Conditions: Tumors
Keywords: Lenvatinib Lenvima E7080 Phase 1b/2 Pembrolizumab Keytruda Solid tumors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 357
Healthy volunteers: no

Brief summary:
This is an open-label Phase 1b/2 trial of lenvatinib (E7080) plus pembrolizumab in participants with selected solid tumors. Phase 1b will determine and confirm the maximum tolerated dose (MTD) for lenvatinib in combination with 200 milligrams (mg) (intravenous \[IV\], every 3 weeks \[Q3W\]) pembrolizumab in participants with selected solid tumors (i.e. non-small cell lung cancer, renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, melanoma or leiomyosarcoma). Phase 2 (Expansion) will evaluate the safety and efficacy of the combination in 7 cohorts at the MTD from Phase 1b (lenvatinib 20 mg/day orally + pembrolizumab 200 mg Q3W, IV).

Detailed description:

Arms:
arm 1: Participants with one of the tumors: non-small cell lung cancer, renal cell carcinoma, endometrial cancer, urothelial cancer, squamous cell carcinoma of the head and neck, melanoma or leiomyosarcoma.

Interventions: intervention 1: Lenvatinib intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Lenvatinib will be administered with water orally once a day (with or without food) continuously in 21-day treatment cycle. intervention 2: Pembrolizumab will be administered as a dose of 200 mg Q3W, IV in 21-day treatment cycle.

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol  
E7080-A001-111 
 
 
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Final: 30 July 2021 
Confidential 
Page 1 of 155  
 
1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol Number: 
E7080-A001-111 
Study Protocol Title: 
A Multicenter, Open-Label Phase 1b/2 Trial of Lenvatinib 
(E7080) Plus Pembrolizumab in Subjects With Selected Solid 
Tumors 
Sponsor: 
Eisai Inc. 
155 Tice Boulevard 
Woodcliff Lake,  
New Jersey 07677 
US 
Eisai Ltd. 
European Knowledge Centre 
Mosquito Way 
Hatfield, Hertfordshire 
AL10 9SN UK 
Investigational Product 
Name: 
Lenvatinib (E7080) and Pembrolizumab 
(MK-3475/KEYTRUDA®) 
Indication: 
Solid tumors 
Phase: 
Phase 1b/2 
Approval Date(s):  
22 Apr 2015 
14 Jan 2016 
30 Mar 2016 
26 Oct 2016 
23 May 2017 
22 Dec 2017 
31 Jul 2018 
19 Apr 2019 
24 Aug 2020 
30 July 2021 
 
Original Protocol 
Protocol Amendment 1 
Protocol Amendment 2 
Protocol Amendment 3 
Protocol Amendment 4 
Protocol Amendment 5 
Protocol Amendment 6 
Protocol Amendment 7 
Protocol Amendment 8 
Protocol Amendment 9 
 
IND Number: 
72010 
EudraCT Number: 
2017-000300-26 
GCP Statement: 
This study is to be performed in full compliance with 
International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) and all applicable local Good Clinical Practice 


Clinical Study Protocol  
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(GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary 
information of Eisai (the sponsor).  Any viewing or 
disclosure of such information that is not authorized in 
writing by the sponsor is strictly prohibited.  Such 
information may be used solely for the purpose of reviewing 
or performing this study. 


Clinical Study Protocol  
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REVISION HISTORY 
Amendment 09 
Date:  30 July 2021 
Change 
Rationale 
Affected Protocol Sections 
Revised and added text to clarify 
when treatment in the study would 
be discontinued, subject choice, 
completion of 35 treatments 
(approximately 2 years) with 
pembrolizumab, and lost to follow 
up.  
Added text to specify that the 
subjects who discontinued 
pembrolizumab for any reason and 
were still receiving lenvatinib 
study drug, will be transitioned to 
commercial lenvatinib if local 
country regulations permit.    
To clarify when treatment in the 
study would be discontinued. 
 
 
 
 
To define when subjects could 
be transitioned to treatment with 
commercial lenvatinib. 
• 
Synopsis, Study Design 
• 
Section 9.1 
 
 
 
 
• 
Synopsis, Study Design 
• 
Section 9.1 
Revised the frequency of tumor 
assessments in the Phase Ib and 
Phase 2 Extension Phase per local 
standard of care but not less 
frequent than every 6 months. 
Tumor assessments will not be 
collected during the Follow-Up 
period of the Extension Phase. 
To align with the standard of 
care for treatment of patients in 
the disease population and to 
clarify that the tumor assessment 
results will not be collected in 
the Follow-Up Period of the 
Extension Phase after the 
primary endpoint analysis in the 
study has been completed.  
• 
Synopsis, Study Design 
• 
Section 9.1 
• 
Section 9.5.1.3 
• 
Section 9.5.2, Table 8, 
footnote (m, n, o), Table 9, 
footnote (m, n, o) 
Added text to specify, the Follow-
Up Period will consist of the Off-
Tx Visit.  No further visits will be 
conducted.  The sponsor has 
decided to terminate survival 
follow-up for all subjects currently 
in survival follow-up. 
Survival follow-up data will no 
longer be collected after the Off-
Tx Visit and after 30 days from 
the last dose of study drugs. 
To clarify the duration of the 
Follow Up Period and data 
collection in the Follow Up 
Period. 
• 
Synopsis, Study Phases 
• 
Section 9.1.3.2 
• 
Section 9.3.3 
• 
Section 9.5.2 Table 8, v, bb 
and Table 9, v, bb 
Added text to clarify that subjects 
who undergo the Off-Tx visit will 
undergo safety follow-up for AEs 
for 30 days from the last dose of 
study treatment and for SAEs 90 
days after the last dose or 30 days 
following the last dose if the 
To clarify the timing of the AE 
and SAE collection following 
the Off-Tx Visit in the Follow-
Up Period. 
• 
Section 9.1 


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subject initiates new anticancer 
therapy, whichever is earlier.  
Revised the text to restart 
lenvatinib at least 2 weeks after 
major procedures. 
To align with the current 
protocol template and the label 
update. 
• 
Synopsis, Study Treatment 
Dose Modification 
• 
Section 9.4.1.1.1 
Updated the Dose-Modification 
and Toxicity Management 
Guidelines for Immune-Related 
AEs Associated with 
Pembrolizumab. 
The dose modification and 
toxicity management guidelines 
for immune-related adverse 
events and table were updated as 
requested by the US FDA in an 
effort to harmonize the 
presentation of safety 
information across all FDA-
approved PD-1/L1 antibody 
prescribing information. 
• 
Synopsis, Study Treatment 
Dose Modification 
• 
Section 9.4.1.2 Table 4 
Added text for the Management of 
QT Prolongation. 
To align with the current 
protocol template and the label 
update. 
• 
Section 9.4.1.1.8 
Added text for Management of 
Osteonecrosis of the Jaw. 
To align with the current 
protocol template and the label 
update. 
• 
Section 9.4.1.1.9 
Added text to indicate that as of 
Amendment 09, pre-baseline scans 
will no longer need to be provided 
for the renal cell carcinoma (RCC) 
cohort. 
To clarify that pre-baseline 
scans for RCC subjects are not 
required. 
• 
Synopsis, Efficacy 
Assessments 
• 
Section 9.5.1.3. 
Added text to specify, all study-
related medical or dental decisions 
must be made by an investigator 
who is a qualified physician. 
To align with the current 
protocol template. 
• 
Section 9.5.1 
Added oral examinations to be 
conducted during physical 
examinations prior to and 
periodically during lenvatinib 
treatment. 
To align with the current 
protocol template. 
• 
Synopsis, Safety 
• 
Section 9.5.1.2.1 
• 
Section 9.5.1.5 
• 
Section 9.5.1.5.5 
• 
Section 9.5.2, Table 8 and 
Table 9, footnote (e) 
Added text for collecting and 
reporting death.  All deaths will be 
collected for 30 days following the 
last dose of study treatment and 
To revise the time in the Follow-
Up Period when death events 
will be collected. 
• 
Section 9.5.1.5.1 


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Amendment 08 
Date:  24 Aug 2020 
reported on the Survival Case 
Report Form. 
Added text for monitoring QT 
prolongation and the method used 
to calculate QTc. 
To align with the current 
protocol template. 
• 
Section 9.5.1.5.6 
Added text to clarify investigator 
assessment will be based upon 
institutional reports. 
To align with the current 
protocol template. 
• 
Section 9.5.1.5.7 
Revised the frequency of 
MUGA/ECHO scans in the Phase 
Ib and Phase 2 Extension Phase to 
“as clinically indicated”. 
To align with the standard of 
care for treatment of patients in 
the disease populations.  
• 
Section 9.5.2, Table 8, 
footnote (z), Table 9, 
footnote (y) 
Revised the frequency of Weight 
and Body temperature in the Phase 
1b and Phase 2 Extension Phase to 
“as clinically indicated”. 
To align with the standard of 
care for treatment of patients in 
the disease population.  
• 
Section 9.5.2, Table 8, 
footnote (d), Table 9, 
footnote (d) 
Minor typographical and 
grammatical changes were made 
throughout the document. 
 
To correct or clarify text. 
• 
Throughout 
Change 
Rationale 
Affected Protocol Sections 
Scans acquired after data cutoff 
for final efficacy analysis will no 
longer be sent to the imaging core 
lab (ICL). 
Independent imaging review no 
longer required after final 
efficacy analysis data cut. 
 
Synopsis, Efficacy Assessments 
 
Section 9.5.1.3 
Added text for the renal cell 
cancer (RCC) cohort subjects that 
were pretreated with 
anti-PD-1/PD-L1 monoclonal 
antibody (mAb), to allow 
collection of available pre-
Baseline scans that demonstrate 
previous progression, and will be 
sent to an ICL. 
To allow for potential 
independent imaging review 
(IIR) of pre-Baseline scans for 
confirmed progression on the 
prior anti-PD-1/PD-L1 mAb. 
Synopsis, Efficacy Assessments 
 
Section 9.5.1.3 


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Revision to Amendment 07 
Date: 19 Apr 2019 
The pharmacokinetic 
(PK)/pharmacodynamics (PD) 
analyses are removed.  
PK/PD analyses are not an 
objective of this study. 
Synopsis, Pharmacokinetic-
Pharmacodynamic; Statistical 
Methods 
 
Section 9.7.1.1.3, Section 
9.7.1.2, Section 9.7.1.7.1, and 
Section 9.7.1.7.2 
The dose-normalized PK profile 
for lenvatinib in combination with 
pembrolizumab from this study 
will be compared graphically to 
that from subjects with different 
tumor types from completed 
studies of those receiving 
lenvatinib monotherapy. 
To compare the PK profile from 
this combination treatment study 
with that from lenvatinib 
monotherapy to assess any 
drug–drug interaction between 
lenvatinib and pembrolizumab. 
Synopsis, Pharmacokinetic; 
Statistical Methods 
 
Section 9.7.1.7.1 
To clarify that the blood sample 
for peripheral blood mononuclear 
cells (PBMCs) and plasma 
isolation was to be collected from 
Amendment 01. 
To clarify when this sample 
collection was implemented. 
Section 9.5.1.4.2 
Change 
Rationale 
Affected Protocol Sections 
Added text to indicate that the 
renal cell carcinoma (RCC) cohort 
will be expanded from 
approximately 120 to 
approximately 145 evaluable 
subjects. 
To permit approximately 100 
evaluable subjects in the RCC 
subset that were previously 
treated with an anti-PD-1/PD-L1 
treatment to be enrolled. 
Clinical Protocol Synopsis, 
Section 9.1, Figure 2 and 
footnotes, Section 9.3, Section 
9.7.2, and Section 9.7.3. 
Inclusion Criterion 1, PD-1 
Treatment Progression sub-
criterion (b), modified as follows:  
b) Has demonstrated disease 
progression after PD-1/PD-L1 as 
defined by Response Evaluation 
Criteria in Solid Tumors 
(RECIST) v1.1.  The initial 
evidence of disease progression 
(PD) is to be confirmed by a 
second assessmen no less than 
To clarify that the initial 
RECIST v1.1 evidence of PD is 
to be confirmed by a second 
assessment in all subjects. 
Clinical Protocol Synopsis, 
Section 9.1, Section 9.3.1 


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Revision to Amendment 06 
Date: 31 Jul 2018 
4 weeks from the date of the first 
documented PD. 
Added Table 13 and information 
to show the 95% confidence 
intervals (CI) for a range of 
observed ORRs from 25% to 45% 
in RCC subjects who had 
previously failed an anti-PD-1/PD-
L1 treatment with a sample size of 
100 subjects. 
To show how the increase in 
sample size following the 
second interim analysis 
improves the 95% CI of the 
ORR  
Section 9.7.2 
Added text to indicate that the 
regimen with an anti-PD-1/PD-L1 
mAb must be the most recent 
therapy  
To clarify that “the regimen with 
an anti-PD-1/PD-L1 mAb must 
be the most recent therapy”  
Clinical Protocol Synopsis, 
Section 9.1, Section 9.3.1 
Minor editorial changes 
To correct errors or clarify text.  
Throughout protocol 
Change 
Rationale 
Affected Protocol Sections 
Minor editorial changes 
To correct errors or clarify text, 
and to update study personnel 
Throughout, and Protocol 
Signature Page 
Increased the planned number of 
investigational sites to up to 25 
sites in the United States (US) and 
European Union (EU). 
To accommodate expansion of 
enrollment of the subset of 
subjects with renal cell 
carcinoma (RCC) who 
progressed after treatment with 
an anti-PD-1/PD-L1 monoclonal 
antibody (mAb). 
Clinical Protocol Synopsis, 
Section 6, and Section 9.3. 
Added text to indicate that the 
RCC cohort will be expanded to 
approximately 120 evaluable 
subjects. 
To clarify that, as of 
Amendment 06, 
“approximately” 120 subjects, 
rather than “up to” 120 subjects 
with RCC (per Amendment 05), 
would be enrolled. 
Clinical Protocol Synopsis, 
Section 9.1, Figure 2 footnote, 
Section 9.3, Section 9.7.2, and , 
and Section 9.7.3. 


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Assessments of tumor response 
based on independent imaging 
review (IIR) using Response 
Evaluation Criteria in Solid 
Tumors (RECIST v1.1) for 
subjects with endometrial cancer 
and for subjects with RCC were 
added to the exploratory 
objectives, and exploratory 
efficacy assessments were added 
to the corresponding exploratory 
endpoint. 
To add the standard RECIST 
v1.1 analysis of tumor 
assessment for subjects with 
RCC.  
Clinical Protocol Synopsis, 
Section 8.3, Section 9.7.1.1.3, 
and Section 9.7.1.6.3. 
Modified the Phase 2 expansion of 
enrollment in the RCC cohort to 
cap the number of treatment-naïve 
subjects at approximately 12 and 
to increase the number of 
previously treated subjects who 
progressed on or after treatment 
with an anti-PD-1/PD-L1 agent to 
33. 
To clarify that treatment-naïve 
subjects will no longer be 
enrolled and to increase 
enrollment of previously treated 
subjects who progressed after 
treatment with an anti-PD-1/PD-
L1agent to obtain additional 
efficacy and safety data in this 
subset of patients. 
Clinical Protocol Synopsis, 
Section 9.1, Figure 2, 
Section 9.3.1, Section 9.7.2, and 
Section 9.7.3. 
Revised Exclusion Criterion 12 
text to clarify that subjects who 
have had an allogenic tissue/solid 
organ transplant are to be 
excluded. 
To update text in accordance 
with current pembrolizumab 
label. 
Clinical Protocol Synopsis and 
Section 9.3.2. 
Added text to indicate that the 
second interim analysis will 
include the 11 treatment-naïve 
RCC subjects included in the first 
interim analysis plus the 45 
additional RCC subjects enrolled 
after completion of the first 
interim analysis. 
To clarify which subjects with 
RCC will be included in the 
second interim analysis. 
Clinical Protocol Synopsis, 
Section 9.1, Section 9.7.2, and 
Section 9.7.3. 
Specified that the decision to 
continue to expand enrollment of 
the subset of RCC subjects who 
progressed on or after previous 
treatment with an anti-PD-1/PD-
L1 agent will be based on review 
of efficacy and safety data from 
the second interim analysis. 
To clarify that further expansion 
of the RCC cohort based on 
results of the second interim 
analysis would be limited to 
previously treated subjects with 
RCC who progressed on or after 
anti PD-1/PD-L1 treatment. 
Clinical Protocol Synopsis, and 
Section 9.7.2, and Section 9.7.3. 


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Revisions to Amendment 05 
Date:  22 Dec 2017 
Specified that available mutation 
status, including mismatch repair 
(MMR) or microsatellite 
instability (MSI) status, will be 
collected on the electronic case 
report form (eCRF). 
To ensure that MMR and MSI 
data are collected on the eCRF 
for possible evaluation. 
Clinical Protocol Synopsis and 
Section 9.5.1.4.2 
Updated Table 12 for the second 
interim analysis in the RCC 
cohort. 
To adjust the objective response 
rate (ORR) estimate and 2-sided 
95% confidence interval of the 
ORR for the second interim 
analysis based on updated 
enrollment numbers.  
Section 9.7.2 
Updated reference list 
To delete references that were 
no longer cited in the protocol. 
Section 10 
Change 
Rationale 
Affected Protocol Sections 
Minor editorial changes 
To correct errors or clarify text.  
Throughout 
Abbreviation list was updated. 
To ensure updated abbreviation 
list. 
List of abbreviations and 
definition of terms 
In the Phase 2 expansion, added 
the option to increase enrollment 
in the renal cell carcinoma (RCC) 
cohort to up to 120 subjects based 
on the results of 2 interim 
analyses, after 22 and 56 subjects 
have sufficient follow-up to be 
evaluated for response.   
Added text to specify that after the 
first interim analysis, 
approximately 20 treatment- naïve 
subjects and an additional 25 
previously treated subjects who 
have received 1 or 2 prior 
therapies and have progressed on 
treatment with an anti-PD-1/PD-
L1 monoclonal antibody (mAb) 
will be enrolled.  
To obtain additional efficacy 
and safety data for the 
combination at the 
recommended Phase 2 dose 
(RP2D) for these defined RCC 
subject subsets.  
  
 
Clinical Protocol Synopsis, 
Section 9.1, Section 9.7.2, 
Section 9.7.3 


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As part of the second interim 
analysis, whether the cohort will 
be further expanded to 120 
subjects, and the proportion of 
subjects remaining to be enrolled 
who are treatment naïve vs those 
having 1 or 2 previous lines of 
therapy will be decided based on 
clinical review of both efficacy 
and safety data. 
Added exploratory objective, 
endpoint, and efficacy assessment 
to evaluate tumor response in 
subjects with RCC using 
independent imaging review (IIR). 
IIR assessment of tumor 
response for RCC subjects has 
been added to obtain unbiased 
independent review results to 
support investigator assessments 
and regulatory authority 
expectations. 
Clinical Protocol Synopsis, 
Section 8.3, Section 9.5.1.3, 
Section 9.7.1.1.3, 
Section9.7.1.6.3 
Revised Figure 2 – Study Design. 
To reflect revised study design 
with the expansion of the RCC 
cohort. 
Section 9.1 (Figure 2) 
Number of subjects was updated 
to reflect that the RCC cohort may 
be further expanded to up to 
120 evaluable subjects. 
To reflect the changes in sample 
in the RCC cohort.  
Clinical Protocol Synopsis 
(Number/Type of Subjects), 
Section 9.3 
Added new text to Inclusion 
Criterion 1 so as of Amendment 
05, for the RCC cohort, subjects 
are either treatment naïve or must 
have progressed on treatment with 
an anti-PD-1/PD-L1 mAb 
administered either as 
monotherapy, or in combination 
with other checkpoint inhibitors or 
other therapies. 
For the previously treated RCC 
subjects, it was specified that PD-
1 treatment progression is defined 
by meeting all of the following 
criteria: 
a) Has received at least 2 doses of 
an approved anti-PD-1/PD-L1 
mAb 
b) Has demonstrated disease 
progression after PD-1/PD-L1 as 
defined by RECIST v1.1.  The 
initial evidence of disease 
progression (PD) is to be 
confirmed by a second assessment 
no less than 4 weeks from the date 
of the first documented PD, in the 
absence of rapid clinical 
progression.  
To ensure there is a consistent 
application of the desired 
pre-study disease progression 
after prior anti-PD-1/PD-L1 
definition in this previously 
treated RCC subset and to 
decrease the risk of including 
subjects with 
pseudo-progression. 
Clinical Protocol Synopsis, 
Section 9.1, Section 9.3.1. 


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c) Progressive disease has been 
documented within 12 weeks from 
last dose of anti-PD-1/PD-L1 mAb 
(refractory disease) or ≥12 weeks 
from last dose of anti-PD-1/PD-L1 
mAb (late relapses). 
Modified Inclusion Criterion 1 for 
Phase 2 of the study to specify that 
previously treated subjects must 
have progressed pre-study.   
Also, it is required that subjects 
have received no more than 2 prior 
lines of therapy. Additional text 
stating “unless discussed with the 
sponsor” was deleted. 
To clarify that all previously 
treated subjects must have 
progressed pre-study to be 
eligible for enrollment in 
Phase 2.   
The rationale for the deletion is 
that no subjects who have 
received more than 2 prior lines 
of therapy will be permitted into 
the study. 
Clinical Protocol Synopsis, 
Section 9.3.1 
Wording of Exclusion Criterion 17 
modified to clarify that the 
exclusion of prior treatment with 
any anti-PD-1 or anti-PD-L1 agent 
does not apply for the previously 
treated RCC subset where prior 
treatment with one regimen 
containing an anti-PD-1/PD-L1 
mAb is required. 
Criterion 17 was also amended to 
emphasize that there will be “no 
exceptions” for prior lenvatinib 
treatment. 
To clarify that the exclusion 
does not apply for this defined 
previously treated RCC subject 
subset. 
Clinical Protocol Synopsis, 
Section 9.3.2 
 
Added text to clarify that 
“Treatment cycles will be counted 
continuously regardless of dose 
interruptions.” 
To provide a more consistent 
definition when treatment cycles 
are numbered or tabulated. 
Clinical Protocol Synopsis, 
Section 9.4.1.1, Section 9.4.5, 
and to Table 8 and Table 9 
footnote ‘b’. 
Updated and replaced the 
pembrolizumab 200 mg dose 
justification. 
Updated from Merck 
pembrolizumab standard 
protocol template language. 
Section 7.2 
The pembrolizumab dose 
modification table was replaced 
with an updated table.   
Updated from Merck 
pembrolizumab standard 
protocol template language. 
Clinical Protocol Synopsis and 
Section 9.4.1.2, Table 4 
Updated treatment guidelines for 
Grades 3 or 4 infusion reaction.  
Updated from Merck 
pembrolizumab standard 
protocol template language. 
Section 9.4.1.2.1, Table 5  
Updated supportive care 
guidelines for pembrolizumab. 
Updated from Merck 
pembrolizumab standard 
protocol template language. 
Section 9.4.1.2.1 
Added collection of Karnofsky 
Performance Status at Screening 
for RCC subjects only.  
To be able to retrospectively 
apply the International 
Metastatic Renal Cell 
Carcinoma Database 
Consortium (IMDC) model 
criteria to determine each 
Section 9.5.1.1, Table 8, Table 9  
Appendix 8 was added 


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Revisions to Amendment 04 
Date: 23 May 2017 
subject’s IMDC prognostic risk 
group (Favorable, Intermediate, 
or Poor Risk) for RCC subjects 
for future reporting purposes.  
Added information in NOTE for 
events of clinical interest. 
Updated from Merck 
pembrolizumab standard 
protocol template language. 
Section 9.5.1.5.2 
Updated text for definition of 
disease control rate (DCR) - 
stating that the irSD duration 
should be ≥5 weeks (previously 
mentioned as minimum duration 
from CID1 to irSD ≥5 weeks). 
To standardize definition for 
DCR. 
Statistical Methods of Clinical 
Protocol Synopsis, 
Section 9.7.1.1.2 
Added dataset definitions for 
(1) Renal Cell Carcinoma, (2) 
Non-Small Cell Lung Cancer, and 
(3) Melanoma Analysis Sets 
To clarify the populations from 
this study that are included in 
each cohort’s analysis set.  
Statistical Methods of Clinical 
Protocol Synopsis, 
Section 9.7.1.2 
Added the possibility of 
conducting efficacy and safety 
subgroup analyses for RCC cohort 
for treatment naïve subjects, 
subjects who were previously 
treated with an anti-PD-1/PD-L1 
therapy, and subjects who were 
previously treated without an anti 
PD-1/PD-L1 therapy.  
To evaluate the efficacy and 
safety in these subsets of 
patients. 
Clinical Protocol Synopsis 
(Efficacy Analyses, Safety 
Analyses), Section 9.7.1.6 
(Efficacy), Section 9.7.1.8 
(Safety)  
Clarified that adverse events will 
be summarized by subgroups (age, 
race, and sex), if necessary. 
The words “if necessary” were 
added to clarify that this 
subgroup analysis would 
performed if requested. 
Section 9.7.1.8.2 
Added sample size rationale for 
the RCC cohort expansion. 
To elucidate statistical 
ramifications of the selected 
sample sizes. 
Clinical Protocol Synopsis 
(Sample Size Rationale), 
Section 9.7.2, Section 9.7.3 
Table 12 was added  
Revised link to updated Keytruda 
Package Insert/SmPC. 
To ensure most recent package 
insert is referenced in the 
protocol. 
Section 10 (References), 
Section 12 (Appendix 7) 
Revised link to updated 
LENVIMA and KISPLYX 
Package Inserts/SmPCs. 
To ensure most recent package 
insert is referenced in the 
protocol. 
Section 10 (References) 
Reference list was updated to add 
additional references cited in 
Section 9.5.1.1. 
To add references cited in the 
protocol. 
Section 10 (References) 
Removed citation to “David, et al., 
in press.” 
To correct citation error. 
Section 7.1.2 


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Change 
Rationale 
Affected Protocol Sections 
Added name and address of Eisai 
Ltd as sponsor for the European 
Union (EU), and added EudraCT 
number to Title Page. 
To accommodate opening of 
sites in the EU to enrollment. 
Section 1 
Added text to indicate that the 
study must also be conducted in 
accordance with the European 
Good Clinical Practice Directive 
2005/28/EC and Clinical Trial 
Directive 2001/20/EC. 
To accommodate opening of 
sites in the EU to enrollment. 
Section 5.2 
Revised number of study sites 
from 5 in the US to up to 10 in the 
US and EU. 
To update number of study sites 
to accommodate opening of sites 
in the EU to enrollment.  
Clinical Protocol Synopsis and 
Section 9.3 
Revised the definition of the end 
of study to:  the time of data cutoff 
for the final analysis or the time of 
last subject/last treatment, 
whichever occurs later.   
To reflect the most recent 
definition of end-of-study in the 
protocol template. 
Section 5.1 and Section 9.1  
Inclusion Criterion 1 modified as 
follows: 
• 
Phase 2:  Histologically 
and/or cytologically 
confirmed metastatic selected 
solid tumor types with 0-2 
prior lines of systemic therapy 
(unless discussed with the 
sponsor).  
To clarify Inclusion Criterion 1 
for subjects enrolling in Phase 2 
of the study. 
Clinical Protocol Synopsis, 
Section 9.3.1 
Inclusion Criterion 11 modified to 
clarify steroid washout 
requirements. 
To clarify that subjects with 
brain metastases at baseline 
must be off steroids for at least 
28 days before starting study 
treatment. 
Clinical Study Synopsis and 
Section 9.3.1  
Inclusion Criterion 12 
contraceptive language was 
modified. 
Contraceptive language was 
modified to ensure compliance 
with current lenvatinib safety 
information. 
Clinical Study Synopsis and 
Section 9.3.1 
Changed title of lenvatinib dose 
reduction recommendation table, 
and added text in the footnote to 
specify that a discussion with the 
sponsor is required to resume 
lenvatinib treatment if it is 
interrupted for more than 21 days 
due to treatment-related toxicity.  
To clarify that dose reduction 
recommendations for lenvatinib 
are for treatment-related toxicity 
and to clarify that a discussion 
with the sponsor to reinstate 
lenvatinib treatment after a 
21-day interruption is only 
required if the interruption is 
due to lenvatinib-related 
toxicity. 
Clinical Protocol Synopsis, 
Section 9.4.1.1.1, Table 2, and 
Table 3 
Revised text to clarify that brain 
scans must be performed for all 
subjects, including those with head 
To clarify that brain scans must 
be performed for all subjects 
including those with HNSCC. 
Clinical Protocol Synopsis, 
Section 9.5.1.3, Table 8, and 
Table 9 


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and neck squamous cell carcinoma 
of the head and neck (HNSCC), at 
Screening, when clinically 
indicated, and to confirm immune-
related complete response (irCR) 
within 1 week of response. 
Revised text to clarify that bone 
scans must be performed for all 
subjects, except HNSCC subjects, 
at Screening, every 24 weeks, 
when clinically indicated, and at 
confirmation of irCR. Also, added 
text to indicate that if a bone scan 
is required, and the timing doesn’t 
coincide with a scheduled 
computed tomography (CT)/ 
magnetic resonance imaging 
(MRI) timepoint, it should be 
performed at the closest scheduled 
CT/MRI timepoint. 
To clarify the timing of 
performance of bone scans. 
Section 9.5.1.3, Table 8, and 
Table 9 
Revised background information 
on pembrolizumab. 
Updated Merck pembrolizumab 
standard protocol template 
language. 
Section 7.1.1 
Added and updated approved 
indications for lenvatinib and 
pembrolizumab in the US and EU, 
updated the lenvatinib label 
reference, and added references 
for Summary of Product 
Characteristics for lenvatinib and 
pembrolizumab. 
To add relevant background 
information for EU sites and 
investigators and to update 
approved indications and label 
references. 
Section 7.1.1, Section 7.1.2, 
Section 10, and Appendix 7 
Revised text for management of 
proteinuria. 
To ensure consistency in the 
management of proteinuria 
among the lenvatinib clinical 
studies.  
Section9.4.1.1.3 and 
Section 9.5.2.1, (Table 9) 
Added requirement that 
pembrolizumab treatment is to be 
discontinued for subjects with 
recurrent Grade 2 pneumonitis.  
Updated Merck pembrolizumab 
standard protocol template 
language. 
Clinical Protocol Synopsis and 
Section 9.4.1.2 (Table 4). 
Added additional background 
information on pembrolizumab.  
Updated Merck pembrolizumab 
standard protocol template 
language. 
Section 9.4.2.2. 
Management of hypertension 
section clarified that on the second 
and third reoccurrence of 
hypertension that lenvatinib 
administration should be 
interrupted, the dose should be 
reduced and only restarted once 
the subjects has been on a stable 
regimen of antihypertensive 
therapy and  acceptable blood 
pressures are recorded.   
Change made to ensure 
consistency in the management 
of hypertension across 
lenvatinib clinical studies.  
Section 9.4.1.1.2 


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Revised and clarified text for 
measurement of blood pressure 
(BP) as follows: 
• 
defined assessment of BP as 
the mean of 3 measurements 
at least 5 minutes apart,  
• 
clarified that subjects with 
elevated BP (≥140 mmHg 
systolic or ≥90 mmHg 
diastolic) were to have 
2 assessments at least 1 hour 
apart, and  
• 
clarified that subjects with 
systolic BP ≥160 mmHg or 
diastolic BP ≥100 mmHg 
must have their BP monitored 
every 2 weeks (on Day 1 and 
Day 15 or more frequently, as 
clinically indicated) until 
systolic BP has been 
≤150 mmHg and diastolic BP 
has been ≤95 mmHg for 
3 consecutive months 
To ensure consistency in BP 
measurements among the 
lenvatinib clinical studies. 
Section 9.5.1.5.4 and 
Section 9.5.2.1 (Table 9) 
Added blood sample collection for 
potential gene expression analysis. 
To obtain samples from Phase 2 
subjects for possible gene 
expression analysis. 
Clinical Protocol Synopsis, 
Section 9.5.1.4.2, Section 
9.5.2.1, Table 9 
Added text to footnote b to refer 
the reader to management of 
hypertension section for more 
specific dose modification 
guidelines for hypertension.  
Clarification, since more 
specific dose modification 
guidelines for hypertension is 
contained in Section 9.4.1.1.2. 
Clinical Protocol Synopsis, 
Section 9.4.1.2 (Table 2, 
Footnote b) 
Revised New York Heart 
Association (NYHA) Cardiac 
Disease Classification. 
To specify that the NYHA 
Classification applies to only 
subjects with heart failure and to 
clarify the Class categories. 
Appendix 4 
Added the following text to 
9.5.1.1: “FIGO grade (Creasman, 
2009) will be collected from all 
endometrial carcinoma subjects if 
available.” 
To obtain information on the 
stage of endometrial cancer 
from the subjects in Study -111. 
These data will be used to see if 
they have prognostic value when 
lenvatinib plus pembrolizumab 
are co-administered. 
Section 9.5.1.1 and reference 
added to 10 REFERENCE LIST. 
Added the following text: 
“Patients can receive up to 
35 treatments (approximately 
2 years) with pembrolizumab.” 
Updated Merck pembrolizumab 
standard protocol template 
language. 
 
“Overall Design” element of 
both the Clinical Protocol 
Synopsis and Section 9 
Investigational Plan, as well as in 
footnotes z. and aa. of Table 8 
and Table 9 respectively, of 
Section 9.5.2.1 Schedule of 
Procedures/ Assessments. 


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Revisions to Amendment 03 
Date: 26 Oct 2016 
Change 
Rationale 
Affected Protocol Sections 
Changed “urothelial cancer” to 
“urothelial carcinoma”, and 
“endometrial cancer” to 
“endometrial carcinoma” 
throughout the protocol 
Change made for consistency of 
terminology with Amendment 
02. 
Throughout the protocol. 
Added the recommended Phase 2 
dose of the combination  
determined during Phase 1 
To clarify dosage of the 
combination to be used in Phase 
2. 
Clinical Protocol Synopsis  
Added exploratory objective and 
endpoint to evaluate tumor 
response in the endometrial 
carcinoma cohort using 
independent imaging review (IIR).  
IIR assessment of tumor 
response results added to obtain 
unbiased results to support 
investigator assessments and 
potential regulatory filing. 
Clinical Protocol Synopsis, 
Section8.3, Section 9.7.1.1.3, 
Section 9.7.1.6.3 
In the Phase 2 expansion, added 
the option to increase enrollment 
in the endometrial carcinoma 
cohort to up to 120 subjects based 
on the results of 2 interim analyses 
after 21 and 60 subjects have 
sufficient follow-up to be 
evaluated for response.   
To obtain additional efficacy 
and safety data for the 
combination at the RP2D 
(lenvatinib 20 mg/day plus 
pembrolizumab 200 mg IV 
Q3W) in endometrial carcinoma 
based on clinical results. 
Clinical Protocol Synopsis, 
Section 9.1, Section 9.7.2, 
Section 9.7.3 
Inclusion criterion 1 modified to 
add requirement for previous 
therapy for the non-small cell lung 
cancer and melanoma cohorts 
To add a criterion for the non-
small cell lung cancer and 
melanoma cohorts, considering 
the current treatment practice. 
Clinical Protocol Synopsis, 
Section 9.3.1 
Exclusion criterion 20 modified to 
clarify that subjects with a history 
of non-infectious pneumonitis that 
required steroids and subjects with 
current pneumonitis are to be 
excluded. 
To ensure exclusion of subjects 
with non-infectious pneumonitis 
requiring steroid treatment, and 
subjects with current 
pneumonitis based on safety 
information from ongoing 
combination pembrolizumab 
clinical trials. 
Clinical Protocol Synopsis, 
Section 9.3.2 
Added text to separate dose 
modification instructions for 
lenvatinib- and pembrolizumab-
related toxicity. 
To further separate and clarify 
dose modification instructions 
for lenvatinib-related and 
pembrolizumab-related toxicity 
Clinical Protocol Synopsis, 
Section 9.4.1.1.1 
Added blood sample collection for 
potential pharmacogenomic 
analysis. 
To obtain samples from Phase 2 
subjects for possible 
pharmacogenomic analysis. 
Clinical Protocol Synopsis, 
Section 9.5.1.4.2, Section 
9.5.2.1, Table 9 
Updated list of approved 
indications for pembrolizumab in 
the US. 
To provide latest information on 
the approved indications for 
pembrolizumab in the US. 
Section 7.1.1 


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Revisions to Amendment 02 
Date: 30 Mar 2016 
Text added to clarify the definition 
of a prior systemic therapy for 
enrollment in Phase 2. 
Clarification of the definition of 
prior systemic therapy for the 
study sites. 
Section 9.4.7 
Added collection of peripheral 
blood mononuclear cells (PBMCs) 
to Schedule of Assessments 
To define the term PBMC and to 
clarify timing of collection of 
PBMCs.  
Section 9.5.2.1, Table 9 
Modified efficacy analysis plan to 
include a possible sensitivity 
analysis of the combination of 
lenvatinib + pembrolizumab 
comparing treatment-naïve 
subjects versus subjects with prior 
lines of systemic therapy. 
To evaluate selected efficacy 
parameters in treatment-naïve 
subjects versus previously 
treated subjects. 
Section 9.7.1.6 
Safety analysis plan modified to 
include a possible evaluation of 
safety of the combination of 
lenvatinib + pembrolizumab in 
treatment-naïve subjects versus 
subjects with prior lines of 
systemic therapy. 
To evaluate selected safety 
parameters in treatment-naïve 
subjects versus previously 
treated subjects. 
Section 9.7.1.8 
Change 
Rationale 
Affected Protocol Sections 
Limited renal cell carcinoma to 
“predominantly clear cell” renal 
cell carcinoma and clarified that 
subjects with uveal melanoma 
were excluded.  Changed 
endometrial cancer and urothelial 
cancer to endometrial carcinoma 
and urothelial carcinoma, 
respectively. 
To clarify that only subjects 
with “predominantly clear cell” 
renal cell carcinoma, melanoma 
(excluding uveal melanoma), 
endometrial carcinoma, and 
urothelial carcinoma are allowed 
in these 4 tumor type cohorts. 
Clinical Protocol Synopsis 
Inclusion Criteria and 
Section 9.3.1 - Inclusion 
Criterion 1.   
Exclusion Criterion 17 modified to 
allow, for the melanoma and 
NSCLC cohorts only, previous 
treatment by one PD-1, anti-PD-
L1, or anti-PD-L2 agent.  Previous 
treatment with a PD-1, anti-PD-
L1, or anti-PD-L2 agent is still 
excluded for the other 4 cohorts. 
To increase the rate of 
enrollment in the melanoma and 
NSCLC cohorts since (1) 
programmed death receptor-1 
(PD-1)-blocking antibodies have 
been approved in these 2 
indications and (2) the study 
sites participating in this 
protocol are tertiary cancer care 
centers which typically will not 
treat first-line subjects. 
Clinical Protocol Synopsis 
Exclusion Criteria and Section 
9.3.2 - Exclusion Criterion 17.   
For asymptomatic Grade ≥3 
elevations of amylase and lipase, 
the sponsor’s medical monitor can 
authorize continued treatment of 
the subjects.  
Some of the study investigators 
noted that asymptomatic Grade 
3 or 4 elevations in amylase and 
lipase are not uncommon in 
subjects receiving VEGF/TKIs 
and Checkpoint inhibitors.  They 
Clinical Protocol Synopsis - 
Study Treatment Dose 
Modifications for Lenvatinib and 
Pembrolizumab, Section 
9.4.1.1.1, Table 2 Dose 
Modifications for Lenvatinib, 


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Revisions to Amendment 01 
Date: 14 Jan 2016 
Change 
Rationale 
Affected Protocol 
Sections 
Exploratory Objectives 
Update to align with the planned 
biomarker analysis in the 
exploratory objective 
Add supporting languages in 
order to make the planned 
analysis clear.   
• 
Clinical Protocol synopsis 
• 
Section 8.3 
Inclusion Criteria #1 
Add an exception that subject 
who has not received nivolumab 
Nivolumab and pembrolizumab 
have been approved for 
melanoma and NSCLC and may 
be approved for additional tumor 
• 
Clinical Protocol synopsis 
• 
Section 9.3.1 
indicated that subjects will be 
lost unnecessarily (since the 
investigators cannot wait until 
amylase resolves to Grade 0-1, 
they have to take subjects off) 
while subjects are 
asymptomatic.  They also noted 
that, in other studies with 
VEGF/TKIs and Checkpoint 
inhibitors, the protocol includes 
the language that such subjects 
can continue treatment if 
asymptomatic and after 
discussion with the sponsor. 
Section 9.4.1.2, Table 4 Dose 
Modification Guidelines for 
Pembrolizumab-Related Adverse 
Events 
Added general guidelines for 
holding periods of lenvatinib due 
to minor and major procedures. 
To align this study with earlier 
Eisai protocols. 
Clinical Protocol Synopsis - 
Study Treatment Dose 
Modification for Lenvatinib and 
Section 9.4.1.1.1 Dose 
Modifications for Lenvatinib 
Mandatory requirement for freshly 
obtained biopsies from subjects in 
the NSCLC cohort changed to say 
that all efforts should be made to 
obtain the fresh biopsies. 
Based on advice from the study 
investigators that study 
enrollment will be difficult with 
mandatory requirements for 
freshly obtained biopsies. 
Clinical Protocol Synopsis  - 
Pharmacodynamic/ 
Pharmacogenomic and Section 
9.5.1.4.2 Pharmacodynamic, 
Pharmacogenomic, and Other 
Biomarker, Assessments, and 
Table 9 - Phase 2 – Schedule of 
Procedures/Assessments in the 
Pretreatment, Treatment, and 
Extension Phases 
Revised Pembrolizumab’s 
[Keytruda (US)] list of approved 
indications by country.   
Requested by Merck following a 
pembrolizumab labeling change 
in February 2016. 
Section 7.1.1 PD-1 Inhibitors and 
Pembrolizumab 
Paragraph relating to reporting of 
events of clinical interest (ECI) as 
serious within 24 hours removed. 
Merck notified Eisai that the 
ECI guidance document has 
been retired and it no longer 
requires ECI to be reported as 
serious within 24 hours.   
Section 9.5.1.5.2 Serious 
Adverse Events and Events 
Associated With Special 
Situations 


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or pembrolizumab can be 
enrolled in this study even if 
nivolumab or pembrolizumab is 
an approved therapy. 
types.  Although these are 
“approved therapies” since 
pembrolizumab is in the same 
class of drugs as nivolumab an 
Investigator could still enroll 
subjects with these tumors into 
Phase 1b in lieu of the approved 
nivolumab or pembrolizumab 
therapy. 
Inclusion Criteria #15 
Change to note that either 
“Archival tumor tissue or a newly 
obtained biopsy must be 
available prior to the first dose of 
study drug for biomarker 
analysis. Patients with 
inaccessible tumors for biopsy 
specimens can be enrolled 
without a biopsy upon 
consultation and agreement by 
the sponsor.” 
Allows subjects without 
sufficient archival tissue for 
biomarker analysis an alternate 
path for enrollment into the study.   
Also, provide the exception in 
case of patients with inaccessible 
tumors upon consultation and 
agreement by the sponsor.  
• 
Clinical Protocol synopsis 
• 
Section 9.3.1 
• 
Section 9.5.1.4.2 
• 
Section 9.5.2.1, Tables 8 
and 9 
Exclusion Criteria #2 
Change to “Subjects must have 
recovered adequately from any 
toxicity and/or complications 
from major surgery prior to 
starting therapy.” 
Recovery from major surgery is 
dependent upon the extent of the 
surgery as well as the physical 
state of the individual. The 
revised criterion allows the 
Investigator to determine the 
appropriate recovery period for 
each patient dependent upon that 
patient’s well-being. 
• 
Clinical Protocol synopsis 
• 
Section 9.3.2 
Exclusion Criteria #21 
Change to “Has received a live-
virus vaccination within 30 days 
of planned treatment start. 
Seasonal flu vaccines that do not 
contain live virus are permitted.” 
Updated by the latest 
pembrolizumab protocol template 
provided by Merck to make it 
specified. (“Pembrolizumab Text 
for Eisai PN146 27-Oct-2015.”) 
• 
Clinical Protocol synopsis 
• 
Section 9.3.2 
Update Dose Modification 
Guideline for Pembrolizumab-
Related Adverse Events 
Updated by the latest 
pembrolizumab protocol template 
provided by Merck 
(“Pembrolizumab Text for Eisai 
PN146 27-Oct-2015”). 
• 
Clinical Protocol synopsis 
• 
Section 9.4.1.2 
Update the introduction of 
pembrolizumab 
Updated by the latest 
pembrolizumab protocol template 
provided by Merck. 
(“Pembrolizumab Text for Eisai 
PN146 27-Oct-2015”). 
• 
Section 7.1.1 
Delete the description of Events 
of Clinical Interest (ECI) 
Guidance Document 
Merck notified Eisai that the ECI 
guidance document has been 
retired.   
• 
Section 9.4.1.2 
• 
Section 9.5.1.5.2 
• 
Section 9.5.4.1 
• 
Section 9.4.1.2.1 


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Reporting of ECI is no longer 
required 
• 
Section 9.5.4.3.2 
Laboratory Measurements: 
Delete the description of 
retrospective analysis for thyroid 
antibodies 
Aliquots of the samples will not 
be stored for potential 
retrospective analysis for thyroid 
antibodies.   
• 
Section 9.5.1.5.3, Table 7 
Clarify the planned analysis in 
Phase 2 
The change clarifies that there is 
no statistical analysis based 
Interim Analysis.   Sponsors and 
Investigators enrolling patients 
into the cohort will discuss the 
totality of the efficacy and safety 
data from the first 10 subjects and 
develop a consensus on whether 
expanding the cohort to 20 
subjects is warranted. 
• 
Section 9.7.3 
 


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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.  E7080, MK-3475 
Name of Active Ingredient:  Lenvatinib and Pembrolizumab 
Study Protocol Title:   
A Multicenter, Open-Label Phase 1b/2 Trial of  Lenvatinib (E7080) Plus Pembrolizumab in 
Subjects With Selected Solid Tumors  
Investigators 
To be determined 
Sites 
Up to 25 centers in the United States and the European Union (EU). 
Study Period and Phase of Development:  Phase 1b/2 
Objectives 
Primary Objectives 
• 
Phase 1b – Determination and confirmation of the maximum tolerated dose (MTD):  
- 
To determine and confirm the MTD for lenvatinib in combination with 200 mg 
(intravenous [IV], every 3 weeks [Q3W]) pembrolizumab in subjects with selected solid 
tumors. 
• 
Phase 2 – Expansion In Selected Tumor Types (Expansion):  
- 
To evaluate the objective response rate (ORR) as of Week 24 (ORR(Week 24): complete 
response [CR] + PR [CR(Week 24) + PR(Week 24)]) of lenvatinib in combination with 
pembrolizumab in each of the cohorts, using immune-related Response Evaluation Criteria 
in Solid Tumors (irRECIST). 
Secondary Objectives (for both Phase 1b and 2) 
• 
To assess:  
- 
Tolerability and safety profile of lenvatinib in combination with pembrolizumab 
- 
ORR by irRECIST of lenvatinib in combination with pembrolizumab in subjects with solid 
tumors 
- 
Progression-free survival  (PFS) by irRECIST 
- 
Overall survival (OS)  
- 
Duration of response (DOR) by irRECIST 
- 
Disease control rate (DCR: CR + PR + stable disease [SD]) by irRECIST 
- 
Durable stable disease rate (durable SD [SD ≥23 weeks]) by irRECIST 
- 
Clinical benefit rate (CBR: CR, PR + durable SD) by irRECIST  
- 
the pharmacokinetic (PK) profile of lenvatinib during combination treatment. 
Exploratory Objectives 
• 
To explore tumor response (eg, PR, CR, SD, PD) based on modified RECIST 1.1 assessments 
• 
To explore tumor response in subjects with endometrial carcinoma (EC) and renal cell 
carcinoma based on independent imaging review (IIR) using irRECIST, modified Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 and RECIST 1.1. 


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• 
To investigate the relationship between candidate efficacy biomarkers and anti-tumor activity 
of lenvatinib in combination with pembrolizumab: 
a. To evaluate the relationship between programmed cell death protein 1 ligand (PD-L1) 
expression levels and other relevant biomarkers (eg, tumor infiltrating lymphocytes, T-cell 
repertoire, ribonucleic acid [RNA] signature profiles) in tumor samples and anti-tumor 
activity of lenvatinib in combination with pembrolizumab. 
b. To evaluate differences in tumor tissue characteristics in biopsies taken post treatment with 
lenvatinib in combination with pembrolizumab versus baseline. 
Study Design 
Overall Design: 
This is a multicenter, open-label study with a Phase 1b and a Phase 2 component. 
Phase 1b - MTD:  This phase will determine and confirm the MTD of lenvatinib in combination 
with pembrolizumab.  Subjects in Phase 1b will have one of the following tumors: non-small cell 
lung cancer (NSCLC), renal cell carcinoma, EC, urothelial carcinoma (UC), squamous cell 
carcinoma of the head and neck, or melanoma.  Ten to 30 subjects will be enrolled in Phase 1b.  
The dose of 1 of the 2 study drugs, pembrolizumab, will not change during the MTD phase, while 
the second study drug, lenvatinib, will start at 24 mg and then be reduced, if necessary, to either 
20 mg or 14 mg. 
Phase 2 - Expansion:  Subjects will be assigned by tumor type to 1 of 6 cohorts to receive the 
MTD, which was established as the recommended Phase 2 dose (RP2D) in the Phase 1b portion of 
this study, (lenvatinib 20 mg/day orally + pembrolizumab 200 mg every 3 weeks [Q3W] IV) to 
assess the safety and efficacy of the combination in the selected tumor-types.  Each cohort will 
consist of subjects with 1 of the tumor types listed in the Phase 1b section above. 
For subjects in Phase 1b and Phase 2, toxicity will be managed by treatment interruption, dose 
reduction and/or treatment discontinuation in accordance with prespecified dose modification 
instructions.  Treatment will continue until disease progression, development of unacceptable 
toxicity, subject choice, withdrawal of consent, completion of 35 treatments (approximately 2 
years) with pembrolizumab, lost to follow up or discontinuation of this study by the sponsor.  
Patients can receive up to 35 treatments (approximately 2 years) with pembrolizumab.  Subjects 
who discontinue pembrolizumab for any reason and are still receiving lenvatinib study drug will be 
transitioned to commercial lenvatinib if local country regulations permit.  Subjects who discontinue 
pembrolizumab after 35 treatments may continue treatment with lenvatinib alone unless any other 
criteria above apply. 
Phase 1b - MTD:  Dosing will begin at the full dose of both drugs due to the well-established 
safety profiles of lenvatinib and pembrolizumab, the non-overlapping mechanisms of action, and 
the desire to treat patients at doses shown to be effective in previous studies. Lower dose levels of 
lenvatinib will be explored as necessary depending on observed toxicity. Phase 1b will begin with 
Dose Level 1; lenvatinib 24 mg/day orally and pembrolizumab 200 mg every 3 weeks IV will be 
administered to subjects with selected solid tumors on a 21-day treatment cycle.  Two dose de-
escalation steps are included: Dose Level 2 (lenvatinib 20 mg/day orally + pembrolizumab 200 mg 
Q3W, IV) and Dose Level 3 (lenvatinib 14 mg/day orally + pembrolizumab 200 mg Q3W, IV).  
For determination of MTD, only dose limiting toxicities (DLTs) during the first cycle of treatment 
will be assessed.  The determination of the DLT will be made jointly by the sponsor and 
investigators after safety data from each dose level have been reviewed. 
If 0 of 3 subjects in a given dose level cohort experiences a DLT, then 7 more subjects will be 
enrolled into that dose level to confirm the MTD.  If 1 of 3 subjects has a DLT, then 3 more 


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subjects will be enrolled into that dose level for a total of 6 subjects.  If only 1 of these 6 subjects 
has a DLT, then 4 more subjects will be enrolled into that dose level to confirm the MTD.  
If 2 or more subjects at a dose level experience a DLT, then, following consultation with the PIs 
the study will proceed with enrollment in the next defined lower dose (Dose Level 2 or 3), with 
dose reduction of lenvatinib to 20 or 14 mg once a day, respectively, in combination with 200 mg 
pembrolizumab Q3W. 
For confirming the MTD, DLTs and intolerable toxicities (that cannot be managed with dose 
interruption and/or reduction) during the first cycle of treatment for the 10 evaluable subjects at 
that dose level will be assessed.  The MTD will be confirmed if no more than 3 subjects experience 
DLTs during the first 3 weeks (Cycle 1) of treatment.  If the MTD is not confirmed at a dose level, 
then enrollment will proceed to the next lower dose level.  The sponsor and investigators will 
review all subjects’ safety and clinical data to jointly determine the RP2D of the combination of 
lenvatinib with pembrolizumab. 
If 2 or more subjects have a DLT in Dose Level 3, enrollment in the study will stop.   
A DLT is defined as any of the following: 
• 
Any of the hematological or nonhematological toxicities noted in the table below considered to 
be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1. 
• 
Failure to administer ≥75% of the planned dosage of lenvatinib as a result of treatment-related 
toxicity during Cycle 1. 
• 
Subjects who discontinue treatment due to treatment-related toxicity. 
• 
Greater than 2 week delay in starting Cycle 2 because of a treatment-related toxicity, even if 
the toxicity does not meet DLT criteria. 
 
Dose Limiting Toxicities 
Toxicity Category 
Toxicity CTCAE Grade 
Hematologic 
Grade 4 neutropenia for ≥ 7 days 
 
Grade 3 or Grade 4 febrile neutropeniaa 
 
Thrombocytopenia <25,000/mm3 associated with bleeding and/or 
that requires platelet transfusion 
Other nonhematologic 
toxicity 
Any other Grade 4 or a Grade 5 toxicity 
Grade 3 toxicities  lasting >3 days excluding: 
Nausea, vomiting, and diarrhea controlled by medical intervention 
within 72 hours. 
Grade 3 rash in the absence of desquamation, no mucosal 
involvement, does not require steroids, and resolves to Grade 1 by 
the next scheduled dose of pembrolizumab. 
 
Grade 3 hypertension not able to be controlled by medication  
 
Grade 3 or above gastrointestinal perforation 
 
Grade 3 or above wound dehiscence requiring medical or surgical 
intervention 
 
Any grade thromboembolic event 
 
Any Grade 3 nonhematologic laboratory value if: 
Medical intervention is required to treat the subject, or the 
abnormality leads to hospitalization 


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ANC = absolute neutrophil count, CTCAE = Common Terminology Criteria for Adverse Events v4.03. 
a. Febrile neutropenia Grade 3 or Grade 4:   
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained 
temperature of ≥38 °C (100.4 °F) for more than one hour. 
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained 
temperature of ≥38 °C (100.4 °F) for more than one hour, with life-threatening consequences and urgent 
intervention indicated 
 
Only toxicities with a clear alternative explanation (eg, due to disease progression) or transient 
(≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms 
based on investigator determination can be deemed a non-DLT. 
All subjects enrolled in Phase 1b will be assessed for DLTs during the DLT assessment window of 
Cycle 1 (Treatment Phase).  Subjects who discontinue study treatment prior to completing the 
Treatment Phase for any reason other than DLT will be replaced.  Once they complete the 
Treatment Phase, each subject still receiving study treatment will transition into the Extension 
Phase.  Tumor assessments will continue during the Extension Phase.  As of Amendment 09, tumor 
assessments will continue during the Extension Phase as per local standard of care but not less 
frequent than every 6 months.  Tumor assessments will not be collected during the Follow-Up 
period of the Extension Phase.  
 
Phase 2 - Expansion: 
After the MTD is confirmed, and depending on the safety and efficacy observed, 6 cohorts will be 
enrolled.  Each of these cohorts will enroll subjects with only 1 type of tumor (ie, NSCLC, 
predominantly clear cell renal cell carcinoma, EC, UC, melanoma (excluding uveal melanoma), or 
squamous cell carcinoma of the head and neck).  Lenvatinib in combination with pembrolizumab 
will be administered at the RP2D.  The intent is to enroll 20 subjects in each of the 6 cohorts, with 
possible expansion of enrollment in the endometrial and renal cell carcinoma cohorts.  For all 6 
cohorts, data from the first 10 subjects in each cohort will be reviewed by the sponsor and 
investigators.  At least 3 subjects must show responses in order to determine continued enrollment 
to 20 evaluable subjects.  
As of Amendment 3, the EC cohort may be further expanded to approximately 120 evaluable 
subjects.  The decision to expand enrollment will be based on the efficacy results of 2 interim 
analyses that will take place when 21 and 60 subjects have sufficient follow-up to be evaluated for 
response.  At the first interim analysis (N = 21), if there are more than 3 responses, then 
approximately 40 additional subjects will be enrolled.  At the second interim analysis (N = 60), if 
there are more than 12 responses, approximately 60 additional subjects will be enrolled.  If there 
are 12 or fewer responses, the sponsor may decide whether to expand enrollment based on clinical 
outcome, eg, ORR and DOR.   
As of Amendment 07, the renal cell carcinoma cohort may be further expanded to approximately 
145 evaluable total renal cell carcinoma (RCC) subjects to allow for approximately 100 evaluable 
subjects who have received 1 or 2 prior therapies that included an anti- programmed cell death 
protein 1 (PD-1)/ PD-1 ligand 1 (PD-L1) mAb.  The decision to expand enrollment will be based 
on the results of 2 interim analyses.  The first interim analysis will take place when 22 subjects, 
11 treatment naïve and 11 previously treated without an anti-PD-1/PD-L1 monoclonal antibody 
(mAb), have sufficient follow-up to be evaluated for response.  At the first interim analysis (N=22), 
if there are more than 5 responses, then approximately 45 additional subjects will be enrolled.  It is 
anticipated that the additional 45 subjects will consist of approximately 12 treatment naïve subjects 
enrolled under Amendment 05 and approximately 33 previously treated subjects who have received 


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1 or 2 prior therapies and have progressed on treatment with an anti-PD-1/PD-L1 mAb.  The 
second interim analysis will include these 45 additional subjects and the 11 treatment naïve 
subjects included in the first interim analysis, and will take place when these 56 subjects have 
sufficient follow-up to be evaluated for response.  At the second interim analysis, whether the 
previously treated RCC subset will be further expanded will be decided based on clinical review of 
both efficacy and safety data. 
 
Study Phases 
The study will be conducted in 3 phases:  a Pretreatment Phase, a Treatment Phase, and an 
Extension Phase. 
The Pretreatment Phase will last no longer than 28 days and includes: 
A Screening Period, to obtain informed consent and establish protocol eligibility, and a Baseline 
Period, to confirm protocol eligibility prior to treatment.  
The Treatment Phase will begin with the administration of the first dose of study drug to the first 
subject in Cycle 1 and will continue in 21-day (3-week) cycles.  The Treatment Phase consists of 1 
treatment period as described below.  
Treatment Period 
Phase 1b:  The Treatment Period for each subject ends after completing Cycle 1 of treatment or 
they discontinue early.  Those subjects who discontinue study treatment in Cycle 1 transition to the 
Off Treatment (Off-Tx) Visit of the Follow-up Period of the Extension Phase.  Those who 
complete Cycle 1 transition to the Treatment Period of the Extension Phase.   
Phase 2:  The Treatment Period for each subject ends after completing 8 cycles of treatment unless 
the subject discontinues early.  Those who discontinue study treatment before completing 8 cycles 
transition to the Off-Tx Visit of the Follow-up Period of the Extension Phase.  Those that complete 
8 cycles transition to the Treatment Period of the Extension Phase.   
Extension Phase 
The Extension Phase consists of a treatment period and a follow-up period. 
Treatment Period (Extension Phase):  Subjects still receiving study treatment at the end of the 
Treatment Phase will continue to receive the same treatment.  Those subjects that discontinue study 
treatment transition to the Off-Tx Visit of the Follow-up Period of the Extension Phase.  Note that 
all AEs must be captured for 30 days after last dose of study treatment.  
Follow-up Period (Extension Phase):  
As of Amendment 9, the Follow-Up Period will consist of the Off-Tx Visit.  No further visits will 
be conducted.  The sponsor has decided to terminate survival follow-up for all subjects currently in 
survival follow-up.  Survival follow-up data will no longer be collected after the Off-Tx Visit and 
after 30 days from the last dose of study drug. 
The Follow-up Period consists of the Off-Tx Visit and the Follow-up Visits.  The Off-Tx Visit 
will occur within 30 days following the last dose of study treatment.  It applies to the Phase 1b 
subjects that discontinued study treatment early, before completing Cycle 1, and to the Phase 2 
subjects who discontinued study treatment early, before completing 8 cycles.  Following the 
completion of the Off-Tx Visit, subjects will transition to the Follow-up Period of the Extension 
Phase.  Follow-up Visits continue as long as the study subject is alive unless the subject withdraws 
consent or until the sponsor terminates the study.  In the Follow-up Period, subjects will be treated 
by the investigator according to the prevailing local standard of care.  Subjects will be followed 
every 12 weeks (±1 week) for survival and subsequent anticancer treatments.  The sponsor may 


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decide to terminate survival follow-up anytime during the Extension Phase or when all subjects 
have discontinued study treatment.  
Number/Type of Subjects 
Phase 1b - Depending on the number of dose levels explored, the Phase 1b part of this study will 
enroll between 10 and 30 evaluable subjects with selected solid tumors. 
Phase 2 of this study will enroll subjects in 6 cohorts.  A sample size of 10 evaluable subjects will 
be enrolled per cohort, with the possibility of expansion to 20 evaluable subjects per cohort.  As of 
Amendment 3 the enrollment for the EC cohort may be further expanded to approximately 120 
evaluable subjects.  As of Amendment 7, the enrollment for the renal cell carcinoma cohort may be 
further expanded to approximately 145 evaluable subjects. 
Inclusion Criteria 
1. Phase 1b: Histologically and/or cytologically confirmed metastatic selected solid tumor types 
that have progressed after treatment with approved therapies or for which there are no 
standard effective therapies available.  If nivolumab or pembrolizumab is an approved 
therapy for the subject’s tumor type, but the subject has not been treated with it, the 
Investigator may enroll the subject in this study.   
Phase 2:  Histologically and/or cytologically confirmed metastatic selected solid tumor types 
with 0-2 prior lines of systemic therapy.  If previously treated, subject has progressed after 
previous treatment. 
As of Amendment 03, for the NSCLC and melanoma cohorts, subjects must have progressed 
on or after prior treatment with one anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
As of Amendment 05, for the renal cell carcinoma cohort, subjects are either treatment naïve 
or must have progressed on treatment with an anti-PD-1/PD-L1 mAb administered either as 
monotherapy, or in combination with other checkpoint inhibitors or other therapies.   
As of Amendment 06, for the RCC cohort, all subjects must have progressed on treatment 
with an anti-PD-1/PD-L1 mAb administered either as monotherapy, or in combination with 
other checkpoint inhibitors or other therapies, and as of Amendment 07, the regimen with an 
anti-PD-1/PD-L1 mAb must be the most recent therapy.   
PD-1 treatment progression is defined by meeting all of the following criteria: 
a) Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb. 
b) Has demonstrated disease progression after PD-1/PD-L1 as defined by RECIST v1.1. 
The initial evidence of disease progression (PD) is to be confirmed by a second 
assessment no less than 4 weeks from the date of the first documented PD  
c) Progressive disease (PD) has been documented within 12 weeks from last dose of 
anti-PD-1/PD-L1 mAb (refractory disease) or ≥12 weeks from last dose of anti-PD-
1/PD-L1 mAb (late relapses) 
Selected tumor types of both phases:  NSCLC, predominantly clear cell renal cell carcinoma, 
EC, UC, squamous cell carcinoma of the head and neck, or melanoma (excluding uveal 
melanoma). 
2. Life expectancy of 12 weeks or more 
3. Phase 2:  Measurable disease meeting the following criteria: 
• 
At least 1 lesion of ≥10 mm in the longest diameter for a non-lymph node or ≥15 mm 
in the short-axis diameter for a lymph node that is serially measurable according to 
irRECIST using computerized tomography/magnetic resonance imaging (CT/MRI). 


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• 
Lesions that have had external beam radiotherapy or loco-regional therapies such as 
radiofrequency ablation must show subsequent evidence of substantial size increase 
to be deemed a target lesion. 
4. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) of 0 to 1 
5. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤150/90 mmHg at screening and no change in antihypertensive medications 
within 1 week prior to the Cycle 1 (D1) 
6. Adequate renal function defined as creatinine ≤1.5 x upper limitis of normal (ULN) or 
calculated creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula with 
creatinine levels >1.5 x ULN 
7. Adequate bone marrow function:  
• 
Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 x 103/µL) 
• 
Platelets ≥100,000/mm3 (≥100 x 109/L) 
• 
Hemoglobin ≥9.0 g/dL 
8. Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤1.5 
9. Adequate liver function as evidenced by bilirubin ≤1.5 times the ULN and alkaline 
phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) 
≤3 × ULN (in the case of liver metastases ≤5 × ULN).  In case ALP is >3 × ULN (in the 
absence of liver metastases) or >5 × ULN (in the presence of liver metastases) AND the 
subject also is known to have bone metastases, the liver specific ALP isoenzyme must be 
separated from the total and used to assess the liver function instead of the total ALP  
10. Males or females age ≥18 years at the time of informed consent.   
11. Subjects with known brain metastases will be eligible if they have completed the primary 
brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or complete 
surgical resection) and if they have remained clinically stable, asymptomatic, and off of 
steroids for at least 28 days before starting study treatment.  
12. All females must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of beta-human chorionic gonadotropin [β-hCG]) at the Screening 
Visit and the Baseline Visit.  A pregnancy test needs to be performed within 72 hours of the 
first dose of study drug.  Females of childbearing potential* must agree to use a highly 
effective method of contraception for the entire study period and for 120 days after study 
discontinuation, ie:  
◦ 
total abstinence (if it is their preferred and usual lifestyle)  
◦ 
an intrauterine device (IUD) or hormone-releasing system (IUS) 
◦ 
a contraceptive implant 
◦ 
an oral contraceptive** (with additional barrier method) 
OR 
◦ 
have a vasectomized partner with confirmed azoospermia. 
For sites outside of the EU, it is permissible that if a highly effective method of contraception is 
not appropriate or acceptable to the subject, then the subject must agree to use a medically 
acceptable method of contraception, ie, double barrier methods of contraception such as condom 
plus diaphragm or cervical/vault cap with spermicide. 


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NOTES: 
*All females will be considered to be of childbearing potential unless they are postmenopausal 
(amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other 
known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total 
hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). 
**Must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks 
before dosing with study drug and for the duration of the study. 
13. Male subjects who are partners of women of childbearing potential must use a condom + 
spermicide and their female partners if of childbearing potential must use a highly effective 
method of contraception (see methods described in Inclusion Criterion #12) beginning at 
least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, and 
for 120 days after the last dose of study drug, unless the male subjects are totally sexually 
abstinent or have undergone a successful vasectomy with confirmed azoospermia or unless 
the female partners have been sterilized surgically or are otherwise proven sterile.   
14. Voluntary agreement to provide written informed consent and the willingness and ability to 
comply with all aspects of the protocol. 
15. Archival tumor tissue or a newly obtained biopsy must be available prior to the first dose of 
study drug for biomarker analysis. In the case archival tissue cannot be provided, patients 
with inaccessible tumors for biopsy specimens can be enrolled without a biopsy upon 
consultation and agreement by the sponsor. 
Note: In case of submitting unstained cut slides, freshly cut slides should be submitted to the 
testing laboratory within 14 days from when the slides are cut. 
Exclusion Criteria 
1. Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is shorter) 
or any investigational agent within 30 days prior to the first dose of study drugs.  All acute 
toxicities related to prior treatments must be resolved to Grade ≤1. 
2. Subjects must have recovered adequately from any toxicity and/or complications from major 
surgery prior to starting therapy. 
3. Subjects having >1+ proteinuria on urinalysis will undergo 24-h urine collection for 
quantitative assessment of proteinuria.  Subjects with urine protein ≥1 g/24-hour will be 
ineligible. 
4. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
might affect the absorption of lenvatinib 
5. New York Heart Association congestive heart failure of grade II or above, unstable angina, 
myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated with 
significant cardiovascular impairment within the past 6 months 
6. Prolongation of QTc interval to >480 msec 
7. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first 
dose of study drug 
8. Active infection (any infection requiring systemic treatment) 
9. Subject is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B, or 
Hepatitis C. 
10. Serious nonhealing wound, ulcer, or bone fracture 
11. Known intolerance to either of the study drugs (or any of the excipients) 


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12. History of organ allograft (subject has had an allogenic tissue/solid organ transplant) 
13. Biologic response modifiers (eg, granulocyte colony-stimulating factor) within 4 weeks 
before study entry.  Chronic erythropoietin therapy is permitted provided that no dose 
adjustments were made within 2 months before first dose of study treatment. 
14. Any medical or other condition which, in the opinion of the investigator, would preclude 
participation in a clinical trial 
15. Females who are pregnant or breastfeeding 
16. Excluding the primary tumor leading to enrollment in this study, any other active malignancy 
(except for definitively treated melanoma in-situ, basal or squamous cell carcinoma of the 
skin, or carcinoma in-situ of the bladder or cervix) within the past 24 months 
17. Prior treatment with lenvatinib (no exceptions) or any PD-1, anti-PD-L1, or anti-PD-L2 
agent, except:  
◦ 
the melanoma and NSCLC cohorts, where prior treatment with one anti-PD-1, anti-
PD-L1, or anti-PD-L2 agent is allowed 
◦ 
the previously treated renal cell carcinoma subjects (as of Amendment 05) where prior 
treatment with one regimen containing an anti-PD-1/PD-L1 mAb is required. 
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.  
The use of physiologic doses of corticosteroids (up to 7.5mg/d of prednisone or equivalent) 
may be approved after consultation with the sponsor.  
19. No active autoimmune disease that has required systemic treatment in past 2 years (ie, with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal 
or pituitary insufficiency, etc.) is not considered a form of systemic treatment.  
20. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
21. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted. 
Study Treatments 
Lenvatinib is provided as 4-mg and 10-mg capsules. Lenvatinib will be administered with water 
orally once a day (with or without food) in 21-day cycles at approximately the same time each day.  
Treatment cycles will be counted continuously regardless of dose interruptions.  On D1 of each 
cycle, it will be administered approximately within 1 hour after completion of pembrolizumab 
administration. 
Pembrolizumab may be provided as a sterile, preservative-free, white to off-white lyophilized 
powder in single-use vials.  Each vial is reconstituted and diluted for IV infusion.  Each 2 mL of 
reconstituted solution contains 50 mg of pembrolizumab.   
Alternatively, pembrolizumab may be provided as a sterile, preservative-free, clear to slightly 
opalescent, colorless to slightly yellow solution that requires dilution for IV infusion. Each vial 
contains 100 mg of pembrolizumab in 4 mL of solution.  Each 1 mL of solution contains 25 mg of 
pembrolizumab. Pembrolizumab will be administered as a dose of 200 mg as a 30-minute IV 
infusion, Q3W (25 minutes to 40 minutes are acceptable).  The Pharmacy Manual contains specific 
instructions for the preparation of the pembrolizumab infusion and administration of infusion 
solution. 
Study Treatment Dose Modification 
Lenvatinib 


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Lenvatinib dose reduction and interruption for subjects who experience lenvatinib-related toxicity 
will be in accordance with the dose reduction instructions shown in the tables below.  For 
management of hypertension and proteinuria, refer to the main protocol text for instructions before 
consulting the table below, as appropriate.  Any dose reduction below 4 mg/day must be discussed 
with the sponsor.  Once the dose has been reduced, it cannot be increased at a later date. Dose 
reductions of lenvatinib in Phase 2 occur in succession starting at the RP2D dose identified in 
Phase 1b. 
Lenvatinib 
Treatment-related 
Toxicitya,b 
During Therapy 
Adjusted Dosef 
Grade 1, Tolerable Grade 2 
 
Continue treatment 
No change 
Intolerable Grade 2c,d and Grade 3g 
First occurrence 
Interrupt lenvatinib until resolved to 
tolerable Grade 2, or Grade 0-1  
Reduce lenvatinib by 1 dose level 
Second occurrence  
(same toxicity or new 
toxicity) 
Interrupt lenvatinib until resolved to 
tolerable  Grade 2, or Grade 0-1  
Reduce lenvatinib by 1 more dose level 
Third occurrence 
(same toxicity or new 
toxicity) 
Interrupt lenvatinib until resolved to 
tolerable  Grade 2, or Grade 0-1  
Reduce lenvatinib by 1 more dose level 
Fourth occurrence 
(same toxicity or new 
toxicity) 
Interrupt lenvatinib until resolved to 
tolerable Grade 2, or Grade 0-1  
Reduce lenvatinib by 1 more dose level  
Grade 4e,g: Discontinue lenvatinib 
a. 
An interruption of lenvatinib treatment for more than 21 days (due to lenvatinib treatment-related toxicities) 
will require a discussion with the Sponsor before treatment can be resumed. 
b. 
Excluding alopecia.  Initiate optimal medical management for nausea, vomiting, hypothyroidism, 
hypertension, and/or diarrhea prior to any lenvatinib interruption or dose reduction.  For treatment-related 
hypertension, refer to Management of Hypertension (Section 9.4.1.1.2) for dose modification guidelines. 
c. 
Applicable only to Grade 2 toxicities judged by subject and/or physician to be intolerable. 
d. 
Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie, 
Grade 1 weight loss). These subjects will restart the study drug(s) at a lower dose once their weight remains 
stable for at least 1 week and they reached the normal body mass index (BMI) (if the weight loss occurred 
but  it is still above normal BMI, they can restart the study treatment at a lower dose once the weight has 
been stable for at least 1 week). Normal BMI should be used as the new baseline for further dose reductions. 
e. 
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
f. 
Refer to table below for adjusted dose. 
g. 
For asymptomatic Grade ≥3 elevations of amylase and lipase, the Sponsor`s Medical Monitor should be 
consulted to obtain permission to continue treatment. 
 
Dose Reduction Recommendations for Lenvatinib Treatment-Related Toxicity 
Initial Lenvatinib Dose (mg, QD) 
Adjusted Dose To Be Administered (mg, QD) 
Reduction 1 
Reduction 2 
Reduction 3 
Reduction 4 
24 
20 
14 
10 
8a 
20 
14 
10 
8 
4a 


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14 
10 
8 
4a 
 
QD = once a day 
a: Consult the sponsor for further dose reduction recommendations.  
 
General guidelines for holding periods of lenvatinib due to procedures: 
For minor procedures, lenvatinib should be stopped 2 days before the procedure and restarted 
2 days after, once there is evidence of adequate healing and no risk of bleeding.  Needle biopsies 
(fine needle aspirations and core needle aspiration) are usually considered minor procedures. 
For major procedures, lenvatinib should be stopped at least 1 week (5 half-lives) before the 
procedure and then restarted once there is clear wound healing and no risk of bleeding, but at least 
2 weeks after the procedure.  It is up to the investigator to determine if it is a major or minor 
procedure.  Usually a major procedure implies general anesthesia. 
 
Pembrolizumab 
Pembrolizumab dose interruption for subjects who experience pembrolizumab-related toxicity will 
be in accordance with the table below. 
Adverse events (AEs) (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These AEs may occur shortly after the first dose or several 
months after the last dose of treatment.  Pembrolizumab must be withheld for drug-related toxicities 
and severe or life-threatening AEs as per the table below.  See Protocol for supportive care 
guidelines, including use of corticosteroids. 
 
 
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse Events Associated with Pembrolizumab 
Immune-
related 
Adverse Event 
Toxicity Grade 
(CTCAE v4.0) 
Action with 
Pembrolizumab 
Corticosteroids and/or 
Other Therapies 
Monitoring and  
Follow-up 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. 
Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to 
≤ Grade 1 after corticosteroid taper. 
 
Pneumonitis 
Grade 2 
Withhold 
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or 
equivalent) followed by 
taper. 
Add prophylactic 
antibiotics for 
opportunistic infections. 
Monitor participants for 
signs and symptoms of 
pneumonitis. 
Evaluate participants with 
suspected pneumonitis 
with radiographic imaging 
and initiate corticosteroid 
treatment. 
Recurrent Grade 
2, 3 or 4 
Permanently 
discontinue 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 


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Recurrent Grade 
3 or Grade 4  
Permanently 
discontinue 
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or 
equivalent) followed by 
taper. 
 
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation (ie, 
peritoneal signs and 
ileus). 
Participants with ≥ Grade 
2 diarrhea suspecting 
colitis should consider GI 
consultation and 
performing endoscopy to 
rule out colitis 
Participants with diarrhea/ 
colitis should be advised 
to drink liberal quantities 
of clear fluids.  If 
sufficient oral fluid intake 
is not feasible, fluid and 
electrolytes should be 
substituted via IV 
infusion. 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 
Withhold 
Administer 
corticosteroids (initial 
dose of 0.5 to 1 mg/kg 
prednisone or 
equivalent) followed by 
taper. 
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or 
equivalent) followed by 
taper. 
Monitor with liver 
function tests (consider 
weekly or more frequently 
until liver enzyme value 
returned to baseline or is 
stable) 
Grade 3 or 4 
Permanently 
discontinue 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
Newly onset 
T1DM or Grade 
3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withholda 
Initiate insulin 
replacement therapy for 
participants with T1DM. 
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia.  
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated. 
Monitor for signs and 
symptoms of hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency). 
Grade 3 or 4 
Withhold or 
permanently 
discontinue 
Hyperthyroidism 
Grade 2 
Continue 
Treat with nonselective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate.  
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyronine) per 
standard of care. 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 2 
Withhold 


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Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury. 
Grade 3 or 4 
Permanently 
discontinue 
Administer 
corticosteroids 
(prednisone 1to 2 mg/kg 
or equivalent) followed 
by taper. 
Monitor changes of renal 
function. 
Myocarditis 
Grade 1  
Withhold 
Based on severity of AE 
administer 
corticosteroids. 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes. 
Grade 2, 3 or 4 
Permanently 
discontinue 
All other irAEs 
Persistent 
Grade 2 
Withhold 
 
 
Grade 3 
Withhold or 
discontinue based 
on eventb.   
Based on severity of AE 
administer 
corticosteroids. 
Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes. 
Recurrent Grade 
3 or Grade 4  
Permanently 
discontinue 
 
 
AE(s) = adverse event(s), ALT = alanine aminotransferase, AST = aspartate aminotransferase, CTCAE = Common 
Terminology Criteria for Adverse Events, DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI = 
gastrointestinal, IO=immuno-oncology; irAE = immune-related adverse event, IV = intravenous; SJS=Stevens-
Johnson Syndrome; T1DM = Type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of 
normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the 
investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
b Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, 
encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs (eg, vasculitis and 
sclerosing cholangitis). 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (eg, elective surgery, unrelated medical events, subject vacation, and/or 
holidays). Subjects should be placed back on study treatment within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor.  The reason for interruption should be 
documented in the subject's study record. 
Duration of Treatment  
Study duration for each subject is estimated to be: 
• Pretreatment Phase: 4 weeks 
• Treatment Phase: 
o Phase 1b: 3 weeks (1 cycle) 
o Phase 2: 24 weeks (8 cycles) 
• Phase 1b and 2 Extension Phase: Subjects will continue to receive study treatment until 
disease progression, development of unacceptable toxicity, subject choice, withdrawal of 
consent, completion of 35 treatments (approximately 2 years) with pembrolizumab, lost to 
follow up or discontinuation of this study by the sponsor.  Subjects who discontinued 
pembrolizumab for any reason and are still receiving lenvatinib study drug, will be transitioned 
to commercial lenvatinib if local country regulations permit.  


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Efficacy Assessments: 
Tumor assessments will be performed by the investigators based on both irRECIST and modified 
RECIST 1.1.  Treatment decisions by the investigator will be based on irRECIST.  All scans for 
tumor assessments performed during the study should be archived in accordance with the standard 
local practice. The Scans from Phase 1b must be accessible in the event of a sponsor request to 
submit them for central review.  For Phase 2, images acquired for tumor assessments will be sent to 
an imaging core laboratory (ICL)for archiving and potential independent analysis.  As of 
Amendment 3, tumor assessment scans for the EC subjects will be assessed by IIR.  As of 
Amendment 5, tumor assessment scans for the renal cell carcinoma subjects will also be assessed 
by IIR.  As of Amendment 08, for subjects enrolled in the RCC cohort who were previously treated 
with anti-PD-1/PD-L1 mAb, available pre-Baseline scans that demonstrate previous progression, 
will be collected by sites and sent to an ICL designated by the sponsor for quality assessment and 
archival, and potential future independent review.  
As of Amendment 08,  scans acquired after data cutoff for final efficacy analysis, in any cohort, 
will no longer be sent to the imaging core lab.  As of Amendment 09, pre-baseline scans for RCC 
subjects are not required. 
Tumor assessments will be carried out during the Pretreatment Phase and then every 6 weeks 
(during the sixth week; counting from C1D1) until Week 24, then every 9 weeks during treatment 
cycles in both the Treatment Phase and the Extension Phase. As of Amendment 09, tumor 
assessments will continue during the Extension Phase as per local standard of care but not less 
frequent than every 6 months.  Tumor assessments will not  be collected during the Follow-Up 
period of the Extension Phase.  Magnetic resonance imaging /MRI scans of chest, abdomen, and 
pelvis and of other known sites of disease will be obtained at Screening (within 28 days prior to 
Cycle 1 Day 1), at all tumor assessment time points, and as indicated clinically  and as per local 
standard of care.  Color photographs containing a millimeter scale must be taken of all skin lesions 
being used as target lesions.  Historical standard of care scans that are performed with scanning 
parameters consistent with the requirements for this protocol within 28 days prior to dosing are 
acceptable.  Subjects with squamous cell carcinoma of the head and neck must also have head and 
neck scans performed.   
 
Magnetic resonance imaging may be used instead of CT for head, neck, abdomen, and pelvis; 
however, the chest must be assessed using CT.  Chest disease may not be followed using chest x-
ray.   
A brain scan (CT with contrast or MRI pre- and post-gadolinium) must be performed at Screening 
to assess potential central nervous system (CNS) disease and/or metastases.  For subjects with 
previously treated eligible brain metastases, a brain scan must be performed at all tumor assessment 
time points.  For all subjects, a follow-up brain scan must be performed to confirm immune-related 
complete response (irCR) within 1 week of response confirmation, or if clinically indicated.   
The tumor assessment schedule should not be affected by interruptions in study treatment. 
Subjects going Off-Tx without disease progression will also undergo tumor assessments per the 
Schedule of Procedures/Assessments until disease progression is documented or another anticancer 
therapy is initiated.   
The same method of assessment must be used at all-time points as was used at Screening. 
Throughout the study it is critical that the same imaging methodology be applied and contrast be 
consistently provided unless IV contrast becomes medically contraindicated during the course of 
treatment or the dose of contrast needs to be adjusted based on the subject’s health status.   


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Bone scans will be performed at Screening, every 24 weeks, or sooner if clinically indicated, and at 
confirmation of irCR (except for subjects with squamous cell carcinoma of the head and neck).  
Lesions identified on bone scans must be verified and followed with correlative cross-sectional 
imaging.   
In order for immune-related stable disease (irSD) to be considered the best overall response, it must 
occur ≥5 weeks following the first dose of study drug. 
The first radiological assessment of tumor response status will be performed at Week 6 (±1 week), 
unless there is clinical indication warranting earlier radiologic imaging.  If imaging at Week 6 
shows irSD, treatment will be continued and tumor assessments will be conducted at the next 
regularly scheduled imaging time point, ie, at Week 12 (±1 week).  Responses (irPR [PR] or irCR) 
should be confirmed no less than 4 weeks after the initial response, but generally at the next 
scheduled tumor assessment time point.   
If the time point tumor assessment is PD, treatment should continue and tumor assessments be 
repeated at least 4 weeks later, but generally at the next scheduled tumor assessment time point in 
order to confirm immune-related progression disease (irPD).  If repeat imaging shows a reduction 
in the tumor burden compared to the initial tumor assessment demonstrating PD, treatment may be 
continued as per treatment schedule.  If repeat imaging confirms irPD, subjects will be 
discontinued from study treatment.  In determining the tumor time point response, investigators 
should consider all target lesions as well as nontarget lesions and new lesions.  The decision to 
continue study treatment after the first evidence of PD is at the investigator’s discretion based on 
the clinical status of the subject. 
Subjects may continue receiving study treatment while waiting for confirmation of PD if they are 
clinically stable as defined by the following criteria: 
• 
Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• 
No decline in ECOG PS 
• 
Absence of rapid progression of disease  
• 
Absence of progressive tumor at critical anatomical sites (eg, cord compression) requiring 
urgent alternative medical intervention 
If irPD is confirmed and the subject is experiencing extraordinary clinical benefit, the site must 
contact the sponsor to discuss continuing treatment. 
Tumor assessments per modified RECIST 1.1 will follow Eisenhauer, et al. (2009); however, up to 
10 target lesions, up to 5 per organ, may be selected (as opposed to a maximum of 5 target lesions, 
up to 2 per organ). 
Pharmacokinetic: 
Plasma concentrations of lenvatinib will be measured.   
Dose-normalized PK profile for lenvatinib in combination with pembrolizumab from this study 
will be compared graphically to that from patients with different tumor types from completed 
studies of those receiving lenvatinib monotherapy. 
Pharmacodynamic/Pharmacogenomic: 
Blood and Tissue Biomarkers:  Blood samples for the development of exploratory predictive 
biomarkers will be collected prior to the first dose of study drug, on Cycle 1 Day 15, and on D1 of 
all subsequent cycles during Treatment Phase, and at the Off-Tx assessment.  Subjects will be 
required to provide an archival tumor tissue sample and/or a fresh biopsy of tumor before treatment 
for biomarker analyses (patients with inaccessible tumors for biopsy specimens can be enrolled 
without a biopsy upon consultation and agreement by the sponsor).  For subjects in the NSCLC 


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cohort every effort is to be made to obtain a fresh biopsy of tumor at the beginning of Cycle 2 
(optional for other cohorts on study) if they have recovered adequately from the biopsy taken prior 
to starting therapy and to provide the acquired tissue for these biomarker analyses.  Biomarker 
discovery and/or validation will be performed to identify blood or tumor biomarkers that may be 
useful to predict subject response to lenvatinib and/or pembrolizumab, as determined by evaluation 
of response-related and/or safety-related outcomes as well as for potential use in diagnostic 
development.  Blood samples from subjects receiving lenvatinib and pembrolizumab may be 
analyzed using global proteomic methods, enzyme-linked immunosorbent assay (ELISA), 
multiplex bead-based immunoassay, or other assays/methods or new technology.  In addition, 
biomarkers identified in other lenvatinib clinical studies may also be assessed in the biomarker 
samples collected from subjects enrolled in this study.  The decision to perform exploratory 
biomarker analysis may be based on the clinical outcome of this study and/or the signals observed 
in other clinical studies or other information available at that time. 
Archived, formalin-fixed paraffin-embedded (FFPE) tissue or a newly obtained biopsy will be 
collected from all subjects for potential assessment of mutations and other genetic alterations 
and/or proteins including PD-1/PD-L1 status and other relevant biomarkers (eg, tumor infiltrating 
lymphocytes, T-cell repertoire, ribonucleic acid [RNA] signature profiles) which may be important 
in the development and progression of cancer as well as for potential use in diagnostic 
development.  Appropriate technology/methodologies will be used based on the amount of tumor 
tissue available. 
For all tumor types except NSCLS, optional fresh paired tumor biopsies will be collected from 
consented subjects to examine markers including markers of target engagement, relevant 
pharmacodynamic biomarkers, and potential markers of response.  Fresh biopsies should be limited 
to readily accessible tumor lesions (eg, skin, peripheral lymph nodes, liver metastases that can be 
readily accessed using CT guidance).  Subjects should have the biopsy before administration of the 
first dose of study drug and at a time point 3-6 weeks after the first dose (if they have recovered 
adequately from the biopsy taken prior to starting therapy).  For NSCLC, every effort is to be made 
to obtain a fresh tumor biopsy; subjects will have fresh tumor biopsies collected from consented 
subjects before administration of the first dose of study drug and at a time point 3-6 weeks after the 
first dose (if they have recovered adequately from the biopsy taken prior to starting therapy). 
A blood sample for peripheral blood mononuclear cells  and plasma isolation will be collected from 
enrolled subjects.  Cell free nucleic acid isolated from plasma samples may be used to obtain 
circulating tumor DNA (ctDNA) and explore tumor genetic alterations such as mutations observed 
in archival tumor samples as well as those which develop during drug treatment.   
In Phase 2, as of Amendment 4, a blood sample for nucleic acid analysis will be collected for 
potential assessment of gene expression profiling.  In Phase 2, as of Amendment 3, a blood sample 
will be collected for potential pharmacodynamics and pharmacogenomics analysis.  Variation in 
lenvatinib exposure or the occurrence of AEs observed in the study population may be evaluated by 
correlating single–nucleotide polymorphisms with PK, safety, or pharmacodynamic data.  Genomic 
DNA extracted from blood samples may be used to confirm whether the DNA sequence variants 
observed in DNA extracted from tumor material are limited to the tumor, for potential 
microsatellite instability analysis, and for potential immune response monitoring. 
As of Amendment 06, available known mutation status including mismatch repair (MMR) or 
microsatellite instability (MSI) status will be collected on the case report form. 
Data obtained will be used for research to assist in developing safer and more effective treatments 
and will not be used to change the diagnosis of the subject or alter the therapy of the subject.  The 
DNA will not be used to determine or predict risks for diseases that an individual subject does not 
currently have.  Any sample or derivatives (DNA, RNA, and protein) may be stored for up to 


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15 years to assist in any research scientific questions related to lenvatinib/pembrolizumab, cancer, 
and/or for potential diagnostic development.  
Instructions for the processing, storage, and shipping of samples will be provided in the Laboratory 
Manual. 
 
Safety: 
Safety assessments will consist of monitoring and recording all AEs and serious adverse events, 
using Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03; regular laboratory 
evaluation for hematology, blood chemistry, and urine values; regular performance of physical 
examinations (including oral examinations), periodic measurement of vital signs, and ECGs. 
Bioanalytical Methods 
Lenvatinib will be quantified using validated HPLC-tandem mass spectroscopy method.  
Statistical Methods 
Study Endpoints 
ORR(Week 24) is defined as the proportion of subjects who have best overall response (BOR) of 
irCR(Week 24) or irPR(Week 24) as of the Week 24 tumor assessment time point. 
ORR is defined as the proportion of subjects who have BOR of irCR or irPR at the time of data 
cutoff. 
PFS is defined as the time from the first study dose date to the date of first documentation of 
confirmed disease progression or death (whichever occurs first).  
OS is measured from the start date of the treatment period until date of death from any cause. 
Subjects who are lost to follow-up and the subjects who are alive at the date of data cutoff will be 
censored at the date the subject was last known alive. 
DCR is defined as the proportion of subjects who have BOR of irCR or irPR or irSD (duration of 
irSD ≥5 weeks). 
CBR is defined as the proportion of subjects who have BOR of irCR or irPR or durable irSD 
(duration of irSD ≥23 weeks). 
DOR is defined as the duration of irCR or irPR. 
Durable SD rate is defined as the proportion of subjects whose BOR is irSD and the duration of 
irSD is ≥23weeks. 
As exploratory analyses, tumor response endpoints will be evaluated for the subjects in the 
endometrial and renal cell carcinoma analysis sets using the IIR assessments.   
Analysis Sets: 
Safety Analysis Set will include all subjects who received any amount of study drug.  This will be 
the analysis set for all safety evaluations. 
MTD Analysis Set will include all subjects who completed Cycle 1 of treatment of Phase 1b or 
discontinued early due to DLT.  This will be the analysis set to determine MTD. 
Full Analysis Set (Intent-to-Treat [ITT] Analysis Set) will include all subjects who entered the 
study treatment period. 
PK Analysis Set: All the subjects who have received at least 1 dose of lenvatinib and have 
evaluable concentration data. 
Pharmacodynamic Analysis Set will include all subjects who have received at least 1 dose of 
study drug (lenvatinib or pembrolizumab) and have evaluable pharmacodynamic data. 


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Endometrial Carcinoma Analysis Set: will include all EC subjects from Phase 1b and Phase 2. 
Renal Cell Carcinoma Analysis Set will include all renal cell carcinoma subjects from Phase 1b 
and Phase 2. 
Non-Small Cell Lung Cancer Analysis Set will include all NSCLC subjects from Phase 1b and 
Phase 2. 
Melanoma Analysis Set will include all melanoma subjects from Phase 1b and Phase 2. 
Efficacy Analyses 
Selected efficacy analyses may be performed if needed for subjects with the combination of 
lenvatinib and pembrolizumab as the first line treatment versus other subjects with prior systemic 
therapies. For the renal cell carcinoma cohort, efficacy subgroup analyses may be presented for 
treatment naïve subjects, subjects who were previously treated with an anti-PD-1/PD-L1 therapy, 
and subjects who were previously treated without an anti-PD-1/PD-L1 therapy. 
Analysis of Primary Endpoint for Phase 1b: 
The primary objective of Phase 1b is to determine the DLTs, MTD, and to establish the RP2D.  
The efficacy endpoints in Phase 1b will be summarized and listed by dose level based on the Safety 
Analysis Set.  No statistical comparison will be performed.  
Analysis of Efficacy Endpoints for Phase 2: 
Efficacy analyses will primarily be based on the Full Analysis Set.  Efficacy (eg, ORR(Week 24), 
ORR, BOR during the Treatment and Extension Phases, PFS, DCR, durable SD, CBR) will be 
assessed by irRECIST and modified RECIST 1.1.  The efficacy endpoints will be summarized and 
listed by cohort.  No statistical comparison will be performed. 
Analysis of Primary Efficacy Endpoint for Phase 2: 
The primary efficacy endpoint in Phase 2 is ORR as of Week 24 (ORR(Week 24)) based on irRECIST 
based on the Full Analyses Set.  Estimated ORR(Week 24) and the exact 95% confidence intervals 
(CI) using the method of Clopper–Pearson will be presented.  The primary efficacy analysis will be 
performed when all subjects in the same cohort have completed 8 cycles of treatment, discontinued 
due to disease progression, developed unacceptable toxicity, withdrew consent, or the study is 
terminated by the Sponsor. 
Analysis of Secondary Efficacy Endpoints for Phase 2: 
The secondary efficacy endpoint will be OS, PFS, DCR, CBR, DOR, and durable SD (SD ≥23 
weeks) by irRECIST as appropriate.   
Median time to PFS and 95% CI will be provided for the data from this study by cohort as well as 
historical control data if available, and PFS will be analyzed using Kaplan–Meier (KM) product-
limit estimates along with KM plots. Three-month, 6-month, 9-month and 1-year PFS rates will be 
estimated from KM and corresponding 95% CI will be calculated. 
Median survival time and the 95% CI, the survival rates at 12, 18 and 24 months will be calculated 
using KM product-limit estimates for each cohort and presented with 2-sided 95% CIs.  KM plots 
for OS will be provided. 
Disease Control Rate, CBR, and durable SD rate will be provided with exact 95% CI using the 
method of Clopper and Pearson.   
Analysis of Exploratory Efficacy Endpoints: 
The tumor response endpoints will be explored based on modified RECIST 1.1 assessments, and 
will be summarized and listed by cohort.  No statistical comparison will be performed between 
irRECIST and modified RECIST 1.1 results.   


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The tumor response endpoints will also be evaluated for the subjects in the endometrial and renal 
cell carcinoma analysis sets using IIR assessment using irRECIST, modified RECIST 1.1 and 
RECIST 1.1 as exploratory analyses.  A concordance analysis will be performed comparing IIR 
and investigator assessments. 
Pharmacokinetic and/or Pharmacodynamic Analyses 
Pharmacokinetic: 
To assess any drug–drug interaction between lenvatinib and pembrolizumab, the dose-normalized 
PK profile for lenvatinib in combination with pembrolizumab from this study will be compared 
graphically to that from patients with different tumor types from completed studies of those 
receiving lenvatinib monotherapy. 
Pharmacodynamic: 
The effect of lenvatinib-pembrolizumab combination therapy on soluble, tissue, genetic and/or 
imaging biomarkers will be summarized using descriptive statistics using the pharmacodynamic 
analysis set.  
Safety Analyses: 
Safety analyses will be performed on the Safety Set.  Safety data will be summarized using 
descriptive statistics.  Categorical variables will be summarized by number and percentage.  
Continuous variables will be summarized using n (number of subjects with available data), mean, 
standard deviation (SD), median, and range (minimum and maximum) unless otherwise specified. 
Laboratory test results will be summarized using 3 categories, hematology, liver and renal, and 
other clinical chemistry.  Hematology and clinical chemistry parameters that are graded by CTCAE 
v 4.03 will be summarized by CTCAE grade.  Shifts from baseline to the worst CTCAE grade will 
be tabulated.   
Selected safety analyses may be performed if needed for subjects with the combination of 
lenvatinib and pembrolizumab as the first line treatment versus other subjects with prior systemic 
therapies.  For the renal cell carcinoma cohort, safety subgroup analyses may be presented for 
treatment naïve subjects, subjects who were previously treated with an anti-PD-1/PD-L1 therapy, 
and subjects who were previously treated without an anti-PD-1/PD-L1 therapy. 
Sample Size Rationale 
Phase 1b: A sample size of 10 to 30 subjects will be enrolled to assess MTD.  This is not based on 
statistical power considerations.  
Phase 2:  A sample size of 10 evaluable subjects will be enrolled per cohort, with the possibility of 
expansion to 20 evaluable subjects per cohort, depending on the evaluation by the sponsor and 
investigators of the efficacy and safety results observed with the initial 10 evaluable subjects in 
each cohort.    
As of Amendment 3, the EC cohort may be further expanded to approximately 120 evaluable 
subjects.  For this expansion decision, 2 interim analyses will take place when 21 and 60 subjects 
have sufficient follow-up to be evaluated for response.  The decision to expand enrollment will be 
based on the results of 2 interim analyses, which will spend β= 0.012 and β= 0.024 at the first and 
second interim analyses, respectively.  Based on an assumption of H0:  16% ORR and H1:  34% 
ORR, at 2-sided α = 0.02, this design will give 97% statistical power with 120 subjects.  At the first 
interim analysis (N = 21), if there are more than 3 responses, then approximately 40 additional 
subjects will be enrolled.  At the second interim analysis (N = 60), if there are more than 12 
responses, approximately 60 additional subjects will be enrolled.  If there are 12 or fewer 
responses, the sponsor may decide whether to expand enrollment based on clinical outcome, eg, 


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ORR and DOR.  If the expansion beyond 60 subjects does not happen, this design for the EC 
cohort has approximately 86% power at 2-sided α = 0.02. 
As of Amendment 7, the renal cell carcinoma cohort may be further expanded to approximately 
145 total evaluable subjects to allow for approximately 100 evaluable subjects who have received 1 
or 2 prior therapies that included an anti-PD-1/PD-L1 mAb.  The decision to expand enrollment 
will be based on the results of 2 interim analyses.  The first interim analysis will take place when 
22 subjects (11 treatment naïve and 11 previously treated without an anti-PD-1/PD-L1 mAb) have 
sufficient follow-up to be evaluated for response. At the first interim analysis (N = 22), if there are 
more than 5 responses, then approximately 45 additional subjects will be enrolled. It is anticipated 
that the additional 45 subjects will consist of approximately 12 treatment naïve subjects enrolled 
under Amendment 5 and approximately 33 previously treated subjects who have received 1 or 2 
prior therapies and have progressed on treatment with an anti-PD-1/PD-L1 mAb.  The second 
interim analysis will include these 45 additional subjects and the 11 treatment naïve subjects 
included in the first interim analysis and will take place when these 56 subjects have sufficient 
follow-up to be evaluated for response.  At the second interim analysis, whether the previously 
treated renal cell carcinoma subset will be further expanded will be decided based on clinical 
review of both efficacy and safety data. 
 


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
REVISION HISTORY...............................................................................................................3 
2 
CLINICAL PROTOCOL SYNOPSIS .............................................................................21 
3 
TABLE OF CONTENTS .................................................................................................41 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................45 
5 
ETHICS............................................................................................................................49 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................49 
5.2 
Ethical Conduct of the Study .................................................................................50 
5.3 
Subject Information and Informed Consent ...........................................................50 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................51 
7 
INTRODUCTION ...........................................................................................................51 
7.1 
Indication ...............................................................................................................51 
7.1.1 
PD-1 Inhibitors and Pembrolizumab ...........................................................51 
7.1.2 
Lenvatinib ....................................................................................................52 
7.2 
Study Rationale ......................................................................................................53 
8 
STUDY OBJECTIVES ....................................................................................................55 
8.1 
Primary Objectives .................................................................................................55 
8.2 
Secondary Objectives (for both Phase 1b and 2) ...................................................55 
8.3 
Exploratory Objectives ..........................................................................................55 
9 
INVESTIGATIONAL PLAN ..........................................................................................56 
9.1 
Overall Study Design and Plan ..............................................................................56 
9.1.1 
Pretreatment Phase .......................................................................................62 
9.1.1.1 
Screening Period ..................................................................................62 
9.1.1.2 
Baseline Period ....................................................................................63 
9.1.2 
Treatment Phase ...........................................................................................63 
9.1.2.1 
Treatment Period ..................................................................................63 
9.1.3 
Extension Phase ...........................................................................................63 
9.1.3.1 
Treatment Period ..................................................................................63 
9.1.3.2 
Follow-Up Period.................................................................................63 
9.2 
Discussion of Study Design ...................................................................................64 
9.3 
Selection of Study Population ................................................................................64 
9.3.1 
Inclusion Criteria .........................................................................................64 
9.3.2 
Exclusion Criteria ........................................................................................67 
9.3.3 
Removal of Subjects From Therapy or Assessment ....................................69 
9.4 
Treatments..............................................................................................................70 
9.4.1 
Treatments Administered .............................................................................70 


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9.4.1.1 
Lenvatinib ............................................................................................70 
9.4.1.2 
Pembrolizumab ....................................................................................75 
9.4.2 
Identity of Investigational Products .............................................................81 
9.4.2.1 
Chemical Name, Structural Formula of Lenvatinib .............................81 
9.4.2.2 
Information of Pembrolizumab ............................................................81 
9.4.2.3 
Labeling for Study Drug ......................................................................82 
9.4.2.4 
Storage Conditions ...............................................................................82 
9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................82 
9.4.4 
Selection of Doses in the Study ...................................................................82 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................82 
9.4.6 
Blinding........................................................................................................83 
9.4.7 
Prior and Concomitant Therapy ...................................................................83 
9.4.7.1 
Drug–Drug Interactions .......................................................................84 
9.4.7.2 
Prohibited Concomitant Medications/Vaccinations ............................84 
9.4.8 
Treatment Compliance .................................................................................85 
9.4.9 
Drug Supplies and Accountability ...............................................................86 
9.5 
Study Assessments .................................................................................................87 
9.5.1 
Assessments .................................................................................................87 
9.5.1.1 
Demography .........................................................................................87 
9.5.1.2 
Baseline Assessments ..........................................................................87 
9.5.1.3 
Efficacy Assessments ...........................................................................88 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................91 
9.5.1.5 
Safety Assessments ..............................................................................93 
9.5.2 
Schedule of Procedures/Assessments ..........................................................99 
9.5.2.1 
Schedule of Procedures/Assessments ..................................................99 
9.5.2.2 
Description of Procedures/Assessments Schedule .............................114 
9.5.3 
Appropriateness of Measurements .............................................................114 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ............................................................114 
9.5.4.1 
Reporting of Serious Adverse Events ................................................114 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .....................................................................................115 
9.5.4.3 
Reporting of Events Associated with Special Situations ...................116 
9.5.4.4 
Expedited Reporting ..........................................................................116 
9.5.4.5 
Breaking the Blind .............................................................................117 
9.5.4.6 
Regulatory Reporting of Adverse Events ..........................................117 
9.5.5 
Completion/Discontinuation of Subjects ...................................................117 


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9.5.6 
Abuse or Diversion of Study Drug ............................................................117 
9.5.7 
Confirmation of Medical Care by Another Physician ...............................118 
9.6 
Data Quality Assurance .......................................................................................118 
9.6.1 
Data Collection ..........................................................................................118 
9.6.2 
Clinical Data Management ........................................................................118 
9.7 
Statistical Methods ...............................................................................................118 
9.7.1 
Statistical and Analytical Plans ..................................................................119 
9.7.1.1 
Study Endpoints .................................................................................119 
9.7.1.2 
Definitions of Analysis Sets...............................................................120 
9.7.1.3 
Subject Disposition ............................................................................121 
9.7.1.4 
Demographic and Other Baseline Characteristics .............................121 
9.7.1.5 
Prior and Concomitant Therapy .........................................................121 
9.7.1.6 
Efficacy Analyses ..............................................................................121 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses .................................................................122 
9.7.1.8 
Safety Analyses ..................................................................................123 
9.7.1.9 
Extension Phase Analyses..................................................................125 
9.7.2 
Determination of Sample Size ...................................................................125 
9.7.3 
Interim Analysis .........................................................................................129 
9.7.4 
Other Statistical/Analytical Issues .............................................................130 
9.7.5 
Procedure for Revising the Statistical Analysis Plan .................................130 
10 REFERENCE LIST .......................................................................................................131 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .....134 
11.1 
Changes to the Protocol .......................................................................................134 
11.2 
Adherence to the Protocol ....................................................................................134 
11.3 
Monitoring Procedures.........................................................................................134 
11.4 
Recording of Data ................................................................................................135 
11.5 
Identification of Source Data ...............................................................................135 
11.6 
Retention of Records ............................................................................................136 
11.7 
Auditing Procedures and Inspection ....................................................................136 
11.8 
Handling of Study Drug .......................................................................................136 
11.9 
Publication of Results ..........................................................................................137 
11.10 Disclosure and Confidentiality ............................................................................137 
11.11 Discontinuation of Study .....................................................................................137 
11.12 Subject Insurance and Indemnity .........................................................................138 
12 APPENDICES ...............................................................................................................139 
 


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LIST OF IN-TEXT TABLES 
Table 1  
Dose-Limiting Toxicities ...........................................................................59 
Table 2 
Dose Modifications for Lenvatinib Treatment-Related Toxicity ..............70 
Table 3 
Dose Reduction Recommendations for Lenvatinib Treatment-Related 
Toxicity ......................................................................................................71 
Table 4 
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab .........................76 
Table 5  
Infusion Reaction Treatment Guidelines ...................................................79 
Table 6 
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease .......................................................................................................91 
Table 7 
Clinical Laboratory Tests ...........................................................................97 
Table 8 
Phase 1b: Determination of the Maximum Tolerated Dose:  Schedule 
of Procedures/Assessments in the Pretreatment, Treatment, and 
Extension Phases ......................................................................................100 
Table 9 
Phase 2 – Expansion in Selected Tumor Types Safety and Efficacy 
Cohort(s):  Schedule of Procedures/Assessments in the Pretreatment, 
Treatment, and Extension Phases ............................................................106 
Table 10 
2-sided 95% Confidence Interval for the ORR of 10% to 90% 
(10 subjects and 20 subjects) ...................................................................126 
Table 11 
Boundaries for the Decision to Expand Enrollment in the Endometrial 
Carcinoma Cohort ....................................................................................127 
Table 12 
Estimate and 2-sided 95% Confidence Interval of the ORR (RCC 
Subjects for the Second Interim Analysis)...............................................128 
Table 13 
Two-sided 95% Confidence Interval of the ORR, N=100 (RCC 
Subjects Previously Treated with an Anti-PD-1/PD-L1 mAb) ................128 
 
LIST OF IN-TEXT FIGURES 
Figure 1  
Phase 1b – Determination and Confirmation of the Maximum 
Tolerated Dose ...........................................................................................58 
Figure 2 
Phase 2 – Expansion In Selected Tumors ..................................................61 
LIST OF APPENDICES 
Appendix 1 
Immune-related Response Evaluation Criteria in Solid Tumors .............140 
Appendix 2  
Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 145 
Appendix 3  
Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.03...........................................................................................................146 
Appendix 4 
New York Heart Association (NYHA) Cardiac Disease Classification ..147 
Appendix 5 
Clinical Studies Evaluating Drug–Drug Interactions with Lenvatinib ....148 
Appendix 6 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 149 
Appendix 7 
KEYTRUDA® Package Insert .................................................................152 
Appendix 8 
Karnofsky Performance Status Scale .......................................................153 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
18F-NaF-PET 
18F Sodium Fluoride (NaF) positron emission tomography 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
β 
beta 
BMI 
body mass index 
BOR 
best overall response 
BP 
blood pressure  
C#/D# 
Cycle#/Day# 
CA 
Competent Authority 
CBR 
clinical benefit rate 
CCG 
CRF completion guideline 
cf-nucleic acid 
cell free nucleic acid 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLIA 
clinical laboratory improvement amendments 
Cmax 
maximum concentration 
CNS 
central nervous system 
CPMP 
Committee for Proprietary Medicinal Products 
CR 
complete response 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
curriculum vitae 
CYP 
cytochrome P450 
D1 
Day 1 
D15 
Day 15 


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DCR 
disease control rate 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSDR 
durable stable disease rate 
EC 
endometrial carcinoma 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
HNSCC 
squamous cell carcinoma of head and neck 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICL 
imaging core laboratory 
IEC 
Independent Ethics Committee 
IIR 
independent imaging review 
INR 
international normalized ratio 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
irCR 
immune-related complete response 
irPD 
immune-related progression disease 
irPR 
immune-related partial response 
IRR 
independent radiologic review 
irRECIST 
immune-related RECIST 
irSD 
immune-related stable disease 
ITT 
intent to treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
Intravenous 
KIT 
a stem cell factor receptor 
KM 
Kaplan–Meier 


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KPS 
Karnofsky performance status  
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LDi 
longest diameter 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR 
mismatch repair 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
N 
number 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
Off-Tx 
Off Treatment 
ONJ 
osteonecrosis of the jaw  
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 (or 2) 
PD-1 ligand 1 (or 2) 
PET 
Positron emission tomography 
PFS 
progression-free survival 
PG 
pharmacogenomics 
P-gp 
P-glycoprotein 
PI 
principal investigator 
PK 
Pharmacokinetics 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
PS 
performance status 
PT 
preferred term 
pTNM 
pathological tumor-node-metastasis  
Q3W 
every 3 weeks 


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QD 
once a day 
QT 
time from the beginning of the QRS complex to the end of the T wave 
QTc 
calculated QT  
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SDi 
short axis 
SOC 
system organ class 
SOD 
sum of diameters 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TKI 
tyrosine kinase inhibitor 
UC 
urothelial carcinoma 
TAM 
tumor- associated macrophage 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
VEGFR1-3 
vascular endothelial growth factor receptor 1, 2, 3 
 


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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with ICH E6 (Good Clinical 
Practice [GCP]), Section 3, and any local regulations.  Any protocol amendment or revision 
to the ICF will be resubmitted to the IRB/IEC for review and approval, except for changes 
involving only logistical or administrative aspects of the study (eg, change in Clinical 
Research Associate [CRA], change of telephone number).  Documentation of IRB/IEC 
compliance with the ICH E6 and any local regulations regarding constitution and review 
conduct will be provided to the sponsor. 
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) (or if regionally required, the head of the medical institution) with a copy to 
the sponsor before study start and the release of any study drug to the site by the sponsor or 
its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC (or if regionally required, the investigator and the relevant 
IRB via the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required. 
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
(CA) within 90 days.  The definition for end of the study for each cohort is the time of data 
cutoff for the final analysis or the time of last subject/last treatment, whichever occurs later.  
It is estimated that the study duration will be 24 months. The sponsor should also provide the 
IRB/IEC with a summary of the study’s outcome. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given. 


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5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
• 
Principles of the World Medical Association Declaration of Helsinki 2013 
• 
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use 
• 
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312 
• 
European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved EU member states. 
• 
Other applicable regulatory authorities’ requirements or directives 
 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF before any 
study-specific procedures are performed.  No subject can enter the study before his/her 
informed consent has been obtained. 
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations.  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 


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parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.   
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented. 
For assessments with pharmacodynamic, pharmacogenomic (PG), or other biomarker 
assessments, subjects will be asked to sign an additional consent for these assessments (see 
Section 9.5.1.4.2). 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 25 investigational site(s) in the US and EU. 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and, if applicable, of the contract research organization(s) (CRO(s)) are listed 
in the Investigator Study File provided to each site. 
7 
INTRODUCTION 
Study E7080-A001-111, which will be conducted in patients, has 2 goals.  One is to 
determine the maximum tolerated dose (MTD) of the combination of a programmed cell 
death protein 1 (PD-1) inhibitor (pembrolizumab) with the tyrosine kinase inhibitor (TKI) 
lenvatinib.  The second is to assess the safety and efficacy of the combination in selected 
tumors. 
7.1 
Indication  
7.1.1 
PD-1 Inhibitors and Pembrolizumab 
Antitumor immunity is often ineffective due to the tight regulation associated with the 
maintenance of immune homeostasis (Stagg, 2013).  Recent studies have shown that cancer 
cells, as well as stromal cells and immune cells in the cancer microenvironment can 
upregulate expression of the B7 family of inhibitory molecules.  These are peripheral 
membrane proteins found on activated antigen presenting cells (Coico, et al., 2003).  
Compelling evidence indicates that B7 proteins can suppress T‑cell responses (Chen, 2004; 
Sharpe and Freeman, 2002) aiding tumor immune evasion.  These negative signals are 
largely provided by two members of the B7-family.  One of these is PD-1, also known as 
B7‑H1.  PD-1 limits T cell effector functions within tissues by negatively regulating 
antitumor CD8 T cell responses.  By upregulating ligands for PD-1, tumor cells block 
antitumor immune responses in the tumor microenvironment.  Indeed, expression of the PD-1 
ligand (PD-L1) has been shown to be associated with poor prognosis in melanoma and 
hepatocellular carcinoma (Topalian, et al., 2012; Gadiot, et al., 2011; Gao, et al., 2009). 


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Clinically, blockade of PD-1 or PD-L1, using monoclonal antibodies (mAbs), has 
demonstrated substantial clinical activity in patients with metastatic melanoma, RCC, non-
small cell lung cancer (NSCLC), bladder, head and neck cancers, and other tumors (Philips 
and Atkins, 2015; Robert, et al., 2014; Hamid and Carvajal, 2013; Brahmer, et al., 2012). 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) mAb with high specificity 
of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and programmed 
cell death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high 
affinity and potent receptor blocking activity for PD-1.  Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an intravenous (IV) 
immunotherapy for advanced malignancies.  Keytruda™ (pembrolizumab) is indicated for 
the treatment of patients across a number of indications.  For more details on specific 
indications refer to the Investigator’s Brochure. 
Pembrolizumab has demonstrated initial clinical efficacy in single arm monotherapy trials in 
subjects with NSCLC, head and neck squamous cell carcinoma, urothelial carcinoma (UC), 
gastric cancer, triple negative breast cancer and Hodgkin’s Lymphoma as determined by 
response rate.  Ongoing clinical trials are being conducted in these tumor types as well as a 
number of other advanced solid tumor indications and hematologic malignancies.  For study 
details please refer to the Investigator’s Brochure. 
7.1.2 
Lenvatinib 
Lenvatinib is an oral, multi–TKI active against ret proto-oncogene, vascular endothelial 
growth factor receptor (VEGFR)1–3, FGFR1–3, a stem cell factor receptor (KIT), and 
platelet-derived growth factor receptor α (Yamamoto, et al., 2014; Tohyama, et al., 2014; 
Okamoto, et al., 2013; Matsui, et al., 2008a; Matsui, et al., 2008b).  It is approved in the US 
for the treatment of patients with locally recurrent or metastatic, progressive, radioactive 
iodine-refractory differentiated thyroid cancer, and in combination with everolimus for 
patients with advanced renal cell carcinoma following 1 prior antiangiogenic therapy.  In the 
EU, lenvatinib is indicated for the treatment of adult patients with progressive, locally 
advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, 
refractory to radioactive iodine, and in combination with everolimus for the treatment of 
adult patients with advanced renal cell carcinoma following 1 prior vascular endothelial 
growth factor-targeted therapy.  As outlined below, data from Phase 2 clinical studies 
showed lenvatinib has antitumor activity in multiple other tumors. 
In patients with locally advanced or metastatic nonsquamous NSCLC, treated with lenvatinib 
24 mg once daily + best supportive care, lenvatinib was found to be active with longer 
survival in these subjects who had had 2 or more lines of prior treatment.  Overall survival 
(OS) was the primary objective of this study.   
In a study (E7080-G000-204) to evaluate the antitumor activity of lenvatinib 24 mg orally 
once daily in female subjects with surgically unresectable endometrial carcinoma (EC) who 
have disease progression following 1 prior platinum-based, systemic chemotherapy regimen, 
the ORR (complete response [CR] + partial response [PR]) was 14.3% based on the 
assessments by independent radiologic review (IRR), the primary endpoint of the study.  The 


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ORR based on investigator assessments was 21.1%, indicating that lenvatinib is active as a 
second-line treatment in subjects with advanced EC. 
A study was conducted to determine the activity of lenvatinib in previously treated subjects 
with unresectable Stage III or Stage IV melanoma (E7080-G000-206).  The primary endpoint 
of the study was ORR, based on IRR assessment for the intent-to-treat (ITT) population.  The 
ORR was 8.6% in subjects with melanoma not harboring the V600E BRAF mutation and 
9.0% in subjects with melanoma harboring the activating BRAF mutations (mainly the 
V600E mutation).  All were PRs. 
7.2 
Study Rationale 
The effect of combining lenvatinib with PD-1/L1 mAbs has been investigated in the CT26 
colorectal cancer syngeneic model PD-L1 mAb) as well as the LL/2 lung cancer syngeneic 
model (PD-1 mAb) (Data on File).  Combination treatment with lenvatinib and PD-1/L1 
mAb showed significant and superior antitumor effects compared with either compound 
alone.  Tumor-associated macrophage (TAM) cells express PD-L1 at a higher level than 
cancer cells in the CT26 syngeneic model, and lenvatinib significantly decreased the TAM 
population (Data on File).  Because TAM cells produced interleukin 10 (IL-10) and 
transforming growth factor, beta 1 (TGFβ) (Noy and Pollard, 2014), lenvatinib might 
increase antitumor immunity in the CT26 model and up-regulate the effect of the PD-1 signal 
inhibitors.  
For the assessment of MTD, the lenvatinib doses selected are 24 mg, 20 mg, and 14 mg once 
a day (QD) all in conjunction with 200 mg pembrolizumab every 3 weeks (Q3W).  24 mg is 
the recommended dose for locally recurrent or metastatic, progressive, radioactive iodine-
refractory differentiated thyroid cancer (LENVIMA Package Insert/SmPC).  20 mg and 14 
mg are the first and second doses in lenvatinib’s dose reduction scheme for all tumors 
(except hepatocellular carcinoma) for which data are available.   
The planned dose of pembrolizumab for this study is 200 mg Q3W.  Based on the totality of 
data generated in the Keytruda® development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications and regardless of tumor type.  As outlined 
below, this dose is justified by: 
• 
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W)  
• 
Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications 
• 
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy).  Five studies compared 2 mg/kg Q3W versus 10 mg/kg 


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Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006).  All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure.  
The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses 
studied.  Subsequently, flat dose-exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the 
tumor type.  These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK 
data in KN001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
physiologically-based PK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression.  This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed dose was 
selected for evaluation across all pembrolizumab protocols.  
No dose reduction is allowed for pembrolizumab in this study.  
 


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8 
STUDY OBJECTIVES 
8.1 
Primary Objectives 
• 
Phase 1b – Determination and confirmation of the MTD:  
To determine and confirm the MTD for lenvatinib in combination with 200 mg (IV, 
Q3W) pembrolizumab in subjects with selected solid tumors. 
• 
Phase 2 – Expansion In Selected Tumor Types (Expansion):  
To evaluate ORR as of Week 24 (ORR(Week 24): CR + partial response [CR(Week 24) + 
PR(Week 24)]) of lenvatinib in combination with pembrolizumab in each of the cohorts 
using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). 
8.2 
Secondary Objectives (for both Phase 1b and 2) 
To assess:  
• 
Tolerability and safety profile of lenvatinib in combination with pembrolizumab 
• 
ORR by irRECIST of lenvatinib in combination with pembrolizumab in subjects with 
solid tumors 
• 
Progression-free survival  (PFS) by irRECIST 
• 
OS  
• 
Duration of response (DOR) by irRECIST 
• 
Disease control rate (DCR:  CR + PR + stable disease [SD]) by irRECIST 
• 
Durable stable disease rate (DSDR [SD ≥23 weeks]) by irRECIST 
• 
Clinical benefit rate (CBR:  CR, PR + durable SD) by irRECIST  
• 
PK profiles of lenvatinib during combination treatment. 
8.3 
Exploratory Objectives 
• 
To explore tumor response (eg, PR, CR, SD, PD) based on modified RECIST 1.1 
assessments 
• 
To explore tumor response in subjects with EC and renal cell carcinoma based on 
independent imaging review (IIR) using irRECIST, modified RECIST 1.1, and RECIST 
v1.1. 
• 
To investigate the relationship between candidate efficacy biomarkers and anti-tumor 
activity of lenvatinib in combination with pembrolizumab: 
a. To evaluate the relationship between PD-L1 expression levels and other relevant 
biomarkers (eg, tumor infiltrating lymphocytes, T-cell repertoire, ribonucleic acid 
[RNA] signature profiles) in tumor samples and anti-tumor activity of lenvatinib in 
combination with pembrolizumab. 
b. To evaluate differences in tumor tissue characteristics in biopsies taken post 
treatment with lenvatinib in combination with pembrolizumab versus baseline. 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
Overall Design: 
E7080-A001-111 is a multicenter, open-label study in subjects with selected solid tumors.  
All subjects in the study will receive lenvatinib and pembrolizumab while participating in the 
study.  The study has 2 phases, Phase 1b and Phase 2.  In Phase 1b, 10 to 30 evaluable 
subjects will be enrolled in 1 to 3 dose levels to determine the recommended Phase 2 dose 
(RP2D).  In Phase 2, a sample size of 10 evaluable subjects will be enrolled per cohort, with 
the possibility of expansion to 20 evaluable subjects per cohort, depending on the evaluation 
by the sponsor and investigators on the efficacy and safety results observed with the initial 
10 evaluable subjects in each cohort.   
The EC cohort may be further expanded to approximately 120 subjects.  The decision to 
expand enrollment will be based on the results of 2 interim analyses that will take place when 
21 and 60 subjects have sufficient follow-up to be evaluated for response.  At the first interim 
analysis (N = 21), if there are more than 3 responses, then approximately 40 additional 
subjects will be enrolled.  At the second interim analysis (N = 60), if there are more than 12 
responses, approximately 60 additional subjects will be enrolled.  If there are 12 or fewer 
responses, the sponsor may decide whether to expand enrollment based on clinical outcome, 
eg, ORR and DOR.   
The renal cell carcinoma cohort may be further expanded to approximately 145 total renal 
cell carcinoma (RCC) subjects to allow for approximately 100 evaluable subjects who have 
received 1 or 2 prior therapies that included an anti-programmed cell death protein 1 (PD)-
1/PD-L1 mAb.  The decision to expand enrollment will be based on the results of 2 interim 
analyses.  The first interim analysis will take place when 22 subjects (11 treatment naïve and 
11 previously treated without an anti-PD-1/PD-L1 mAb) have sufficient follow-up to be 
evaluated for response.  At the first interim analysis (N = 22), if there are more than 5 
responses, then approximately 45 additional subjects will be enrolled.  It is anticipated that the 
additional 45 subjects will consist of approximately 12 treatment naïve subjects enrolled 
under Amendment 05 and approximately 33 previously treated subjects who have received 1 
or 2 prior therapies and have progressed on treatment with an anti-PD-1/PD-L1 mAb, 
administered either as monotherapy, or in combination with other checkpoint inhibitors or 
other therapies, and as of Amendment 07, the regimen with an anti-PD-1/PD-L1 mAb must 
be the most recent therapy.  PD-1 treatment progression is defined by meeting all of the 
following criteria: 
a) Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb 
b) Has demonstrated disease progression after PD-1/PD-L1 as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1. The initial evidence of disease 
progression (PD) is to be confirmed by a second assessment no less than 4 weeks 
from the date of the first documented PD 


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c) Progressive disease (PD) has been documented within 12 weeks from last dose of 
anti-PD-1/PD-L1 mAb (refractory disease) or ≥12 weeks from last dose of 
anti-PD-1/PD-L1 mAb (late relapses) 
The second interim analysis will include these 45 additional subjects and the 11 treatment 
naïve subjects included in the first interim analysis, and will take place when these 56 
subjects have sufficient follow-up to be evaluated for response.  At the second interim 
analysis, whether the previously treated renal cell carcinoma subset will be further expanded will 
be decided based on clinical review of both efficacy and safety data. 
For subjects in Phase 1b and Phase 2, toxicity will be managed by treatment interruption, 
dose reduction, and/or treatment discontinuation in accordance with the dose modification 
instructions outlined in Table 2 and Table 4 below.  Treatment will continue until disease 
progression, development of unacceptable toxicity, subject choice, withdrawal of consent, 
completion of 35 treatments (approximately 2 years) with pembrolizumab, lost to follow up 
or discontinuation of this study by the sponsor.  Patients can receive up to 35 treatments 
(approximately 2 years) with pembrolizumab.  Subjects who discontinue pembrolizumab after 35 
treatments may continue treatment with lenvatinib alone unless any other criteria above apply.  
Subjects who discontinued pembrolizumab for any reason and are still receiving lenvatinib study 
drug, will be transitioned to commercial lenvatinib if local country regulations permit. 
Phase 1b - MTD: 
Dosing will begin at the full dose of both drugs due to the well-established safety profiles of 
lenvatinib and pembrolizumab, the nonoverlapping mechanisms of action, and the desire to 
treat patients at doses shown to be effective in previous studies.  Lower dose levels of 
lenvatinib will be explored as necessary depending on observed toxicity. 
Phase 1b will determine and confirm the MTD of lenvatinib in combination with 
pembrolizumab.  Subjects in Phase 1b will have one of the following tumors: non-small cell 
lung cancer, renal cell carcinoma, EC, UC, squamous cell carcinoma of head and neck 
(HNSCC), or melanoma.  The dose of 1 of the 2 study drugs, pembrolizumab, will not 
change during the MTD phase, while the second study drug, lenvatinib, will start at 24 mg 
and then be reduced, if necessary, to either 20 mg or 14 mg.  Phase 1b is illustrated in Figure 
1. 
Phase 1b will begin at Dose Level 1: lenvatinib 24mg/day orally and pembrolizumab 200 mg 
every 3 weeks, IV will be administered to subjects with selected solid tumors on a 21-day 
treatment cycle.  Two dose de-escalation steps are included: Dose Level 2 (lenvatinib 
20 mg/day orally + pembrolizumab 200 mg Q3W, IV) and Dose Level 3 (lenvatinib 
14 mg/day orally + pembrolizumab 200 mg Q3W, IV).  For determination of MTD, only 
dose limiting toxicities (DLTs), as defined in Table 1, during the first cycle of treatment, will 
be assessed.  The determination of the DLT will be made jointly by the sponsor and 
investigators after safety data from each dose level have been reviewed. 
If 0 of 3 subjects in a given dose level cohort experiences a DLT, then 7 more subjects will 
be enrolled into that dose level to confirm the MTD.  If 1 of 3 subjects has a DLT, then 3 


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more subjects will be enrolled into that dose level for a total of 6 subjects.  If only 1 of these 
6 subjects has a DLT, then 4 more subjects will be enrolled into that dose level to confirm the 
MTD.  
As shown in Figure 1, if 2 or more subjects at a dose level experience a DLT, then, following 
consultation with the PIs the study will proceed with  enrollment in the next defined lower 
dose (Dose Level 2 or 3), with dose reduction of lenvatinib to 20 or 14 mg QD, respectively, 
in combination with 200 mg pembrolizumab Q3W. 
For confirming the MTD, DLTs and intolerable toxicities (that cannot be managed with dose 
interruption and/or reduction) during the first cycle of treatment for the 10 evaluable subjects 
at that dose level will be assessed.  The MTD will be confirmed if no more than 3 subjects 
experience DLTs during the first 3 weeks (Cycle 1) of treatment.  If the MTD is not 
confirmed at a dose level, then enrollment will proceed to the next lower dose level.  The 
sponsor and investigators will review all subjects’ safety and clinical data to jointly 
determine the RP2D of the combination of lenvatinib with pembrolizumab. 
If 2 or more subjects have a DLT in Dose Level 3, enrollment in the study will stop.   
 
 
                
Figure 1  
Phase 1b – Determination and Confirmation of the Maximum 
Tolerated Dose 
DLT = dose limiting toxicity, IV = intravenous, MTD = maximum tolerated dose, PO = orally, Q3W – every 3 
weeks 
a: where DLTs are considered lenvatinib related. 
Dose Level 1 
24 mg lenvatinib (PO, daily) 
+ 200 mg pembrolizumab (IV, Q3W) 
MTD 
0/3 DLT 
1/6 DLT 
Confirmation: 
4 Subjects 
Dose Level 2 
20 mg lenvatinib (PO, daily) 
+ 200 mg pembrolizumab (IV, Q3W) 
MTD 
0/3 DLT 
1/6 DLT 
Confirmation: 
 7 Subjects 
≥ 2/3 or ≥ 2/6 DLTsa 
Confirmation: 
 4 Subjects 
Dose Level 3 
14 mg lenvatinib (PO, daily) 
+ 200 mg pembrolizumab (IV, Q3W) 
Confirmation: 
7 Subjects 
MTD 
0/3 DLT 
1/6 DLT 
Confirmation: 
 7 Subjects 
Confirmation: 
 4 Subjects 
≥ 2/3 or ≥ 2/6 DLTsa 


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A DLT is defined as any of the following: 
- 
Any of the hematological or nonhematological toxicities noted in Table 1 considered 
to be at least possibly related to lenvatinib and/or pembrolizumab occurring during 
Cycle 1. 
- 
Failure to administer ≥75% of the planned dosage of lenvatinib as a result of 
treatment-related toxicity during Cycle 1. 
- 
Subjects who discontinue treatment due to treatment-related toxicity. 
- 
Greater than 2 week delay in starting Cycle 2 because of a treatment-related toxicity, 
even if the toxicity does not meet DLT criteria. 
Table 1  
Dose-Limiting Toxicities 
Toxicity Category 
Toxicity CTCAE Grade 
Hematologic 
• 
Grade 4 neutropenia for ≥7 days 
 
• 
Grade 3 or Grade 4 febrile neutropeniaa 
 
• 
Thrombocytopenia <25,000/mm3 associated with bleeding and/or which requires 
platelet transfusion 
Other 
nonhematologic 
toxicity 
• 
Any other Grade 4 or a Grade 5 toxicity 
• 
Grade 3 toxicities lasting >3 days excluding: 
• 
Nausea, vomiting, and diarrhea controlled by medical intervention within 72 
hours. 
• 
Grade 3 rash in the absence of desquamation, no mucosal involvement, does 
not require steroids, and resolves to Grade 1 by the next scheduled dose of 
pembrolizumab. 
 
• 
Grade 3 hypertension not able to be controlled by medication  
 
• 
Grade 3 or above gastrointestinal perforation 
 
• 
Grade 3 or above wound dehiscence requiring medical or surgical intervention 
 
• 
Any grade thromboembolic event 
 
Any Grade 3 nonhematologic laboratory value if: 
• 
Medical intervention is required to treat the subject, or 
• 
The abnormality leads to hospitalization 
ANC = absolute neutrophil count, CTCAE = Common Terminology Criteria for Adverse Events v4.03. 
a. 
Febrile neutropenia Grade 3 or Grade 4:   
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained temperature of ≥38 °C 
(100.4 °F) for more than one hour. 
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained temperature of ≥38 °C 
(100.4 °F) for more than one hour, with life-threatening consequences and urgent intervention indicated 
 
Only toxicities with a clear alternative explanation (eg, due to disease progression) or 
transient (≤72 hours), abnormal laboratory values without associated clinically significant 
signs or symptoms based on investigator determination, can be deemed a non-DLT. 
All subjects enrolled in Phase 1b will be assessed for DLTs during the DLT assessment 
window of Cycle 1 (Treatment Phase).  Subjects who discontinue study treatment prior to 
completing the Treatment Phase for any reason other than DLT will be replaced.  Once they 
complete the Treatment Phase, each subject still receiving study treatment will transition into 
the Extension Phase.  Tumor assessments will continue during the Extension Phase.  As of 


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Amendment 09, tumor assessments will continue during the Extension Phase as per the local 
standard of care but not less frequent than every 6 months. Tumor assessments will not be 
collected during the Follow-Up period of the Extension Phase.  
Phase 2 – Expansion: 
Subjects will be assigned by tumor type into 1 of 6 cohorts (minimum of 10 or 20 evaluable 
subjects per cohort) to receive the MTD, which was established as the RP2D in the Phase 1b 
portion of this study (lenvatinib 20 mg/day orally + pembrolizumab 200 mg Q3W, IV) to 
assess the safety and efficacy of the combination in the selected tumor-types.  Each cohort 
will consist of subjects with one of the tumor types listed in the Phase 1b section above.  
Phase 2 is illustrated in Figure 2.   
After the MTD is confirmed, and depending on the safety and efficacy observed, 6 cohorts 
will be enrolled (Figure 2).  Each of these cohorts will only enroll subjects with one type of 
tumor (ie, NSCLC, predominantly clear cell RCC, EC, UC, melanoma (excluding uveal), 
HNSCC).  RP2D combination doses will be administered.  The intention is to enroll 20 
subjects in each of the 6 cohorts.  Data from the first 10 subjects in each cohort will be 
reviewed by the sponsor and investigators.  At least 3 subjects must show response in order 
to determine continued enrollment up to 20 subjects.   
The EC cohort may be further expanded to approximately 120 evaluable subjects.  The 
decision to expand enrollment will be based on the results of 2 interim analyses that will take 
place when 21 and 60 subjects have sufficient follow-up to be evaluated for response.  At the 
first interim analysis (N = 21), if there are more than 3 responses, then approximately 40 
additional subjects will be enrolled.  At the second interim analysis (N = 60), if there are 
more than 12 responses, approximately 60 additional subjects will be enrolled.  If there are 
12 or fewer responses, the sponsor may decide whether to expand enrollment based on 
clinical outcome, eg, ORR and DOR.   
The renal cell carcinoma cohort may be further expanded to approximately 145 total 
evaluable subjects to allow for approximately 100 evaluable subjects who have received 1 or 
2 prior therapies that included an anti-PD-1/PD-L1 mAb.  The decision to expand enrollment 
will be based on the results of 2 interim analyses.  The first interim analysis will take place 
when 22 subjects (11 treatment naïve and 11 previously treated without an anti-PD-1/PD-L1 
treatment) have sufficient follow-up to be evaluated for response.  At the first interim 
analysis (N = 22), if there are more than 5 responses, then approximately 45 additional 
subjects will be enrolled.  It is anticipated that the additional 45 subjects will consist of 
approximately 12 treatment naïve subjects enrolled under Amendment 05 and approximately 
33 previously treated subjects who have received 1 or 2 prior therapies and have progressed 
on treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy, or in 
combination with other checkpoint inhibitors or other therapies, and as of Amendment 07, 
the regimen with an anti-PD-1/PD-L1 mAb must be the most recent therapy.  PD-1 treatment 
progression is defined by meeting all of the following criteria: 
a) Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb. 
b) Has demonstrated disease progression after PD-1/PD-L1 as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1. The initial evidence of PD is to 


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be confirmed by a second assessment no less than 4 weeks from the date of the first 
documented PD  
c) Progressive disease has been documented within 12 weeks from last dose of anti-PD-
1/PD-L1 mAb (refractory disease) or ≥12 weeks from last dose of anti-PD-1/PD-L1 
mAb (late relapses) 
 
The second interim analysis will include these 45 additional subjects and the 11 treatment 
naïve subjects included in the first interim analysis and will take place when these 56 
subjects have sufficient follow-up to be evaluated for response.  At the second interim 
analysis, whether the previously treated renal cell carcinoma subset will be further expanded will 
be decided based on clinical review of both efficacy and safety data. 
 
 
Figure 2 
Phase 2 – Expansion In Selected Tumors 
approx. = approximately EC = endometrial carcinoma; HNSCC = squamous cell carcinoma of head and neck; 
Mel = melanoma (excluding uveal); MTD = maximum tolerated dose;  NSCLC = non-small cell lung cancer; 
ORR = objective response rate; RCC = renal cell carcinoma (predominantly clear cell), UC = urothelial 
carcinoma;  


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a: 
Based on the efficacy and safety results from the first 10 subjects in each cohort, an additional 10 subjects 
 
may be enrolled for a total of 20 subjects in each cohort. 
b: The endometrial and renal cell carcinoma cohorts may be expanded to approximately 120 and 145 
 
evaluable subjects, respectively.                                                                                                                              
c: 
This RCC subset includes previously treated subjects who have received 1 or 2 prior therapies and have 
 
progressed on treatment with an anti- programmed cell death protein 1 (PD)-1/ PD-1 ligand 1 (PD-L1) 
mAb. 
Once they complete the Treatment Phase, each subject still receiving study treatment will 
transition into the Extension Phase.  Tumor assessments will continue during the Treatment 
Period of the Extension Phase.  As of Amendment 09, subjects in the treatment period of the 
extension phase who discontinue pembrolizumab for any reason and remain on lenvatinib 
study treatment will transition to lenvatinib commercial supply if local country regulations 
permit.  As of Amendment 09, tumor assessments will continue during the Extension Phase 
as per the local standard of care but not less frequent than every 6 months.  Tumor 
assessments will not be performed or collected during the Follow-Up period of the Extension 
Phase.  Subjects who undergo the Off-Tx visit will undergo safety follow-up for AEs for 30 
days from the last dose of study treatment.  Serious adverse event (SAEs) will be collected 
for 90 days after the last dose or 30 days following the last dose if the subject initiates new 
anticancer therapy, whichever is earlier.  Transition to commercial lenvatinib will be 
considered new anticancer therapy.  After the end of the safety follow-up period, no data will 
be collected subsequently. The data cutoff for each Phase 2 cohort will occur when the 
evaluable subjects in that cohort complete 8 cycles of treatment or discontinue early. 
The study will be conducted in 3 phases: a Pretreatment Phase, a Treatment Phase, and an 
Extension Phase. 
The definition of the end of the study for each cohort is the time of data cutoff for the final 
analysis or the time of last subject/last treatment, whichever occurs later. 
9.1.1 
Pretreatment Phase 
The Prerandomization Phase will last for 28 days and will include a Screening Period and a 
Baseline Period. 
9.1.1.1 
Screening Period 
Screening will occur between Day -28 and Day -3.  The purpose of the Screening Period is to 
obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3. Tumor assessments performed up to 28 days 
prior to dosing are acceptable as screening tumor assessments if they are consistent with the 
requirements for this protocol.  
The Screening Disposition case report form (CRF) page must be completed to indicate 
whether the subject is eligible to participate in the study and to provide reasons for screen 
failure, if applicable. 


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9.1.1.2 
Baseline Period 
The purpose of the Baseline Period is to confirm protocol eligibility as specified in the 
inclusion/exclusion criteria. Baseline assessments may be performed from Day -3 to Day -1 
or on C (C) 1 D1 prior to dosing.  
Subjects who complete the Baseline Period and meet the criteria for inclusion/exclusion 
(Sections 9.3.1 and 9.3.2) will begin the Treatment Phase. 
9.1.2 
Treatment Phase 
The Treatment Phase will begin with the administration of the first dose of study treatment to 
the first subject in Cycle 1 and continues in 21-day (3-week) cycles.  The Phase 1b and 
Phase 2 Treatment Periods are described below:  
9.1.2.1 
Treatment Period 
• Phase 1b:  The Treatment Period for each subject ends after they complete Cycle 1 of 
treatment or they discontinue early.  Those that discontinue study treatment in Cycle 1 
transition to the Off Treatment (Off-Tx) Visit of the Follow-up Period of the Extension 
Phase.  Those that complete Cycle 1 transition to the Treatment Period of the Extension 
Phase.   
• Phase 2:  The Treatment Period for each subject ends after they complete 8 cycles of 
treatment unless they discontinue early.  Those that discontinue study treatment before 
completing 8 cycles transition to the Off-Tx Visit of the Follow-up Period of the 
Extension Phase.  Those that complete 8 cycles transition to the Treatment Period of the 
Extension Phase.   
9.1.3 
Extension Phase 
The Extension Phase consists of 2 periods, the Treatment Period and the Follow-up Period.  
9.1.3.1 
Treatment Period 
Subjects still receiving study treatment at the end of the Treatment Phase will continue to 
receive the same study treatment in the Treatment Period of the Extension Phase.  Those 
subjects that discontinue study treatment transition to the Off-Tx Visit of the Follow-up 
Period of the Extension Phase.  Note that all AEs must be captured for 30 days after last dose 
of study medication. 
9.1.3.2 
Follow-Up Period 
As of Amendment 9, the Follow-Up Period will consist of the Off-Tx Visit.  No further visits 
will be conducted.  The sponsor has decided to terminate survival follow-up for all subjects 
currently in survival follow-up.  


