cells 
is mediated through Y1062 signaling through SHC-RAS-MAP kinase. Oncogene. 2003;22: 
4406-4412. 
19. Liu D, Hu S, Hou P, Jiang D, Condouris S, Xing M. Suppression of BRAF/MEK/MAP 
kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the 
V600E BRAF mutant. Clin Cancer Res. 2007;13: 1341-1349. 
20. Chakravarty D, Santos E, Ryder M, et al. Small-molecule MAPK inhibitors restore 
radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J Clin 
Invest. 2011;121: 4700-4711. 
21. Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-Enhanced Radioiodine Uptake in 
Advanced Thyroid Cancer. New England Journal of Medicine. 2013;368: 623-632. 
22. Wicki A, Wild D, Pretre V, et al. Synergism of peptide receptor-targeted Auger electron 
radiation therapy with anti-angiogenic compounds in a mouse model of neuroendocrine tumors. 
EJNMMI Res. 2014;4: 9. 
23. Tuttle RM. Optimal management of a biochemical incomplete response to therapy in 
differentiated thyroid cancer: aggressive treatment or cautious observation? Endocrine. 2014;46: 
363-364. 
 
 
 
 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
47 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
48 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
[Note to authors:  This appendix consists of an “information sheet” to be handed to the patient at 
the time of enrollment.  Use or modify the text as appropriate for the study agent, so that the patient 
is aware of the risks and can communicate with their regular prescriber(s) and pharmacist.  A 
convenient wallet-sized information card is also included for the patient to clip out and retain at 
all times.  If you choose to use them, please note that the information sheet and wallet card will 
require IRB approval before distribution to patients.] 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
study drug, [insert study drug name]. This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
Lenvatinib interacts with the heart’s electrical activity (QTc prolongation).  
 
• The heart’s electrical activity may be affected by lenvatinib. The study doctor may be 
concerned about QTc prolongation and any other medicine that is associated with greater 
risk for having QTc prolongation.   
• This drug can cause elevated blood pressure. The study doctor may be concerned about the 
removal of any anti-blood pressure medications from the patient’s medication regimen.  
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Lenvatinib may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular medicines, 
or if you start taking a new medicine while you take part in this study.  When you talk about your 
current medications with your doctors, include medicine you buy without a prescription (over-the-
counter remedy), or any herbal supplements such as St. John’s Wort.  It is helpful to bring your 
medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical 
trial.  
 
These are the things that you and they need to know:  
 
Lenvatinib must be used very carefully in patients with high blood pressure.  Before you enroll 
onto the clinical trial, your study doctor will work with your regular health care providers to review 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
49 
any medicines and herbal supplements  that are considered part of your blood pressure regimen.  
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist 
to determine if there could be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.  
Your study doctor’s name is Taofeek K. Owonikoko, MD, PhD and he or she can be 
contacted at 404-778-1900. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study  
drug Lenvatinib.  This clinical trial is sponsored by Taofeek 
Owonikoko, MD, PhD.  Lenvatinib may interact with drugs that are 
[processed by your liver, or use certain transport proteins in your 
body or affects the electrical activity of your heart].  Because of this, 
it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that you may take.  
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is Taofeek K. Owonikoko, MD, PhD and 
can be contacted at 404-778-1900.  


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
50 
APPENDIX C 
PILL DIARY AND BP RECORD 
Study Title 
A PHASE 2 STUDY OF LENVATINIB IN COMBINATION WITH 
RADIOACTIVE IODINE THERAPY IN PATIENTS WITH PROGRESSIVE 
RAI-SENSITIVE DIFFERENTIATED THYROID CANCER 
Lenvatinib Pill Diary  
 
 
 
Subject Initials 
 
Subject ID 
 
Cycle # 
 
Research Coordinator 
Name: 
Phone: 
Pager: 
Cohort# 
Original Lenvatinib Dose 
…………………… 
BP - Baseline 
# of Dose Reductions  
 
Current Lenvatinib Dose 
:…………….. 
Current BP  
…………………………… 
Instructions: 
 
 
1. Please take the prescribed pills as instructed 
 
2. Please record the date and time you take your medications. On visit days, medications should be taken 
in the clinic unless otherwise instructed 
 
3. Please bring medication and pill diary to each study visit.  
Day 
Date 
Lenvatinib (Y/N) 
 
BP AM/PM 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
22 
 
 
 


Winship Cancer Institute  
Protocol #: Winship4271-18 
Version Date: 01.04.2021 
51 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 
 
I attest that I received the study medications listed on this pill diary. 
 
Patient Signature  
 
 
……………………………………… 
 
Date: ……………………………………… 
 
This section to be completed by a Research Personnel (Investigator, CRN/CRC) 
Dosing Cycle Start Date: 
Dosing Cycle End Date: 
Lenvatinib Lot Number: 
………… 
#  of Bottles / # of Tablets Dispensed :  
 ____4mg      ____10mg 
 
 
Any Interruptions?  
(Yes/No)…………. 
Length of Dose Interruption: 
 
Reason for Interruption: 
 
Reason for Dose Reduction: 
 
Additional Comments: