Clinical trial NCT03290079
Conditions: Neuroendocrine Tumors Neuroendocrine Carcinoma Neuroendocrine Cancer
Keywords: well-differentiated neuroendocrine tumors
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2017-12-15; Completion date: 2024-05-13
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to:

* Assess overall radiographic response rate (ORR)
* Assess progression-free survival (PFS)
* Test the safety and tolerability of Pembrolizumab in combination with lenvatinib

Detailed description:

Arms: arm 1: Pembrolizumab 200 mg will be administered as a 30 minute intravenous (IV) infusion every 3 weeks, in addition to 20 mg Lenvatinib by mouth every day of each 3 week cycle. Estimated average length of treatment per participant: 4 months.
Interventions: intervention 1: Pembrolizumab intervention 2: Lenvatinib
Intervention descriptions: intervention 1: 200 mg Pembrolizumab by IV on Day 1 of each 3 week cycle. intervention 2: 20 mg Lenvatinib by mouth every day of each 3 week cycle

Protocol documents:
Prot_SAP_000.pdf: 
 
Phase II Study of Pembrolizumab and Lenvatinib in Advanced Well-
Differentiated Neuroendocrine Tumors 
NCT03290079 
 
Version 5.0 
December 10, 2018 


 
 
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SPONSOR:  Merck 
 
TITLE:  Phase II study of pembrolizumab and lenvatinib in advanced well-
differentiated neuroendocrine tumors 
 
 
IND NUMBER: 135156 
 
Principal Investigator 
 
Jonathan Strosberg, MD 
H. Lee Moffitt Cancer Center,  
12902 Magnolia Dr. 
Tampa, FL 33612 
jonathan.strosberg@moffitt.org 
Phone: 813-745-3636 
Fax:  813-745-7229 
 
 
Statistician:  
Michael Schell, PhD 
H. Lee Moffitt Cancer Center,  
12902 Magnolia Dr. 
Tampa, FL 33612 
michael.schell@moffitt.org 
Phone: 813-745-6061 
Fax:  813-745-5855 
 
 


 
 
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Table of contents 
2.0 
TRIAL DESIGN.......................................................................................................... 5 
3.0 
OBJECTIVES & HYPOTHESES ............................................................................. 5 
3.1 
Primary Objective & Hypothesis .......................................................................... 5 
3.2 
Secondary Objectives ............................................................................................. 5 
3.3 
Exploratory Objective ............................................................................................ 6 
4.0 
BACKGROUND & RATIONALE ............................................................................ 6 
4.1 
Background ............................................................................................................. 6 
4.1.1 Pharmaceutical and Therapeutic Background ...................................................... 6 
4.1.2 Preclinical and Clinical Trial Data ........................................................................ 7 
4.2 
Rationale .................................................................................................................. 8 
4.2.1 Rationale for the Trial and Selected Subject Population ...................................... 8 
4.2.2 Rationale for Dose Selection/Regimen/Modification ........................................... 8 
4.2.3 Rationale for Endpoints ...................................................................................... 10 
5.0 
METHODOLOGY ................................................................................................... 11 
5.1 
Entry Criteria ........................................................................................................ 11 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 11 
5.1.2 Subject Inclusion Criteria.................................................................................... 11 
5.1.3 Subject Exclusion Criteria .................................................................................. 13 
5.2 
Trial Treatments ................................................................................................... 15 
5.2.1 Dose Selection/Modification .............................................................................. 16 
5.2.2 Timing of Dose Administration .......................................................................... 24 
5.2.3 Trial Blinding/Masking ....................................................................................... 25 


 
 
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5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 25 
5.3.1 Acceptable Concomitant Medications ................................................................ 25 
5.3.2 Prohibited Concomitant Medications.................................................................. 25 
5.4 
Diet/Activity/Other Considerations ..................................................................... 26 
5.4.1 Diet ...................................................................................................................... 26 
5.4.2 Contraception ...................................................................................................... 26 
5.4.3 Use in Pregnancy ................................................................................................ 28 
5.4.4 Use in Nursing Women ....................................................................................... 29 
5.5 
Subject Withdrawal/Discontinuation Criteria ................................................... 29 
5.6 
Subject Replacement Strategy ............................................................................. 30 
5.7 
Clinical Criteria for Early Trial Termination ................................................... 30 
6.0 
TRIAL FLOW CHART ........................................................................................... 31 
6.1 
Study Flow Chart .................................................................................................. 31 
7.0 
TRIAL PROCEDURES ........................................................................................... 33 
7.1 
Trial Procedures ................................................................................................... 33 
7.1.1 Administrative Procedures .................................................................................. 33 
7.1.2 Clinical Procedures/Assessments ........................................................................ 35 
7.1.3 Laboratory Procedures/Assessments .................................................................. 36 
7.1.4 Other Procedures ................................................................................................. 38 
7.1.5 Visit Requirements .............................................................................................. 38 
7.2 
Assessing and Recording Adverse Events .......................................................... 39 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor and to Merck ................................................................................... 40 


 
 
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7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................. 41 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck.............. 41 
7.2.4 Evaluating Adverse Events ................................................................................. 44 
7.2.5 Sponsor Responsibility for Reporting Adverse Events ...................................... 48 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 48 
8.1 
Statistical Analysis Plan Summary ..................................................................... 48 
8.2 
Statistical Analysis Plan ....................................................................................... 48 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 48 
9.1 
Investigational Product ........................................................................................ 48 
9.2 
Packaging and Labeling Information ................................................................. 49 
9.3 
Clinical Supplies Disclosure ................................................................................. 49 
9.4 
Storage and Handling Requirements .................................................................. 49 
9.5 
Returns and Reconciliation .................................................................................. 49 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 50 
10.1 
Compliance with Trial Registration and Results Posting Requirements ........ 50 
10.2 
Data Management ................................................................................................. 50 
11.0 
APPENDICES ........................................................................................................... 51 
11.1 
ECOG Performance Status .................................................................................. 51 
11.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 51 
11.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................ 51 
12.0 
REFERENCES .......................................................................................................... 52 
 


 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab in advanced well-differentiated neuroendocrine 
tumors 
Trial Phase 
II 
Clinical Indication 
Metastatic progressive neuroendocrine tumors of lung,  thymic, small 
bowel,  colorectal and unknown primary origin 
Trial Type 
Single arm, phase II Simon 2-stage design 
Type of control 
N/A 
Route of administration 
IV 
Trial Blinding 
N/A 
Treatment Groups  
N/A 
Number of trial subjects 
35 
Estimated enrollment period 
24 months 
Estimated duration of trial 
4 years 
Duration of Participation 
2 years 
Estimated average length of 
treatment per patient 
9 months 
 
 
 
 
2.0 TRIAL DESIGN 
Trial Design: 2-stage, single arm, open-label phase II study  
3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objective & Hypothesis 
 Objective: To assess the overall radiographic response rate (ORR) associated with 
pembrolizumab in patients with advanced, progressive well-differentiated neuroendocrine 
tumors 
Hypothesis:   Well-differentiated neuroendocrine tumors (any grade) will be sensitive to 
combination VEGF and PD-1 inhibition resulting in a clinically meaningful response rate  
3.2 
Secondary Objectives 
 Objective:  To assess progression-free survival (PFS) in this population based on 
RECIST 1.1  
 Objective: To assess duration of response (DOR) by RECIST 1.1 
 Objective:  To assess overall survival (OS) in this population 
 Objective:  To assess safety and tolerability 


 
 
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3.3 
Exploratory Objective 
 Objective: Correlate response with PD-L1 tumor expression, tumor mutation burden 
(TMB), and MSI status 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochures (IB)/approved labeling for detailed background 
information on pembrolizumab and lenvatinib. 
4.1.1 Pharmaceutical and Therapeutic Background 
4.1.1.1 Pembrolizumab  
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  
The structure of murine PD-1 has been resolved.  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 


 
 
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regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells.  Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors.  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues.  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 pathway 
plays a critical role in tumor immune evasion and should be considered as an attractive target 
for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  Keytruda® (pembrolizumab) has been approved in the United 
States for the treatment of patients non-small cell lung cancer (1st and 2nd line), head and 
neck cancer, and melanoma. 
 
4.1.1.2 Lenvatinib 
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of 
vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), 
and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in 
pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal 
cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the 
platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET.1 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochures and package inserts for Preclinical and Clinical data. 


 
 
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4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
The treatment landscape of advanced neuroendocrine tumors (NET) has advanced rapidly in 
the past decade, with several systemic therapeutic options for patients with metastatic 
disease.2-7  However, immunotherapy drugs have not been shown to be highly active in well-
differentiated gastroenteropancreatic or lung NETs, or in poorly differentiated 
neuroendocrine carcinomas originating outside the lung.  Preliminary evidence suggests that 
PD-1 inhibitor monotherapy is relatively ineffective, with response rates <10% in most 
subsets of NETs.   
Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI) which inhibits the kinase activities 
of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), 
and VEGFR3 (FLT4) has been recently reported to be effective in NETs progressing after 
several lines of therapy (ESMO).  Response rates were 40% in pancreatic NETs, and 18.5% 
in gastrointestinal NETs.8   
Recent data supports the hypothesis that combining antiangiogenic treatment with immune 
checkpoint inhibition can be synergistic. Several trials have been conducted evaluating the 
combinations of antiangiogenic agents with checkpoint inhibitors in renal cell carcinoma 
(mRCC) and anaplastic thyroid carcinoma (ATC) with promising results9-12.  Checkmate-
016, comparing nivolumab + sunitinib and nivolumab + pazopanib showed an ORR of 52 
and 45%, and a PFS of 48.9 and 31.4 months, respectively. A study evaluating 
pembrolizumab and lenvatinib in mRCC showed an ORR of 69%, with half of the patients 
exhibiting PR. Lenvatinib plus pembrolizumab has shown striking results in endometrial 
cancer.  In a phase Ib/II basket study (KEYNOTE 146 trial; NCT02501096), of heavily 
pretreated patients, ORR at week 24 was 45% and the overall ORR was 47.2%. This study 
led the FDA to grant a breakthrough therapy designation for the combination of lenvatinib 
and pembrolizumab in 8/2018.    
Given the encouraging results in other trials, and the fact that VEGFR-TKIs typically 
produce fast but non-durable responses and checkpoint inhibitors produce slow but durable 
responses, this is combination therapy is of particular interest to explore in NET tumors. 
Pancreatic NETs will be excluded due to the already high response rate observed with 
lenvatinib monotherapy. 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
4.2.2.1 Pembrolizumab 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 


 
 
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subjects with advanced solid tumors.  All three dose levels were well tolerated and no dose-
limiting toxicities were observed.  This first in human study of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 
mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule utilized in 
Cohorts A, B, C and D of this protocol to test for initial tumor activity.  Recent data from 
other clinical studies within the pembrolizumab program has shown that a lower dose of 
pembrolizumab and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days).  This early PK and pharmacodynamic data provides scientific rationale 
for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  Pembrolizumab has been found to have a wide 
therapeutic range based on the melanoma indication.  The differences in exposure for a 200 
mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
pembrolizumab in the melanoma indication. The exposure margins are based on the notion of 
similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 
2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed 
that there was no significant impact of tumor burden on exposure. In addition, exposure was 
similar between the NSCLC and melanoma indications. Therefore, there are no anticipated 
changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with 
tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 


 
 
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fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
 