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Survival follow-up data will no longer be collected after the Off-Tx Visit and after 30 days 
from the last dose of study drugs.  
The Follow-up Period consists of the Off-Tx Visit and the Follow-up Visits. 
• 
The Off-Tx Visit will occur within 30 days after the last dose of study treatment. It 
applies to the Phase 1b subjects who discontinued study treatment early, before 
completing Cycle 1, and to the Phase 2 subjects who discontinued study treatment 
early, before completing 8 cycles.  Following the completion of the Off-Tx Visit, 
subjects will transition to the Follow-up Period of the Extension Phase. 
• 
In the Follow-up Period, subjects will be treated by the investigator according to the 
prevailing local standard of care.  Subjects will be followed every 12 weeks (±1 week) 
for survival, with tumor assessments performed as detailed in the Schedule of 
Procedures/Assessments, and subsequent anticancer treatments.  Follow-up Visits 
continue as long as the study subject is alive unless the subject withdraws consent or 
until the sponsor terminates the study.  The sponsor may decide to terminate survival 
follow-up anytime during the Extension Phase or when all subjects have discontinued 
study treatment. 
9.2 
Discussion of Study Design 
The study design follows well-established designs for Phase 1b/2 oncology studies, including 
ongoing studies featuring co-administration of oncology drugs with different mechanisms of 
action and PD-1 inhibitors.  The design allows for rapid identification of tumors types which 
will respond to the combination of a TKI with a PD-1 inhibitor.  The tumor types to be 
studied in this study (NSCLC, renal cell carcinoma, EC, UC, HNSCC, or melanoma) have 
shown response to lenvatinib and/or a PD-1 inhibitor in other studies where the drug products 
were individually administered.  
9.3 
Selection of Study Population 
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug. The subjects from Phase 1b and Phase 2 
will be enrolled at up to 25 sites from the US and the EU. 
Phase 1b - Depending on the number of dose levels explored, Phase 1b will enroll between 
10 and 30 evaluable subjects with selected solid tumors. 
Phase 2 may enroll approximately 20 subjects in each cohort.  The EC and the RCC cohorts 
may be further expanded to approximately 120 and 145 evaluable subjects, respectively.    
9.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 


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1. Phase 1b:  Histologically and/or cytologically confirmed metastatic selected solid tumor 
types that have progressed after treatment with approved therapies or for which there are 
no standard effective therapies available.  If nivolumab or pembrolizumab is an 
approved therapy for the subject’s tumor type, but the subject has not been treated with 
it, the Investigator may enroll the subject in this study. 
Phase 2:  Histologically and/or cytologically confirmed metastatic selected solid tumor 
types with 0-2 prior lines of systemic therapy.  If previously treated, subject has 
progressed after previous treatment. 
As of Amendment 03, for the NSCLC and melanoma cohorts, subjects must have 
progressed on or after prior treatment with one anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent. 
As of Amendment 05, for the RCC cohort, subjects are either treatment naïve or must 
have progressed on treatment with an anti-PD-1/PD-L1 mAb administered either as 
monotherapy, or in combination with other checkpoint inhibitors or other therapies.   
As of Amendment 06, for the RCC cohort, all subjects must have progressed on 
treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy, or in 
combination with other checkpoint inhibitors or other therapies, and as of Amendment 
07, the regimen with an anti-PD-1/PD-L1 mAb must be the most recent therapy. PD-1 
treatment progression is defined by meeting all of the following criteria: 
a. Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb 
b. Has demonstrated disease progression after PD-1/PD-L1 as defined by 
RECIST v1.1. The initial evidence of PD is to be confirmed by a second 
assessment no less than 4 weeks from the date of the first documented PD  
c. Progressive disease has been documented within 12 weeks from last dose of 
anti-PD-1/PD-L1 mAb (refractory disease) or ≥12 weeks from last dose of 
anti-PD-1/PD-L1 mAb (late relapses) 
Selected tumor types of both phases:  NSCLC, predominantly clear cell renal cell 
carcinoma, EC, UC, squamous cell carcinoma of the head and neck, or melanoma 
(excluding uveal melanoma). 
2. Life expectancy of 12 weeks or more 
3. Phase 2:  Measurable disease meeting the following criteria: 
a. 
At least 1 lesion of ≥10 mm in the longest diameter (LDi) for a non-lymph node or 
≥15 mm in the short-axis diameter for a lymph node that is serially measurable 
according to irRECIST using computerized tomography/magnetic resonance 
imaging (CT/MRI). 
b. 
Lesions that have had external beam radiotherapy  or loco-regional therapies such 
as radiofrequency) ablation must show subsequent evidence of substantial size 
increase to be deemed a target lesion. 


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4. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS) of 0 to 1. 
5. Adequately controlled blood pressure (BP) with or without antihypertensive 
medications, defined as BP ≤150/90 mmHg at screening and no change in 
antihypertensive medications within 1 week prior to the C(C) 1 D1. 
6. Adequate renal function defined as creatinine ≤1.5 × (upper limits of normal (ULN) or 
calculated creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula with 
creatinine levels >1.5 × ULN. 
7. Adequate bone marrow function:  
• Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 × 103/µL) 
• Platelets ≥ 100,000/mm3 (≥100 × 109/L) 
• Hemoglobin ≥ 9.0 g/dL 
8. Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤1.5. 
9. Adequate liver function as evidenced by bilirubin ≤1.5 times the ULN and alkaline 
phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase 
(AST) ≤3 × ULN (in the case of liver metastases ≤5 × ULN).  In case ALP is >3 × ULN 
(in the absence of liver metastases) or >5 × ULN (in the presence of liver metastases) 
AND the subject also is known to have bone metastases, the liver specific ALP 
isoenzyme must be separated from the total and used to assess the liver function instead 
of the total ALP.  
10. Males or females age ≥18 years at the time of informed consent.   
11. Subjects with known brain metastases will be eligible if they have completed the 
primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery or 
complete surgical resection) and if they have remained clinically stable, asymptomatic 
and off of steroids for at least 28 days before starting study treatment. 
12. All females must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of beta-human chorionic gonadotropin [β-hCG]) at the 
Screening Visit and the Baseline Visit.  A pregnancy test needs to be performed within 
72 hours of the first dose of study drug.  Females of childbearing potential* must agree 
to use a highly effective method of contraception for the entire study period and for 
120 days after study discontinuation, ie: 
◦ total abstinence (if it is their preferred and usual lifestyle)  
◦ an intrauterine device (IUD) or hormone-releasing system (IUS) 


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◦ a contraceptive implant 
◦ an oral contraceptive** (with additional barrier method) 
OR 
◦ have a vasectomized partner with confirmed azoospermia. 
 
For sites outside of the EU, it is permissible that if a highly effective method of 
contraception is not appropriate or acceptable to the subject, then the subject must agree 
to use a medically acceptable method of contraception, ie, double barrier methods of 
contraception such as condom plus diaphragm or cervical/vault cap with spermicide. 
 
NOTES: 
*All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically 
(ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with 
surgery at least 1 month before dosing). 
**Must be on a stable dose of the same oral hormonal contraceptive product for at least 
4 weeks before dosing with study drug and for the duration of the study. 
13. Male subjects who are partners of women of childbearing potential must use a condom + 
spermicide and their female partners if of childbearing potential must use a highly 
effective method of contraception (see methods described in Inclusion Criterion #12) 
beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire 
study period, and for 120 days after the last dose of study drug, unless the male subjects 
are totally sexually abstinent or have undergone a successful vasectomy with confirmed 
azoospermia or unless the female partners have been sterilized surgically or are 
otherwise proven sterile.   
14. Voluntary agreement to provide written informed consent and the willingness and ability 
to comply with all aspects of the protocol. 
15. Archival tumor tissue or a newly obtained biopsy must be available prior to the first 
dose of study drug for biomarker analysis. In the case archival tissue cannot be provided, 
patients with inaccessible tumors for biopsy specimens can be enrolled without a biopsy 
upon consultation and agreement by the sponsor. 
Note: In case of submitting unstained cut slides, freshly cut slides should be submitted to 
the testing laboratory within 14 days from when the slides are cut. See Section 9.5.1.4.2 
in the protocol for an explanation. 
9.3.2 
Exclusion Criteria 
1. Prior anticancer treatment within 28 days (or 5 times the half-life, whichever is shorter) 
or any investigational agent within 30 days prior to the first dose of study drugs.  All 
acute toxicities related to prior treatments must be resolved to Grade ≤1. 


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2. Subjects must have recovered adequately from any toxicity and/or complications from 
major surgery prior to starting therapy. 
3. Subjects having >1+ proteinuria on urinalysis will undergo 24-hour urine collection for 
quantitative assessment of proteinuria.  Subjects with urine protein ≥1 g/24-hour will be 
ineligible. 
4. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
might affect the absorption of lenvatinib 
5. New York Heart Association (NYHA) congestive heart failure of grade II or above, 
unstable angina, myocardial infarction within the past 6 months, or serious cardiac 
arrhythmia associated with significant cardiovascular impairment within the past 6 
months 
6. Prolongation of QTc interval to >480 msec 
7. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the 
first dose of study drug 
8. Active infection (any infection requiring systemic treatment) 
9. Subject is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B 
or Hepatitis C  
10. Serious nonhealing wound, ulcer, or bone fracture 
11. Known intolerance to either of the study drugs (or any of the excipients) 
12. History of organ allograft (subject has had an allogenic tissue/solid organ transplant) 
13. Biologic response modifiers (eg, granulocyte colony-stimulating factor within 4 weeks 
before study entry.  Chronic erythropoietin therapy is permitted provided that no dose 
adjustments were made within 2 months before first dose of study treatment. 
14. Any medical or other condition which, in the opinion of the investigator, would preclude 
participation in a clinical study 
15. Females who are pregnant or breastfeeding 
16. Excluding the primary tumor leading to enrollment in this study, any other active 
malignancy (except for definitively treated melanoma in-situ, basal or squamous cell 
carcinoma of the skin, or carcinoma in-situ of the bladder or cervix) within the past 24 
months 
17. Prior treatment with lenvatinib (no exceptions) or any PD-1, anti-PD-L1, or anti-PD-L2 
agent, except:  


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◦ 
the melanoma and NSCLC cohorts, where prior treatment with one anti-PD-1, 
anti-PD-L1, or anti-PD-L2 agent is allowed.  
◦ 
the previously treated renal cell carcinoma subjects (as of Amendment 05) where 
prior treatment with one regimen containing an anti-PD-1/PD-L1 mAb is 
required. 
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of study 
treatment.  The use of physiologic doses of corticosteroids (up to 7.5mg/d of prednisone 
or equivalent) may be approved after consultation with the sponsor.  
19. No active autoimmune disease that has required systemic treatment in past 2 years (ie, 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
20. Has a history of  (non-infectious) pneumonitis that required steroids, or current 
pneumonitis 
21. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal 
flu vaccines that do not contain live virus are permitted. 
9.3.3 
Removal of Subjects From Therapy or Assessment 
As of Amendment 09, the Follow-Up Period will consist of the Off-Tx Visit.  No further 
visits will be conducted. The sponsor has decided to terminate survival follow-up for all 
subjects currently in survival follow-up. 
Survival follow-up data will no longer be collected after the Off-Tx Visit and after 30 days 
from the last dose of study drugs.  
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason.  
The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Follow-Up Period and complete protocol-specified off-tx 
visits, procedures, and survival follow-up unless the subject withdraws consent.  The 
investigator should confirm whether a subject will withdraw from study treatment but agree 
to continue protocol-specified, off-tx study visits, procedures, and survival follow-up, or 
whether the subject will withdraw consent.  If a subject withdraws consent, the date will be 
documented in the source documents.  The Discontinuation From Treatment CRF page will 
be completed indicating the primary reason for discontinuation and all other reason(s) 
contributing to the subject’s discontinuation from treatment.  In addition, the date of last dose 
of study drug(s) will be recorded on the Study Drug Dosing CRF page. 


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During the Follow-Up Period, subjects who have discontinued study treatment without 
progression should have disease assessments until disease progression is documented or 
another anticancer therapy is initiated. 
All subjects will be followed for survival until death, except where a subject withdraws 
consent or the sponsor chooses to halt survival follow-up after completion of the primary 
study analysis. As of Amendment 09, survival follow-up data will no longer be collected. 
9.4 
Treatments 
9.4.1 
Treatments Administered 
9.4.1.1 
Lenvatinib 
Lenvatinib will be administered with water orally once a day (with or without food) in 
21-day cycles at approximately the same time each day.  Treatment cycles will be counted 
continuously regardless of dose interruptions.  On (D1) of each cycle, it will be administered 
approximately 1 hour after completion of pembrolizumab administration.  
9.4.1.1.1 CRITERIA FOR INTERRUPTION OF TREATMENT, DOSE REDUCTION AND RESUMPTION 
OF TREATMENT 
Lenvatinib dose reduction and interruption for subjects who experience lenvatinib-related 
toxicity will be in accordance with the guidelines provided in Table 2.  Once the dose has 
been reduced, it may not be increased at a later date. 
For management of hypertension and proteinuria, refer to main protocol text for instructions 
before consulting the table below, as appropriate.  (See Table 3 for dose reductions.  Any 
dose reduction below 4 mg/day must be discussed with the sponsor.  Once the dose has been 
reduced, it cannot be increased at a later date.)  Dose reductions of lenvatinib in Phase 2 
occur in succession starting at the RP2D dose identified in Phase 1b. 
 
Table 2 
Dose Modifications for Lenvatinib Treatment-Related Toxicity 
Lenvatinib Treatment-
Related Toxicitya,b 
During Therapy 
Adjusted Dosef 
 
Grade 1, Tolerable Grade 2 
 
Continue treatment 
No change 
Intolerable Grade 2c,d and Grade 3g  
First occurrence 
Interrupt lenvatinib until resolved 
to tolerable  Grade 2 or Grade 0-1 
Reduce lenvatinib by one dose 
levelb 
Second occurrence  
(same toxicity or new toxicity) 
Interrupt lenvatinib until resolved 
to tolerable  Grade 2 or Grade 0-1 
Reduce lenvatinib by one more 
dose level 
Third occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib until resolved 
to tolerable  Grade 2 or Grade 0-1 
Reduce lenvatinib by one more 
dose level 
Fourth occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib until resolved 
to tolerable  Grade 2 or Grade 0-1 
Reduce lenvatinib by one more 
dose level  


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Grade 4e,g: Discontinue lenvatinib 
a. 
An interruption of lenvatinib treatment for more than 21 days (due to lenvatinib treatment-related toxicities) will 
require a discussion with the sponsor before treatment can be resumed. 
b. Excluding alopecia. Initiate optimal medical management for nausea, vomiting, hypothyroidism, hypertension 
and/or diarrhea prior to any lenvatinib interruption or dose reduction.  For treatment-related hypertension, refer 
to Management of Hypertension (Section 9.4.1.1.2) for dose modification guidelines. 
c. 
Applicable only to Grade 2 toxicities judged by subject and/or physician to be intolerable. 
d. Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie, Grade 
1 weight loss). These subjects will restart the study drug(s) at a lower dose once their weight remains stable for 
at least 1 week and they reached the normal body mass index (BMI) (if the weight loss occurred but  it is still 
above normal BMI, they can restart the study treatment at a lower dose once the weight has been stable for at 
least 1 week). Normal BMI should be used as the new baseline for further dose reductions. 
e. 
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
f. 
Refer to Table 3 for adjusted dose. 
g. For asymptomatic Grade ≥3 elevations of amylase and lipase, the sponsor’s medical monitor should be consulted 
to obtain permission to continue treatment.  
 
General guidelines for holding periods of lenvatinib due to procedures: 
For minor procedures, lenvatinib should be stopped 2 days before the procedure and restarted 
2 days after, once there is evidence of adequate healing and no risk of bleeding.  Needle 
biopsies (fine needle aspirations and core needle aspiration) are usually considered minor 
procedures. 
For major procedures, lenvatinib should be stopped at least 1 week (5 half-lives) before the 
procedure and then restarted once there is clear wound healing and no risk of bleeding, but at 
least 2 weeks after the procedure.  It is up to the investigator to determine if it is a major or 
minor procedure.  Usually a major procedure implies general anesthesia. 
Table 3 
Dose Reduction Recommendations for Lenvatinib Treatment-
Related Toxicity 
Initial  
Lenvatinib Dose 
(mg, QD) 
Adjusted Dose To Be Administered (mg, QD) 
 
Reduction 1 
Reduction 2 
Reduction 3 
Reduction 4 
24 
20 
14 
10 
8a 
20 
14 
10 
8 
4a 
14 
10 
8 
4a 
 
QD = once a day 
a.  Consult sponsor for further dose reduction recommendations. 
 
9.4.1.1.2 MANAGEMENT OF HYPERTENSION 
Hypertension is a recognized side effect of treatment with drugs inhibiting vascular 
endothelial growth factor (VEGF) signaling.  Investigators should therefore ensure that 
subjects enrolled to receive treatment with lenvatinib have BP of ≤150/90 mm Hg at the time 


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of study entry and, if known to be hypertensive, have been on a stable dose of 
antihypertensive therapy for at least 1 week before C1D1.  Early detection and effective 
management of hypertension are important to minimize the need for lenvatinib dose 
interruptions and reductions.   
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg) is confirmed on 2 assessments a minimum of 1 hour apart.  One 
BP assessment is defined as the mean value of 3 measurements at least 5 minutes apart.  The 
choice of antihypertensive treatment should be individualized to the subject’s clinical 
circumstances and follow standard medical practice.  For previously normotensive subjects, 
appropriate antihypertensive therapy should be started when systolic BP ≥140 mm Hg or 
diastolic BP ≥90 mm Hg is first observed on 2 assessments a minimum of 1 hour apart.  For 
those subjects already on antihypertensive medication, treatment modification may be 
necessary if hypertension persists.  For subjects with hypertension and proteinuria, 
appropriate therapy, eg, angiotensin-converting enzyme inhibitor or angiotensin-II receptor 
antagonist, is preferred (Kilfoy, et al., 2009).  
Lenvatinib should be withheld in any instance where a subject is at imminent risk to develop 
a hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension (eg, BP ≥160/100 mm Hg, significant risk factors for cardiac disease, 
intracerebral hemorrhage, or other significant co-morbidities).  Once the subject has been on 
the same hypertensive medications for at least 48 hours and the BP is controlled, lenvatinib 
should be resumed as described below. 
During the Treatment Period, both in the Treatment Phase and in the Extension Phase, 
subjects with systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have their BP 
monitored on Day 15 or more frequently as clinical indicated until systolic BP has been 
≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 3 consecutive months.  If a repeat 
event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the subject must 
resume the Day 15 evaluation until systolic BP has been ≤150 mm Hg and diastolic BP has 
been ≤95 mm Hg for 3 consecutive months. 
The following guidelines should be followed for the management of systolic BP 
≥160 mm Hg or diastolic BP ≥100 mm Hg confirmed on repeat measurements after 1 hour: 
1. Continue lenvatinib and institute antihypertensive therapy for subjects not already 
receiving antihypertensive medication 
2. For those subjects already on antihypertensive medication, dose of the current agent may 
be increased, if appropriate, or 1 or more agents of a different class of antihypertensive 
should be added. 
3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted.  It should 
be restarted at one lower dose level as specified in Table 3 only when systolic BP 
≤150 mm Hg and diastolic BP ≤95 mm Hg and the subject has been on a stable dose of 
antihypertensive medication for at least 48 hours 


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- 
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the first dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted.  It should be 
restarted at an additional dose reduction as specified in Table 3 only when systolic BP 
≤150 mmHg and diastolic BP ≤95 mmHg and the subject has been on a stable dose of 
antihypertensive medication for at least 48 hours. 
- 
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted.  It should be 
restarted at a third dose reduction as specified in Table 3 only when systolic BP 
≤150 mmHg and diastolic BP ≤95 mmHg and the subject has been on a stable dose of 
antihypertensive medication for at least 48 hours. 
 
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences): 
• 
Institute appropriate medical management 
• 
Discontinue study drug 
9.4.1.1.3 MANAGEMENT OF PROTEINURIA 
Regular assessment of proteinuria should be conducted as detailed in the Schedule of 
Procedures/Assessments (Table 8).  Guidelines for assessment and management of 
proteinuria: 
1. Grading will be based on the 24-hour urinary protein result.  Management of lenvatinib 
administration will be based on the grade of proteinuria according to instructions 
contained in Table 2,“Dose Modifications for Lenvatinib Treatment-Related Toxicity,” 
2. A 24-hour urine collection (within 72 hours) to verify the grade of proteinuria for protein 
quantitation is required in the following situations: 
− 
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on study drug 
− 
A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level 
− 
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is 2+, 3+, or 4+ 
3. Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 
(or more frequently as clinically indicated) until the results have been 1+ or negative for 
3 consecutive months. 
Grading of proteinuria should be performed according to CTCAE v4.03 (Appendix 3) but 
will be based on the 24-hour urine collection for total protein result, if a 24-hour urine was 
performed at that time point. 


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For subjects with lenvatinib-related toxicity, the dose reduction and/or interruption 
instructions provided in Table 2 of the study protocol should be followed. 
9.4.1.1.4 MANAGEMENT OF HEPATOTOXICITY 
Regular monitoring of liver function tests (eg, alanine transaminase [ALT], aspartate 
transaminase [AST], bilirubin levels) should be conducted as detailed in the Schedule of 
Procedures/Assessments and as clinically indicated.  If signs occur indicating a decrease in 
liver function by 1 grade or more from baseline, the instructions contained in Table 2 of the 
protocol should be followed, “Study Treatment Dose Reduction and Interruption 
Instructions”.  Appropriate supportive care should be provided together with close 
monitoring.  If hepatic failure occurs the study drug must be discontinued. 
9.4.1.1.5 MANAGEMENT OF THROMBOEMBOLIC EVENTS 
Subjects should be advised to pay attention to the symptoms suggestive of venous 
thromboembolic events, which include acute onset of dyspnea, chest pain, cough, 
hemoptysis, tachypnea, tachycardia, cyanosis, DVT signs including lower-extremity 
swelling, redness and warmth to touch or tenderness.  In case any of these signs or symptoms 
appear, subjects should be instructed to report such signs and symptoms promptly to the 
treating physician.  If a thromboembolic event is confirmed, instructions contained in Table 2 
of the protocol should be followed, “Study Treatment Dose Reduction and Interruption 
Instructions.” Appropriate supportive care should be provided together with close 
monitoring. If a subject experiences life-threatening (Grade 4) thromboembolic reactions, 
including pulmonary embolism, the study drug must be discontinued.   
9.4.1.1.6 MANAGEMENT OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME 
(PRES) 
In clinical studies with lenvatinib, events of posterior reversible encephalopathy syndrome 
(PRES) were reported in less than 1% of lenvatinib-treated subjects.  Posterior reversible 
encephalopathy syndrome is a neurological disorder that can present with headache, seizure, 
lethargy, confusion, altered mental function, blindness, and other visual or neurological 
disturbances.  Mild to severe hypertension may be present.  An MRI is necessary to confirm 
the diagnosis of PRES.  Appropriate measures should be taken to control blood pressure.  In 
subjects with signs or symptoms of PRES, dose interruptions, reductions, or discontinuation 
may be required per instructions included in Table 2.  Please refer to Section 7 of the 
Investigator's Brochure for further information on lenvatinib, including the full set of special 
warnings and precautions for use (Section 7.4.4). 
9.4.1.1.7 MANAGEMENT OF HYPOCALCEMIA 
Serum calcium should be monitored every 3 weeks per the Schedule of 
Procedures/Assessments.  Hypocalcemia should be treated per institutional guidelines (eg, 
using, as appropriate, calcium, magnesium, and Vitamin D supplementation) until resolution. 


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9.4.1.1.8 MANAGEMENT OF QT PROLONGATION 
Lenvatinib should be withheld in the event of development of QT interval prolongation ≥ 500 
msec.  Lenvatinib should be resumed at a reduced dose when QTc prolongation is resolved to 
<480 msec or baseline.  Monitor potassium, calcium and magnesium, and replenish as 
appropriate. 
9.4.1.1.9  MANAGEMENT OF OSTEONECROSIS OF THE JAW 
Perform an oral examination prior to treatment with lenvatinib and periodically during 
lenvatinib treatment.  Advise participants regarding good oral hygiene practices.  Avoid 
invasive dental procedures, if possible, while on lenvatinib treatment, particularly in 
participants at higher risk.  For participants requiring invasive dental procedures, 
discontinuation of bisphosphonate treatment may reduce the risk of osteonecrosis of the jaw 
(ONJ).  Withhold lenvatinib if ONJ develops and restart based on clinical judgement of 
adequate resolution. 
9.4.1.2 
Pembrolizumab 
Pembrolizumab (200 mg) will be administered as a 30-minute IV infusion, Q3W (infusions 
lasting between 25 minutes to 40 minutes are acceptable).  The Pharmacy Manual contains 
specific instructions for the preparation of the pembrolizumab infusion and administration of 
infusion solution. 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
Study treatment with pembrolizumab may be administered up to 3 days before or after the 
scheduled D1 of each cycle due to administrative reasons. 
Adverse events (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These AEs may occur shortly after the first dose or 
several months after the last dose of treatment.  Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 4 below.  See 
Section 9.4.1.2.1 for supportive care guidelines, including use of corticosteroids.


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Table 4 
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events 
Associated with Pembrolizumab 
Immune-related 
Adverse Event 
Toxicity Grade 
(CTCAE v4.0) 
Action with 
Pembrolizumab 
Corticosteroids and/or Other 
Therapies 
Monitoring and Follow-up 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last 
pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
Pneumonitis 
Grade 2 
Withhold 
Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper. 
Add prophylactic antibiotics for 
opportunistic infections. 
Monitor participants for signs and symptoms 
of pneumonitis. 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment. 
Recurrent Grade 2, 3 
or 4 
Permanently 
discontinue 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper. 
 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus). 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to rule 
out colitis.  
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Recurrent Grade 3 or 
Grade 4 
Permanently 
discontinue 


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Table 4 
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events 
Associated with Pembrolizumab 
Immune-related 
Adverse Event 
Toxicity Grade 
(CTCAE v4.0) 
Action with 
Pembrolizumab 
Corticosteroids and/or Other 
Therapies 
Monitoring and Follow-up 
AST or ALT 
elevation or 
Increased Bilirubin 
Grade 2 
Withhold 
Administer corticosteroids (initial 
dose of 0.5 to 1 mg/kg prednisone or 
equivalent) followed by taper. 
Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper. 
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable). 
Grade 3 or 4 
Permanently 
discontinue 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
Newly onset T1DM 
or Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withholda 
Initiate insulin replacement therapy 
for participants with T1DM. 
Administer anti-hyperglycemic in 
participants with hyperglycemia.  
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency). 
Grade 3 or 4 
Withhold or 
permanently 
discontinue 
Hyperthyroidism 
Grade 2 
Continue 
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care 
Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis: grading 
according to 
increased creatinine 
Grade 2 
Withhold 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper 
Monitor changes of renal function. 
Grade 3 or 4 
Permanently 
discontinue 


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Table 4 
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events 
Associated with Pembrolizumab 
Immune-related 
Adverse Event 
Toxicity Grade 
(CTCAE v4.0) 
Action with 
Pembrolizumab 
Corticosteroids and/or Other 
Therapies 
Monitoring and Follow-up 
or acute kidney 
injury. 
 
 
Myocarditis 
Grade 1  
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes. 
Grade 2,  3 or 4 
Permanently 
discontinue 
All other immune-
related AEs 
Persistent Grade 2 
Withhold 
 
 
Grade 3 
Withhold or 
discontinue based on 
eventb.   
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology or exclude other causes. 
Recurrent Grade 3 or 
Grade 4  
Permanently 
discontinue 
 
 
AE(s) = adverse event(s), ALT = alanine aminotransferase, AST = aspartate aminotransferase, CTCAE = Common Terminology Criteria for Adverse Events, 
DRESS = Drug Rash with Eosinophilia and Systemic Symptom; GI = gastrointestinal, IO=immuno-oncology; irAE = immune-related adverse event, IV = intravenous, 
SJS = Stevens-Johnson Syndrome; T1DM = Type 1 diabetes mellitus; TEN = Toxic Epidermal Necrolysis; ULN = upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
 
a The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or 
≤ Grade 2, pembrolizumab may be resumed. 
b Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically 
important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
 
 
 


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Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (eg, elective surgery, unrelated medical events, subject vacation, 
and/or holidays).  Subjects should be placed back on study treatment within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the sponsor.  The reason for 
interruption should be documented in the subject's study record. 
9.4.1.2.1 SUPPORTIVE CARE GUIDELINES FOR PEMBROLIZUMAB 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 9.4.1.2.  Where appropriate, these guidelines include the use of oral or IV treatment 
with corticosteroids, as well as additional antiinflammatory agents if symptoms do not 
improve with administration of corticosteroids.  Note that several courses of steroid tapering 
may be necessary as symptoms may worsen when the steroid dose is decreased.  For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.  
Note:  If after the evaluation of the event, it is determined not to be related to 
pembrolizumab, the investigator does not need to follow the treatment guidance.  Refer to 
Section 9.4.1.2 for guidelines regarding dose modification and supportive care.  
It may be necessary to perform additional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
Table 5  
Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 h 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
Subject may be 
premedicated 1.5h (±30 
minutes) prior to infusion 
of pembrolizumab with: 
 
Diphenhydramine 50 mg 
orally (or equivalent dose 
of antihistamine). 
 


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Table 5  
Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(eg, from 100 mL/h to 50 mL/h).  Otherwise 
dosing will be held until symptoms resolve 
and the subject should be premedicated for 
the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study treatment administration. 
Acetaminophen 500-1000 
mg orally (or equivalent 
dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine 
should be used immediately. 
Subject is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. 


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Table 5  
Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
ANC = absolute neutrophil count, CTCAE = Common Terminology Criteria for Adverse Events v4.03, h = 
hour, IV = intravenous, NCI = National Cancer Institute, NSAID = nonsteroidal antiinflammatory drug. 
9.4.2 
Identity of Investigational Products 
Lenvatinib and pembrolizumab will be supplied by the sponsor in appropriately labeled 
containers.   
Lenvatinib will be provided as 4-mg and 10-mg capsules.  Lenvatinib is formulated with 
calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, low-
substituted hydroxypropylcellulose, and talc. 
Pembrolizumab may be provided as a sterile, preservative-free, white to off-white 
lyophilized powder in single-use vials.  Each vial will be reconstituted and diluted for IV 
infusion.  Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is 
formulated in L-histidine (3.1 mg), polysorbate-80 (0.4 mg), sucrose (140 mg). The solution 
may contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.   
Alternatively, pembrolizumab may be provided as a sterile, preservative-free, clear to slightly 
opalescent, colorless to slightly yellow solution that requires dilution for IV infusion. Each 
vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 
25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 
mg), sucrose (70 mg), and Water for Injection. 
9.4.2.1 
Chemical Name, Structural Formula of Lenvatinib 
LENVIMA is the mesylate salt of lenvatinib. Its chemical name is 4-[3-chloro-4-(N’-
cyclopropylureido)phenoxy]-7-methoxyquinoline-6 carboxamide methanesulfonate.  The 
molecular formula is C21H19ClN4O4 • CH4O3S, and the molecular weight of the mesylate 
salt is 522.96.  The chemical structure of lenvatinib mesylate is: 
N
H3CO
H2N
O
O
Cl
N
H
N
H
O
H3C SO3H
 
9.4.2.2 
Information of Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) mAb with high specificity 
of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with 


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programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2).  
Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is 
in clinical development as an IV immunotherapy for advanced malignancies.  Keytruda™ 
(pembrolizumab) is indicated for the treatment of patients across a number of indications.  
For more details on specific indications refer to the Investigator’s Brochure. 
9.4.2.3 
Labeling for Study Drug 
Lenvatinib and pembrolizumab will be labeled in accordance with text that is in full 
regulatory compliance with each participating country and is translated into the required 
language(s) for each of those countries. 
9.4.2.4 
Storage Conditions 
Study drugs will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or is responsible for ensuring that 
the temperature is monitored throughout the total duration of the study and that records are 
maintained; the temperature should be monitored continuously by using either an in-house 
validated data acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means, such that minimum and maximum thermometric values over a 
specific time period can be recorded and retrieved as required. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will receive 
lenvatinib in combination with pembrolizumab.  There is no randomization in this study. 
9.4.4 
Selection of Doses in the Study 
For the assessment of MTD, the lenvatinib doses selected are 24 mg, 20 mg, and 14 mg QD 
all in combination with 200 mg pembrolizumab Q3W given IV.  While 24 mg is the 
recommend dose for locally recurrent or metastatic, progressive, radioactive iodine-
refractory differentiated thyroid cancer (LENVIMA Package Insert/SmPC),  20 mg and 
14 mg are the first and second doses in lenvatinib’s dose reduction scheme for all tumors 
(except hepatocellular carcinoma) for which data are available.  While 2 mg/kg is the 
recommended dose for pembrolizumab for melanoma (KEYTRUDA Package Insert/SmPC), 
a 200 mg Q3W fixed dose regimen is planned to be used in this study (see Section 7.2).  
9.4.5 
Selection and Timing of Dose for Each Subject 
Lenvatinib will be administered with water orally once a day (with or without food) in 
21-day cycles at approximately the same time each day.  Treatment cycles will be counted 
continuously regardless of dose interruptions.  On D1 of each cycle, it will be administered 
approximately within 1 hour after completion of pembrolizumab administration. 


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Pembrolizumab will be administered as a dose of 200 mg as a 30-minute IV infusion, Q3W 
(infusion durations of 25 minutes to 40 minutes are acceptable).  The Pharmacy Manual 
contains specific instructions for the preparation of the pembrolizumab infusion and its 
administration.  Subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting.  Study treatment of pembrolizumab may 
be administered up to 3 days before or after the scheduled D1 of each cycle due to 
administrative reasons. 
9.4.6 
Blinding 
The study will not be blinded. 
9.4.7 
Prior and Concomitant Therapy 
Prior therapy must be documented by the following criteria prior to entry into study. 
• 
Any single agent therapy, and any combination of cytotoxic, hormonal, biological 
targeted agents, and/or humanized antibodies, scheduled to be administered as a 
preplanned treatment, given concomitantly, sequentially or both, is considered 1 regimen. 
• 
Planned neoadjuvant chemotherapy (to debulk the tumor prior to surgical intervention) 
plus postoperative adjuvant chemotherapy is considered 1 regimen. 
• 
For chemotherapy:  if, due to toxicity, the dosing of one or more of the components must 
be reduced, or one or more of the components of the regimen must be omitted, or one of 
the components must be replaced with another similar drug, the changed version of the 
original regimen is not considered a new regimen.  However, if a new component, 
dissimilar to any of the original components, is added to the regimen, the new 
combination is considered a new regimen.    
• 
For prior VEGF/VEGFR-targeted agents, treatment with each agent will be counted 
individually, regardless of the duration of administration. 
• 
If the treatment is interrupted for surgery or radiotherapy or any other reason and then 
continues with an unchanged schedule and components, that treatment is considered as 1 
regimen despite the interruption. 
 
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of informed consent) until 30 days after the final 
dose of study drug will be recorded.  Additionally, all diagnostic, therapeutic, or surgical 
procedures relating to malignancy should be recorded.  Any medication that is considered 
necessary for the subject’s health and that is not expected to interfere with the evaluation of 
or interact with lenvatinib or pembrolizumab may be continued during the study. 
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) lenvatinib or pembrolizumab. 


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Aspirin, nonsteroidal antiinflammatory drugs, and low-molecular-weight heparin (LMWH) 
are permissible but should be used with caution.  Granulocyte colony-stimulating factor  or 
equivalent may be used in accordance with American Society of Clinical Oncology (ASCO), 
institutional, or national guidelines.  Erythropoietin may be used according to ASCO, 
institutional, or national guidelines, but the subject should be carefully monitored for 
increases in red blood cell counts. 
The investigator will record on the Adverse Event CRF any AE for which the concomitant 
medication/therapy was administered. 
9.4.7.1 
Drug–Drug Interactions 
Lenvatinib’s weak in vitro inhibitory and induction potential on cytochrome P450 (CYP) 
enzymes (Study No. XT063020) suggests a low risk of lenvatinib interference with the PK of 
other drugs metabolized by CYP P450 enzymes which are co-administered in usual clinic 
practice.  Nonclinical studies identify CYP3A4 as an important enzyme responsible for 
human hepatic metabolism of lenvatinib.  However, clinical studies conducted to test these 
findings showed that co-administration of lenvatinib with CYP3A4/P-glycoprotein (P-gp) 
inhibitors or inducers is not of clinical concern (see Appendix 5 for a summary of clinical 
findings).   
No formal pharmacokinetic drug interaction studies have been conducted with 
pembrolizumab.  Pembrolizumab is a mAb; pharmacokinetic interactions with lenvatinib 
(and vice-versa) are not expected. 
9.4.7.2 
Prohibited Concomitant Medications/Vaccinations 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination 
may be required.  The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the subject's primary physician.  However, the decision to 
continue the subject on study therapy or vaccination schedule requires the mutual agreement 
of the investigator, the sponsor, and the subject. 
9.4.7.2.1 PROHIBITED CONCOMITANT MEDICATIONS 
Subjects should not receive other antitumor therapies while on study.  If a subject receives 
additional antitumor therapies, such as chemotherapy, hormone therapy, palliative 
radiotherapy, or immunotherapy, this will be judged to represent evidence of disease 
progression, and continuation of the study medication and further participation in the study 
must be discussed and agreed upon with the sponsor.  
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study: 


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• 
Anticancer therapies such as chemotherapy, TKIs, antitumor interventions (surgical 
resection, thoracocentesis, etc.), or immunotherapy 
• 
Investigational agents other than lenvatinib and pembrolizumab 
• 
Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be considered 
as an exception on a case by case basis after consultation with the Sponsor.  Administration 
of palliative radiation therapy will be considered clinical progression for the purposes of 
determining PFS. 
• 
Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacille Calmette-
Guérin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed.  However, intranasal influenza vaccines 
(eg, Flu-Mist®) are live attenuated vaccines, and are not allowed. 
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the sponsor. 
Note:  Inhaled steroids are allowed for management of asthma or seasonal allergies. 
For subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study medication 
and further participation in the study must be discussed and agreed upon with the sponsor.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications that are prohibited in this clinical study. 
For clarification, the following concomitant medications are also allowed: 
• 
Thyroid hormone suppressive therapy (including therapy to treat hypothyroidism and 
hyperthyroidism) 
• 
Adjuvant hormonal therapy for history of definitively treated breast or prostate cancer  
• 
Anticoagulants including LMWH, warfarin, anti-Xa agents  
• 
Antiinflammatory agents (n.b., use of steroids is not permitted except as outlined in 
Sections 9.4.1.2.1 to manage immune-related AEs) 
• 
Bisphosphonates or denosumab 
• 
Supportive care guideline for pembrolizumab (see Section 9.4.1.2.1) 
• 
Antihypertensive therapy (including additional antihypertensive treatment as appropriate 
if BP increases once the patient has been enrolled) 
9.4.8 
Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study. 


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9.4.9 
Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor: 
• 
A signed and dated confidentiality agreement 
• 
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator 
• 
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted 
• 
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study 
• 
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number 
• 
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol 
• 
An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
where applicable 
• 
Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable 
• 
A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license or medical registration number on the CV 
• 
A signed and dated clinical studies agreement 
The investigator and the study staff  will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements. 
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.   
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study drugs 
that occurs at the site.  All forms will be provided by the sponsor.  Any comparable forms 
that the site wishes to use must be approved by the sponsor. 
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 


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FDA).  As applicable, all unused study drugs and empty and partially empty containers from 
used study drugs are to be returned to the investigator by the subject and, together with 
unused study drugs that were shipped to the site but not dispensed to subjects, are to be 
returned to the sponsor’s designated central or local depot(s) during the study or at the 
conclusion of the study, unless provision is made by the sponsor for destruction of study 
drugs and containers at the site.  Destruction at the site will only occur under circumstances 
where regulation or supply type prohibits the return of study drugs to the central or local 
depot(s).  Approval for destruction to occur at the site must be provided by the sponsor in 
advance.  Upon completion of drug accountability and reconciliation procedures by the site’s 
personnel and documentation procedures by the sponsor’s personnel, study drugs that are to 
be returned to the sponsor’s designated central or local depot(s) must be boxed, sealed, and 
shipped back to the central or local depot(s) following all local regulatory requirements.  In 
some regions, study drugs may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs are approved for destruction at 
the site, destruction will occur following the site’s standard procedures and certificates of 
destruction will be provided to the sponsor. 
Drug accountability will be reviewed during site visits and at the completion of the study. 
9.5 
Study Assessments 
9.5.1 
Assessments 
All study-related medical or dental decisions must be made by an investigator who is a 
qualified physician. 
9.5.1.1 
Demography 
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race and ethnicity.  Baseline characteristics 
will include ECOG-PS, NYHA cardiac disease classification, and pathological tumor-node-
metastasis (pTNM) staging at initial diagnosis (Appendix 2 and Appendix 4).  FIGO grade 
(Creasman, 2009) will be collected from all EC subjects if available.  The Karnofsky 
performance status (KPS) (Appendix 8) will also be collected from all RCC subjects only to 
permit the calculation of the International Metastatic Renal Cell Carcinoma Database 
Consortium prognostic risk group (Favorable, Intermediate, or Poor ) (Ko, et al., 2015; Heng, 
et al., 2013; Heng, et al., 2009). 
9.5.1.2 
Baseline Assessments 
9.5.1.2.1 MEDICAL HISTORY AND PHYSICAL EXAMINATIONS 
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All clinically significant medical and surgical history must be noted in the Medical 
History and Current Medical Conditions CRF. 


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Physical examinations will be performed as designated in the Schedule of Procedures/ 
Assessments (Table 8 and Table 9).  A comprehensive physical examination including oral 
examination will include evaluations of the head, eyes, ears, nose, throat, jaws, neck, chest 
(including heart and lungs), abdomen, limbs, skin, and a complete neurological examination.  
Documentation of the physical examination will be included in the source documentation at 
the site.  Significant findings at the Screening Visit will be recorded on the Medical History 
and Current Medical Conditions CRF.  Changes from screening physical examination 
findings that meet the definition of an AE will be recorded on the Adverse Events CRF.   
9.5.1.3 
Efficacy Assessments 
All efficacy endpoints, other than OS, will be based on the tumor assessments performed 
by the investigators using both irRECIST and modified RECIST 1.1.  Treatment decisions 
by the Investigator will be based on irRECIST.  All scans for tumor assessments 
performed during the study should be archived in accordance with the standard local 
practice.  The scans from Phase 1b must be accessible in the event of a sponsor request to 
submit them for central review.  For Phase 2, images acquired for tumor assessments will 
be sent to an imaging core laboratory (ICL)for archiving and potential independent 
analysis.  As of Amendment 3, tumor assessment scans for the EC subjects will be assessed 
by IIR.  As of Amendment 5, tumor assessment scans for the renal cell carcinoma subjects 
will also be assessed by IIR.  As of Amendment 08, scans acquired after data cutoff for 
final efficacy analysis, in any cohort, will no longer be sent to the ICL. 
Renal Cell Carcinoma PD-1 pre-treated cohort 
As of Amendment 08, for subjects enrolled in the RCC cohort who were previously treated 
with anti-PD-1/PD-L1 mAb, available pre-Baseline scans will be collected by sites and sent 
to an ICL designated by the sponsor for quality assessment and archival, and potential future 
independent review. 
Pre-Baseline scans in this context are as follows: 
• 
nadir scan on prior anti-PD-1/PD-L1 mAb therapy (additional scans on prior 
anti-PD-1/PD-L1 mAb therapy may be submitted if the nadir scan is unavailable); 
• 
initial progression on prior approved anti-PD-1/PD-L1 mAb therapy; 
• 
confirmed progression on prior anti-PD-1/PD-L1 mAb therapy (preferably no less than 4 weeks 
from the date of the first documented PD, as of Amendment 7).  
As of Amendment 09, pre-baseline scans for RCC subjects are not required. 
Tumor assessments will be carried out during the Pretreatment Phase and then every 6 weeks 
(during the 6th week; counting from C1D1) until Week 24, then every 9 weeks during 
treatment cycles in both the Treatment Phase and the Extension Phase.  As of Amendment 
09, tumor assessments will continue during the Extension Phase as per local standard of care 
but not less frequent than every 6 months.  Tumor assessments will not be collected during 
the Follow-Up period of the Extension Phase.  CT/MRI scans of chest, abdomen, and pelvis 
and of other known sites of disease will be obtained at Screening (within 28 days prior to C1 
D1), at all tumor assessment time points, and as indicated clinicallyand as per local standard 


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of care.   Color photographs containing a millimeter scale must be taken of all skin lesions 
being used as target lesions.  Historical standard of care scans that are performed with 
scanning parameters consistent with the requirements for this protocol within 28 days prior to 
dosing are acceptable.  Subjects with HNSCC must also have head and neck scans 
performed.  
The computed tomography (CT) scan should be a diagnostic quality spiral or multidetector 
CT with oral and iodinated IV contrast, and the MRI scan should be performed with IV 
gadolinium chelate.  Scans of the neck, abdomen, pelvis, and other areas of the body may be 
done with MRI instead of CT, but evaluation of the chest must be done with CT.  If iodinated 
IV contrast is contraindicated, the chest evaluation should be done with non-contrast CT, and 
the abdomen and pelvis evaluation should be performed using either CT with oral contrast 
(without IV contrast) or MRI with gadolinium chelate IV contrast (the latter is preferred). 
Spiral/multidetector CT should be performed with a 5-mm contiguous slice reconstruction 
algorithm.  If body MRI scans are performed, contiguous slices of 5 mm are also 
recommended.  
Low-dose non-contrast CT transmission scans from a positron emission tomography-CT 
(Positron emission tomography [PET]-CT) combination scanner are not acceptable.  
Ultrasound should not be used for radiographic tumor assessment.  Chest disease may not be 
followed using chest x-ray.   
A brain scan (CT with contrast or MRI pre- and post-gadolinium) must be performed at 
screening to assess potential CNS disease and/or metastases.  For subjects with previously 
treated eligible brain metastases, a brain scan must be performed at all tumor assessment time 
points.  For all subjects, a follow-up brain scan must be performed to confirm immune-
related complete response (irCR) within 1 week of response confirmation, or if clinically 
indicated.   
The tumor assessment schedule should not be affected by interruptions in study treatment. 
Subjects going Off-Tx without disease progression will also undergo tumor assessments per 
the Schedule of Procedures/Assessments until disease progression is documented or another 
anticancer therapy is initiated.   
The same method of assessment used at screening must be used at all time points. 
Throughout the study it is critical that the same imaging methodology be applied and contrast 
be consistently provided unless IV contrast becomes medically contraindicated during the 
course of treatment or the dose of contrast needs to be adjusted based on the subject’s health 
status.   
Bone scans will be performed for all subjects (except for subjects with HNSCC) at screening, 
every 24 weeks, or sooner if clinically indicated, and at confirmation of irCR. A bone scan 
(99m-technetium polyphosphonate scintigraphy, whole body bone MRI, or 18F-NaF-PET) to 
assess bone metastases will be performed within 6 weeks prior to C1D1 (historical scans are 
acceptable) and then every 24 weeks (within that 24th week) from C1D1 for all tumor types 
except for HNSCC, or sooner if clinically indicated.  For those visits where the bone scan 


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does not coincide with the schedule for the acquisition of the CT/MRI scans (ie, Weeks 48 
and 72), the bone scan should be added to the closest CT/MRI time point (eg, Weeks 51 and 
69).  In subjects whose body CT/MRI scans indicate that irCR has been achieved, except for 
subjects with HNSCC, a bone scan will be required at confirmation of irCR to exclude new 
bone metastases.  The same methodology and acquisition techniques used at screening 
should be used throughout the study to ensure comparability. Lesions detected on bone scans 
must be followed with cross-sectional imaging.     
In order for immune-related stable disease (irSD) to be considered the best overall response, 
it must occur ≥5 weeks following the first dose of study drug. 
The first radiological assessment of tumor response status will be performed at Week 6 
(±1 week), unless there is clinical indication warranting earlier radiologic imaging.  If 
imaging at Week 6 shows irSD, treatment will be continued and tumor assessments will be 
conducted at the next regularly scheduled imaging time point, ie, at Week 12 (±1 week).  
Responses (immune-related partial response [irPR] or irCR [complete response]) should be 
confirmed no less than 4 weeks after the initial response, but generally at the next scheduled 
tumor assessment time point. 
If the time point tumor assessment is PD, treatment should continue and tumor assessments 
repeated at least 4 weeks later, but generally at the next scheduled tumor assessment time 
point in order to confirm immune-related progression disease (irPD). If repeat imaging shows 
a reduction in the tumor burden compared to the initial tumor assessment demonstrating PD, 
treatment may be continued as per treatment schedule.  If repeat imaging confirms irPD, 
subjects will be discontinued from study treatment.  In determining the tumor time point 
response, investigators should consider all target lesions as well as nontarget lesions and new 
lesions.  
The decision to continue study treatment after the first evidence of PD is at the Investigator’s 
discretion based on the clinical status of the subject as described in Table 6 below.   
Subjects may continue receiving study treatment while waiting for confirmation of PD if they 
are clinically stable as defined by the following criteria: 
• 
Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• 
No decline in ECOG PS 
• 
Absence of rapid progression of disease  
• 
Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
If irPD is confirmed and the subject is experiencing extraordinary clinical benefit, site must 
contact Sponsor to discuss continuing treatment. 


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Tumor assessments per modified RECIST 1.1 will follow Eisenhauer, et al. (2009), however, 
up to 10 target lesions, up to 5 per organ, may be selected (as opposed to the maximum of 
5 target lesions, up to 2 per organ, mentioned in Eisenhauer, et al., 2009). 
Table 6 
Imaging and Treatment After First Radiologic Evidence of 
Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st 
radiologic 
evidence of 
PD 
Repeat imaging at >4 
weeks (next TA time 
point) to confirm PD 
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting 
confirmatory scans  
Repeat imaging at >4 
weeks to confirm PD 
per physician discretion 
only 
Discontinue 
treatment 
Subsequent 
scan 
confirms 
PD 
No additional imaging 
required 
Discontinue 
treatment 
No additional imaging 
required 
N/A 
Subsequent 
scan shows 
SD, PR or 
CR 
Continue regularly 
scheduled imaging 
assessments  
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments  
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per investigator’s 
discretion 
CR = complete response, PR = partial response, SD = stable disease, PD = progression disease, N/A = not 
applicable. 
 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
A schedule of lenvatinib PK, pharmacodynamic, and pharmacogenomic sampling is shown 
in the Schedule of Procedures/Assessments (Table 8 and Table 9). 
9.5.1.4.1 PHARMACOKINETIC ASSESSMENTS 
Plasma concentrations of lenvatinib will be measured.   
Blood samples will be collected as specified in Table 8 and Table 9.  See the Laboratory 
Manual for a description of collection, handling, and shipping procedures for PK samples. 
Samples from all subjects will be analyzed.  Plasma concentrations of analytes will be 
quantified by liquid chromatography with tandem mass spectrometry (LCMS/MS) 
methodology using a previously validated assay. 
Blood will also be drawn where possible at the first report of a serious adverse event (SAE) 
or severe unexpected AE and at its resolution. 


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A population PK model for lenvatinib will be developed using the program NONMEM.  The 
model will be parameterized in terms of clearance and volume of distribution 
9.5.1.4.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS 
A schedule of biomarker sampling is shown in the Schedule of Procedures/Assessments 
(Table 8 and Table 9).   
Blood samples for the development of exploratory predictive biomarkers will be collected 
prior to the first dose of study drug, on C1D15, and on D1 of all subsequent cycles during 
Treatment Phase, and at the Off-Tx assessment.  Subjects will be required to provide an 
archival tumor tissue sample and/or a fresh biopsy of tumor before treatment for biomarker 
analyses (patients with inaccessible tumors for biopsy specimens can be enrolled without a 
biopsy upon consultation and agreement by the sponsor). For subjects in the NSCLC cohort 
every effort is to be made to obtain a fresh biopsy of tumor at the beginning of C2 (optional for 
other cohorts on study) if they have recovered adequately from the biopsy taken prior to 
starting therapy and to provide the acquired tissue for these biomarker analyses.  Biomarker 
discovery and/or validation will be performed to identify blood or tumor biomarkers which 
may be useful to predict subject response to lenvatinib and/or pembrolizumab, as determined 
by evaluation of response-related and/or safety-related outcomes as well as for potential use 
in diagnostic development.  Blood samples from subjects receiving lenvatinib and 
pembrolizumab may be analyzed using global proteomic methods, enzyme-linked 
immunosorbent assay (ELISA), multiplex bead-based immunoassay, or other assays/methods 
or new technology.  In addition, biomarkers identified in other lenvatinib clinical studies may 
also be assessed in the biomarker samples collected from subjects enrolled in this study.  The 
decision to perform exploratory biomarker analysis may be based on the clinical outcome of 
this study and/or the signals observed in other clinical studies or other information available 
at that time. 
Archived, formalin-fixed paraffin-embedded (FFPE) tissue or a newly obtained biopsy will 
be collected from all subjects for potential assessment of mutations and other genetic 
alterations and/or proteins including PD-1/PD-L1 status and other relevant biomarkers (eg, 
tumor infiltrating lymphocytes, T-cell repertoire, ribonucleic acid [RNA] signature profiles), 
which may be important in the development and progression of cancer as well as for 
potential use in diagnostic development.  Appropriate technology/methodologies will be used 
based on the amount of tumor tissue available.  
Note: For PD-1/PD-L1 status, submission of FFPEtumor tissue sample blocks are preferred; 
if submitting unstained slides, the slides should be freshly cut and submitted to the 
testing laboratory within 14 days from the site slide sectioning date; otherwise, a new 
specimen will be requested. 
As of Amendment 06, available known mutation status, including mismatch repair (MMR) or 
microsatellite instability (MSI) status, will be collected on the electronic case report form 
(eCRF). 


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For all tumor types except NSCLC, optional fresh paired tumor biopsies will be collected 
from consented subjects to examine markers including markers of target engagement, 
relevant pharmacodynamic biomarkers, and potential markers of response.  Fresh biopsies 
should be limited to readily accessible tumor lesions (eg, skin; peripheral lymph nodes; liver 
metastases which can be readily accessed using CT guidance).  Subjects should have the 
biopsy before administration of the first dose of study drug and at a time point 3-6 weeks 
after the first dose (if they have recovered adequately from the biopsy taken prior to starting 
therapy).  For NSCLC every effort is to be made to obtain a fresh tumor biopsy; subjects will 
have fresh tumor biopsies collected from consented subjects before administration of the first 
dose of study drug and at a time point 3-6 weeks after the first dose (if they have recovered 
adequately from the biopsy taken prior to starting therapy). 
As of Amendment 01, a blood sample for peripheral blood mononuclear cells (PBMCs) and 
plasma isolation will be collected from enrolled subjects.  Cell free nucleic acid isolated from 
plasma samples may be used to obtain circulating tumor DNA (ctDNA) and explore tumor 
genetic alterations such as mutations observed in archival tumor samples as well as those 
which develop during drug treatment.  
In Phase 2, as of Amendment 4, a blood sample for nucleic acid analysis will be collected for 
potential assessment of gene expression profiling.  In Phase 2, as of Amendment 3, a blood 
sample will be collected for potential pharmacodynamics and pharmcogenomic analysis.  
Variation in lenvatinib exposure or the occurrence of AEs observed in the study population 
may be evaluated by correlating single–nucleotide polymorphisms with PK, safety, or 
pharmacodynamic data.  Genomic DNA extracted from blood samples may be used to 
confirm whether the DNA sequence variants observed in DNA extracted from tumor material 
are limited to the tumor, for potential microsatellite instability analysis, and for potential 
immune response monitoring.  Data obtained will be used for research to assist in developing 
safer and more effective treatments and will not be used to change the diagnosis of the 
subject or alter the therapy of the subject.  The DNA will not be used to determine or predict 
risks for diseases that an individual subject does not currently have.  Any sample or 
derivatives (DNA, RNA, and protein) may be stored for up to 15 years to assist in any 
research scientific questions related to lenvatinib/pembrolizumab, cancer and/or for potential 
diagnostic development.  
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual. 
9.5.1.5 
Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 grades (for both increasing and 
decreasing severity), and SAEs; regular monitoring of hematology, blood chemistry, and 
urine values; periodic measurement of vital signs and ECGs; echocardiograms or multigated 
acquisition (MUGA) scans including left ventricular ejection fraction (LVEF); and 
performance of physical examinations including oral examinations as detailed in Section 
9.5.1.2.1.   


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9.5.1.5.1 ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the investigational products are 
lenvatinib and pembrolizumab.  
The criteria for identifying AEs in this study are: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE.) 
• 
Any new disease or exacerbation of an existing disease. However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE. 
• 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug 
• 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline) 
• 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not. 
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF and for 30 days after the last dose of study treatment. Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported.  SAEs will be collected for 90 days after the last dose or 30 days following the last 
dose if the subject initiates new anticancer therapy, whichever is earlier. An AE will not be 
reported on the Adverse Event CRF if other anticancer treatment is started. All SAEs will be 
reported on the Adverse Event CRF.  All deaths will be collected for 30 days following the 
last dose of study treatment and reported on the Survival CRF. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 


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and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such. 
Progression of malignant disease (PD) should not be recorded as an AE in studies where it is 
included as an endpoint for underlying disease.  If the progression leads to an untoward 
medical occurrence (increased pain, pleural effusion, etc), then this medical occurrence 
should be the AE. 
All AEs must be followed for 30 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization. 
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 
Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to Common Terminology Criteria 
for Adverse Event (CTCAE v4.03) (Appendix 3).  Investigators will report CTCAE grades 
for all AEs (for both increasing and decreasing severity).   
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
• 
Temporal relationship of the onset of the event to the initiation of the study treatment 
• 
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
• 
Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• 
The presence of risk factors in the study subject known to increase the occurrence of the 
event 
• 
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
Classification of Causality 
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question: 
Is there a reasonable possibility that the study drug caused the AE? 
Yes (related) 
A causal relationship between the study drug and the AE is a reasonable 
possibility. 
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility. 


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9.5.1.5.2 SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
Events of clinical interest for this study include: 
1.  an elevated AST or ALT laboratory value that is greater than or equal to 3 × ULN and 
an elevated total bilirubin lab value that is greater than or equal to 2 × ULN and, at 
the same time, an ALP laboratory value that is less than 2 × ULN, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing. 
Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The study site guidance 
for assessment and follow up of these criteria can be found in the Investigator Trial 
File Binder (or equivalent).  It may also be appropriate to conduct additional 
evaluation for an underlying etiology in the setting of abnormalities of liver blood 
tests including AST, ALT, bilirubin, and ALP that do not meet the criteria noted 
above.  In these cases, the decision to proceed with additional evaluation will be made 
through consultation between the study investigators and the Sponsor Clinical 
Director.  However, abnormalities of liver blood tests that do not meet the criteria 
noted above are not events of clinical interest for this trial. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; and AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.   
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 


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The following hospitalizations are not considered to be SAEs because there is no AE (ie, 
there is no untoward medical occurrence) associated with the hospitalization: 
• 
Hospitalizations for respite care  
• 
Planned hospitalizations required by the protocol 
• 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration) 
• 
Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
• 
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution. 
9.5.1.5.3 LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 7.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 8 and Table 9) shows the visits 
and time points at which blood for clinical laboratory tests and urine for urinalysis will be 
collected in the study.   
Table 7 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential 
INRb 
Clinical Chemistry 
 
 Electrolytes 
Bicarbonate, calcium, chloride, magnesium, phosphorus, 
potassium, sodium  
 Liver function tests 
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin 
 Renal function tests 
Blood urea nitrogen, creatinine 
 Thyroid function testsa 
TSH and free T4 levels  
 Other 
Albumin, cholesterol, glucose, lactate dehydrogenase, total protein, 
triglycerides, amylase, lipase 
Urinalysis 
Glucose, ketones, pH, protein, RBCs, specific gravity 
RBC = red blood cell, T4 = thyroxine, WBC = white blood cell, INR, International Normalized Ratio. 
a. 
Thyroid function will be assessed every 2 cycles. 
b. Only at screening/baseline and when clinically indicated. 


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All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and results reviewed prior to 
administration/dispensing of study drug at the beginning of each treatment cycle.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the CRF Completion Guidelines (CCG).  In these 
instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event CRF. 
9.5.1.5.4 VITAL SIGNS AND WEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic and diastolic BP [mmHg], heart rate [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained at the visits designated in the Schedule of Procedures/Assessments (Table 8 and 
Table 9) by a validated method.  Blood pressure and heart rate will be measured after the 
subject has been resting for 5 minutes.  All BP measurements should be performed on the 
same arm, preferably by the same person.  One BP assessment is defined as the mean value 
of 3 measurements at least 5 minutes apart. 
For subjects with an elevated BP (ie, systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), 
confirmation should be obtained by performing two assessments a minimum of 1-hour apart.   
Subjects with systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have their BP 
monitored every 2 weeks (on D1 and Day 15 or more frequently, as clinically indicated) until 
systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive 
months.  See subsection for management of hypertensive subjects (Section 9.4.1.1.2). 
Height will be measured at the Screening Visit only.   
9.5.1.5.5 PHYSICAL EXAMINATIONS 
Physical examinations including oral examinations will be performed as designated in the 
Schedule of Procedures/Assessments (Table 8 and Table 9).  Documentation of the physical 
and oral examination will be included in the source documentation at the site.  Only changes 
from screening physical or oral examination findings that meet the definition of an AE will 
be recorded on the Adverse Events CRF. 
9.5.1.5.6 ELECTROCARDIOGRAMS 
Electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 8 and Table 9).  Complete, standardized, 12-lead ECG 
recordings that permit all 12 leads to be displayed on a single page with an accompanying 
lead II rhythm strip below the customary 3 × 4 lead format are to be used.  In addition to a 
rhythm strip, a minimum of 3 full complexes should be recorded from each lead 
simultaneously.  Subjects must be in the recumbent position or sitting for a period of 5 
minutes prior to the ECG.  The Fridericia correction method for calculating QTc will be 
used.   


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An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.5.1) and the CCGs.  In these instances, the AE corresponding to the ECG 
abnormality will be recorded on the Adverse Events CRF. 
QT prolongation has been seen in some lenvatinib studies.  Monitor electrocardiograms 
every cycle (as specified in the Schedule of Assessments) in patients with congenital long QT 
syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known 
to prolong the QT interval, including Class Ia and III antiarrhythmics.  Refer to the 
Lenvatinib package insert. 
9.5.1.5.7 ECHOCARDIOGRAM OR MULTIPLE GATED ACQUISITION SCAN  
A MUGA scan (using technetium-based tracer) or an echocardiogram will be performed to 
assess LVEF as designated in the Schedule of Procedures/Assessments (Table 8 and Table 
9).  MUGA or echocardiogram scans should be performed locally in accordance with the 
institution’s standard practice.  MUGA scans are the preferred modality; however, whichever 
modality is used for an individual subject at baseline should be repeated for all subsequent 
LVEF assessments for that subject.  LVEFs as assessed by the institution will be entered onto 
the CRF.  Investigator assessment will be based upon institutional reports. 
All scans performed during the study should be archived in accordance with the standard 
local practice.  They must be accessible in the event of a sponsor request to submit them for 
central review.    
9.5.2 
Schedule of Procedures/Assessments 
9.5.2.1 
Schedule of Procedures/Assessments 
Table 8 (Phase 1b) and Table 9 (Phase 2) present the schedule of procedures and assessments 
for the study. 


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Table 8 
Phase 1b: Determination of the Maximum Tolerated Dose:  Schedule of Procedures/Assessments in 
the Pretreatment, Treatment, and Extension Phases 
CRF 
Phase 
Pretreatment 
Treatment 
Extension 
 
Period 
Screenin
ga,b 
Baseline
a,b 
Treatment  
(Cycle 1b ) 
Treatment 
(Cycle 2b & Beyond) 
Follow-Up Periodbb 
 
Visit 
1 
2 
3 
 
4 
 
5 
  
6, 8, 10, 
12, etc. 
7, 9, 11, 
13, etc. 
Off-Treatment 
Visitu 
Follow-up Visits (Off-Tx 
Visit + 1 day & Beyond) 
 
Day 
-28 to -3 
-3 to -1 
1 
8 
15 
1 
15 
+30 days after 
last dose 
Every 12 weeksy 
 
Assessments 
 
 
 
 
 
 
 
 
 
S 
Informed consent 
X 
 
 
 
 
 
 
 
 
S 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
S 
Demographic data 
X 
 
 
 
 
 
 
 
 
S 
ECOG PS/NYHAc 
X 
X 
 
 
 
X 
 
X 
 
 
KPSc 
X 
 
 
 
 
 
 
 
 
S 
pTNM staging at diagnosis 
X 
 
 
 
 
 
 
 
 
NS 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
S 
Prior medications 
X 
 
 
 
 
 
 
 
 
S 
Vital signsd 
X 
X 
X 
 
X 
Xd 
Xd,w 
X 
 
NS 
Physical examinatione 
X 
Xf 
 
 
X 
X 
 
X 
 
NS 
12-lead ECGg 
X 
 
X 
 
 
X 
 
X 
 
S 
MUGA scan or 
echocardiogramz 
X 
 
Xz 
 
 
S 
Clinical chemistry & 
hematologyi 
X 
X 
 
 
X 
X 
 
X 
 


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Table 8 
Phase 1b: Determination of the Maximum Tolerated Dose:  Schedule of Procedures/Assessments in 
the Pretreatment, Treatment, and Extension Phases 
CRF 
Phase 
Pretreatment 
Treatment 
Extension 
 
Period 
Screenin
ga,b 
Baseline
a,b 
Treatment  
(Cycle 1b ) 
Treatment 
(Cycle 2b & Beyond) 
Follow-Up Periodbb 
 
Visit 
1 
2 
3 
 
4 
 
5 
  
6, 8, 10, 
12, etc. 
7, 9, 11, 
13, etc. 
Off-Treatment 
Visitu 
Follow-up Visits (Off-Tx 
Visit + 1 day & Beyond) 
 
Day 
-28 to -3 
-3 to -1 
1 
8 
15 
1 
15 
+30 days after 
last dose 
Every 12 weeksy 
 
Assessments 
 
 
 
 
 
 
 
 
 
S 
Thyroid function testsi 
X 
X 
 
 
 
X 
 
X 
 
S 
Urinalysis (Dipstick)j 
X 
X 
 
 
X 
X 
Xx 
X 
 
S 
Pregnancy testk 
X 
X 
 
 
 
 
 
 
 
S 
Lenvatinib treatment 
 
 
Throughout 
 
 
NS 
Pembrolizumab treatmentaa 
 
 
X 
 
 
X 
 
 
 
NS 
Lenvatinib PK blood 
samplesl 
 
 
X 
 
X 
X 
 
 
 
S 
Tumor assessments: CT 
(MRI)m 
X 
 
Counting from C1D1, for the first 24 
weeks, during Week 6, 12, 18, and 24 (±1 
week), or sooner, if clinically indicated, 
until documentation of confirmed PD.  
After 24 weeks, tumor assessments must 
be performed every 9 weeks counting 
from C1D1 (during Week 33, 42, 51, 60, 
etc.) (±1 week), or sooner if clinically 
indicated, until documentation of 
confirmed PD. Responses and PD must 
be confirmed at least 4 weeks later 
X 
(unless done 
within previous 4 
weeks) or subject 
discontinued for 
PD 
Xm 


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Table 8 
Phase 1b: Determination of the Maximum Tolerated Dose:  Schedule of Procedures/Assessments in 
the Pretreatment, Treatment, and Extension Phases 
CRF 
Phase 
Pretreatment 
Treatment 
Extension 
 
Period 
Screenin
ga,b 
Baseline
a,b 
Treatment  
(Cycle 1b ) 
Treatment 
(Cycle 2b & Beyond) 
Follow-Up Periodbb 
 
Visit 
1 
2 
3 
 
4 
 
5 
  
6, 8, 10, 
12, etc. 
7, 9, 11, 
13, etc. 
Off-Treatment 
Visitu 
Follow-up Visits (Off-Tx 
Visit + 1 day & Beyond) 
 
Day 
-28 to -3 
-3 to -1 
1 
8 
15 
1 
15 
+30 days after 
last dose 
Every 12 weeksy 
 
Assessments 
 
 
 
 
 
 
 
 
 
(usually at the next tumor assessment 
time point).m  
NS 
CT or MRI of the brainn 
X 
 
For subjects with previously treated 
eligible brain metastases, brain scan must 
be performed at all tumor assessment 
time points.  For all subjects, a follow-up 
brain scan must be performed to confirm 
immune related-complete response 
(irCR) within 1 week of response 
confirmation, or if clinically indicated. 
X 
(unless done 
within 4 weeks) 
X 
NS 
Bone scano 
X 
 
Bone scans (except for subjects with HNSCC) will be 
performed at screening, every 24 weeks, or sooner if 
clinically indicated, and at confirmation of irCR.   
 
S 
Archival tumor block or 
slidesp, s 
Xp 
 
 
 
 
 
 
 
 
S 
Fresh Tumor Biopsies 
(additional consent 
required) q 
 
Xq 
 
 
 
Xq 
 
 
 
NS 
Blood sample for 
biomarkersr 
 
X 
 
 
X 
X 
 
X 
 


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Table 8 
Phase 1b: Determination of the Maximum Tolerated Dose:  Schedule of Procedures/Assessments in 
the Pretreatment, Treatment, and Extension Phases 
CRF 
Phase 
Pretreatment 
Treatment 
Extension 
 
Period 
Screenin
ga,b 
Baseline
a,b 
Treatment  
(Cycle 1b ) 
Treatment 
(Cycle 2b & Beyond) 
Follow-Up Periodbb 
 
Visit 
1 
2 
3 
 
4 
 
5 
  
6, 8, 10, 
12, etc. 
7, 9, 11, 
13, etc. 
Off-Treatment 
Visitu 
Follow-up Visits (Off-Tx 
Visit + 1 day & Beyond) 
 
Day 
-28 to -3 
-3 to -1 
1 
8 
15 
1 
15 
+30 days after 
last dose 
Every 12 weeksy 
 
Assessments 
 
 
 
 
 
 
 
 
 
NS 
Blood sample for cf-
nucleic acidr 
 
X 
 
 
X 
X 
 
X 
 
NS 
Phone Contact h 
 
 
 
X 
 
 
 
 
 
S 
Concomitant medicationst 
Throughout 
X  
S 
AEs/SAEst 
Throughout 
 
S 
Survivalv 
Throughout 
18F-NaF-PET = 18F Sodium Fluoride (NaF) PET; AE = adverse event, BP = blood pressure, cf-nucleic acid = circulating free nucleic acid, C = cycle, CT = computerized 
tomography, CRF = case report form, EC = endometrial carcinoma, D = day, ECOG PS = Eastern Cooperative Oncology Group Performance Status, HNSCC = squamous cell 
carcinoma of head and neck, irCR = immune-related complete response, irPR = immune-related partial response, irRECIST = immune-related Response Evaluation Criteria in 
Solid Tumors, KPS = Karnofsky performance status, LVEF = left ventricular ejection fraction, M = melanoma, MUGA = multigated acquisition, MRI = magnetic resonance 
imaging, NSCLC = non-small cell lung cancer, NYHA = New York Heart Association, PD = disease progression or progressive disease, PET = positron emission tomography, 
PK = pharmacokinetics, pTNM = pathological tumor-node-metastasis, RCC = renal cell carcinoma, RR = respiratory rate, SAE = serious adverse event, UC = urothelial 
carcinoma, w/in = within.  
 
a. 
The screening period extends from Day -28 to Day -3.  Subjects must be screened within 28 days prior to C1/D1.  The screening assessment can serve as the baseline 
assessment, if performed within 72 h before C1/D1.  The baseline assessment can be performed from Day -3 to C1/D1 (prior to the first dose of study drug).  Informed 
consent may be obtained 8 weeks prior to the start of study drug.  The results of all screening assessments and evaluations must be completed and reviewed by the investigator 
prior to the Baseline Visit. 
b. 
Efforts should be made to conduct study visits on the day scheduled (±3 days).  Treatment cycles will be counted continuously regardless of dose interruptions.  Clinical 
laboratory assessments may be conducted anytime within 72 h prior to the scheduled visit, unless otherwise specified. 


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c. 
ECOG PS will be evaluated at the Screening and Baseline Visits, on C2D1, and on Day 1 at every subsequent cycle thereafter.  NYHA will only be assessed at the Screening 
Visit.  ECOG and NYHA assessment guidelines are provided in the Appendix of the protocol.  Karnofsky performance status will only be assessed for RCC cohort subjects 
(in addition to ECOG PS) and only at Screening.  The KPS scale is provided in the Appendix 8 of the protocol. 
d. 
Assessments will include vital signs (resting BP, HR, RR, and body temperature), weight, and height.  Height will be measured at the Screening Visit only.  Elevated BP 
(systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) should be confirmed by 2 assessments 1 hour apart.  One BP assessment is defined as the mean value of 3 
measurements at least 5 minutes apart.  If systolic BP is ≥160 mmHg or diastolic BP is ≥100 mmHg, BP should be confirmed by repeat measurements after an hour.  As of 
Amendment 09, weight and body temperature will be assessed as clinically indicated in the Extension Phase.  
e. 
A comprehensive physical examination (including a neurological examination) will be performed at the Screening or Baseline Visit, on C1D15, on D1 of each subsequent 
cycle, and at the Off-Tx Visit assessment.  A symptom-directed physical examination will be performed on C1D1 and at any time during the study as clinically indicated.  As 
of Amendment 09, including oral examination. 
f. 
Required if screening physical examination was performed >7 days prior to C1Day 1. 
g. 
Single, 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 min prior to the ECG.  During the Treatment Phase, ECGs will be collected on Day 1 of 
every cycle. 
h. 
Phone contact will take place on Day 8 (±2 days) of C1 to assess subjects for development of early toxicity.  An unscheduled visit will occur prior to C1D15 if deemed 
necessary by the investigator 
i. 
Clinical laboratory tests will be performed by the local laboratory.  Assessments should be performed within 72 h prior to the visit.  Clinical chemistry and hematology results 
must be reviewed prior to administration of study drug on C1D1 and within 48 hours after receiving quick estimation.  If there is ≥ Grade 3 clinically significant hematologic 
or clinical chemistry toxicity, repeat laboratory test and AEs assessment at least every 7 days (until improvement to < Grade 3).  Thyroid function will be assessed every 2 
cycles (C3D1, C5D1, etc.). 
j. 
Urinalysis will be performed at Screening, Baseline, C1D15, and each study visit of every cycle thereafter.  Urinalysis will include glucose, hemoglobin (or blood), ketones, 
pH, protein, specific gravity.  If urinalysis suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and sensitivity test should be performed at 
the institution’s laboratory.  If urine protein is ≥2+ on urinalysis, then see Footnote W. 
k. 
A serum and/or urine pregnancy test will be performed at the Screening Visit and the Baseline Visit in women of childbearing potential (ie, premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months). 
l. 
Study Treatment PK blood samples drawn 0.5-4 hours, and 6-10 hours post lenvatinib dose on C1D1, prior to dose and 0.5-4 hours, and 6-10 hours post lenvatinib dose on 
C1D15, and prior to pembrolizumab dose and 2-12 hours post lenvatinib dose on C2D1.  Study Treatment PK blood samples drawn prior to pembrolizumab dose only on Day 
1 of Cycles 3, 4, 5, and 6. 
m. Screening tumor assessments using CT of the chest, abdomen, and pelvis and other areas of known disease or newly suspected disease should be performed within 28 days 
prior to C1D1.  Subjects with HNSCC must also have scans performed of the head and neck. Scans of the abdomen, pelvis, and other areas of the body may be done with MRI 
instead of CT, but evaluation of the chest should be done with CT.  CT scans should be performed with oral and iodinated IV contrast and MRI scans with IV gadolinium 
chelate unless there is a medical contraindication to contrast.  If iodinated IV contrast is contraindicated, chest CT should be done without IV contrast.  Treatment Phase:  
tumor assessments of the (head, neck), chest, abdomen, and pelvis, and other areas where scans were performed at screening or for newly suspected disease should be 
performed as indicated in the Schedule of Procedures/Assessments above (or sooner if there is evidence of PD) and should use the same methodology (CT or MRI) and scan 
acquisition techniques (including use or nonuse of IV contrast) as were used for the screening assessments.  Objective responses must be confirmed at least 4 weeks later (eg, 
generally at the next tumor assessment time point). Suspected PD must also be confirmed at least 4 weeks after the imaging that initially indicated progression.  As of 
Amendment 09 in the Treatment Period of the Extension Phase, tumor assessments will be performed as per local standard of care but not less frequent than every 6 months 
As of Amendment 09 in the Follow-Up Period of Extension Phase, tumor assessments will not be collected.  
n. 
Screening brain scans will be performed by MRI pre- and post- gadolinium or CT with contrast within 4 weeks prior to C1D1.  During the Treatment Phase, CT/MRI of the 
brain will be performed if clinically indicated, and within a target of 1 week after a subject achieves an irCR.  For subjects with a history of treated brain metastases, brain 
scans will be performed at every tumor assessment time point. The same methodology and scan acquisition techniques used at screening should be used throughout the study 
to ensure comparability.  As of Amendment 09 in the Treatment Period of the Extension Phase, tumor assessments will be performed as per local standard of care but not less 
frequent than every 6 months.  As of Amendment 09 in the Follow-Up Period of Extension Phase, tumor assessments will not be collected. 


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o. 
A bone scan (99m-technetium polyphosphonate scintigraphy, whole body bone MRI, or 18F-NaF-PET) to assess bone metastases will be performed within 6 weeks prior to 
C1D1 (historical scans are acceptable) and then every 24 weeks (within that 24th week) from C1D1 for all tumor types except for HNSCC, or sooner if clinically indicated.  
In subjects whose body CT/MRI scans indicate irCR has been achieved, except for subjects with HNSCC, a bone scan will be required at confirmation of irCR to exclude new 
bone metastases.  The same methodology and acquisition techniques used at screening should be used throughout the study to ensure comparability.  Lesions detected on bone 
scans must be followed with cross-sectional imaging.  As of Amendment 09 in the Treatment Period of the Extension Phase, tumor assessments will be performed as per local 
standard of care but not less frequent than every 6 months.  As of Amendment 09 in the Follow-Up Period of Extension Phase, tumor assessments will not  be collected 
p. 
An archival tumor tissue sample must be available prior to first dose. If archival tumor tissue sample is not available, please see footnotes. 
q. 
Optional fresh paired tumor biopsies will be collected at the baseline and the beginning of Cycle 2 from consented subjects (additional separate consent required) to examine 
markers including markers of target engagement, relevant pharmacodynamic biomarkers, and potential markers of response.  
r. 
Collection of blood sample to obtain plasma, serum, or other components to be used for biomarker studies.  Samples will be obtained at baseline, C1D15, D1 of all subsequent 
cycles up to and including C18, and at the off-treatment assessment. 
s. 
Subjects with NSCLC require a newly obtained tumor biopsy for biomarker analysis which must be obtained prior to the first dose.  If an archival tumor sample for biomarker 
analysis is not available from subjects with RCC, EC, UC, M, or HNSCC, then a newly obtained tumor biopsy must be obtained prior to the first dose.  If a newly obtained 
biopsy is required, it is preferred that the biopsy is obtained from a non-target lesion.  Subjects must have recovered adequately from the biopsy prior to starting therapy. 
t. 
Concomitant meds are recorded for 30 days after last dose.   
u. 
The off-treatment assessment should occur within 30 days after the final dose of study treatment. 
v. 
Survival data will be collected every 12 weeks until end of Treatment Phase (when subjects move into Extension Phase).  All anticancer therapy will be recorded until time of 
death or termination of survival follow up.  As of Amendment 09, the Follow-up Period will consist of the Off-Tx Visit.  No further visits will be conducted. The sponsor has 
decided to terminate survival follow-up for all subjects currently in survival follow-up.  Survival follow-up data will no longer be collected after the Off-Treatment Visit and after 
30 days from the last dose of study drugs.  
 
w. Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored on D15 or more frequently as clinically indicated until systolic BP has 
been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive months.  If a new event of systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg occurs, the 
subject must resume the Day 15 evaluation until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive months.   
x. 
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 or more frequently as clinically indicated until the results have been 1+ or negative for 
3 consecutive months.  If a new event of proteinuria ≥2+ occurs, the subject must resume the Day 15 urine dipstick testing for evaluation of proteinuria until results are 1+ 
y. 
As long as the study subject is alive and/or until completion of the primary analysis, unless the subject withdraws consent or the sponsor terminates the study.  Subjects will 
be followed-up every 12 weeks (±1 week) for survival and subsequent anticancer treatments.   
z. 
During the Treatment and Extension Phases, MUGA scans or echocardiograms will be performed to assess LVEF every 24 weeks. As of Amendment 09, MUGA scans or 
echocardiograms will be performed to assess LVEF as clinically indicated during the Extension Phase.   
aa. Patients can receive up to 35 treatments (approximately 2 years) with pembrolizumab. 
bb. As of Amendment 09, the Follow-up Period will consist of the Off-Tx Visit.  No further visits will be conducted. The sponsor has decided to terminate survival follow-up 
for all subjects currently in survival follow-up. 
 
 
 


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Table 9 
Phase 2 – Expansion in Selected Tumor Types Safety and Efficacy Cohort(s):  Schedule of 
Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases 
 
Phase 
Pretreatment 
Treatment Phase 
Extension Phase 
 
Period 
Screeninga,
b 
Baselinea,
b 
Treatment 
Period (Cycle 
1b )  
Treatment 
Period 
(Cycle 2b to 8) 
 
Treatment 
Period 
(Cycle 9b & 
Beyond) 
Follow-Upbb 
 
Visit 
1 
2 
3  
4 
5  
6, 8, 
10, 12, 
etc. 
7, 9, 
11, 13, 
etc. 
 
20, 22, 
24, 
etc. 
21, 23, 
25, etc. 
 
Off-
Treatment 
Visit u 
Follow-up 
Visits (Off-
Tx Visit + 1 
day & 
Beyond) 
 
Day 
-28 to -3 
-3 to -1 
1 
8 
15 
1 
15 
 
1 
15 
Days +30 
after last 
dose 
Every 12 
weeksx 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS/NYHAc 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
KPSc 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
pTNM staging at diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signsd 
X 
X 
X 
 
X 
X 
Xw 
X 
Xw 
X 
 
 
Physical examinatione 
X 
Xf 
 
 
X 
X 
 
X 
 
X 
 
 
12-lead ECGg 
X 
 
X 
 
 
X 
 
X 
 
X 
 


Clinical Study Protocol  
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Final: 30 July 2021 
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Table 9 
Phase 2 – Expansion in Selected Tumor Types Safety and Efficacy Cohort(s):  Schedule of 
Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases 
 
Phase 
Pretreatment 
Treatment Phase 
Extension Phase 
 
Period 
Screeninga,
b 
Baselinea,
b 
Treatment 
Period (Cycle 
1b )  
Treatment 
Period 
(Cycle 2b to 8) 
 
Treatment 
Period 
(Cycle 9b & 
Beyond) 
Follow-Upbb 
 
Visit 
1 
2 
3  
4 
5  
6, 8, 
10, 12, 
etc. 
7, 9, 
11, 13, 
etc. 
 
20, 22, 
24, 
etc. 
21, 23, 
25, etc. 
 
Off-
Treatment 
Visit u 
Follow-up 
Visits (Off-
Tx Visit + 1 
day & 
Beyond) 
 
Day 
-28 to -3 
-3 to -1 
1 
8 
15 
1 
15 
 
1 
15 
Days +30 
after last 
dose 
Every 12 
weeksx 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA or echocardiogramy 
X 
 
X 
 
 
 
Clinical chemistry & hematologyi 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
 
Thyroid function testi 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
Urinalysis (Dipstick)j 
X 
X 
 
 
X 
X 
Xw 
X 
Xw 
X 
 
 
Pregnancy testk 
X 
X 
 
 
 
 
 
 
 
 
 
 
Lenvatinib treatment 
 
 
Throughout 
 
 
 
 
 
Pembrolizumab treatmentaa 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Lenvatinib PK blood samplesl 
 
 
X 
 
X 
X 
 
 
 
 
 
 
Tumor assessments: CT (MRI)m 
X 
 
Counting from C1D1, for the first 24 weeks, during 
Week 6, 12, 18, and 24 (±1 week), or sooner, if 
clinically indicated, until documentation of confirmed 
PD.  After 24 weeks, tumor assessments must be 
X 
(unless 
done within 
4 weeks) 
X 


Clinical Study Protocol  
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Final: 30 July 2021 
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Table 9 
Phase 2 – Expansion in Selected Tumor Types Safety and Efficacy Cohort(s):  Schedule of 
Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases 
 
Phase 
Pretreatment 
Treatment Phase 
Extension Phase 
 
Period 
Screeninga,
b 
Baselinea,
b 
Treatment 
Period (Cycle 
1b )  
Treatment 
Period 
(Cycle 2b to 8) 
 
Treatment 
Period 
(Cycle 9b & 
Beyond) 
Follow-Upbb 
 
Visit 
1 
2 
3  
4 
5  
6, 8, 
10, 12, 
etc. 
7, 9, 
11, 13, 
etc. 
 
20, 22, 
24, 
etc. 
21, 23, 
25, etc. 
 
Off-
Treatment 
Visit u 
Follow-up 
Visits (Off-
Tx Visit + 1 
day & 
Beyond) 
 
Day 
-28 to -3 
-3 to -1 
1 
8 
15 
1 
15 
 
1 
15 
Days +30 
after last 
dose 
Every 12 
weeksx 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
performed every 9 weeks counting from C1D1 (during 
Week 33, 42, 51, 60, etc.) (±1 week), or sooner if 
clinically indicated, until documentation of confirmed 
PD. Responses and PD must be confirmed no less than 
4 weeks later (usually at the next tumor assessment 
time point). 
 
CT or MRI of the brainn 
X 
 
A brain scan (CT with contrast or MRI pre- and 
post-gadolinium) must be performed at screening to 
assess potential CNS disease and/or metastases.  For 
subjects with previously treated eligible brain 
metastases, a brain scan must be performed at all 
tumor assessment time points.  For all subjects, a 
follow-up brain scans must be performed to confirm 
irCR within 1 week of response confirmation, or if 
clinically indicated 
X 
(unless 
done within 
4 weeks) 
X 


Clinical Study Protocol  
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Final: 30 July 2021 
Confidential 
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Table 9 
Phase 2 – Expansion in Selected Tumor Types Safety and Efficacy Cohort(s):  Schedule of 
Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases 
 
Phase 
Pretreatment 
Treatment Phase 
Extension Phase 
 
Period 
Screeninga,
b 
Baselinea,
b 
Treatment 
Period (Cycle 
1b )  
Treatment 
Period 
(Cycle 2b to 8) 
 
Treatment 
Period 
(Cycle 9b & 
Beyond) 
Follow-Upbb 
 
Visit 
1 
2 
3  
4 
5  
6, 8, 
10, 12, 
etc. 
7, 9, 
11, 13, 
etc. 
 
20, 22, 
24, 
etc. 
21, 23, 
25, etc. 
 
Off-
Treatment 
Visit u 
Follow-up 
Visits (Off-
Tx Visit + 1 
day & 
Beyond) 
 
Day 
-28 to -3 
-3 to -1 
1 
8 
15 
1 
15 
 
1 
15 
Days +30 
after last 
dose 
Every 12 
weeksx 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scano 
X 
 
Bone scans (except for subjects with HNSCC) will be performed at 
Screening, every 24 weeks, or sooner if clinically indicated, and at 
confirmation of irCR  
 
 
Archival tumor block or slidesp, s 
Xp 
 
 
 
 
 
 
 
 
 
 
 
Fresh Tumor Biopsies (additional 
consent required)q 
 
Xq 
 
 
 
Xq 
 
 
 
 
 
 
Blood sample for biomarkersr 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
Blood sample for 
PBMC/cf-nucleic acidr 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
RNA Blood sample for Gene 
Expressionr 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
Whole blood sample for PG/PDz 
 
X 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol  
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Final: 30 July 2021 
Confidential 
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Table 9 
Phase 2 – Expansion in Selected Tumor Types Safety and Efficacy Cohort(s):  Schedule of 
Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases 
 
Phase 
Pretreatment 
Treatment Phase 
Extension Phase 
 
Period 
Screeninga,
b 
Baselinea,
b 
Treatment 
Period (Cycle 
1b )  
Treatment 
Period 
(Cycle 2b to 8) 
 
Treatment 
Period 
(Cycle 9b & 
Beyond) 
Follow-Upbb 
 
Visit 
1 
2 
3  
4 
5  
6, 8, 
10, 12, 
etc. 
7, 9, 
11, 13, 
etc. 
 
20, 22, 
24, 
etc. 
21, 23, 
25, etc. 
 
Off-
Treatment 
Visit u 
Follow-up 
Visits (Off-
Tx Visit + 1 
day & 
Beyond) 
 
Day 
-28 to -3 
-3 to -1 
1 
8 
15 
1 
15 
 
1 
15 
Days +30 
after last 
dose 
Every 12 
weeksx 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Contact h 
 
 
 
X 
 
 
 
 
 
 
 
 
Concomitant medicationst 
Throughout 
X 
 
AEs/SAEst 
Throughout 
 
 
Survivalv 
Throughout 
18F-NaF-PET = 18F Sodium Fluoride (NaF) PET; AE = adverse event, , BP = blood pressure, cf-nucleic acid = circulating free nucleic acid, C = cycle, CNS = central nervous 
system, CT = computerized tomography, D = day, DNA = deoxyribonucleic acid, EC = endometrial carcinoma, ECOG PS = Eastern Cooperative Oncology Group 
Performance Status, HNSCC = squamous cell carcinoma of head and neck, irCR = immune-related complete response, irPR = immune-related partial response, irRECIST = 
immune-related Response Evaluation Criteria in Solid Tumors, KPS = Karnofsky performance status, LVEF = left ventricular ejection fraction, M = melanoma (excluding 
uveal), MUGA = multigated acquisition, MRI = magnetic resonance imaging, NS = not standard, NSCLC = non-small cell lung cancer, NYHA = New York Heart Association, 
PBMC = peripheral blood mononuclear cells, PD = disease progression, PET = positron emission tomography, PG = pharmacogenomics, PK = pharmacokinetics, pTNM = 
pathological tumor-node-metastasis, RCC = renal cell carcinoma (predominantly clear cell), RR = respiratory rate, UC = urothelial carcinoma, S = standard, SAE = serious 
adverse event, w/in = within. 
 
a. 
The screening period extends from Day -28 to Day -3.  Subjects must be screened within 28 days prior to C1D1.  The screening assessment can serve as the baseline 
assessment, if performed within 72 h before C1D1.  The baseline assessment can be performed from Day -3 to C1D1 (prior to the first dose of study drug).  Informed 


Clinical Study Protocol  
E7080-A001-111 
 
 
 
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Final: 30 July 2021 
Confidential 
Page 111 of 155 
 
consent may be obtained 8 weeks prior to the start of study drug.  The results of all screening assessments and evaluations must be completed and reviewed by the 
investigator prior to the Baseline Visit. 
b. 
Efforts should be made to conduct study visits on the day scheduled (±3 days).  Treatment cycles will be counted continuously regardless of dose interruptions.  Clinical 
laboratory assessments may be conducted anytime within 72 h prior to the scheduled visit, unless otherwise specified. 
c. 
ECOG PS will be evaluated at the Screening and Baseline Visits, on Cycle 2/Day 1, and on Day 1 at every subsequent cycle thereafter.  NYHA will only be assessed at the 
Screening Visit.  ECOG and NYHA assessment guidelines are provided in the Appendix of the protocol.  Karnofsky performance status will only be assessed for RCC 
cohort subjects (in addition to ECOG PS) and only at Screening.  The KPS scale is provided in the Appendix 8 of the protocol. 
d. 
Assessments will include vital signs (resting BP, HR, RR, and body temperature), weight, and height.  Height will be measured at the Screening Visit only.  Elevated BP 
assessment (ie, systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) should be confirmed by a repeat assessment after a minimum of 1 hour.  One BP assessment is defined 
as the mean value of 3 measurements at least 5 minutes apart.  Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored every 
2 weeks (on Day 1 and Day 15 or more frequently, as clinically indicated) until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive 
months.  If a new event of systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg occurs, the subject must resume the Day 15 evaluation until systolic BP has been 
≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive months.  As of Amendment 09, weight and body temperature will be assessed as clinically indicated 
in the Extension Phase.  
e. 
A physical examination will be performed at the Screening or Baseline Visit, on C1D15, on D1 of each subsequent cycle, and at the Off-Tx Visit assessment.  A symptom-
directed physical examination will be performed on C1D1 and at any time during the study, as clinically indicated.  As of Amendment 09, oral examination will be 
included 
f. 
Required if screening physical examination was performed >7 days prior to C1D1. 
g. 
Single, 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 min prior to the ECG.  During the Treatment and Extension Phases, ECGs will be 
collected every cycle. 
h. 
Phone contact will take place on Day 8 (±2 days) of C1 to assess subjects for development of early toxicity.  An unscheduled visit will occur prior to C1D15 if deemed 
necessary by the investigator. 
i. 
Clinical laboratory tests will be performed by the local laboratory.  Assessments should be performed within 72 h prior to the visit.  Clinical chemistry and hematology 
results must be reviewed prior to administration of study drug on C1D1 and within 48 hours after receiving quick estimation.  If there is ≥ Grade 3 clinical significant 
hematologic or clinical chemistry toxicity, repeat laboratory test and AEs assessment at least every 7 days (until improvement to < Grade 3).  Thyroid function will be 
assessed every 2 Cycles (C3D1, C5D1, etc.). 
j. 
Urinalysis will be performed at Screening, Baseline, C1D5, and each study visit of every cycle thereafter.  Urinalysis will include glucose, hemoglobin (or blood), ketones, 
pH, protein, specific gravity.  If urinalysis suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and sensitivity test should be performed 
at the institution’s laboratory.  If urine protein is ≥2+ on urinalysis, then see Footnote W. 
k. 
A serum and/or urine pregnancy test will be performed at the Screening Visit and the Baseline Visit in women of childbearing potential (ie, premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months). 
l. 
Study Treatment PK blood samples drawn 0.5-4 hours, and 6-10 hours post lenvatinib dose on C1D1, prior to dose and 0.5-4 hours, and 6-10 hours post lenvatinib dose on 
C1D15, and prior to pembrolizumab dose and 2-12 hours post lenvatinib dose on C2D1.  Study treatment PK blood samples drawn predose only on D1 of Cycles 3, 4, 5, 
and 6. 
m. Screening tumor assessments using CT of the neck/chest/abdomen/pelvis and other areas of known disease or newly suspected disease should be performed within 28 days 
prior to C1D1.  Subjects with HNSCC must also have scans performed of the head and neck. Scans of the abdomen, pelvis, and other areas of the body may be done with MRI 
instead of CT, but evaluation of the chest should be done with CT.  CT scans should be performed with oral and iodinated IV contrast and MRI scans with IV gadolinium 
chelate unless there is a medical contraindication to contrast.  If iodinated IV contrast is contraindicated, chest CT should be done without IV contrast.  Treatment Phase:  
tumor assessments of the (head, neck)/chest/abdomen/pelvis and other areas of known disease at screening or newly suspected disease should be performed as indicated in the 
Schedule of Assessments/Procedures above during the Treatment Phase (or sooner if there is evidence of PD) and should use the same methodology (CT or MRI) and scan 
acquisition techniques (including use or nonuse of IV contrast) as were used for the screening assessments. Objective responses must be confirmed at least 4 weeks later (eg, 
generally at the next tumor assessment time point). Suspected PD must also be confirmed at least 4 weeks after the imaging that initially indicated progression.  As of 


Clinical Study Protocol  
E7080-A001-111 
 
 
 
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Final: 30 July 2021 
Confidential 
Page 112 of 155 
 
Amendment 09 in the Treatment Period of the Extension Phase, tumor assessments will be performed as per local standard of care but not less frequent than every 6 months 
As of Amendment 09 in the Follow-Up Period of Extension Phase, tumor assessments will not be collected. 
n. 
Screening brain scans will be performed by MRI pre- and post- gadolinium or CT with contrast within 4 weeks prior to C1D1.  During the Treatment Phase, CT/MRI of the 
brain will be performed if clinically indicated, and within a target of 1 week after a subject achieves an irCR.  For subjects with a history of treated brain metastases, brain 
scans will be performed at every tumor assessment time point. The same methodology and scan acquisition techniques used at screening should be used throughout the 
study to ensure comparability.  As of Amendment 09 in the Treatment Period of the Extension Phase, tumor assessments will be performed as per local standard of care but 
not less frequent than every 6 months.  As of Amendment 09 in the Follow-Up Period of Extension Phase, tumor assessments will not be collected 
o. 
A bone scan (99m-technetium polyphosphonate scintigraphy, whole body bone MRI, or 18F-NaF-PET) to assess bone metastases will be performed within 6 weeks prior to 
C1D1 (historical scans are acceptable) and then every 24 weeks within that 24th week) from C1D1 for all tumor types except for HNSCC, or sooner if clinically indicated.  In 
subjects whose body CT/MRI scans indicate CR has been achieved, except for subjects with HNSCC, a bone scan will be required at confirmation of irCR to exclude new 
bone metastases.  The same methodology and acquisition techniques used at screening should be used throughout the study to ensure comparability. Lesions detected on bone 
scans must be followed with cross-sectional imaging. As of Amendment 09 in the Treatment Period of the Extension Phase, tumor assessments will be performed as per local 
standard of care but not less frequent than every 6 months.  As of Amendment 09 in the Follow-Up Period of Extension Phase, tumor assessments will not be collected 
p. 
An archival tumor tissue sample must be available prior to first dose. If archival tumor tissue sample is not available, please see footnote s.  
q. 
Optional fresh paired tumor biopsies will be collected at the baseline and the beginning of C2 from consented subjects (additional separate consent required) to examine 
markers including markers of target engagement, relevant pharmacodynamic biomarkers, and potential markers of response.  
r. 
Collection of blood sample to obtain plasma, serum, nucleic acid, or other components to be used for biomarker studies.  Samples will be obtained at baseline, C1D15, D1 
of all subsequent cycles up to and including C18, and at the off-treatment assessment. 
s. 
For subjects with NSCLC, every effort is to be made to obtain a newly obtained tumor biopsy for biomarker analysis which must be obtained prior to the first dose.  If an 
archival tumor sample for biomarker analysis is not available from subjects with RCC, EC, UC, M, or HNSCC, then a newly obtained tumor biopsy must be obtained prior to 
the first dose.  If a new biopsy is obtained, it is preferred that the biopsy is obtained from a non-target lesion.  Subjects must have recovered adequately from the biopsy prior 
to starting therapy. 
t. 
Concomitant meds are recorded for 30 days after last dose.   
u. 
The off-treatment assessment should occur within 30 days after the final dose of study treatment. 
v. 
Survival data will be collected every 12 weeks until end of the Treatment Phase (when subjects move into Extension Phase).  All anticancer therapy will be recorded until 
time of death or termination of survival follow up. As of Amendment 09, the Follow-up Period will consist of the Off-Tx Visit.  No further visits will be conducted. The sponsor 
has decided to terminate survival follow-up for all subjects currently in survival follow-up.  Survival follow-up data will no longer be collected after the Off-Tx Visit and after 30 
days from the last dose of study drugs.  
w. Urine dipstick testing for subjects with proteinuria ≥2+ should be performed locally on D15 (or more frequently as clinically indicated) until the results have been 1+ or 
negative for 3 consecutive months.  Urine dipstick testing should be performed preferably at the investigational site (but may be performed locally by the primary care 
physician or a local laboratory if the subject does not have to come for a visit to the site).  If a new event of proteinuria ≥2+ occurs, the subject must resume the D15 urine 
dipstick testing for evaluation of proteinuria until results are 1+ or negative for 3 consecutive months.  For subjects with a history of dipstick proteinuria ≥2+, see Section 
9.4.1.1.3 for management of proteinuria. 
x. 
As long as the study subject is alive and/or until completion of the primary analysis, unless the subject withdraws consent or the sponsor terminates the study.  Subjects will 
be followed every 12 weeks (±1 week) for survival and subsequent anticancer treatments.   
y. 
During the Treatment and Extension Phases, MUGA scans or echocardiograms will be performed to assess LVEF every 24 Weeks. As of Amendment 09, MUGA scans or 
echocardiograms will be performed to assess LVEF as clinically indicated during Extension Phase. 
z. 
Collection of whole blood to obtain genomic DNA for PG/PD analysis will be obtained during baseline.  If sampling is not performed during baseline, sampling may occur 
at any subsequent visit in which other blood sampling is scheduled to occur. 
aa. Patients can receive up to 35 treatments (approximately 2 years) with pembrolizumab. 


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bb. As of Amendment 09, the Follow-up Period will consist of the Off-Tx Visit.  No further visits will be conducted. The sponsor has decided to terminate survival follow-up 
for all subjects currently in survival follow-up. 
 


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9.5.2.2 
Description of Procedures/Assessments Schedule 
Refer to Table 8 (for Phase 1b) and Table 9 (for Phase 2) for the description and timing of 
each procedure and assessment in the Pretreatment and Treatment Phase and the Extension 
Phase, respectively. 
9.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies involving 
subjects with solid tumors. 
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, and assessment of AEs, are standard evaluations to ensure subject 
safety. 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations 
9.5.4.1 
Reporting of Serious Adverse Events 
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 24 hours from the date the investigator becomes aware of the event. 
Deaths and life-threatening events should be reported immediately by telephone.  The 
immediate report should be followed up within 24 hours by emailing or faxing the 
completed SAE form. 
Serious adverse events, regardless of causality assessment, must be collected through 90 days 
after the subject’s last dose, or 30 days following the last dose if the subject initiates new 
anticancer therapy, whichever is earlier. All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion. 
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File. 
For urgent safety issues, please ensure all appropriate medical care is administered to 
the subject and contact the appropriate study team member listed in the Investigator Study 
File. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality. 


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Any follow-up information received on SAEs should be forwarded within 24 hours of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor. 
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File. 
Eisai will provide a Safety Reporting Plan (SRP) for lenvatinib and pembrolizumab.  The 
plan will address the following: 
• 
Holder of the Global Safety Database 
• 
Procedures and timelines for the processing of SAEs 
• 
The distribution of expedited SAE reports  
• 
Responsibility for submission to Health Authorities and notifications to investigators and  
the EC/IRB 
• 
Adverse Events of Special Interest reports including pregnancy reports, and overdose 
• 
Case closure 
• 
SAE reconciliation 
• 
Translation of source documents 
• 
Schematic of work flow and timelines 
 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 120 days of the last study treatment or 30 days following last study treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported.  Also, any 
exposure to study drug through breastfeeding during study treatment or within 120 days of 
the last study treatment, or 30 days following the last study treatment if the subject initiates a 
new anticancer therapy, whichever is earlier, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]). 


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Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 24 hours from the date the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study 
9.5.4.3 
Reporting of Events Associated with Special Situations 
9.5.4.3.1 REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG 
OVERDOSE, MISUSE, ABUSE, OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose  
Misuse 
Intentional and inappropriate use of study drug not in accordance with the 
protocol  
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 
Medication error Any unintentional event that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of site personnel 
or the subject.   
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF. 
Note:  Overdose for pembrolizumab is defined as a dose greater than 5 times the 200 mg 
dose. 
9.5.4.4 
Expedited Reporting 
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 


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specific time frames).  For this reason, it is imperative that sites provide complete SAE 
information in the manner described above. 
9.5.4.5 
Breaking the Blind 
Not applicable. 
9.5.4.6 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements. 
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states. 
9.5.5 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 8 and Table 9). 
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.   
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, progression of disease, withdrawal of 
consent, pregnancy, study terminated by sponsor, or other.  In addition to the primary reason, 
the subject may indicate 1 or more secondary reason(s) for discontinuation.  Study 
disposition information will be collected on the Subject Disposition CRF. 
For Phase 1b study, subjects who discontinue study treatment prior to completing the 
Treatment Phase for any reason other than a DLT will be replaced.  Subjects who discontinue 
study treatment prior to completing the Phase 2 Treatment Phase for reasons such as lost to 
follow-up, subject choice, withdrawal of consent, and pregnancy may be replaced. 
9.5.6 
Abuse or Diversion of Study Drug 
Not applicable. 


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9.5.7 
Confirmation of Medical Care by Another Physician 
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.   
9.6.1 
Data Collection 
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined by 
ICH guidelines, the CRF is a printed, optical, or electronic document designed to record all 
of the protocol-required information to be reported to the sponsor on each study subject. 
Data collection on the CRF must follow the instructions described in the CCGs.  The 
investigator has ultimate responsibility for the collection and reporting of all clinical data 
entered on the CRF.  The investigator or designee as identified on Form FDA 1572 must sign 
the completed CRF to attest to its accuracy, authenticity, and completeness. 
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities. 
9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system. 
9.7 
Statistical Methods 
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked.  Statistical analyses will be performed using SAS 
software or other validated statistical software as required.  Details of the statistical analyses 
will be included in a separate statistical analysis plan (SAP). 


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9.7.1 
Statistical and Analytical Plans 
The statistical analyses of the core study data are described in this section.  Further details of 
the analytical plan will be provided in the SAP, which will be finalized before database lock. 
9.7.1.1 
Study Endpoints 
9.7.1.1.1 PRIMARY ENDPOINTS 
Primary Efficacy Endpoint for Phase 1b: 
The primary objective of Phase 1b is to determine the DLTs, MTD, and to establish the 
RP2D.  The efficacy endpoints in Phase 1b will be summarized and listed by dose level 
based on the Safety Analysis Set.  No statistical comparison will be performed.  
 
Primary Efficacy Endpoint for Phase 2: 
The primary objective of Phase 2 is to evaluate ORR(Week 24) in each of the cohorts using 
irRECIST.  ORR(Week 24) is defined as the proportion of subjects who have best overall 
response (BOR) of irCR(Week 24) or irPR(Week 24) as of the Week 24 tumor assessment time 
point.  The primary efficacy analysis for each cohort will be performed when all subjects in 
that cohort have completed 8 cycles of treatment, discontinued due to disease progression, 
developed unacceptable toxicity, withdrew consent, or the study is terminated by the sponsor. 
9.7.1.1.2 SECONDARY ENDPOINTS (BOTH PHASE 1B AND PHASE 2) 
The secondary efficacy endpoints will be ORR, PFS, OS, DCR, CBR, DOR, and durable SD 
rate (SD ≥23 weeks) by irRECIST as appropriate.  The secondary efficacy endpoints are 
defined as follows. 
 
• 
ORR is defined as the proportion of subjects who have BOR of irCR or irPR at the time 
of data cutoff.   
• 
PFS is defined as the time from the first study dose date to the date of first 
documentation of confirmed disease progression or death (whichever occurs first).  If a 
subject has not experienced disease progression or death, then the subject’s data will be 
censored at the date of the last available tumor assessment. 
• 
OS is measured from the start date of the treatment period until date of death from any 
cause. Subjects who are lost to follow-up and the subjects who are alive at the date of 
data cutoff will be censored at the date the subject was last known alive. 
• 
DCR is defined as the proportion of subjects who have BOR of irCR or irPR or irSD 
(duration of irSD ≥5 weeks). 
• 
CBR is defined as the proportion of subjects who have BOR of irCR or irPR or durable 
irSD (duration of irSD ≥23 weeks). 
• 
DOR is defined as the time from the date the criteria are met for an irCR or irPR 
(whichever is recorded first) to the date the disease progression is objectively 


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documented.  If a subject has no record of disease progression, then the subject’s data 
will be censored at the last available tumor assessment. 
• 
Durable SD rate is defined as the proportion of subjects whose BOR is irSD and the 
duration of irSD is ≥23weeks. 
Determination of the plasma PK profile of lenvatinib while subjects are receiving 
combination therapy also is a secondary endpoint.   
9.7.1.1.3 EXPLORATORY ENDPOINTS  
The exploratory endpoints include: 
• Tumor response endpoints based on investigator assessment using modified RECIST 1.1  
• Tumor response endpoints for the subjects in the endometrial and renal cell carcinoma 
analysis sets based on IIR assessments using irRECIST, modified RECIST 1.1, and 
RECIST v1.1 
• To identify and explore blood and tumor biomarkers which correlate with clinical 
endpoints of this study including safety and efficacy 
9.7.1.2 
Definitions of Analysis Sets 
Safety Analysis Set will include all subjects who received any amount of study drug.  This 
will be the analysis set for all safety evaluations. 
MTD Analysis Set will include all subjects who have completed C1 treatment of Phase 1b or 
discontinued early due to DLT.  This will be the analysis set to determine MTD. 
Full Analysis Set (Intent-to-Treat [ITT] Analysis Set) will include all subjects who 
entered the study treatment period. Efficacy analyses will primarily be based on the Full 
Analysis Set.   
PK Analysis Set All the subjects who have received at least one dose of study drug 
(lenvatinib) and have evaluable concentration data. 
Pharmacodynamic Analysis Set will include all subjects who have received at least one 
dose of study drug (lenvatinib or pembrolizumab) and have evaluable pharmacodynamic 
data. 
Endometrial Carcinoma Analysis Set will include all EC subjects from Phase 1b and Phase 
2. 
Renal Cell Carcinoma Analysis Set will include all renal cell carcinoma subjects from 
Phase 1b and Phase 2. 
Non-Small Cell Lung Cancer Analysis Set will include all NSCLC subjects from Phase 1b 
and Phase 2. 


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Melanoma Analysis Set will include all melanoma subjects from Phase 1b and Phase 2. 
9.7.1.3 
Subject Disposition 
The number (percentage) of treated subjects will be summarized as well as subjects who 
completed the study/discontinued from the study and reasons for discontinuation by 
treatment cohort.   
9.7.1.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the FAS will be summarized for each 
treatment cohort and all treatment cohorts combined using descriptive statistics.  Continuous 
demographic and baseline variables include age, sex, race, region, ECOG-PS, NYHA cardiac 
disease classification, and pTNM staging.   
9.7.1.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary drug codes.  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug 
and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug up to 30 days after the subject’s last dose.  All 
medications will be presented in subject data listings. 
9.7.1.6 
Efficacy Analyses 
All efficacy analyses that are conducted at the end of the Treatment Phase will be based on 
the Full Analysis Set.  Selected efficacy analyses may be performed if needed for subjects 
with the combination of lenvatinib and pembrolizumab as the first line treatment versus other 
subjects with prior systemic therapies. For the renal cell carcinoma cohort, efficacy subgroup 
analyses may be presented for treatment naïve subjects, subjects who were previously treated 
with an anti-PD-1/PD-L1 therapy, and subjects who were previously treated without an 
anti-PD-1/PD-L1 therapy. 
 
9.7.1.6.1 PRIMARY EFFICACY ANALYSIS 
The primary efficacy endpoint in Phase 2 is ORR(Week 24) based on irRECIST.  Estimated 
ORR(Week 24) and the exact 95% (CI) using the method of Clopper–Pearson will be presented.  
The primary efficacy analysis of each cohort will be performed when all subjects in that 
cohort have completed 8 cycles of treatment, discontinued due to disease progression, 
developed unacceptable toxicity, subject choice, withdrew consent, lost to follow up or the 
study is terminated by the sponsor. 
9.7.1.6.2 SECONDARY EFFICACY ANALYSES 
The following secondary efficacy analyses will be performed on the data collected from the 


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Phase 2 portion of the study for each treatment cohort. 
 
ORR: ORR and corresponding 95% CI based on exact binomial distribution will estimated 
for each treatment cohort.  
PFS: The distribution of PFS will be estimated using Kaplan–Meier methodology.  Median 
time to PFS and 95% CI will be provided for each treatment cohort.  Three-month, 6-month, 
9-month, and 1-year PFS rate will be estimated using the Kaplan–Meier method and 
corresponding 95% CIs will be provided.  
OS (overall survival): All events of death will be included, regardless of whether the event 
occurred while the subject was still taking study drug, or after the subject discontinued study 
drug.  If a subject has no record of death, then the data will be censored at the date the subject 
was last known to be alive, or the data cutoff date, whichever is earlier.  The distribution of 
OS will be estimated using Kaplan–Meier methodology.  Median survival time and the 
corresponding 95% CI, survival rates at 12, 18, and 24 months, and corresponding 95% CIs 
will be estimated using Kaplan–Meier method for each treatment cohort.  
DCR:  Disease control rate and exact 95% CI will be estimated for each treatment cohort.  
CBR: Clinical benefit rate and exact 95% CI will be estimated for each treatment cohort.  
DOR: The distribution of the duration of response will be estimated using Kaplan–Meier 
Methodology. Median DOR and 95% CI will be provided for each treatment cohort.  
Durable SD rate: DSDR and exact 95% CI will be estimated for each treatment cohort.  
9.7.1.6.3 EXPLORATORY EFFICACY ANALYSES 
The tumor response endpoints will be explored based on modified RECIST 1.1 assessments, 
and will be summarized and listed by cohort.  No statistical comparison will be performed 
between irRECIST and modified RECIST 1.1 results.   
The tumor response endpoints will also be evaluated for the subject in the endometrial and 
renal cell carcinoma analysis sets using IIR assessment using irRECIST, modified RECIST 
1.1, and RECIST v1.1 as exploratory analyses.  A concordance analysis will be performed 
comparing IIR and investigator assessments.   
Blood and tumor biomarkers which correlate with efficacy endpoints will be explored.  
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 PHARMACOKINETIC ANALYSES 
To assess any drug–drug interaction between lenvatinib and pembrolizumab, the dose-
normalized PK profile for lenvatinib in combination with pembrolizumab from this study 


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will be compared graphically to that from patients with different tumor types from completed 
studies receiving lenvatinib monotherapy. 
9.7.1.7.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER 
ANALYSES 
The effect of lenvatinib-pembrolizumab combination therapy on soluble, tissue, genetic 
and/or imaging biomarkers will be summarized using descriptive statistics using the 
pharmacodynamic analysis set. 
9.7.1.8 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment cohorts, will be summarized on an “as treated” basis using descriptive statistics 
(eg, n, mean, standard deviation, median, minimum, maximum for continuous variables; n 
[%] for categorical variables).  Safety variables include treatment-emergent adverse events 
(TEAEs), clinical laboratory parameters, vital signs, 12-lead ECG results, and 
echocardiogram results, including LVEF.  Study D1 will be defined as the date of 
administration of the first dose of study drug. 
Selected safety analyses may be performed if needed for subjects with the combination of 
lenvatinib and pembrolizumab as the first line treatment versus other subjects with prior 
systemic therapies.  For the renal cell carcinoma cohort, safety subgroup analyses may be 
presented for treatment naïve subjects, subjects who were previously treated with an anti-PD-
1/PD-L1 therapy, and subjects who were previously treated without an anti-PD-1/PD-L1 
therapy. 
 
9.7.1.8.1 EXTENT OF EXPOSURE 
The number of cycles/days on treatment, quantity of study drug administered, and the 
number of subjects requiring dose reductions, treatment interruption, and treatment 
discontinuation due to AEs will be summarized. 
9.7.1.8.2 ADVERSE EVENTS 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA lower level term closest to the 
verbatim term.  The linked MedDRA preferred term (PT) and primary system organ class 
(SOC) are also captured in the database. 
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or  
• 
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  


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• 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
The TEAEs will be summarized by treatment cohort.  The incidence of TEAEs will be 
reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will 
be counted only once within an SOC and PT, even if the subject experienced more than 1 
TEAE within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will 
also be summarized by highest CTCAE grade. 
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]). 
Treatment-related TEAEs include those events considered by the investigator to be related to 
study treatment.  The number (percentage) of subjects with treatment-related TEAEs will 
also be summarized by highest CTCAE grade). 
Adverse events will be summarized using the Safety Analysis Set.  The number of AEs and 
number and incidence (%) of subjects with AEs will be summarized by cohort/dose level and 
overall.  To obtain the incidence (%), the number of subjects with at least 1 event and the 
percentage of subjects with AEs by SOC and by PT will be calculated.  Incidence (%) by 
causal relationship with study drug and by severity (CTCAE v4.03) will also be calculated.  
For clinically significant events, time of onset and recovery will be reported. 
Adverse events will be summarized by the following subgroups:  age (≤65 years, >65 years), 
sex (male, female), and race (white, black, other) if necessary. 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each cohort.  A subject data listing of all AEs leading to death 
will be provided. 
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT for each cohort.  A subject data listing of all 
SAEs will be provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each cohort. A subject data listing of all 
AEs leading to discontinuation from study drug will be provided. 
9.7.1.8.3 LABORATORY VALUES 
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment will be summarized by visit 
and treatment using descriptive statistics.  Qualitative parameters listed in Section 9.5.1.5.3 


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will be summarized using frequencies (number and percentage of subjects), and changes 
from baseline to each postbaseline visit and to the end of treatment will be reported using 
shift tables.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results. 
Laboratory parameters will be categorized according to CTCAE v4.03 grades, and shifts 
from baseline CTCAE grades to maximum and final postbaseline grades will be assessed.  
CTCAE v4.03 will be used to identify subjects with treatment-emergent markedly abnormal 
laboratory values (TEMAV).  A more detailed definition of TEMAV will be specified in the 
SAP.  A summary of TEMAVs will be presented by visit and overall and by treatment group. 
9.7.1.8.4 VITAL SIGNS 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, resting HR, 
respiratory rate, temperature, and weight) and changes from baseline will be presented by 
visit and treatment cohort. 
9.7.1.8.5 ELECTROCARDIOGRAMS 
Change from baseline to each postbaseline visit and to the end of treatment in ECG findings 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant) will be summarized by visit and treatment group using shift tables.  Descriptive 
statistics for ECG parameters and changes from baseline will be presented by treatment 
cohort. 
9.7.1.8.6 OTHER SAFETY ANALYSES 
Descriptive statistics for LVEF assessed on echocardiogram or MUGA scans and changes 
from baseline will be presented by treatment cohort. 
9.7.1.9 
Extension Phase Analyses 
The Extension Phase data will be analyzed separately and described in the SAP.  
9.7.2 
Determination of Sample Size 
Phase 1b – Determination of the Maximum Tolerated Dose 
The total number of subjects required for the Phase 1b portion of this study will depend upon 
the toxicities observed as the study progresses.  A sample size of approximately 10 to 30 
subjects in Phase 1b will be enrolled to assess MTD.  This is not based on statistical power 
considerations. 
Phase 2 – Expansion in Selected Tumor Types 
A sample size of 10 evaluable subjects will be enrolled per cohort, with the possibility of 
expansion to 20 evaluable subjects per cohort, depending on the evaluation by the sponsor 
and investigators of the efficacy and safety results observed with the initial 10 evaluable 


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subjects in each cohort. For a reference of the precision of ORR estimates in all cohorts 
except the EC and the renal cell carcinoma cohorts, the associated 2-sided 95% CIs for the 
ORR of 10% to 90% for both 10 subjects and 20 subjects, per cohort are provided in Table 
10. 
The EC cohort may be further expanded to approximately 120 evaluable subjects.  The 
decision to expand enrollment will be based on the results of 2 interim analyses which will 
spend 𝛽𝛽=0.012 and 𝛽𝛽 = 0.024 at the first and second interim analysis, respectively.  Based on 
an assumption of H0: 16% ORR and H1: 34% ORR, at 2-sided α = 0.02, this design will give 
97% statistical power with 120 subjects.  At the first interim analysis (N = 21), if there are 
more than 3 responses, then approximately 40 additional subjects will be enrolled.  At the 
second interim analysis (N = 60), if there are more than 12 responses, approximately 60 
additional subjects will be enrolled.  If there are 12 or fewer responses, the sponsor may 
decide whether to expand enrollment based on clinical outcome, eg, ORR and DOR.  If the 
expansion beyond 60 subjects does not happen, this design for the EC cohort has 
approximately 86% power at 2-sided 𝛼𝛼= 0.02.  The boundaries for the decision to expand 
enrollment in the endometrial cohort are presented in Table 11. 
 
Table 10 
2-sided 95% Confidence Interval for the ORR of 10% to 90% 
(10 subjects and 20 subjects) 
ORR (N=10) 
95% CI 
10% 
(0.003, 0.445) 
20% 
(0.025, 0.556) 
30% 
(0.067, 0.653) 
40% 
(0.122, 0.738) 
50% 
(0.187, 0.813) 
60% 
(0.262, 0.878) 
70% 
(0.348, 0.933) 
80% 
(0.444, 0.975) 
90% 
(0.555, 0.998) 
ORR (N=20) 
95% CI 
10% 
(0.012, 0.317) 
20% 
(0.057, 0.437) 
30% 
(0.119, 0.543) 
40% 
(0.191, 0.639) 
50% 
(0.272, 0.728) 
60% 
(0.361, 0.809) 
70% 
(0.457, 0.881) 
80% 
(0.563, 0.943) 


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Table 10 
2-sided 95% Confidence Interval for the ORR of 10% to 90% 
(10 subjects and 20 subjects) 
90% 
(0.683, 0.988) 
CI = confidence interval, ORR = objective response rate. 
 
Table 11 
Boundaries for the Decision to Expand Enrollment in the 
Endometrial Carcinoma Cohort 
Analysis Number 
Cumulative β Spent 
Objective Response Rate 
P-value 
Interim Analysis 1 
(N=21) 
0.012 
0.167 
0.93 
Interim Analysis 2 
(N=60) 
0.024 
0.204 
0.357 
Final Analysis 
(N=120) 
0.03 
0.238 
0.02 
 
As of Amendment 7, the renal cell carcinoma cohort may be further expanded to 
approximately 145 total evaluable subjects to allow for approximately 100 evaluable subjects 
who have received 1 or 2 prior therapies that included an anti-PD-1/PD-L1 mAb.  The 
decision to expand enrollment will be based on the results of 2 interim analyses.  The first 
interim analysis will take place when 22 subjects (11 treatment naïve and 11 previously 
treated without an anti-PD-1/PD-L1 mAb) have sufficient follow-up to be evaluated for 
response.  At the first interim analysis (N = 22), if there are more than 5 responses, then 
approximately 45 additional subjects will be enrolled.  It is anticipated that the additional 
45 subjects will consist of approximately 12 treatment naïve subjects enrolled under 
Amendment 05 and approximately 33 previously treated subjects who have received 1 or 2 
prior therapies and have progressed on treatment with an anti-PD-1/PD-L1 mAb.  The second 
interim analysis will include these 45 additional subjects and the 11 treatment naïve subjects 
included in the first interim analysis and will take place when these 56 subjects have 
sufficient follow-up to be evaluated for response.  Table 12 shows the ORR estimates that are 
close to the minimum anticipated ORR of about 25% in subjects who had previously failed 
an anti-PD-1/PD-L1 treatment and about 60% in treatment naïve subjects, and the 
corresponding 95% CIs in the respective anticipated 33 and 23 subjects for the second 
interim analysis.  At the second interim analysis, whether the previously treated renal cell 
carcinoma subset will be further expanded will be decided based on clinical review of both 
efficacy and safety data. 
 


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Table 12 
Estimate and 2-sided 95% Confidence Interval of the ORR (RCC 
Subjects for the Second Interim Analysis) 
33 subjects who had previously failed an anti-PD-1/PD-L1 therapy 
Number of responses 
Observed ORR 
95% CI 
7 
21.2% 
(0.090, 0.389) 
8 
24.2% 
(0.111, 0.423) 
9 
27.3% 
(0.133, 0.455) 
10 
30.3% 
(0.156, 0.487) 
11 
33.3% 
(0.180, 0.518) 
12 
36.4% 
(0.204, 0.549) 
23 treatment naïve subjects  
Number of responses 
Observed ORR 
95% CI 
13 
56.5% 
(0.345, 0.768) 
14 
60.9% 
(0.385, 0.803)  
15 
65.2% 
(0.427, 0.836) 
16 
69.6% 
(0.471, 0.868) 
17 
73.9% 
(0.516, 0.898) 
CI = confidence interval, ORR = objective response rate, PD-1 = programmed cell death protein, PD-L1 =  PD-
1 ligand, RCC = renal cell carcinoma. 
 
 
 
Table 13 shows the 95% CI for a range of observed ORRs from 25% to 45% in subjects who 
had previously failed an anti-PD-1/PD-L1 treatment with a sample size of 100 subjects.  If 
the observed ORR is 35%, the sample size of 100 subjects will provide a 95% confidence 
interval with a lower bound excluding 25%, and this indicates that with 95% confidence the 
ORR in the combination of lenvatinib and pembrolizumab is greater than 25%. 
 
Table 13 
Two-sided 95% Confidence Interval of the ORR, N=100 (RCC 
Subjects Previously Treated with an Anti-PD-1/PD-L1 mAb) 
100 subjects who had previously failed an anti-PD-1/PD-L1 therapy 
Number of responses 
Observed ORR 
95% CI 
25 
25.0% 
(0.169, 0.347) 
30 
30.0% 
(0.212, 0.400) 
35 
35.0% 
(0.257, 0.452) 


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40 
40.0% 
(0.303, 0.503) 
45 
45.0% 
(0.350, 0.553) 
CI = confidence interval, mAb = monoclonal antibody, ORR = objective response rate, PD-1 = 
programmed cell death protein, PD-L1 =  PD-1 ligand, RCC = renal cell carcinoma. 
 
9.7.3 
Interim Analysis 
The evaluation of efficacy and safety by the sponsor and investigators will occur on the 
initial 10 evaluable subjects while enrollment is ongoing.  Based on the outcome of the 
evaluation the enrollment could be suspended before enrolling the planned 20 subjects in 
each cohort.   
The EC cohort may be expanded to approximately 120 evaluable subjects.  Two interim 
analyses will take place when 21 and 60 subjects have sufficient follow-up to be evaluated 
for response.  The decision to expand enrollment will be based on the results of the 2 interim 
analyses, which will spend β = 0.012 and β = 0.024 at the first and second interim analyses, 
respectively.  Based on an assumption of H0: 16% ORR and H1: 34% ORR, at 2-sided α = 
0.02, this design will give 97% statistical power with 120 subjects.  At the first interim 
analysis (N = 21), if there are more than 3 responses, then approximately 40 additional 
subjects will be enrolled.  At the second interim analysis (N = 60), if there are more than 12 
responses, approximately 60 additional subjects will be enrolled.  If there are 12 or fewer 
responses, the sponsor may decide whether to expand enrollment based on clinical outcome, 
eg, ORR and DOR.  If the expansion beyond 60 subjects does not happen, this design for the 
EC cohort has approximately 86% power at 2-sided α = 0.02.   
The renal cell carcinoma cohort may be further expanded to approximately 145 evaluable 
total RCC subjects to allow for approximately 100 evaluable subjects who have received 1 or 
2 prior therapies that included an anti-PD-1/PD-L1 mAb.   The decision to expand 
enrollment will be based on the results of 2 interim analyses. The first interim analysis will 
take place when 22 subjects (11 treatment naïve and 11 previously treated without an anti-
PD-1/PD-L1 therapy) have sufficient follow-up to be evaluated for response.  At the first 
interim analysis (N = 22), if there are more than 5 responses, then approximately 45 
additional subjects will be enrolled.  It is anticipated that the additional 45 subjects will 
consist of approximately 12 treatment naïve subjects enrolled under Amendment 05 and 
approximately 33 previously treated subjects who have received 1 or 2 prior therapies and 
have progressed on treatment with an anti-PD-1/PD-L1 mAb.  The second interim analysis 
will include these 45 additional subjects and the 11 treatment naïve subjects included in the 
first interim analysis and will take place when these 56 subjects have sufficient follow-up to 
be evaluated for response.  At the second interim analysis, whether the previously treated 
renal cell carcinoma subset will be further expanded will be decided based on clinical review 
of both efficacy and safety data. 


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9.7.4 
Other Statistical/Analytical Issues 
Not applicable. 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report. 


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Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. 
Nature Rev Immunol. 2004;4:336–47. 
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Hamid O, Carvajal RD. Anti-programmed death-1 and anti-programmed death-ligand 1 
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Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors 
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Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, et al. 
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Gadiot J, Hooijkaas A, Kaiser A, van Tinteren H, van Boven H  Blank C. Overall survival 
and PD-L1 expression in metastasized malignant melanoma. Cancer. 2011;117:2192–201.  
Gao Q, Wang X, Qiu S, Yamato I, Sho M, Nakajima Y. et al. Overexpression of PD-L1 
significantly associates with tumor aggressiveness and postoperative recurrence in human 
hepatocellular carcinoma. Clin Cancer Res. 2009;15:971–9. 
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KEYTRUDA Summary of Product Characteristics [Revised 10/2017].  Available from: 
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KISPLYX Summary of Product Characteristics [Revised 07/2017].  Available from: 
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LENVIMA Package Insert [Revised: 07/2017]. Available from: 
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Kilfoy BA, Zheng T, Holford TR, Han X, Ward MH, Sjodin A, et al. International patterns 
and trends in thyroid cancer incidence. 1973-2002. Cancer Causes Control. 2009;20:525-31. 
Ko JJ, Xie W, Kroeger N, Lee JL, Rini BI, Knox JJ, et al. The International Metastatic Renal 
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study. Lancet Oncol. 2015;16(3):293-300. 
Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase inhibitor 
E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-
MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and 
VEGF-R3 kinase. Clin Cancer Res. 2008a;14:5459-65. 
Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T, et al. 
E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against 
stem cell factor producing human small cell lung cancer H146, based on angiogenesis 
inhibition. Int J Cancer. 2008b;122:664-71. 
Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 
2014;41(1):49-61. 
Okamoto K, Kodama K, Takase K, S ugi NH, Yamamoto Y, Iwata M, et al. Antitumor 
activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene 
fusion-driven tumor models. Cancer Lett. 2013;340:97-103. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 
Dec;5(6):649-55. 
Philips GK, Atkins M. Therapeutic uses of anti-PD-1 antibodies. Int Immunol. 2015 
Jan;27(1):39-46. 
Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-
death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced 
melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 
384(9948):1109-17. 
Sharpe AH, Freeman GJ. The B7–CD28 superfamily. Nature Rev Immunol. 2002;2:116–26. 
Shumaker R, Aluri J, Fan J, Martinez G, Thompson, GA, Ren M. Effect of rifampin on the 
pharmacokinetics of lenvatinib in healthy adults. Clin Drug Investig. 2014;34(9):651-9.  
Shumaker R, Aluri J, Fan J, Martinez G, Thompson GA, Ren M. Effects of ketoconazole on 
the pharmacokinetics of lenvatinib (E7080) in healthy participants. Clin Pharmacol Drug 
Dev. 2015;4(2):155–60.   
Stagg J, Allard B. Immunotherapeutic approaches in triple-negative breast cancer: latest 
research and clinical prospects. Ther Adv Med Oncol. 2013;5(3):169-81. 


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Tohyama O, Matsui J, Kodama K, Hata-Sugi N, Kimura T, Okamoto K, et al. Antitumor 
activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor 
tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 
2014;2014:638747. 
Topalian S, Hodi F, Brahmer J, Gettinger S, Smith D, McDermott D, et al. Safety, activity, 
and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54. 
Yamamoto Y, Matsui J, Matsushima T, Obaishi H, Miyazaki K, Nakamura K, et al. 
Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor 
activity in human tumor xenograft models associated with microvessel density and pericyte 
coverage. Vasc Cell. 2014 Sep 6;6:18. 
CTCAE Reference 
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RECIST Reference 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47. 
FIGO Reference 
Creasman, W. Revised FIGO staging for carcinoma of the endometrium. Int J Gynecol 
Obstetrics 2009;105-9. 


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes. 
11.2 Adherence to the Protocol 
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
11.3 Monitoring Procedures 
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the 
local auditing agency and to IRB/IEC review. 
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to, 
the following: 
• 
Clinic, office, or hospital charts 


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• 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production 
• 
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, CT scans, magnetic resonance images, radioactive images, ECGs, 
rhythm strips, EEGs, polysomnographs, pulmonary function tests) regardless of how 
these images are stored, including microfiche and photographic negatives 
• 
Pain, quality of life, or medical history questionnaires completed by subjects 
• 
Records of telephone contacts 
• 
Diaries or evaluation checklists 
• 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• 
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks) 
• 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs 
• 
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source 
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected. 
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
11.5 Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents. For the 
following item(s), the data recorded directly on the CRF are to be considered source data: 
• 
Study drug compliance (eg, the reason for any change of dosage) 
• 
Indication for prior/concomitant medication (drug/therapy) 
• 
Discontinuation information (eg, in the case of lost to follow-up due to the subject choice) 
• 
Sampling date and time for the drug concentration 
• 
Sampling date for the clinical laboratory tests 
• 
Comments and other information on AEs (eg, severity, relationship to study drug, outcome) 


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11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product. 
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records. 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately. 
11.8 Handling of Study Drug 
All study drug will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  The investigator (or a designated pharmacist) 
must maintain an accurate record of the shipment and dispensing of the study drug in a drug 
accountability ledger, a copy of which must be given to the sponsor at the end of the study.  
An accurate record of the date and amount of study drug dispensed to each subject must be 
available for inspection at any time.  The CRA will visit the site and review these documents 
along with all other study conduct documents at appropriate intervals once study drug has 
been received by the site. 
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site. 


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11.9 Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate. 
11.10 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Trial Agreement executed between the sponsor/CRO and the 
institution/investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO. 
11.11 Discontinuation of Study 
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s). 
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above. 


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11.12 Subject Insurance and Indemnity 
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations. 


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12 APPENDICES 
 


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Appendix 1 
Immune-related Response Evaluation Criteria in Solid 
Tumors 
Investigators should follow the guidelines provided here which are an adaptation of RECIST 
1.1 and irRC.  The following guide represents a summary of irRECIST and is meant to help 
investigators in providing more objective and reproducible immune therapy related tumor 
response assessments in solid tumors. 
The key changes for irRECIST are: 
• IrRECIST allows the site to select up to ten (10) target lesions at baseline, five (5) per 
organ, if clinically relevant via CT/MRI scans or by electronic calipers for skin 
lesions.  The ability to continue treatment, if clinically stable, until repeat imaging 
scans ≥4 weeks later (in most cases at the next scanning time point 6 weeks later) to 
confirm immune-relater progressive disease (irPD) 
irRECIST Lexicon 
1.  Baseline Assessments 
Measurable 
(Target) lesions 
 
Measurable lesions must be accurately measured in at least one 
dimension with a minimum size of: 
• 10 mm in the longest diameter (LDi) by CT or MRI scan (or no less 
than double the slice thickness) for non-nodal lesions and ≥15 mm in 
short axis (SDi) for nodal lesions 
• 10 mm in LDi for clinical lesions (must be measured using electronic 
calipers) 
• Identify up to 10 lesions, not more than 5 from one organ system. 
Lymph nodes are considered one organ system 
• Likely to be reproducible across all time points 
• Representative of tumor burden 
• May include lesions in previously irradiated areas ONLY if there is 
demonstrated progression in that lesion after irradiation 
• Sum of diameters (SOD) of all target lesions including nodal and 
non-nodal are reported as baseline SOD, which is used for assessing 
tumor response at follow-up time points 
Bone lesions 
 
Regardless of the imaging modality, blastic bone lesions will not be 
selected as target lesions. Lytic or mixed lytic-blastic lesions with a 
measurable soft tissue component ≥10 mm can be selected as target 
lesions. 
Cystic and 
Necrotic 
Lesions as 
Target Lesions 
Lesions that are partially cystic or necrotic can be selected as target 
lesions. The LDi of such a lesion will be added to the SOD of all target 
lesions at baseline. If other lesions with a nonliquid/nonnecrotic 
component are present, those should be preferred. 


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Lesions with 
Prior Local 
Treatment 
During target lesion selection the radiologist will consider information on 
the anatomical sites of previous intervention (eg, previous irradiation, 
RF-ablation, TACE, surgery).  Lesions undergoing prior intervention will 
not be selected as target lesions unless there has been a demonstration of 
progression in the lesion. 
Nonmeasurable 
(Nontarget) 
lesions 
 
Nontarget lesions will include: 
• Measurable lesions not selected as target lesions.  There is no limit to 
the number of nontarget lesions that can be recorded at baseline 
• Other types of lesions that are confidently felt to represent neoplastic 
tissue, but are difficult to measure in a reproducible manner.  These 
include bone metastases, leptomeningeal metastases, malignant 
ascites, pleural or pericardial effusions, ascites, inflammatory breast 
disease, lymphangitis cutis/pulmonis, cystic lesions, ill-defined 
abdominal masses, etc. 
• Multiple non target lesions from the same organ may be captured as 
a single item on the eCRF (eg, multiple liver metastases) 
Nontarget lesions should be reported as present at baseline 
SOD baseline 
Sum of diameters at baseline = LDi of all non-nodal + SDi of all nodal 
target lesions 
2.  Time point Assessments After Baseline 
Target lesion 
measurements 
Locate image that optimizes the LDi of the non-nodal target lesion or SDi 
of target node(s).  There is no need to go to an identical slice from 
baseline. 
Measure the respective LDi and SDi for all target lesions and calculate 
time point SOD (SOD timepoint). 
Special consideration for target lesions: 
• If target lesion is too small to measure, a default value of 5mm 
should be entered on eCRF. 
• If target lesion is 5-10mm, actual diameter should be entered in the 
eCRF.  
• If target lesion splits into 2 or more lesion then the LDi of split 
lesions will be added and entered in place of that lesion. 
• If two target lesion merged to form one lesion than LDi of one 
should be entered as “0mm” while the other lesion should have the 
diameter of the merged lesion. 
Nontarget 
Lesion 
Assessment 
 
Nontarget lesions are evaluated qualitatively as present, absent, not 
evaluable (NE) or unequivocal progression.  The response of nontarget 
lesions primarily contributes to the overall response assessments of irCR.  
Nontarget lesions do not affect irPR and irSD assessments.  Only a 
massive and unequivocal worsening of nontarget lesions alone, even in 
the presence of stable disease or a partial response in the target lesion is 


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indicative of irPD. IrCR is not possible unless all nontarget lesions are 
absent. 
Definition of 
New Lesion 
Any lesion that was not recorded at baseline.  There is no minimum size 
criteria to identify a new lesion and clinical judgment must be used by 
the PI. 
• May include a lesion in an anatomical location that was not scanned 
at baseline (ie, brain) 
• Should be unequivocal and not due to differences in scanning 
technique 
• If equivocal, should be assessed at next time point; if present, irPD 
is the date the lesion was first seen (not the date confirmed) 
3.  irRECIST Overall Tumor Assessment 
 
 
irCR 
• Complete disappearance of all measurable and nonmeasurable 
lesions (from baseline) and there are no unequivocal new lesions 
(unconfirmed irCR). 
• Lymph nodes must decrease to <10 mm in SDi. 
• Confirmation of response is required ≥4 weeks later, preferably at 
next time point, to be considered a confirmed irCR. 
irPR 
• If the SODtimepoint of TLs decreases by ≥30 % compared to 
SODbaseline and there are no unequivocal new lesions, and no 
progression of nontarget disease, it is an irPR (unconfirmed).  
• Confirmation is required ≥4 weeks later, preferably at next time 
point, to be considered a confirmed irPR. 
irSD 
Failure to meet criteria for irCR or irPR in the absence of irPD. 
• If the sum of the TLs and the status of the nontarget lesions do not 
reach the criteria to meet irPR or irPD (increase ≥20% and at least 5 
mm absolute increase in SOD compared to nadir†) the response is 
irSD. 
• irSD = neither 30% decrease compared to SODbaseline or 20% 
increase  and at least 5 mm absolute change compared to nadir. 
• †SODnadir: Lowest measure SOD of TLs at any time point from 
baseline onward. 
irPD 
Minimum 20% increase and a minimum 5 mm absolute increase in SOD 
compared to nadir, or irPD for nontarget lesion(s) or unequivocal new 
lesion(s). 
• Confirmation of progression is recommended at a minimum of 4 
weeks after the first irPD assessment (preferably at next tumor 
assessment time point). 
The decision to continue study treatment after the first evidence of PD is 
at the investigator’s discretion based on the clinical status of the subject 
as described in table below 


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Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat 
imaging at >4 
weeks (next 
TA time point) 
to confirm PD 
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory scans  
Repeat 
imaging at >4 
weeks to 
confirm PD 
per physician 
discretion only 
Discontinue 
treatment 
Subsequent scan 
confirms PD 
No additional 
imaging 
required 
Discontinue 
treatment 
No additional 
imaging 
required 
N/A 
Subsequent scan 
shows SD, PR or 
CR 
Continue 
regularly 
scheduled 
imaging 
assessments  
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments  
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per investigator’s 
discretion 
 
Subjects may continue receiving study treatment while waiting for 
confirmation of irPD if they are clinically stable as defined by the 
following criteria: 
• Absence of signs and symptoms (including worsening of laboratory 
values) indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease  
• Absence of progressive tumor at critical anatomical sites (eg, cord 
compression) requiring urgent alternative medical intervention 
 
If irPD is confirmed and the subject is experiencing extraordinary clinical 
benefit, site must contact sponsor to discuss continuing treatment 
irNE 
Used in exceptional cases where insufficient data exists due to poor 
quality of scans or missed scans or procedure 
 
 
Derivation of irRECIST overall responses 
Measurable response  
Non-measureable response 
 
Target Lesions 
(% change in SOD)a 
Nontarget Lesions 
Status 
New Lesions 
Status 
Overall Response 
(irRECIST) 
↓100 
Absent 
Absent 
irCRb 
↓100 
Present/NE 
Absent 
irPRb 
↓≥30 
Present/Absent/NE 
Absent 
irPRb 


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↓<30 to <20↑ 
Present/Absent/NE 
Absent 
irSD 
↓100 
↓≥30 
↓<30 to <20↑ 
NE 
Present/Absent/NE 
Present 
irPDb 
↓100 
↓≥30 
↓<30 to <20↑ 
NE 
Unequivocal 
progression 
Any 
irPDb 
↑≥20 from nadir 
Any 
Any 
irPDb 
NE 
Present/Absent/NE 
Absent 
irNEb 
irCR = immune-related complete response, irNE = immune-related not evaluable, irPD = immune-related progression 
disease, ir PR = immune-related partial response,  irSD = immune-related stable disease, NE = Not evaluable, 
irRECIST = immune-related Response Evaluation Criteria in Solid Tumors SOD = sum of diameters 
a:   Decreases assessed relative to baseline, including measureable lesions only. 
b:  Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 weeks 
apart. 
 
 
 
 
 


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Appendix 2  
Eastern Cooperative Oncology Group Performance 
Status (ECOG-PS) 
Scale 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (eg, light house work, office work) 
2 
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair. 
5 
Dead 
Adapted from Oken MM, et al. Am J Clin Oncol. 1982;5:649-55. 
 
 
 


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Appendix 3  
Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03 
The CTCAE v4.03, published 14 June 2010 provides descriptive terminology to be used for 
AE reporting in clinical trials.  A brief definition is provided to clarify the meaning of each 
AE term.  To increase the accuracy of AE reporting, all AE terms in CTCAE v4.03 have 
been correlated with single-concept (MedDRA) terms. 
The CTCAE v4.03 grading refers to the severity of the AE.  The CTCAE grades 1 through 5, 
with unique clinical descriptions of severity for each AE, are based on this general guideline: 
Grade 
CTCAE Status 
1 
Mild:  asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
2 
Moderate:  minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a 
3 
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADLb 
4 
Life-threatening consequences: urgent intervention indicated 
5 
Death related to adverse event 
ADL = activities of daily living, CTCAE = Common Terminology Criteria for Adverse Events. 
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Adapted from the Cancer Therapy Evaluation Program, NCI.  CTCAE v4.03  
 
For further details regarding MedDRA, refer to the MedDRA website at:  
http://www.meddramsso.com 
 
 


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Appendix 4 
New York Heart Association (NYHA) Cardiac Disease 
Classification 
The NYHA Cardiac Disease Classification provides a functional and therapeutic 
classification for the prescription of physical activity for heart failure patients based on 
cardiac functional capacity.  Based on NYHA definitions, subjects are to be classified as 
follows: 
Class 
NYHA Status 
Class I: 
Patients with cardiac disease but without resulting limitation of physical 
activity; ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea or anginal pain. 
Class II: 
Patients with cardiac disease resulting in slight limitation of physical activity; 
they are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
Class III: 
Patients with cardiac disease resulting in marked limitation of activity; they are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
Class IV: 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or angina syndrome 
may be present even at rest.  If any physical activity is undertaken, discomfort 
is increased. 
NYHA = New York Heart Association. 
Source: The Criteria Committee of the New York Heart Association.  Nomenclature and criteria for diagnosis 
of diseases of the heart and great vessels.  9th ed. Boston: Little Brown; 1994. p.253-6. 
 
 


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Appendix 5 
Clinical Studies Evaluating Drug–Drug Interactions 
with Lenvatinib 
Nonclinical studies identify CYP3A4 as a potentially important CPY isozyme responsible for 
metabolism of lenvatinib.  Clinical studies were conducted to test these findings.  
Simultaneous CYP3A4/ P-gp inhibition by ketoconazole slightly (15% to 19%) increases 
systemic exposure to lenvatinib (Shumaker, et al., 2015).  Since no change was observed in 
half-life, tmax, or lag time (tlag), the slight increase in systemic exposure is probably related to 
a decrease in first pass metabolism.  However, since the magnitude of change is small, co-
administration of lenvatinib with CYP3A4/P-gp inhibitors is not of clinical concern.  
The influence of P-gp inhibition on lenvatinib PK has been investigated.  P-gp inhibition was 
accomplished by co-administering a single dose of rifampin with a single dose of lenvatinib.  
Preliminary results suggest P-gp inhibition increases systemic exposure to lenvatinib 26% to 
32%.  Thus, co-administration of lenvatinib with P-gp inhibitors only causes a small increase 
in lenvatinib exposure.  
The influence of simultaneous P-gp and CYP3A4 induction on lenvatinib PK has been 
investigated.  Examination of simultaneous P-gp and CYP3A4 induction on lenvatinib PK 
was accomplished by administering rifampin QD for 21 days (Shumaker, et al., 2014).  A 
single dose of lenvatinib was co-administered with the 15th dose of rifampin.  Based on 
preliminary data, simultaneous P-gp and CYP3A4 induction minimally altered lenvatinib 
exposure as mean Cmax increased about 8% while AUC decreased about 7%.  Co-
administration of lenvatinib with CYP3A4/P-gp inducers is not of clinical concern. 
 


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Appendix 6 
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research 
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic, PG, and other biomarker analysis.  These samples may be used for 
discovery and validation to identify biomarkers that may be used for exploratory evaluation 
of response and/or safety-related outcomes as well as for use in diagnostic development. 
The PG samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential AEs related to study treatment, and to explore the role of genetic 
variability in response.  Samples may be analyzed to determine a subject’s genotypes or 
sequence for a number of genes or non-coding regulatory regions.  The research may include 
the investigation of polymorphisms in genes that are likely to influence the study drug 
pharmacokinetics or therapeutic response. 
Collection of the pharmacodynamic, PG, and other biomarker samples will be bound by the 
sample principles and processes outlined in the main study protocol.  Sample collection for 
pharmacodynamic, PG, and other biomarker analysis is required as per the study protocol 
unless the collection and use of the samples is prohibited by specific country laws. 
Sample Collection and Handling 
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff. 
Security of the Samples, Use of the Samples, Retention of the Samples 
Sample processing, for example DNA and/or RNA extraction, genotyping, sequencing, or 
other analysis will be performed by a laboratory under the direction of the sponsor.  
Processing, analysis, and storage will be performed at a secure laboratory facility to protect 
the validity of the data and maintain subject privacy. 
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party. 
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed. 


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It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw 
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project. 
Subject Privacy and Return of Data 
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All pharmacodynamic and other biomarker 
samples will be single coded.  Genomic DNA samples used to explore the effects on PK, 
treatment response, and safety will be single coded.  Genomic DNA samples that will be 
stored for long-term use (defined as 15 years after the completion of the study) will be double 
coded.  Double coding involves removing the initial code (subject ID) and replacing with 
another code such that the subject can be re-identified by use of 2 code keys.  The code keys 
are usually held by different parties.  The key linking the sample ID to the subject number 
will be maintained separately from the sample.  At this point, the samples will be double-
coded, the first code being the subject number.  Laboratory personnel performing genetic 
analysis will not have access to the “key.”  Clinical data collected as part of the clinical trial 
will be cleaned of subject identifying information and linked by use of the sample ID “key.” 
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection. 
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include: 
• 
Clinical research organizations retained by the sponsor  
• 
Independent ethics committees or institutional review boards that have responsibility for this 
research study  
• 
National regulatory authorities or equivalent government agencies 
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed. 


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Given the research nature of the pharmacodynamic, PG, and other biomarker analysis, it will 
not be possible to return individual data to subjects.  The results that may be generated are 
not currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians. 
If at any time, pharmacodynamic, PG, and/or other biomarker results are obtained that may 
have clinical relevance, IRB review and approval will be sought to determine the most 
appropriate manner of disclosure and to determine whether or not validation in a Clinical 
Laboratory Improvement Amendments (CLIA)-certified setting will be required.  Sharing of 
research data with individual patients should only occur when data have been validated by 
multiple studies and testing has been done in CLIA-approved laboratories. 
 
 
 
 


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Appendix 7 
KEYTRUDA® Package Insert 
The latest KEYTRUDA Package Insert (Revised: 09/2017) is available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s024lbl.pdf  
 
KEYTRUDA Summary of Product Characteristics (Revised: 10/2017) is available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003820/WC500190990.pdf 
 
 


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Appendix 8 
Karnofsky Performance Status Scale 
 
 
 


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PROTOCOL SIGNATURE PAGE 
Study Protocol Number: 
E7080-A001-111 
Study Protocol Title: 
A Multicenter, Open-Label Phase 1b/2 Trial of  Lenvatinib 
(E7080) Plus Pembrolizumab in Subjects With Selected Solid 
Tumors 
Investigational Product 
Name: 
Lenvatinib (E7080/LENVIMA™) and Pembrolizumab 
(MK-3475/KEYTRUDA®)  
IND Number: 
72010 
EudraCT Number: 
2017-000300-26 
 
 
SIGNATURES 
 
 
Authors: 
 
 
 
 
 
  
 
 
Oncology Business Group; Eisai, Inc. 
 
 
 
 
 
 
 
Oncology Business Group; Eisai Co., Ltd 
 
 
 
 
 
  
 
 
 
Oncology Business Group; Eisai Co., Ltd. 
 
 
 
 
 
 
 
 
 
 
Oncology Business Group; Eisai, Inc. 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
E7080-A001-111 
Study Protocol Title: 
A Multicenter, Open-Label Phase 1b/2 Trial of  Lenvatinib 
(E7080) Plus Pembrolizumab in Subjects With Selected Solid 
Tumors 
Investigational Product 
Name: 
Lenvatinib (E7080/LENVIMA™) and pembrolizumab 
(MK-3475/KEYTRUDA®)  
IND Number: 
72010 
EudraCT Number: 
2017-000300-26 
Study Protocol Number: 
E7080-A001-111 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
 
Medical Institution 
 
 
  
  
Investigator 
 Signature 
 Date 
 

SAP_001.pdf: 
Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E7080-A001-111 (Phase 1b/2)
Study Protocol 
Title:
A Multicenter, Open-Label Phase 1b/2 Trial of Lenvatinib (E7080) 
Plus Pembrolizumab in Subjects With Selected Solid Tumors
Date:
September 16, 2020
Version:
Final 4.0


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SUMMARY OF CHANGES FROM SAP VERSIONS 3 TO 4
Version 4 Date:  16 Sep 2020
Change
Rationale
The pharmacokinetic (PK)/pharmacodynamics 
(PD) analyses are removed; and changes in PK 
analyses was made.
To reflect analysis-related changes that were made in 
the protocol amendment 08.


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1
TABLE OF CONTENTS
SUMMARY OF CHANGES FROM SAP VERSIONS 3 TO 4 .............................................2
1
TABLE OF CONTENTS...............................................................................................3
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................5
3
INTRODUCTION.........................................................................................................8
3.1
Study Objectives..................................................................................................8
3.1.1
Primary Objectives.....................................................................................8
3.1.2
Secondary Objectives .................................................................................8
3.1.3
Exploratory Objectives...............................................................................9
3.2
Overall Study Design and Plan.............................................................................9
4
DETERMINATION OF SAMPLE SIZE.....................................................................12
5
STATISTICAL METHODS........................................................................................15
5.1
Study Endpoints.................................................................................................16
5.1.1
Primary Endpoints....................................................................................16
5.1.2
Secondary Endpoint(s) .............................................................................16
5.1.3
Exploratory Endpoints..............................................................................17
5.2
Study Subjects ...................................................................................................18
5.2.1
Definitions of Analysis Sets......................................................................18
5.2.2
Subject Disposition...................................................................................18
5.2.3
Protocol Deviations ..................................................................................19
5.2.4
Demographic and Other Baseline Characteristics......................................19
5.2.5
Prior and Concomitant Therapy................................................................21
5.3
Data Analysis General Considerations................................................................22
5.3.1
Pooling of Centers....................................................................................22
5.3.2
Adjustments for Covariates ......................................................................22
5.3.3
Multiple Comparisons/Multiplicity...........................................................22
5.3.4
Handling of Missing Data, Drop-outs, and Outliers ..................................22
5.4
Efficacy Analyses ..............................................................................................22
5.4.1
Primary Analysis for Phase 1b..................................................................26
5.4.2
Primary Efficacy Analysis for Phase 2......................................................26
5.4.3
Secondary Efficacy Analyses for Both Phase 1b and Phase 2....................26
5.4.4
Exploratory Efficacy Analysis..................................................................29
5.4.5
Other Efficacy Analyses...........................................................................31
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic and Other Biomarker
Analyses ............................................................................................................31
5.5.1
Pharmacokinetic Analyses........................................................................31


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5.5.2
Pharmacodynamic, Pharmacogenomic and Other Biomarker Analyses.....31
5.6
Safety Analyses..................................................................................................31
5.6.1
Extent of Exposure...................................................................................32
5.6.2
Dose Limiting Toxicity ............................................................................33
5.6.3
Deaths, Serious and Other Significant Adverse Events .............................33
5.6.4
Laboratory Values ....................................................................................35
5.6.5
Vital Signs................................................................................................36
5.6.6
Electrocardiograms...................................................................................36
5.6.7
Other Safety Analyses ..............................................................................36
5.7
Exploratory Analyses.........................................................................................37
6
INTERIM ANALYSES...............................................................................................37
7
CHANGES IN THE PLANNED ANALYSES ............................................................38
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................38
9
PROGRAMMING SPECIFICATIONS .......................................................................39
10
STATISTICAL SOFTWARE......................................................................................39
11
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) ...............................................39
12
REFERENCES............................................................................................................39
13
APPENDICES.............................................................................................................41
13.1
Immune-Related Response Evaluation Criteria In Solid Tumors (irRECIST) .....41
13.2
Dose-Limiting Toxicities ...................................................................................46
13.3
Common Terminology Criteria For Adverse Events (CTCAE) V4.03.................47
13.4
New York Heart Association (NYHA) Cardiac Disease Classification................48
13.5
Summary of primary and secondary Efficacy Analyses......................................49
13.6
Common Terminology Criteria for Adverse Events (CTCAE) for Hematology 
& Clinical Chemistry .........................................................................................50


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
Adverse event
ATC
Anatomical Therapeutic Chemical
BLQ
Below limit of quantification
BMI
Body mass index
BOR
Best overall response
C#/D#
Cycle#/Day#
CBR
Clinical benefit rate
CI
Confidence interval
CR
Complete response
CRF
Case report form
CSP
Clinical study protocol
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DBP
Diastolic blood pressure
DCR
Disease control rate
DLT
Dose limiting toxicity
DOR
Duration of response
DTC
Differentiated thyroid cancer
ECG
Electrocardiogram
FDA
Food and Drug Administration (Washington, DC, USA)
INR
International normalized ratio
irRECIST
Immune-related RECIST
ITT
Intention-to-treat


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Abbreviation
Term
IV
Intravenous
MTD
Maximum tolerated dose
KM
Kaplan-Meier
LLN
Lower limit of normal
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum tolerated dose
MUGA
Multiple Gated Acquisition
NA
Not applicable
NE
Not evaluable
NYHA
New York Heart Association
Off-Tx
Off Treatment
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD
Pharmacodynamic
PD-L1
Programmed Death-Ligand 1
PFS
Progression-free survival
PID
Percent intended dose
PK
Pharmacokinetic
PR
Partial response
PT
Preferred term
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 dose
Q3W
Every 3 weeks


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Abbreviation
Term
QD
Once a day
QT
Time from the beginning of the QRS complex to the end of the 
T wave
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Standard deviation
SD
Stable disease
SI
Système international
SOC
System organ class
TEAE
Treatment-emergent adverse event
TLG
Tables, listings, and graphs
TNM
Tumor-node-metastasis
ULN
Upper limit of normal


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3
INTRODUCTION
The Eisai Protocol E7080-A001-111 is a multicenter, open-label Phase 1b/2 trial of lenvatinib 
(E7080) plus pembrolizumab in subjects with selected solid tumors. This statistical analysis 
plan (SAP) describes the procedures and the statistical methods that will be used to analyze 
and report results for the Phase 1b/2 of Eisai Protocol E7080-A001-111 except those for 
pharmacokinetic (PK), pharmacodynamics (PD) and biomarkers. This SAP is based on the 
clinical study protocol amendment 8 (dated 24 Aug 2020).
3.1
Study Objectives
3.1.1
Primary Objectives
The primary objectives are
•
Phase 1b – Determination and confirmation of the maximum tolerated dose (MTD):
To determine and confirm the MTD for lenvatinib in combination with 200 mg 
(intravenous [IV], every 3 weeks [Q3W]) pembrolizumab in subjects with selected solid 
tumors.
•
Phase 2 – Expansion in selected tumor types (Expansion):
To evaluate the objective response rate as of Week 24 (ORR(Week 24): complete response + 
partial   response [CR(Week 24) + PR(Week 24)]) of lenvatinib in combination with 
pembrolizumab in each of the cohorts, using immune-related RECIST (irRECIST).
3.1.2
Secondary Objectives
The secondary objectives for both Phase 1b and 2 are to assess:
•
The tolerability and safety profile of lenvatinib in combination with pembrolizumab
•
ORR by irRECIST of lenvatinib in combination with pembrolizumab in subjects with 
solid tumors
•
Progression-free survival (PFS) by irRECIST
•
Overall survival (OS)
•
Duration of response (DOR) by irRECIST
•
Disease control rate (DCR: CR + PR + stable disease [SD]) by irRECIST
•
Durable stable disease rate (durable SD [SD ≥23 weeks]) by irRECIST


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•
Clinical benefit rate (CBR: CR, PR + durable SD) by irRECIST
•
The Pharmacokinetic (PK) profile of lenvatinib during combination treatment.
3.1.3
Exploratory Objectives
Exploratory objectives are:
•
To explore tumor response (eg, PR, CR, SD, PD) based on modified RECIST 1.1 
assessments
•
To explore tumor response in subjects with endometrial carcinoma and renal cell 
carcinoma based on independent imaging review (IIR) using irRECIST, modified 
RECIST 1.1 and RECIST 1.1.

To investigate the relationship between candidate efficacy biomarkers and anti-tumor 
activity of lenvatinib in combination with pembrolizumab:
a.
To evaluate the relationship between PD-L1 (Programmed Death-Ligand 1) expression 
levels and other relevant biomarkers (eg, tumor infiltrating lymphocytes, T-cell 
repertoire, ribonucleic acid [RNA] signature profiles) in tumor samples and anti-tumor 
activity of lenvatinib in combination with pembrolizumab.
b. To evaluate differences in tumor tissue characteristics in biopsies taken post treatment 
with lenvatinib in combination with pembrolizumab versus baseline
3.2
Overall Study Design and Plan
This is a multicenter, open-label Phase 1b/2 trial of lenvatinib (E7080) plus pembrolizumab in 
subjects with selected solid tumors.
Phase 1b - MTD: This phase will determine and confirm the MTD of lenvatinib in 
combination with pembrolizumab. Ten to 30 subjects will be enrolled in Phase 1b. Subjects in 
Phase 1b will have the following tumors: non-small cell lung cancer, renal cell carcinoma,
endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, 
or melanoma. The dose of pembrolizumab 200 mg every 3 weeks IV will not change during 
the MTD phase, while the second study drug lenvatinib will start at 24 mg and then be reduced, 
if necessary, to either 20 mg or 14 mg. 
For determination of MTD, only dose limiting toxicities (DLTs) during the first cycle of 


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treatment will be assessed.  If 0 of 3 subjects in a given dose level cohort experiences a DLT, 
then 7 more subjects will be enrolled into that dose level to confirm the MTD.  If 1 of 3 subjects 
has a DLT, then 3 more subjects will be enrolled into that dose level for a total of 6 subjects.  
If only 1 of these 6 subjects has a DLT, then 4 more subjects will be enrolled into that dose 
level to confirm the MTD. If 2 or more of these 6 subjects at a dose level experience a DLT, 
then, following consultation with the principal investigator(s) the study will proceed with 
enrollment in the next defined lower dose, with dose reduction of lenvatinib to 20 or 14 mg 
once a day (QD), respectively, in combination with 200 mg pembrolizumab Q3W.
The MTD will be confirmed if no more than 3 of 10 subjects experience DLTs at a dose level 
during the first 3 weeks (Cycle 1) of treatment.   If the MTD is not confirmed at a dose level, 
then enrollment will proceed to the next lower dose level. The sponsor and investigators will 
review all subjects’ safety and clinical data to jointly determine the recommended Phase 2 dose 
(RP2D) of the combination of lenvatinib with pembrolizumab. If 2 or more subjects have a 
DLT in Dose Level 3, enrollment in the study will stop.
Phase 2 - Expansion: After the MTD is confirmed, and depending on the safety and efficacy 
observed, 6 cohorts will be enrolled.  Each of these cohorts will enroll subjects with only 1 
type of tumor (ie, non-small cell lung cancer, predominantly clear cell renal cell carcinoma, 
endometrial carcinoma, urothelial carcinoma, melanoma (excluding uveal melanoma), or 
squamous cell carcinoma of the head and neck).  Lenvatinib in combination with 
pembrolizumab will be administered at the RP2D.  The intent is to enroll 20 subjects in each 
of the 6 cohorts, with possible expansion of enrollment in the endometrial and renal cell 
carcinoma cohorts.  For all 6 cohorts, data from the first 10 subjects in each cohort will be 
reviewed by the sponsor and investigators.  At least 3 subjects must show responses in order 
to determine continued enrollment to 20 evaluable subjects.
The endometrial carcinoma and renal cell carcinoma cohorts will be further expanded to 
approximately 120 evaluable subjects. The decision to expand enrollment will be based on the 
efficacy results of 2 interim analyses. The details of the cohort expansions are provided in
Section 3.


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The study will be conducted in 3 phases: a Pretreatment Phase, a Treatment Phase, and an 
Extension Phase.
Pretreatment Phase: This phase will last no longer than 28 days and includes: a Screening 
Period, to obtain informed consent and establish protocol eligibility, and a Baseline Period, to 
confirm protocol eligibility prior to treatment.
Treatment Phase: This phase will begin with the administration of the first dose of study drug 
in Cycle 1 and will continue in 21-day (3-week) cycles.  The Treatment Phase consists of 1 
treatment period as described below.
Treatment Period in Phase 1b: The Treatment Period for each subject ends after completing 
Cycle 1 of treatment or they discontinue early.  Those subjects who discontinue study treatment 
in Cycle 1 transition to the Off Treatment (Off-Tx) Visit of the Follow-up Period of the 
Extension Phase.  Those who complete Cycle 1 transition to the Treatment Period of the 
Extension Phase.
Treatment Period in Phase 2: The Treatment Period for each subject ends after completing 8 
cycles of treatment unless the subject discontinues early.  Those who discontinue study 
treatment before completing 8 cycles transition to the Off-Tx Visit of the Follow-up Period of 
the Extension Phase. Those that complete 8 cycles transition to the Treatment Period of the 
Extension Phase.
Extension Phase: The Extension Phase consists of a treatment period and a follow-up period.
Treatment Period (Extension Phase):  Subjects still receiving study treatment at the end of the 
Treatment Phase will continue to receive the same treatment.  Those subjects that discontinue 
study treatment transition to the Off-Tx Visit of the Follow-up Period of the Extension Phase.  
Note that all AEs must be captured for 30 days after last dose of study treatment.
Follow-up Period (Extension Phase): The Follow-up Period consists of the Off-Tx Visit and 
the Follow-up Visits. The Off-Tx Visit will occur within 30 days following the last dose of 
study treatment.  It applies to the Phase 1b subjects that discontinued study treatment early, 


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before completing Cycle 1, and to the Phase 2 subjects who discontinued study treatment early, 
before completing 8 cycles.  Following the completion of the Off-Tx Visit, subjects will 
transition to the Follow-up Visits of the Extension Phase. The Follow-up Visits continue as 
long as the study subject is alive unless the subject withdraws consent or until the sponsor 
terminates the study.  Subjects will be followed every 12 weeks (±1 week) for survival and 
subsequent anticancer treatments. The sponsor may decide to terminate survival follow-up anytime 
during the Extension Phase or when all subjects have discontinued study treatment.
Study Duration
Study duration for each subject is estimated to be:
•
Pretreatment Phase: 4 weeks
•
Treatment Phase:
a.
Phase 1b: 3 weeks (1 cycle)
b. Phase 2: 24 weeks (8 cycles)
•
Phase 1b and 2 Extension Phase: Subjects will continue to receive study treatment until 
disease progression, development of unacceptable toxicity, withdrawal of consent, or 
sponsor termination of the study.
4
DETERMINATION OF SAMPLE SIZE
Phase 1b – Determination of the Maximum Tolerated Dose
The total number of subjects required for the Phase 1b portion of this study will depend upon 
the toxicities observed as the study progresses. A sample size of approximately 10 to 30
subjects in Phase 1b will be enrolled to assess MTD.  This is not based on statistical power 
considerations.
Phase 2 – Expansion in Selected Tumor Types
A sample size of 10 evaluable subjects will be enrolled per cohort, with the possibility of 
expansion to 20 evaluable subjects per cohort, depending on the evaluation by the sponsor and 
investigators of the efficacy and safety results observed with the initial 10 evaluable subjects 
in each cohort. For a reference of the precision of ORR estimates in all cohorts except the 
endometrial carcinoma and the renal cell carcinoma cohorts, the associated 2-sided 95% CIs 
for the ORR of 10% to 90% for both 10 subjects and 20 subjects, per cohort are provided in 


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Table 1.
2-sided 95% Confidence Interval for the ORR of 10% to 90% (10 subjects and 20 
subjects).
Table 1.
2-sided 95% Confidence Interval for the ORR of 10% to 90% (10 subjects 
and 20 subjects)
ORR (N=10)
95% CI
10%
(0.003, 0.445)
20%
(0.025, 0.556)
30%
(0.067, 0.653)
40%
(0.122, 0.738)
50%
(0.187, 0.813)
60%
(0.262, 0.878)
70%
(0.348, 0.933)
80%
(0.444, 0.975)
90%
(0.555, 0.998)
ORR (N=20)
95% CI
10%
(0.012, 0.317)
20%
(0.057, 0.437)
30%
(0.119, 0.543)
40%
(0.191, 0.639)
50%
(0.272, 0.728)
60%
(0.361, 0.809)
70%
(0.457, 0.881)
80%
(0.563, 0.943)
90%
(0.683, 0.988)
CI = confidence interval, ORR = objective response rate.
The endometrial carcinoma cohort may be further expanded to approximately 120 evaluable
subjects.  The decision to expand enrollment will be based on the results of 2 interim analyses 
which will spend =0.012 and  = 0.024 at the first and second interim analysis, respectively.  
Based on an assumption of H0: 16% ORR and H1: 34% ORR, at 2-sided α = 0.02, this design 
will give 97% statistical power with 120 subjects.  At the first interim analysis (N = 21), if 
there are more than 3 responses, then approximately 40 additional subjects will be enrolled.  
At the second interim analysis (N = 60), if there are more than 12 responses, approximately 60 


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additional subjects will be enrolled.  If there are 12 or fewer responses, the sponsor may decide 
whether to expand enrollment based on clinical outcome, eg, ORR and DOR. If the expansion 
beyond 60 subjects does not happen, this design for the endometrial carcinoma cohort has 
approximately 86% power at 2-sided = 0.02. The boundaries for the decision to expand 
enrollment in the endometrial cohort are presented in Table 2.
Table 2.
Boundaries for the Decision to Expand Enrollment in the Endometrial 
Carcinoma Cohort
Analysis Number
Cumulative β 
Spent
Objective Response Rate
P-value
Interim Analysis 1 (N=21)
0.012
0.167
0.93
Interim Analysis 2 (N=60)
0.024
0.204
0.357
Final Analysis (N=120)
0.03
0.238
0.02
As of Amendment 6, the renal cell carcinoma cohort may be further expanded to approximately 
120 evaluable subjects. The decision to expand enrollment will be based on the results of 2 
interim analyses.  The first interim analysis will take place when 22 subjects (11 treatment 
naïve and 11 previously treated without an anti-PD-1/PD-L1 mAb) have sufficient follow-up 
to be evaluated for response.  At the first interim analysis (N = 22), if there are more than 
5 responses, then approximately 45 additional subjects will be enrolled.  It is anticipated that 
the additional 45 subjects will consist of approximately 12 treatment naïve subjects enrolled 
under Amendment 05 and approximately 33 previously treated subjects who have received 1 
or 2 prior therapies and have progressed on treatment with an anti-PD-1/PD-L1 mAb.  The 
second interim analysis will include these 45 additional subjects and the 11 treatment naïve 
subjects included in the first interim analysis and will take place when these 56 subjects have 
sufficient follow-up to be evaluated for response.  Table 3 shows the ORR estimates that are 
close to the minimum anticipated ORR of about 25% in subjects who had previously failed an 
anti-PD-1/PD-L1 treatment and about 60% in treatment naïve subjects, and the corresponding 
95% CIs in the respective anticipated 33 and 23 subjects for the second interim analysis.  At 
the second interim analysis, whether the previously treated renal cell carcinoma subset will be 
further expanded will be decided based on clinical review of both efficacy and safety data.


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Table 3.
Estimate and 2-sided 95% Confidence Interval of the ORR (RCC 
Subjects for the Second Interim Analysis)
33 subjects who had previously failed an anti-PD-1/PD-L1 therapy
Number of responses
Observed ORR
95% CI
7
21.2%
(0.090, 0.389)
8
24.2%
(0.111, 0.423)
9
27.3%
(0.133, 0.455)
10
30.3%
(0.156, 0.487)
11
33.3%
(0.180, 0.518)
12
36.4%
(0.204, 0.549)
23 treatment naïve subjects 
Number of responses
Observed ORR
95% CI
13
56.5%
(0.345, 0.768)
14
60.9%
(0.385, 0.803) 
15
65.2%
(0.427, 0.836)
16
69.6%
(0.471, 0.868)
17
73.9%
(0.516, 0.898)
CI = confidence interval, ORR = objective response rate.
5
STATISTICAL METHODS
All descriptive statistics for continuous variables will be reported using n, mean, standard 
deviation (SD), median, 25th percentile (Q1), 75th percentile (Q3), minimum and maximum. 
Categorical variables will be summarized as number (percentage) of subjects. All data will 
focus on the following 4 parts.  Part 1 will focus on Phase 1b including some Phase 2 data. Part 
2-4 will specifically focus on the solid tumor cohorts for their safety and efficacy.  
Phase 1b/2: Selected outputs (e.g., disposition, demographic and baseline and disease 
characteristics, study drug exposure, DLT, and adverse events) will be provided for phase 1b 
subjects. The overall summary of the corresponding Phase 2 data may be included for the 
presentation. 
EC cohort: primarily the data will be summarized by MSI/MMR status (Non-MSI-H/pMMR, 
MSI-H/dMMR, Not Available) and for overall. Efficacy results will be summarized by PD-L1 


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status and by the number of previous anticancer regimens. The Phase 1b and Phase 2 data will 
be combined for the analyses. RCC cohort: Efficacy subgroup analyses may be presented by 
the number of previous anticancer regimens, by PD-L1 status, and by subjects who were 
previously treated with/without an anti-PD-1/PD-L1 therapy. The Phase 1b and Phase 2 data 
will be combined for the analyses, as appropriate.
Four other cohorts: each cohort will be summarized separately. The Phase 1b and Phase 2 data 
will be combined for the analyses, as appropriate.
5.1
Study Endpoints
5.1.1
Primary Endpoints
Primary Efficacy Endpoint for Phase 1b:
The primary objective of Phase 1b is to determine the DLTs, MTD, and to establish the RP2D.    
Primary Efficacy Endpoint for Phase 2:
The primary objective of Phase 2 is to evaluate ORR(Week 24) in each of the cohorts using 
irRECIST. ORR(Week 24) is defined as the proportion of subjects who have the best overall 
response (BOR) of CR(Week24) or PR(Week 24) as of  the Week 24 tumor assessment time point.
Subjects who did not have a tumor response assessment for any reason will be considered non-
responders and will be included in the denominator when calculating the response rate.
5.1.2
Secondary Endpoint(s)
The secondary efficacy endpoints will be ORR, PFS, OS, DCR, CBR, DOR and durable SD
by irRECIST (Appendix 13.1) as appropriate. The secondary efficacy endpoints are defined as 
follows.

ORR is defined as the proportion of subjects who have BOR of partial or complete 
response (PR + CR) at the time of data cut-off.  Subjects who do not have a tumor response 
assessment for any reason will be considered non-responders and will be included in the 
denominator when calculating the response rate.

PFS is defined as the time from the first dose date to the date of the first documentation of 
disease progression or death (whichever occurs first) using irRECIST, see Appendix 13.1. 
If a subject did not experience a disease progression or death, then the subject will be 
censored at the date of the last available tumor assessment.


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
OS is measured from the start date of the treatment period until date of death from any 
cause. Subjects who are lost to follow-up and the subjects who are alive at the date of data 
cutoff will be censored at the date the subject was last known alive.

DCR is defined as the proportion of subjects who have BOR of CR or PR or SD (minimum 
duration from C1D1 to SD ≥5 weeks).

CBR is defined as the proportion of subjects who have BOR of CR or PR or durable SD 
(duration of SD ≥23 weeks).

DOR is defined as the time from the date of the first documentation of the confirmed CR 
or PR (whichever occurs first) to the date of the disease progression objectively 
documented or death (whichever occurs first). If a subject had no record of disease 
progression or did not die before the data cut-off date , then the subject will be censored at 
the last available tumor assessment.

Durable SD rate is defined as the proportion of subjects whose BOR is SD and the 
duration of SD is ≥23weeks.
The safety endpoints include treatment-emergent adverse events (TEAEs), clinical laboratory 
parameters, vital signs, 12-lead ECGs, and echocardiogram/MUGA results including LVEF.
Determination of the plasma PK profile of lenvatinib while subjects are receiving combination 
therapy is also a secondary endpoint.
5.1.3
Exploratory Endpoints
The exploratory endpoints include:

Tumor response endpoints based on modified RECIST 1.1 assessments

Tumor response endpoints for the subjects in the endometrial and renal cell carcinoma 
analysis sets based on IIR assessments using both irRECIST, modified RECIST 1.1 and 
RECIST 1.1.

To identify and explore blood and tumor biomarkers which correlate with clinical 
endpoints of this study including safety and efficacy.


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5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The following analysis sets will be defined:
Safety Analysis Set will include all subjects who received any amount of study drug.  This 
will be the analysis set for all safety evaluations.
Full Analysis Set (Intent-to-Treat [ITT] Analysis Set) will include all subjects who entered 
the study treatment period. Efficacy analyses will primarily be based on the Full Analysis Set.  
Efficacy analaysis will use FAS and the specific cohort analysis set for EC, RCC and other 
cohorts.     
Endometrial Carcinoma Analysis Set will include all endometrial carcinoma subjects from
Phase 1b and Phase 2.    
Renal Cell Carcinoma Analysis Set will include all renal cell carcinoma subjects from Phase 
1b and Phase 2.
Non-Small Cell Lung Cancer Analysis Set will include all non-small cell lung cancer 
subjects from Phase 1b and Phase 2.
Melanoma Analysis Set will include all melanoma subjects from Phase 1b and Phase 2.
Pharmacokinetic (PK) Analysis Set will include all subjects who have received at least one 
dose of lenvatinib and have evaluable lenvatinib concentration data.
Pharmacodynamic (PD) Analysis Set will include all subjects who have received at least 1 
dose of study drug (lenvatinib or pembrolizumab) and have evaluable pharmacodynamic data.
MTD Analysis Set will include all subjects who have completed cycle 1 treatment of Phase 
1b or discontinued early due to DLT. This will be the analysis set to determine MTD.
5.2.2
Subject Disposition
The number and percent of enrolled and treated subjects who were on treatment, and those 
who discontinued study treatment at the time of the data cut-off will be summarized. The 
subjects who discontinued study treatment will be tabulated according to the primary reason 
for discontinuation. The end of study status (e.g., alive, death, withdrew consent, or lost to 
follow-up) at the data cutoff will also be summarized using the data from the survival follow-
up eCRF.


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5.2.3
Protocol Deviations
All protocol deviations will be determined prior to database lock and will be agreed upon by a 
review of individual subject data.  This review will be undertaken in collaboration between the 
Study Director, the Study Statistician, the Study Data Manager and the Study Clinical 
Operations Manager.
5.2.4
Demographic and Other Baseline Characteristics
The demographics and baseline characteristics, including disease history and prior therapy, 
will be summarized using descriptive statistics.

Demographic and other baseline characteristics will be summarized using the Full Analysis 
Set.  For continuous demographic/baseline variables including age (year), height (cm), 
weight (kg) and BMI (body mass index) (kg/m2), results will be summarized and presented 
as n, mean, standard deviation, median, 25% percentile (Q1), 75% percentile (Q3),  
minimum and maximum values.  For categorical variables, the number and percentage of 
subjects will be used.  Categorical variables include age group (<65 years, >=65 years), 
gender, race (White, Black or African American, Japanese, Chinese, Other Asian, 
American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, and Other), 
ethnicity (Hispanic or Latino, not Hispanic or Latino), ECOG performance status, and 
NYHA cardiac disease classification.
Previous anticancer therapies/medications will be summarized as follows:

Number of prior regimen,

Duration of last therapy,

Best response of last anti-cancer therapy (complete response (CR), partial response (PR), 
stable disease (SD), progressive disease (PD), not evaluable (NE), not applicable (NA), 
unknown),

Time from end of last therapy to first dose,

Type of last prior therapy (adjuvant, neoadjuvant, metastatic, locally advanced, and 
unknown),

Prior surgical procedure (yes, no),


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
Time from last prior surgical procedure to first dose,

Subjects with any prior radiotherapy,

Radiotherapy site (lymph node [neck/thoracic/abdominal and pelvic/other], bone 
[skull/spine/thorax/pelvis/extremities], brain, visceral [colorectal mass, lung mass, liver 
mass, chest, abdomen/pelvis], skin [trunk, extremity, head and neck], musculoskeletal [soft 
tissue-trunk, extremity, head and neck], miscellaneous),

Tumor lesion at the site progressed since radiotherapy (yes, no, not evaluated),

Time from last radiotherapy to the first dose.
Other baseline and disease characteristics include:

Programmed Cell Death Protein – Ligand 1 (PD-L1) status.
For subjects with both screening and baseline PD-L1 assessments, PD-L1 Status (Pre-
treatment) is based on the most recent biopsy (baseline) assessment. PD-L1  positive is
determined using a provisional cutoff by IHC per an investigational version of the PD-L1 
IHC 22C3 pharmDx (Agilent, Carpinteria, CA, USA).

FIGO (Fédération Internationale de Gynécologie Obstétrique) grade for endometrial 
carcinoma subjects.

Histologic subtype 

Microsatellite instability (MSI) and/or DNA Mismatch Repair (MMR) will be assessed 
locally and/or centrally for endometrial carcinoma subjects. Overall MSI/MMR Status will 
be determined by taking the central assessment first if both central and local assessments 
were available, then taking MMR result if both MMR and MSI assessments were available.

Karnofsky performance status (KPS) will be summarized for the renal cell carcinoma 
subjects.
Disease history and characteristics at study entry will include:

Time since solid tumor diagnosis to date of the first dose (months),

Tumor type (Non-small cell lung cancer, Renal cell carcinoma, Endometrial cancer, 
Urothelial cancer, Squamous cell carcinoma of the head and neck, Melanoma),


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
Age at diagnosis (in years) summarized both as a continuous and categorical variable (<65, 
>=65),

Pathological Tumor-node-metastasis (TNM) staging at diagnosis,

Target lesions (lymph node [yes/no], non-lymph node [yes/no], and non-target lesions 
[yes/no] based on the measurable disease criteria at study entry.
•
The known mutation status including EGFR, KRAS, NRAS, BRAF, ALK translocation, 
RET translocation, ROS1 translocation, c-MET, IDH-1, IDH-2, Ki-67, P53, PIK3CA and 
others.
A summary table and a subject data listing of medical history will be provided, including 
system organ class and preferred term; current medical condition; date of diagnosis, surgical 
procedure, or onset of symptoms; and end date/on-going.
5.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded on the CRF will be coded using the World 
Health Organization (WHO, Geneva, Switzerland) Drug Dictionary using the March 2016
version or later. The number (percent) of subjects who have taken prior and concomitant 
medications will be summarized on the Full Analysis Set, by Anatomical Therapeutic 
Chemical (ATC) Classification and WHO drug preferred term. Prior medications will be 
defined as medications that stopped prior to the first dose of study drug. Concomitant 
medications will be defined as medications that (1) have started before the first dose of study 
drug and are continuing at the time of the first dose of study drug, or (2) have started on or 
after the date of the first dose of study drug up to 30 days following the last dose of study drug. 
A medication that cannot be determined as prior/concomitant/post-treatment due to 
missing/incomplete dates will be regarded as a concomitant medication. The summary of 
concomitant, 
including
anti-hypertensive, 
anti-diarrheal
and 
corticosteroid
medications/therapies will be provided. 
Prior anti-cancer therapies including anti-cancer medications, anti-cancer procedures and 
radiotherapy will be summarized and listed. Data listings will be provided for all prior and 
concomitant medications.


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5.3
Data Analysis General Considerations
5.3.1
Pooling of Centers 
Subjects from all centers will be pooled for all analyses in Phase 1b and Phase 2.  Center will 
not be considered as a factor in the analysis.
5.3.2
Adjustments for Covariates
Not applicable. 
5.3.3
Multiple Comparisons/Multiplicity
Not applicable. 
5.3.4Handling of Missing Data, Drop-outs, and Outliers
For incomplete dates involving efficacy and safety data such as adverse events, concomitant 
medications,
laboratory 
values, 
vital 
signs, 
electrocardiograms 
(ECGs)
and 
echocardiogram/MUGA data, a conservative imputation will be used for calculation. The
imputation rules will be specified in study analysis dataset specification with more details. For 
endpoints which determine the percentage of responders, patients with unknown response will 
be treated as non-responders.
5.4
Efficacy Analyses
Tumor response will be assessed by both immune-related RECIST (irRECIST) and modified 
version of RECIST 1.1 criteria (mRECIST 1.1) per investigator assessment, and by irRECIST, 
mRECIST 1.1 and RECIST 1.1 per independent imaging review. All efficacy analyses will be 
performed on the Full Analysis Set for the specific cohort analysis set for EC, RCC and other 
cohorts. Tabular summary of key features of the efficacy analyses is described in Appendix 
12.5 (Summary of Efficacy Analyses). Tumor assessments and overall response to the 
treatment according to irRECIST are presented in Appendix 13.1.
The best overall response (BOR) is determined once all the data for the subject is known. For 
this study, a confirmation of complete responses or partial responses is required for both 
irRECIST and modified RECIST 1.1; and following irRECIST, a confirmation of progression 
due to a tumor burden is required unless it is per investigator’s discretion if the subject was 


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clinically unstable. The confirmation assessments should be made ≥4 weeks later. The BOR is 
determined by sequentially checking two adjacent assessments with ≥4 weeks apart (and with 
a few special cases). As an example if a subject had a stable disease at the timepoint 1, a partial 
response at the timepoint 2, a complete response at the timepoint 3, and another complete 
response at the  timepoint 4, then the BOR for this subject is complete response, which was 
confirmed at the timepoint 4. 
To program the BOR per irRECIST: (1)the tumor response data collected via both irRECIST 
and  mRECIST 1.1 CRFs will be used; (2) any further response assessments after the second
PD (confirmed PD per irRECIST) identified under irRECIST should not be considered for the 
BOR determination, however they should be presented in the data listings; (3) all tumor 
assessments as long as the subjects did not start a new anti-cancer therapy should be 
considered; (4) if there are more than 1 consecutive missing tumor assessments, all assessments
afterward should not be considered for the determination of BOR (also see Section 5.4.3 for 
PFS).  The BOR per irRECIST is defined as follows. Table 4 lists general rules in the derivation 
of BOR with two consecutive tumor response results (with a few special cases, see Table 4).

CR
To achieve BOR of CR, CR must be observed at two consecutive tumor assessment visits with 
at least 4 weeks apart before a PD or death (whichever occurs first). If complete responses at 
two consecutive tumor assessment visits were with less than 4 weeks, the confirmation of CR 
at the next assessment visit is required. 
The documented start date of CR as the BOR is defined as the date of the initial CR that was 
confirmed at the next consecutive visit (≥4weeks after the initial CR response).

PR
When BOR of CR is not achieved, BOR of PR can be achieved when the initial PR was
confirmed by a PR or CR at the next consecutive visit (≥4weeks after the initial PR response). 
If the two PRs (or PR and then CR) happened at two consecutive tumor assessment visits 
within 4 weeks, the additional confirmation of the PR is needed. 


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The documented start date of PR as the BOR is defined as the date of the initial PR that was 
confirmed at the next consecutive visit (≥4weeks after the initial PR response).

PD
Following irRECIST, subject may continue treatment at the investigator’s discretion after the 
initial PD due to pseudo-progression, if the subject is clinically stable. If a repeating imaging 
assessment at ≥ 4 weeks after the initial PD was not done, this initial PD response will be 
considered as a real PD. However, if there was subsequent tumor assessment (≥ 4 weeks) that 
showed a CR, PR or SD, regularly scheduled imaging assessments should be continued. The 
BOR will be determined based on all tumor assessments. When a PD is identified and 
confirmed under irRECIST, any further response assessments after the first PD under 
irRECIST should not be considered to determine BOR and PFS (i.e. the assessments up to the 
first PD under irRECIST will be considered for BOR and PFS), however these further 
assessments should be presented in the data listings. 
The documented start date of PD is defined as the date of the initial PD that was confirmed at 
the next consecutive visit (i.e. a consecutive PD was identified ≥4weeks after the initial PD
response), or the date of the initial PD if a repeating imaging assessment was not done, or the 
date of the first PD identified during irRECIST evaluations. 

UNK (Unknown)
If the subject did not have a baseline tumor assessment, then BOR = UNK (Unknown).

NE (Not Evaluable)
If the subject did not have a post-baseline tumor assessment, or the subject only had one post-
baseline tumor assessment of an early SD (duration < 5 weeks) as the overall response, or post-
baseline tumor assessments are not evaluable (i.e. recorded as ‘NE’ as overall responses via 
the CRF, maybe due to missing anatomy or poor image quality), then BOR = NE.

SD
If the BOR is not a confirmed CR/PR, NE, Unknown or PD, then the BOR is stable disease 
(SD). 
Table 4
General Rules Deriving BOR per irRECIST


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Timepoint 1
Overall 
Response
Timepoint 2
(≥ 4 weeks since 
Timepoint 1)
Overall Response
BOR
CR
CR
CR
CR
PR
SD if duration of SD ≥ 5 weeks, otherwise PD
CR
SD
SD if duration of SD ≥ 5 weeks, otherwise PD
CR
PD
SD if duration of SD ≥ 5 weeks, otherwise PD
CR
NE
SD if duration of SD ≥ 5 weeks, otherwise NE.  In 
the special case, if CR is at the next timepoint after 
NE, BOR will be CR.
CR a
SD if duration of SD ≥ 5 weeks, otherwise NE
PR
CR b
PR
PR
PR
PR
PR
SD
SD.  In the special case if PR or CR is at the next 
timepoint after SD, BOR will be PR.
PR
PD
SD if duration of SD ≥ 5 weeks, otherwise PD
PR
NE
SD if duration of SD ≥ 5 weeks, otherwise NE. In 
the special case, if PR or CR is at the next 
timepoint after NE, BOR will be PR.
PR a
SD if duration of SD ≥ 5 weeks, otherwise NE
SD
CR b
SD
SD
PR b
SD
SD
SD
SD
SD
PD
SD if duration of SD ≥ 5 weeks, otherwise PD
SD
NE
SD if duration of SD ≥ 5 weeks, otherwise NE
SD a
SD if duration of SD ≥ 5 weeks, otherwise NE
PD
CR b
SD if duration of SD ≥ 5 weeks, otherwise PD
PD
PR b
SD if duration of SD ≥ 5 weeks, otherwise PD
PD
SD 
SD if duration of SD ≥ 5 weeks, otherwise PD
PD
PD 
PD


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PD
NE
PD
PD a
PD
NE
NE
NE
UNK
UNK
UNK (Unknown) if there was no a baseline 
tumor assessment.
a If this was the only tumor response assessment (e.g. study treatment was discontinued). b The subject should 
be followed for ≥ 4 weeks to confirm the CR/PR.
5.4.1
Primary Analysis for Phase 1b
The primary objective of Phase 1b is to determine the DLTs, MTD, and to establish the RP2D.
The endpoint DLTs in Phase 1b will be summarized based on the MTD Analysis Set.
5.4.2
Primary Efficacy Analysis for Phase 2
The primary efficacy endpoint in Phase 2 is objective response rate as of Week 24 (ORR(Week
24)) based on irRECIST . The primary efficacy analysis of ORR(Week 24) for each cohort may
be performed based on the Full Analysis Set when all subjects in that cohort have completed 
8 cycles of treatment, or discontinued early due to disease progression, unacceptable toxicity, 
consent withdrawn, or the study termination by the Sponsor. Estimated ORR(Week 24) and the 
exact 95% confidence intervals using the method of Clopper–Pearson will be presented.
5.4.3
Secondary Efficacy Analyses for Both Phase 1b and Phase 2
The following secondary efficacy analyses will be performed.
Objective Response Rate (ORR): The ORR is the proportion of patients achieving a best 
overall response of confirmed PR or CR at the time of data cutoff. Subjects who do not have a 
tumor response assessment for any reason will be considered non-responders and will be 
included in the denominator when calculating the response rate. The count and percentage for 
the ORR will be summarized. ORR and corresponding 95% CI based on exact binomial 
distribution will be estimated for each treatment cohort.
Progression-Free Survival (PFS): The PFS is defined as the time from the first study dose 
date to the date of first documentation of confirmed PD using irRECIST or death (whichever 
occurs first). If a subject has not experienced disease progression or death, then the subject’s 


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data will be censored at the date of the last adequate radiologic assessment. The PFS censoring
rules in this SAP and definition of progression date follow the principles of the Food and Drug 
Administration (FDA) “Guidance for Industry Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics (2007)”. Due to the use of pembrolizumab, all tumor assessments 
up to the first PD identified under irRCIST are considered as long as the subjects did not start 
a new anti-cancer therapy. The date of radiological assessment is based on the date of scans 
performed for a time point. The date will be based on the time point required CT/MRI scans 
unless there is a new lesion on the bone scan(s) or brain scan(s) performed to ensure CR or PR, 
or on brain scan(s) performed to ensure CR. Table 5 shows the censoring rules for the 
derivation of PFS.
Table 5
Censoring rules for the derivation of PFS.
No.
Situation
Date of Event (Progression/Death) or
Censoring
Outcome
1
No baseline tumor assessments
Date of first dose 
Censored
2
Progression documented between
scheduled visits
Date of first radiologic PD
assessment
Event
3
No progression
Date of last adequate radiologic 
assessment
Censored
4
New anticancer treatment started
Date of last adequate radiologic 
assessment prior to or on date of new 
anticancer treatment
Censored
5
Death before first PD assessment
Date of death
Event
6
Death between adequate
assessment visits*
Date of death
Event
7
Death or progression after more
than one missed visit/tumor
assessment**
Date of last adequate radiologic 
assessment before missed tumor 
assessments
Censored
CR = complete response, PD = progressive disease, PR = partial response, SD =stable disease,
* Adequate tumor assessment is radiologic assessment at regular interval as defined in the protocol.
** More than one missed visit/adequate tumor assessment is defined as having the duration between
the last adequate tumor assessment and death or PD being longer than 14 weeks - 1 day, which is 97
days ( = ((6+1) x 2 x 7) – 1) for subjects on the every 6 week tumor assessment schedule in the first 8 
cycles of treatment and 20 weeks - 1 day, which is 139 days ( = ((9+1) x 2 x 7) – 1) for subjects on the
every 9 week tumor assessment schedule after Cycle 8 in this study.
The priority of the censoring rules is as follows,
1. If the subject had PD or death, the following sequence will be applied:
•
If a subject did not have a baseline tumor assessment (No. 1), the subject will be censored on the


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date of first dose.
•
If the subject died within 97 days (14 weeks -1 day) following first dose and did not receive a
new anticancer treatment, it will be counted as PFS event at the date of death.
•
If a subject had new anticancer treatment before PD or death (No. 4), the subject will be censored
on the date of the last adequate tumor assessment prior to or on the date of new anticancer 
treatment. 
•
If a subject missed two or more tumor assessments before PD or death (No. 7), the subject
will be censored on the date of the last adequate tumor assessment before PD or death. Note
that if a subject is censored by both this criterion and the anticancer treatment criterion, the earliest
censoring date will be used.
•
Otherwise, if a subject had an event (No. 2, No. 5, or No. 6), the earliest event date will be used.
2. If a subject did not have PD or death, the censoring date will be the earliest censoring date if the
subject met multiple censoring criteria (No. 1, No. 3, No. 4, No. 7).
The distribution of PFS and time curve will be estimated using Kaplan–Meier method. Median 
time to PFS and 95% CI will be provided for each cohort.  Three-month, 6-month, 9-month, 
and 12-month PFS rate will be estimated using the Kaplan–Meier method and corresponding 
95% CIs will be provided.
Overall Survival (OS):  OS is measured from the start date of the treatment phase until date 
of death from any cause. All events of death will be included, regardless of whether the event 
occurred while the subject was still taking study drug, or after the subject discontinued study
drug. If a subject has no record of death, then the data will be censored at the date the subject 
was last known to be alive, or the data cutoff date, whichever is earlier (see Table 6 for 
censoring rules).  The distribution of OS and time curve will be estimated using Kaplan–Meier 
method.  Median survival time and the corresponding 95% CI, survival rates at 12, 18, and 24 
months, and corresponding 95% CIs will be estimated using Kaplan–Meier method for each
treatment cohort.
Table 6
Censoring Rules for Overall Survival Endpoint
Situation
Event Date or Censoring
Outcome
Death during study
Date of death
Death
Death after data cut-off
Date of data cut-off
Censored 
Subject still alive at data cut-off
Date of data cut-off
Censored 


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Situation
Event Date or Censoring
Outcome
Subject lost to follow-up before data cut-off
Date last known to be alive 
Censored 
Disease Control Rate (DCR): The DCR is the proportion of subjects who have BOR of CR 
or PR or SD (minimum duration from C1D1 to SD ≥5 weeks). The count and percentage with 
exact 95% CI for the DCR will be summarized.
Clinical Benefit Rate (CBR): The CBR is the proportion of subjects who have BOR of CR 
or PR or durable SD (duration of SD ≥23 weeks). The count and percentage with exact 95% 
CI for the CBR will be summarized.
Duration of Response (DOR): The DOR is defined as the time from the date of the first 
documentation of the confirmed CR or PR (whichever occurs first) to the date of the disease 
progression objectively documented or death (whichever occurs first). If a subject had no 
record of disease progression or did not die before the data cut-off date, then the subject will 
be censored at the last available tumor assessment. The distribution of DOR will be estimated 
using Kaplan–Meier Method. Median duration of response and 95% CI will be provided.
5.4.4
Exploratory Efficacy Analysis 
The efficacy tumor response endpoints (eg, PR, CR, SD and PD) will be explored based on
modified RECIST 1.1 and RECIST 1.1 assessments. Same as the irRECIST, (1) a confirmation 
of complete responses or partial responses is required; (2) all tumor assessments as long as the 
subjects did not start a new anti-cancer therapy should be considered; (3) if there are more than 
1 consecutive missing tumor assessments, all assessments afterward should not be considered 
for the determination of BOR (also see Section 5.4.3 for PFS). However, different from 
irRECIST, a pseudoprogression is considered as a PD per the modified RECIST 1.1 and 
RECIST 1.1. Therefore, following the modified RECIST 1.1 and RECIST 1.1, any further 
tumor response assessments after the initial PD are not considered to determine BOR. For 
programming, only the tumor response data collected via the CRF of the modified RECIST 
1.1 will be used. The general rules in the derivation of BOR with two consecutive tumor 
response results following the modified RECIST 1.1 and RECIST 1.1 are described in Table 


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7.
Table 7
General Rules Deriving BOR per modified RECIST 1.1 and RECIST 1.1
Timepoint 1
Overall 
Response
Timepoint 2
(≥ 4 weeks since 
Timepoint 1)
Overall 
Response
BOR
CR
CR
CR
CR 
PR
SD if duration of SD ≥ 5 weeks, otherwise PD
CR
SD
SD if duration of SD ≥ 5 weeks, otherwise PD
CR
PD
SD if duration of SD ≥ 5 weeks, otherwise PD
CR
NE
SD if duration of SD ≥ 5 weeks, otherwise NE. In the 
special case, if CR is after NE, BOR will be CR.
CR a
SD if duration of SD ≥ 5 weeks, otherwise NE
PR
CR b
PR
PR
PR
PR
PR
SD
SD. In the special case if PR or CR is after SD, BOR will 
be PR.
PR
PD
SD if duration of SD ≥ 5 weeks, otherwise PD
PR
NE
SD if duration of SD ≥ 5 weeks, otherwise NE. In the 
special case, if PR or CR is after NE, BOR will be PR.
PR a
SD if duration of SD ≥ 5 weeks, otherwise NE
SD
CR b
SD
SD
PR b
SD
SD
SD
SD
SD
PD
SD if duration of SD ≥ 5 weeks, otherwise PD
SD
NE
SD if duration of SD ≥ 5 weeks, otherwise NE
SD a
SD if duration of SD ≥ 5 weeks, otherwise NE
PD c
PD
NE
NE
NE


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UNK
UNK
UNK (Unknown) if there was no a baseline tumor 
assessment. 
a If this was the only tumor response assessment (e.g. study treatment was discontinued).
b The subjects should be followed for ≥ 4 weeks to confirm the CR/PR.
c There is no need to confirm this PD per the modified RECIST 1.1 and RECIST 1.1 (e.g. pseudo-progressions is 
considered as a PD).
5.4.5
Other Efficacy Analyses
No other efficacy analyses are planned for this study.
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic and Other 
Biomarker Analyses
5.5.1
Pharmacokinetic Analyses
To assess any drug–drug interaction between lenvatinib and pembrolizumab, the dose-
normalized PK profile for lenvatinib in combination with pembrolizumab from this study will be 
compared graphically to that from patients with different types of tumor from completed studies 
receiving lenvatinib monotherapy. PK analyses will be performed on Pharmacokinetic Analysis 
Set. Scatter plot, box plot and descriptive statistics including n, mean, SD, percent coefficient 
of variation (% CV), geometric mean, median, minimum and maximum will be used to 
summarize lenvatinib concentration data. All PK data, which include the complete 
bioanalytical results, time and date of blood draws and study drug administration, will be 
presented in subject-by-subject listings. 
5.5.2
Pharmacodynamic, Pharmacogenomic and Other Biomarker Analyses
The effect of lenvatinib-pembrolizumab combination therapy on soluble, tissue, genetic and/or 
imaging biomarkers will be summarized using descriptive statistics using the 
pharmacodynamic analysis set.  A separate analysis plan will be developed for the biomarker 
analyses, and results will be reported separately.
5.6
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, will be presented 
using descriptive statistics (e.g., n, mean, SD, median, Q1, Q3, minimum, maximum) for 
continuous variables; n (%) for categorical variables).  Safety variables include treatment-


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emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, 12-lead ECG 
results, and echocardiogram results including LVEF.  
5.6.1
Extent of Exposure
Summary will be provided for duration of treatment, total dose per subject, dose intensity, 
relative dose intensity (received dose as percentage of planned dose per subject. All parameters 
for extent of exposure will be computed separately for lenvatinib and pembrolizumab.
The end date for lenvatinib will be imputed to the analysis cut-off date if the subject is still on 
treatment at the time of the data cut-off, and the dose will be imputed with the last dose
recorded in the database for that subject. Duration of lenvatinib or pembrolizumab treatment
is calculated as date of last dose – date of first   dose + 1.  Overall duration of treatment is 
defined as the duration between the earliest first dose start date of either medication and the 
latest last dose end date of either medication. For lenvatinib, total dose per subject, dose 
intensity (mg/day/subject), and received dose as percentage of planned dose persubject 
(Calculated as cumulative total dose divided by (planned starting daily dose x treatment 
duration in days)) will be summarized.  Total (cumulative) dose per subject (mg) is defined as 
the sum of all doses actually taken by the subject. For pembrolizumab, dose Intensity (mg/IV 
administration) of pembrolizumab = Total dose received during the study/total number of IV 
administrations.
Number of subjects with dose reductions, dose interruptions, and time to first dose reduction 
will be summarized by counts and percent according to dose data. 
To determine dose reduction and dose interruption, the incorrect doses that were taken by 
mistake should not be considered. Dose reduction refers to the situation that a dose level was 
reduced from the previous dose level without going back. Dose reduction is only applicable to 
lenvatinib, but not for Pembrolizumab as Pembrolizumab dose is always 200mg if it is 
administered. As an example below, the subject had two dose reductions on Day 4 and Day 6.
                                                                               Study Day of     Study Day
          Subject                                Dose per                Start of         of End of
Obs    Identifier    Treatment        Administration      Treatment     Treatment 
---------------------------------------------------------------------------------------------   
  1    1001-10xx    LENVATINIB              20               1             2 


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  2    1001-10xx    LENVATINIB               0                3             3 
  3    1001-10xx    LENVATINIB              14               4             5
  4    1001-10xx    LENVATINIB               8                6             21 
  5    1001-10xx    LENVATINIB               8                22            50
Dose interruption for lenvatinib is defined as follow. The maximum days of dose interruptions 
is the duration of the longest interruption.
•
Only include the scenario that the before and after dose 0 (interruption period), the dose 
levels are the same. For example: 24 mg followed by 0 mg and followed by 24 mg; 20 
mg followed by 0 mg followed by 20 mg. 
•
If dose level reduces from previous dose level after dose interruption period (dose 0), it 
should be counted into dose reduction, but not dose interruption. For example, 24 mg 
followed by 0 mg followed by 20 mg, the period with 0 mg should not be counted into 
dose interruption. 
•
If after dose 0 mg, the subject discontinued from treatment permanently, it should be 
counted as a treatment discontinuation instead of a dose interruption. 
For Pembrolizumab, as long as a dose was administered for a cycle, then there is no an 
interruption for this cycle. 
Number of subjects with drug discontinuations due to AEs will be summarized by frequency 
counts and percentages. 
5.6.2
Dose Limiting Toxicity
Each subject in a dose level in Phase 1b is monitored every week by Eisai clinical team and 
the principal investigators or more frequently if necessary. DLTs are declared by both parties 
as well as the decisions to expand/continue or decrease the dose level cohort. The dose limiting 
toxicities will be presented.  
5.6.3
Deaths, Serious and Other Significant Adverse Events
The adverse event verbatim descriptions (investigator terms from the eCRF) will be classified 
into standardized medical terminology using the Medical Dictionary for Regulatory Activities 


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(MedDRA) version 19.0 or later. Adverse events will be coded to primary System Organ Class 
(SOC) and preferred term (PT) using MedDRA.
A treatment-emergent adverse event (TEAE) is defined as an adverse event that had an onset 
date, or a worsening in severity from baseline (pre-treatment), on or after the first dose of study 
drug up to the last visit, or 30 days following the last dose of study drug. In addition, if an AE 
reemerges during treatment, having been present at pretreatment (Baseline) but stopped before 
treatment, it is also counted as a TEAE. Due to the use of pembrolizumab, serious adverse 
events (SAEs) occurring up to 90 days after the last dose of study drug will be considered as 
treatment-emergent serious adverse events.  
Only those AEs that are treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.  Treatment-
emergent AEs (TEAEs) will be summarized.
The incidence of TEAEs will be reported as the number (percent) of subjects with TEAEs 
within SOC and PT. Subjects will be counted only once within a SOC and PT. If the subject 
experienced more than one TEAE within a specific SOC and PT, the subject will be counted 
with the worst grade for that AE. The number (percent) of subjects with TEAEs will also be 
summarized by highest Common Terminology Criteria for Adverse Events (CTCAE) grade. 
In summary, the following TEAE tables will be provided:

Overview of TEAEs.

TEAEs by SOC, PT, and CTCAE grade.

TEAEs with CTCAE grade >=3 

TEAE with outcome of death.

Treatment-related TEAEs by SOC, PT, and CTCAE grade

Treatment-related TEAEs with CTCAE grade >=3 

Treatment-related TEAEs with outcome of death
The following subject AE listings (regardless treatment emergent or not) will be provided:

All adverse events.


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A subject data listing of all deaths will be provided with the information of primary reasons of 
deaths, deaths within 30 days of last dose, deaths > 30 days of last dose, and treatment-related 
deaths.
The number (percent) of subjects with treatment-emergent serious adverse events will be 
summarized by MedDRA SOC and PT. A subject data listing of all SAEs will be provided. 
The number (percent) of subjects with TEAEs leading to discontinuation, dose reduction, or 
dose interruption from study treatment will be summarized by MedDRA SOC and PT. A 
subject data listing of all AEs leading to discontinuation, dose modification, or dose 
interruption from study treatment will be provided. In summary, the following TEAE tables 
will be provided:

SAEs 

Treatment related SAEs 

TEAEs leading to study drug dose interruption by SOC and PT.

TEAEs leading to study drug dose reduction by SOC and PT.

TEAEs leading to study drug discontinuation by SOC and PT.

Clinically significant TEAEs (CSAE) for lenvatinib, by PT and CTCAE grade (any 
grade vs ≥ 3).

TEAEs of special interest (AEOSI) for pembrolizumab, by PT and CTCAE grade (any 
grade vs ≥ 3).
The following subject AE listings (treatment emergent or not) will be provided:

All deaths for all enrolled subjects.

All serious adverse events (SAEs).

All fatal TEAE

All AEs leading to dose interruption

All AEs leading to dose reduction.

All AEs leading to study drug discontinuation.
5.6.4
Laboratory Values


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Laboratory values that are non-missing and reported as ‘below the detectable limit’ of an assay 
will be replaced by half the detectable limit in the summary tables. Laboratory results will be 
summarized using the Système international (SI) units. Laboratory test results will be assigned 
a low/normal/high (LNH) classification according to whether the value was below (L), within 
(N), or above (H) the laboratory parameter’s reference range. Abnormal laboratory values will 
be identified as those outside the normal range. The abnormal values will be indicated in data 
listings. Laboratory parameters will also be categorized according to CTCAE v4.03 grades, 
and shifts from baseline CTCAE grades to worst grades will be assessed.
For quantitative parameters, the actual value and the change from baseline to each post-
baseline visit, will be summarized by visit using descriptive statistics if needed. Urinalysis 
parameters (qualitative) will be listed.
Only laboratory parameters specified in the protocol will be summarized.  Other laboratory 
parameters collected for some individual subjects will be presented in listings.
5.6.5
Vital Signs
Vital sign values will be evaluated on an individual basis by subject. Descriptive statistics for 
vital signs parameters (diastolic and systolic blood pressure, resting HR, respiratory rate, body 
temperature, and weight) and changes from baseline will be presented.
5.6.6
Electrocardiograms
Electrocardiogram (ECG) assessments will be performed at screening and at Day 1 of each 
cycle. Descriptive statistics for electrocardiogram parameters (HR, PR, QRS, QT, QTcB, 
QTcF and RR) and changes from baseline will be presented by visit. ECG findings (categorized 
as normal; abnormal, not clinically significant; and abnormal, clinically significant) will be 
summarized using shift tables. A subject data listing will also be provided.
5.6.7
Other Safety Analyses
Left ventricular ejection fraction (LVEF) obtained on echocardiogram or MUGA scans will be 
summarized with descriptive statistics for baseline and post-baseline lowest value. Percent 
change of the post-baseline lowest value from baseline will be presented. A subject data listing 


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will be provided.  
5.7
Exploratory Analyses
The exploratory analyses as described in Section 5.5 (Pharmacokinetic, Pharmacodynamic, 
Pharmacogenomic and Other Biomarker Analyses) will be reported separately from the clinical 
study report.
6
INTERIM ANALYSES
The evaluation of efficacy and safety by the sponsor and investigators will occur on the initial 
10 evaluable subjects while enrollment is ongoing.  Based on the outcome of the evaluation 
the enrollment could be suspended before enrolling the planned 20 subjects in each cohort.  
The endometrial carcinoma cohort may be expanded to approximately 120 evaluable subjects.  
Two interim analyses will take place when 21 and 60 subjects have sufficient follow-up to be 
evaluated for response.  The decision to expand enrollment will be based on the results of the 
2 interim analyses, which will spend β= 0.012 and β= 0.024 at the first and second interim 
analyses, respectively.  Based on an assumption of H0: 16% ORR and H1: 34% ORR, at 2-
sided α = 0.02, this design will give 97% statistical power with 120 subjects.  At the first 
interim analysis (N = 21), if there are more than 3 responses, then approximately 40 additional 
subjects will be enrolled.  At the second interim analysis (N = 60), if there are more than 12 
responses, approximately 60 additional subjects will be enrolled.  If there are 12 or fewer 
responses, the sponsor may decide whether to expand enrollment based on clinical outcome, 
eg, ORR and DOR.  If the expansion beyond 60 subjects does not happen, this design for the 
endometrial carcinoma cohort has approximately 86% power at 2-sided α = 0.02.  
The renal cell carcinoma cohort may be further expanded to approximately 120 evaluable 
subjects. The decision to expand enrollment will be based on the results of 2 interim analyses. 
The first interim analysis will take place when 22 subjects (11 treatment naïve and 11 
previously treated without an anti-PD-1/PD-L1 therapy) have sufficient follow-up to be 
evaluated for response. At the first interim analysis (N = 22), if there are more than 5 responses, 
then approximately 45 additional subjects will be enrolled.  It is anticipated that the additional 


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45 subjects will consist of approximately 12 treatment naïve subjects enrolled under 
Amendment 05 and approximately 33 previously treated subjects who have received 1 or 2 
prior therapies and have progressed on treatment with an anti-PD-1/PD-L1 mAb.  The second 
interim analysis will include these 45 additional subjects and the 11 treatment naïve subjects 
included in the first interim analysis and will take place when these 56 subjects have sufficient 
follow-up to be evaluated for response.  At the second interim analysis, whether the previously 
treated renal cell carcinoma subset will be further expanded will be decided based on clinical 
review of both efficacy and safety data.
7
CHANGES IN THE PLANNED ANALYSES
Not applicable. 
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
Study Day 1
Study Day 1 is defined as the day of the first dose of study drug administered.
Baseline
Baseline is defined as a Day 1 pre-dose, the last observation before the start of drug, if the Day 
1 pre-dose is missing.
By-visit analyses
All by-visit analyses will be performed using assessments at corresponding scheduled visits 
recorded in the eCRF. For shift tables, all post-baseline assessments including those at 
scheduled and unscheduled visits will be used.
Incomplete dates
For incomplete dates involving efficacy and safety data, see Section 5.3.4 for data handlings.
Limit of Quantification (BLQ) in pharmacokinetics analyses


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When calculating the mean or median value for the concentrations at a given time point, the 
BLQ values will be assigned as zero. If the proportion of values reported as BLQ is more than 
50%, no summary statistics should be represented at that time point, and the value will be 
treated as missing in mean or median concentration profiles.
More specific details, if any, are given with the discussion of analyses for each endpoint.
Details on the way that BLQ values will be replaced will be described in a separate plan 
detailing the analyses.
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications will be provided in separate 
documents.
10 STATISTICAL SOFTWARE
Statistical programming and analyses will be performed using SAS® (SAS Institute, Inc., Cary, 
NC, USA), version 9 or higher, and/or other validated statistical software as required.
11 MOCK TABLES, LISTINGS AND GRAPHS (TLGS)
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail.
12 REFERENCES
1. Clopper, CJ and Pearson, ES. The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika. 1934;26:404–413.
2. Cox, DR. Regression Models and Life tables. J Roy Stat Soc B. 1972; 20:187-220.
3. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 2009 Jan; 
45 (2): 228-247.
4. FDA Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, 
May 
2007 
[internet; 
cited 
3 
March 
2011] 
Available 
from: 


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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm071590.pdf.
5. Kaplan, E. and Meier, P. Nonparametric Estimation from Incomplete Observations. J Am 
Stat Assoc. 1958;53:457-481.
6. Study Protocol Number: E7080-A001-111: A Multicenter, Open-Label Phase 1b/2 Trial of  
Lenvatinib (E7080) Plus Pembrolizumab in Subjects with Selected Solid Tumors (V1.0 –
22 April 2015).
7. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11
.pdf.


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13 APPENDICES
13.1
Immune-Related Response Evaluation Criteria In Solid Tumors 
(irRECIST)
Investigators should follow the guidelines provided here which are an adaptation of RECIST 
1.1 and immune-related response criteria (irRC). The following guide represents a summary 
of irRECIST and is meant to help investigators in providing more objective and reproducible 
immune therapy related tumor response assessments in solid tumors.
The key changes for irRECIST are:

In contrast to RECIST 1.1, irRECIST allows the site to select up to ten (10) target lesions 
at baseline, five (5) per organ, if clinically relevant via CT/MRI scans or by electronic 
calipers for skin lesions. The ability to continue treatment, if clinically stable, until repeat 
imaging scans ≥ 4 weeks later (in most cases at the next scanning time point 6 weeks later) 
to confirm Progressive Disease (PD)
irRECIST Lexicon
1. Baseline Assessments
Measurable 
(Target) lesions
Measurable lesions must be accurately measured in at least one 
dimension with a minimum size of:
10 mm in the longest diameter (LDi) by CT or MRI scan (or no 
less than double the slice thickness) for non-nodal lesions and 
≥15 mm in short axis (SDi) for nodal lesions
10 mm in LDi for clinical lesions (must be measured using 
electronic calipers)
Identify up to 10 lesions, not more than 5 from one organ system. 
Lymph nodes are considered one organ system
Likely to be reproducible across all time points
Representative of tumor burden
May include lesions in previously irradiated areas ONLY if there 
is demonstrated progression in that lesion after irradiation
Sum of diameters (SOD) of all target lesions including nodal and 
non-nodal are reported as baseline SOD which is used for 
assessing tumor response at follow-up time points
Bone lesions
Regardless of the imaging modality, blastic bone lesions will not be
selected as target lesions. Lytic or mixed lytic-blastic lesions with a 
measurable soft tissue component ≥10 mm can be selected as target 
lesions.


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Cystic and 
Necrotic 
Lesions as 
Target Lesions
Lesions that are partially cystic or necrotic can be selected as target 
lesions. The longest diameter of such a lesion will be added to the 
SOD of all target lesions at baseline. If other lesions with a 
nonliquid/nonnecrotic component are present, those should be 
preferred.
Lesions with 
Prior Local 
Treatment
During target lesion selection the radiologist will consider 
information on the anatomical sites of previous intervention (e.g. 
previous irradiation, RF-ablation, TACE, surgery, etc.). Lesions 
undergoing prior intervention will not be selected as target lesions 
unless there has been a demonstration of progression in the lesion.
Nonmeasurable 
(Non-Target) 
lesions
Non-target lesions will include:
Measurable lesions not selected as target lesions. There is no limit 
to the number of non-target lesions that can be recorded at 
baseline
Other types of lesions that are confidently felt to represent 
neoplastic tissue, but are difficult to measure in a reproducible 
manner. These include bone metastases, leptomeningeal 
metastases, malignant ascites, pleural or pericardial effusions, 
ascites, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, ill-defined abdominal masses, skin 
lesions, etc.
Multiple non-target lesions from the same organ may be captured 
as a single item on the eCRF (e.g. multiple liver metastases)
Non-target lesions should be reported as present at baseline
SOD baseline
Sum of diameters at baseline = LDi of all non-nodal + SDi of all 
nodal target lesions
2. Time Point Assessments After Baseline
Target lesion 
measurements
Locate image that optimizes the LDi of the non-nodal target lesion or 
short axis of target node(s). There is no need to go to an identical 
slice from baseline.
Measure the respective LDi and SDi for all target lesions and 
calculate time point SOD (SOD timepoint).
Special consideration for target lesions:
If target lesion is too small to measure, a default value of 5mm 
should be entered on eCRF.
If target lesion is 5-10mm, actual diameter should be entered in the  
eCRF 
If target lesion splits into 2 or more lesion then the LDi of split 
lesions will be added and entered in place of that lesion
If two target lesion merged to form one lesion than LDi of one 
should be entered as “0mm” while the other lesion should have the 
diameter of the merged lesion


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Nontarget 
Lesion 
Assessment
Nontarget lesions are evaluated qualitatively as present, absent, not 
evaluable (NE) or unequivocal progression. The response of 
nontarget lesions primarily contributes to the overall response 
assessments of CR. Nontarget lesions do not affect PR and SD 
assessments. Only a massive and unequivocal worsening of nontarget 
lesions alone, even in the presence of stable disease or a partial 
response in the target lesion is indicative of PD. CR is not possible 
unless all non-target lesions are absent.
Definition of 
New lesion
Any lesion which was not recorded at baseline. There is no minimum 
size criteria to identify a new lesion and clinical judgment must be 
used by the PI.
May include a lesion in an anatomical location that was not 
scanned at baseline (i.e. brain)
Should be unequivocal and not due to differences in scanning 
technique
If equivocal, should be assessed at next timepoint; if present, PD 
is the date the lesion was first seen (not the date confirmed)
3. irRECIST Overall Tumor Assessment
CR
Complete disappearance of all measurable and nonmeasurable 
lesions (from baseline) and there are no unequivocal new lesions 
(unconfirmed CR).
Lymph nodes must decrease to < 10 mm in short axis.
Confirmation of response is required ≥ 4 weeks later, preferably 
at next time point, to be considered a confirmed CR.
PR
If the SODtimepoint of TLs decreases by ≥ 30 % compared to 
SODbaseline and there are no unequivocal new lesions, and no
progression of nontarget disease, it is an PR (unconfirmed). 
Confirmation is required ≥ 4 weeks later, preferably at next time 
point, to be considered a confirmed PR.
SD
Failure to meet criteria for CR or PR in the absence of PD.
If the sum of the TLs and the status of the nontarget lesions do 
not reach the criteria to meet PR or PD (increase ≥20% and at 
least 5 mm absolute increase in SOD compared to nadir†) the 
response is SD.
SD = neither 30% decrease compared to SODbaseline or 20% 
increase and at least 5 mm absolute change compared to 
nadir.
†SODnadir: Lowest measure SOD of TLs at any time point from 
baseline onward.
PD
Minimum 20% increase and a minimum 5 mm absolute increase in 
SOD compared to nadir, or PD for nontarget lesion(s) or unequivocal 
new lesion(s).


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Confirmation of progression is recommended at a minimum of 4 
weeks after the first PD assessment (preferably at next tumor 
assessment time point).
The decision to continue study treatment after the first evidence of 
PD is at the Investigator’s discretion based on the clinical status of 
the subject as described in table below
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st
radiologi
c 
evidence 
of PD
Repeat 
imaging at 
> 4 weeks 
(next TA 
time point) 
to confirm 
PD
May 
continue 
study 
treatment at 
the 
Investigator
’s 
discretion 
while 
awaiting 
confirmator
y scans 
Repeat 
imaging at >
4 weeks to 
confirm PD 
per 
physician 
discretion 
only
Discontinu
e treatment
Subsequ
ent scan 
confirms 
PD
No 
additional 
imaging 
required
Discontinue 
treatment
No 
additional 
imaging 
required
N/A
Subsequ
ent scan 
shows 
SD, PR 
or CR
Continue 
regularly 
scheduled 
imaging 
assessment
s 
Continue 
study 
treatment at 
the 
Investigator
’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart 
study 
treatment if 
condition 
has 
improved 
and/or 
clinically 
stable per 
Investigato
r’s 
discretion
Subjects may continue receiving study treatment while waiting for 
confirmation of PD if they are clinically stable as defined by the 
following criteria:


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Absence of signs and symptoms (including worsening of 
laboratory values) indicating disease progression
No decline in ECOG performance status
Absence of rapid progression of disease 
Absence of progressive tumor at critical anatomical sites (e.g., 
cord compression) requiring urgent alternative medical 
intervention
If PD is confirmed and the subject is experiencing extraordinary 
clinical benefit, site must contact Sponsor to discuss continuing 
treatment
NE
Used in exceptional cases where insufficient data exists due to poor 
quality of scans or missed scans or procedure
Derivation of irRECIST overall responses
Measurable response 
Nonmeasureable response
Target Lesions
(% change in SOD)*
Non-Target Lesions 
Status
New Lesions Status
Overall Response 
(irRECIST)
100
Absent
Absent
CR¥
100
Present/NE
Absent
PR¥
≥30
Present/Absent/NE
Absent
PR¥
<30 to <20
Present/Absent/NE
Absent
SD
100
≥30
<30 to <20
NE
Present/Absent/NE
Present
PD¥
100
≥30
<30 to <20
NE
Unequivocal 
progression
Any
PD¥
≥20 from nadir
Any
Any
PD¥
NE
Present/Absent/NE
Absent
NE¥
* Decreases assessed relative to baseline, including measureable lesions only.


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¥ Assuming response (CR and PR) and progression (PD) are confirmed by a second, consecutive assessment at 
least 4 week apart.
13.2
Dose-Limiting Toxicities
A Dose-limiting toxicity (DLT) is defined as any of the following as judged by the investigator.

Any of the hematological or nonhematological toxicities noted in the table below 
considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring 
during Cycle 1.

Failure to administer ≥75% of the planned dosage of lenvatinib as a result of treatment-
related toxicity during Cycle 1.

Subjects who discontinue treatment due to treatment-related toxicity.

Greater than 2 week delay in starting Cycle 2 because of a treatment-related toxicity, 
even if the toxicity does not meet DLT criteria.
Dose Limiting Toxicities
Toxicity Category
Toxicity CTCAE Grade
Hematologic
Grade 4 neutropenia for ≥7 days
Grade 3 or Grade 4 febrile neutropeniaa
Thrombocytopenia <25,000/mm3 associated with bleeding and/or that 
requires platelet transfusion
Other
nonhematologic
toxicity
Any other Grade 4 or a Grade 5 toxicity
Grade 3 toxicities  lasting >3 days excluding:
Nausea, vomiting, and diarrhea controlled by medical intervention within 
72 hours.
Grade 3 rash in the absence of desquamation, no mucosal involvement, 
does not require steroids, and resolves to Grade 1 by the next scheduled
dose of pembrolizumab.
Grade 3 hypertension not able to be controlled by medication
Grade 3 or above gastrointestinal perforation
Grade 3 or above wound dehiscence requiring medical or surgical
intervention
Any grade thromboembolic event


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Any Grade 3 nonhematologic laboratory value if:
Medical intervention is required to treat the subject, or the abnormality 
leads to hospitalization
ANC = absolute neutrophil count, CTCAE = Common Terminology Criteria for Adverse
Events v4.03.
a.
Febrile neutropenia Grade 3 or Grade 4:
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a
sustained temperature of ≥38 °C (100.4 °F) for more than one hour.
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a
sustained temperature of ≥38 °C (100.4 °F) for more than one hour, with life-threatening
consequences and urgent intervention indicated
Only toxicities with a clear alternative explanation (eg, due to disease progression) or transient 
(≤72 hours) abnormal laboratory values without associated clinically significant signs or 
symptoms based on investigator determination can be deemed a non-DLT.
All subjects enrolled in Phase 1b will be assessed for DLTs during the DLT assessment 
window of Cycle 1 (Treatment Phase).  Subjects who discontinue study treatment prior to 
completing the Treatment Phase for any reason other than DLT will be replaced.  Once they 
complete the Treatment Phase, each subject still receiving study treatment will transition into 
the Extension Phase. Tumor assessments will continue during the Extension Phase.
13.3
Common Terminology Criteria For Adverse Events (CTCAE) V4.03
The Common Terminology Criteria for Adverse Events (CTCAE v4.03, published 14 June 
2010) provides descriptive terminology to be used for adverse event reporting in clinical trials.  
A brief definition is provided to clarify the meaning of each AE term.  To increase the accuracy
of AE reporting, all adverse event terms in CTCAE v4.03 have been correlated with single-
concept Medical Dictionary for Regulatory Activities (MedDRA) terms.
The Common Terminology Criteria for Adverse Events v4.03 grading refers to the severity of 
the AE.  The Common Terminology Criteria for Adverse Events grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline:
Grade
CTCAE Status


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1
Mild:  asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated
2
Moderate:
minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a
3
Severe or medically significant but not immediately life-threatening: hospitalization 
or prolongation of hospitalization indicated; disabling, limiting self-care ADLb
4
Life-threatening consequences: urgent intervention indicated
5
Death related to adverse event
ADL = activities of daily living, CTCAE = Common Terminology Criteria for Adverse Events.
a: Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing
money, etc.
b: Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications,
and not bedridden.
Adapted from the Cancer Therapy Evaluation Program, NCI. CTCAE v4.03
For further details regarding MedDRA, refer to the MedDRA website at:
http://www.meddramsso.com
13.4
New York Heart Association (NYHA) Cardiac Disease Classification
The New York Heart Association Cardiac Disease Classification provides a functional and 
therapeutic classification for the prescription of physical activity for cardiac subjects.  Based 
on NYHA definitions, subjects are to be classified as follows:
Class
NYHA Status
Class I:
Subjects with no limitation of activities; they suffer no symptoms from ordinary 
activities.
Class II:
Subjects with slight, mild limitation of activity; they are comfortable with rest or 
with mild exertion.
Class III:
Subjects with marked limitation of activity; they are comfortable only at rest.
Class IV:
Subjects who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest.
NYHA = New York Heart Association.
Adapted from The Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels. 9th ed. New York: Little Brown; 1994. p.253-6.


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13.5
Summary of primary and secondary Efficacy Analyses
Based on investigator assessments per irRECIST and mRECIST 1.1 for all 6 tumor cohorts, 
the following will be included in he efficacy analysis on the full analysis set or tumor specific 
analysis sets.
Efficacy Variable
Statistical Method
ORR(Week 24)
Number (percent) of subjects (with PR + CR) at Week 24 and its 
exact 95% CI using method of Clopper-Pearson.
(Only for irRECSIT)  
ORR
Number (percent) of subjects (with PR + CR) and its exact 95% CI 
using method of Clopper-Pearson.  
PFS
Kaplan-Meier method: Median PFS, and progression-free survival 
rate at 3, 6, 9, and 12 months will be presented with 2-sided 
95% CIs. Kaplan-Meier plot will also be provided.
OS*
Kaplan-Meier method: Median OS, and survival rates at 12, 18, 
and 24 months will be presented with 2-sided 95% CIs. Kaplan-
Meier plot will also be provided. 
DCR
Number (percent) of subjects (with CR + PR + stable disease [SD] 
≥ 5 weeks) and its exact 95% CI using method of Clopper-
Pearson. 
CBR
Number (percent) of subjects (with CR, PR + durable SD≥23
weeks) and its exact 95% CI using method of Clopper-Pearson. 
DOR
Kaplan-Meier method: Median DOR with 2-sided 95% CIs will be 
presented.
* The OS endpoint is independent from tumor assessment criteria.
Based on independent imaging review per irRECIST, mRECIST 1.1, RECIST 1.1 for EC and 
RCC cohorts, the following will be included in efficacy analyses on the Endometrial 
Carcinoma Analysis Set and Renal Cell Carcinoma Analysis Set.


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Efficacy Variable
Statistical Method
ORR(Week 24)
Number (percent) of subjects (with PR + CR) at Week 24 and its 
exact 95% CI using method of Clopper-Pearson.
(Only for irRECIST)  
ORR
Number (percent) of subjects (with PR + CR) and its exact 95% CI 
using method of Clopper-Pearson.  
PFS
Kaplan-Meier method: Median PFS, and progression-free survival 
rate at 3, 6, 9, and 12 months will be presented with 2-sided 
95% CIs. Kaplan-Meier plot will also be provided.
DCR
Number (percent) of subjects (with CR + PR + stable disease [SD]  
≥ 5 weeks) and its exact 95% CI using method of Clopper-
Pearson. 
CBR
Number (percent) of subjects (with CR, PR + durable SD≥23
weeks) and its exact 95% CI using method of Clopper-Pearson. 
DOR
Kaplan-Meier method: Median DOR with 2-sided 95% CIs will be 
presented.
13.6
Common Terminology Criteria for Adverse Events (CTCAE) for 
Hematology & Clinical Chemistry
Laboratory 
Parameter
Common Terminology Criteria for Adverse Events (CTCAE)
Grade 1
Grade 2
Grade 3
Grade 4
Hematology
Hemoglobin
< LLN – 10 g/dL
< LLN –
6.2 mmol/L
< 10 – 8 g/dL
< 6.2 – 4.9 mmol/L
< 8 – 6.5 g/dL
< 4.9 – 4 mmol/L
–
Platelet Count
< LLN –
75,000/mm3
< LLN – 75 x 
109/L
< 75,000 –
50,000/mm3
< 75 – 50 x 109/L
< 50,000 –
25,000/mm3
< 50 – 25 x 109/L
< 25,000/mm3
< 25 x 109/L
Leukocytes 
(Total WBC)
< LLN – 3,000/mm3
< LLN – 3 x 109/L
< 3,000 –
2,000/mm3
< 3 – 2 x 109/L
< 2,000 – 1000/mm3
< 2 – 1 x 109/L
< 1,000/mm3
< 1 x 109/L
Lymphocytes 
(hypo)
< LLN – 800/mm3
< LLN – 0.8 x 109/L
< 800 – 500/mm3
< 0.8 – 0.5 x 109/L
< 500 – 200/mm3
< 0.5 – 0.2 x 109/L
< 200/mm3
< 0.2 x 109/L


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Laboratory 
Parameter
Common Terminology Criteria for Adverse Events (CTCAE)
Grade 1
Grade 2
Grade 3
Grade 4
Lymphocytes 
(hyper)
-
> 4,000 –
20,000/mm3
> 4 – 20 x 109/L
> 20,000/mm3
> 20 x 109/L
–
Neutrophils
< LLN – 1,500/mm3
< LLN – 1.5 x 109/L
< 1,500 –
1,000/mm3
< 1.5 – 1 x 109/L
< 1,000 – 500/mm3
< 1 – 0.5 x 109/L
< 500/mm3
< 0.5 x 109/L
Clinical Chemistry
Albumin
< LLN – 3 g/dL
< LLN – 30 g/L
< 3 – 2 g/dL
< 30 – 20 g/L
< 2 g/dL
< 20 g/L
Alkaline 
Phosphatase
> 1 – ≤2.5 x ULN
> 2.5 – ≤5 x ULN
> 5 – ≤20 x ULN
> 20 x ULN
ALT
> 1 – ≤3 x ULN
> 3 – ≤5 x ULN
> 5 – ≤20 x ULN
> 20 x ULN
Amylase
> 1 – ≤1.5 x ULN
> 1.5 – ≤2 x ULN
> 2 – ≤5 x ULN
> 5 x ULN
AST
> 1 – ≤3 x ULN
> 3 – ≤5 x ULN
> 5 – ≤20 x ULN
> 20 x ULN
Bilirubin, Total
> 1 – ≤1.5 x ULN
> 1.5 – ≤3 x ULN
> 3 – ≤10 x ULN
> 10 x ULN
Calcium 
(hyper)
> ULN –
≤11.5 mg/dL
> ULN –
≤2.9 mmol/L
> 11.5 –
≤12.5 mg/dL
> 2.9 –
≤3.1 mmol/L
> 12.5 –
≤13.5 mg/dL
> 3.1 –
≤3.4 mmol/L
> 13.5 mg/dL
> 3.4 mmol/L
Calcium (hypo)
< LLN – 8 mg/dL
< LLN – 2 mmol/L
< 8 – 7 mg/dL
< 2 – 1.75 mmol/L
< 7 – 6 mg/dL
< 1.75 – 1.5 mmol/L
< 6 mg/dL
< 1.5 mmol/L
Cholesterol, 
Total
> ULN – 300 mg/dL
> ULN –
7.75 mmol/L
> 300 – 400 mg/dL
> 7.75 –
10.34 mmol/L
> 400 – 500 mg/dL
> 10.34 –
12.92 mmol/L
> 500 mg/dL
> 12.92 mmol/L
Creatinine
> 1 – ≤1.5 x ULN
> 1.5 – ≤3 x ULN
> 3 – ≤6 x ULN
> 6 x ULN
Glucose 
(hyper)
> ULN –
≤160 mg/dL
> ULN –
≤8.9 mmol/L
> 160 –
≤250 mg/dL
> 8.9 –
≤13.9 mmol/L
> 250 –
≤500 mg/dL
> 13.9 –
≤27.8 mmol/L
> 500 mg/dL
> 27.8 mmol/L
Glucose (hypo)
< LLN – 55 mg/dL
< LLN – 3 mmol/L
< 55 – 40 mg/dL
< 3 – 2.2 mmol/L
< 40 – 30 mg/dL
< 2.2 – 1.7 mmol/L
< 30 mg/dL
< 1.7 mmol/L
Lipase
> 1 – 1.5 x ULN
> 1.5 – ≤2 x ULN
> 2 – 5 x ULN
> 5 x ULN
Magnesium 
(hyper)
> ULN – ≤3 mg/dL
> ULN –
≤1.23 mmol/L
–
> 3 – ≤8 mg/dL
> 1.23 –
≤3.3 mmol/L
> 8 mg/dL
> 3.3 mmol/L


Statistical Analysis Plan
E7080- A001-111
Eisai
Confidential
Page 52 of 53
Laboratory 
Parameter
Common Terminology Criteria for Adverse Events (CTCAE)
Grade 1
Grade 2
Grade 3
Grade 4
Magnesium 
(hypo)
< LLN – 1.2 mg/dL
< LLN –
0.5 mmol/L
< 1.2 – 0.9 mg/dL
< 0.5 – 0.4 mmol/L
< 0.9 – 0.7 mg/dL
< 0.4 – 0.3 mmol/L
< 0.7 mg/dL
< 0.3 mmol/L
Phosphate
< LLN – 2.5 mg/dL
< LLN –
0.8 mmol/L
< 2.5 – 2 mg/dL
< 0.8 – 0.6 mmol/L
< 2 – 1 mg/dL
< 0.6 – 0.3 mmol/L
< 1 mg/dL
< 0.3 mmol/L
Potassium 
(hyper)
> ULN –
≤5.5 mmol/L
> 5.5 – ≤6 mmol/L
> 6 – ≤7 mmol/L
> 7 mmol/L
Potassium 
(hypo)
< LLN – 3 mmol/L
–
< 3 – 2.5 mmol/L
< 2.5 mmol/L
Sodium (hyper)
> ULN –
≤150 mmol/L
> 150 –
≤155 mmol/L
> 155 –
≤160 mmol/L
> 160 mmol/L
Sodium (hypo)
< LLN –
130 mmol/L
–
< 130 – 120 mmol/L
< 120 mmol/L


Statistical Analysis Plan
E7080- A001-111
Eisai
Confidential
Page 53 of 53
SIGNATURE PAGE
Author:  
Signature
Onco
Date
Approval:
Signature
Date
Signature
As
Oncology Business Group, Eisai Inc.
Date
PPD
PPD
PPD