4.2.2.2 Lenvatinib 
The recommended daily dose of lenvatinib is 24 mg (two 10mg capsules and one 4mg 
capsule) orally taken once daily with or without food. Lenvatinib is taken at the same time 
each day. If a dose is missed and cannot be taken within 12 hours, patients should skip that 
dose and take the next dose at the usual time of administration.  
After oral administration of lenvatinib, time to peak plasma concentration (Tmax) typically 
occurred from 1 to 4 hours post-dose. Administration with food did not affect the extent of 
absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours 
to 4 hours. 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
4.2.3.1.1 Primary endpoint: RECIST-based response rate 
Objective radiographic response (ORR) rate is a simple and standard criterion for assessing 
the efficacy of an agent(s) in a single-arm phase II trial.  Numerous prior studies of 
pembrolizumab and lenvatinib have indicated that these agents are capable of yielding a 
clinically meaningful objective response in immunosensitive malignancies.  Therefore ORR 
will be used as the primary endpoint per RECIST 1.1 criteria (see section 11.3). 
4.2.3.1.2 Secondary efficacy endpoints 
Secondary endpoints include: (1) DOR, defined as the time from first documented evidence 
of CR or PR until disease progression or death due to any cause, whichever occurs first, (2) 
PFS, defined as the time from initial treatment to the first documented disease progression 
according to RECIST 1.1, or death due to any cause, whichever occurs first, and (3) OS 
defined as the time from initial treatment until death from any cause.   
Confirmation of PR/CR should be performed with radiographic assessment ≥ 4 weeks after 
initial documentation of PR/CR.  


 
 
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4.2.3.2 Biomarker Research 
While tumoral PD-L1 expression has not been validated as a predictive marker across all 
malignancies, it appears to be a predictive marker for PD-1 inhibitors in some malignancies.  
We have previously found that well-differentiated neuroendocrine tumors can express PD-L1 
(unpublished data). We will assess PD-L1 expression on archival tissue in this study both to 
evaluate the rate of expression of this antigen and also to analyze correlation between 
expression and response. 
Responses to pembrolizumab have been particularly high in microsatellite instability high 
(MSI-H) tumors.   We will therefore test for MSI status by first screening for mismatch 
repair (MMR) deficiency via immunohistochemical (IHC) stains.  Cases that are positive for 
MMR protein deficiency will subsequently be tested for MSI. The prevalence of MSI-H 
tumors in this population of patients is unknown.  
Tumor mutation burden (TMB) has emerged as a highly promising and clinically validated 
biomarker, particularly in the setting of lung cancer. Studies have shown that patients with 
high TMB can predict response to a range of various types of immunotherapy. The 
relationship between tumor DNA mutation burden and response to treatment will be 
explored. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Metastatic well differentiated neuroendocrine tumors of primary lung, thymic, small 
bowel and colorectal origin (including unknown primary) 
 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have evidence of radiographic disease progression with scan documenting 
progression occurring within 8 months of signing informed consent 
 
2. At least two prior lines of systemic treatment.  If the only prior line of treatment was 
adjuvant or neoadjuvant, patient must have completed treatment within 12 months. 
There is no limit to number of prior therapies. 
 
3. Be willing and able to provide written informed consent/assent for the trial. 


 
 
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4. Be  18 years of age on day of signing informed consent. 
5. Have measurable disease based on RECIST 1.1.   
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 14 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Urine protein 
<30mg/dL on urinalysis or ≤1g/24 hours on 24-hour urine 
protein for patients with >30mg/dL on urinalysis 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
8. Female subject of childbearing potential should have a negative serum pregnancy 
within 72 hours prior to receiving the first dose of study medication.   
9. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception,  for 
the course of the study through 120 days after the last dose of study medication. 


 
 
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Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
10. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate 
method of contraception as outlined in Section 5.7.1- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has a poorly differentiated neuroendocrine carcinoma 
2. Has a pancreatic neuroendocrine tumor 
3. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
4. 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 trial 
treatment. 
 
5. Has a known history of active TB   (Bacillus Tuberculosis) 
 
6. Hypersensitivity to pembrolizumab or any of its excipients. 
7. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier. 
8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 


 
 
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- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
9. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer. 
10. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment.  This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability.   
11. Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
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.  
12. Has a history of (non-infectious) pneumonitis that required steroids, or current 
pneumonitis. 
13. Has an active infection requiring systemic therapy. 
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
15. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
18. Has received prior therapy with a tyrosine kinase inhibitor (TKI). (e.g., sunitinib, 
pazopanib, cabozantinib) 


 
 
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19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
21. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
22. Uncontrolled hypertension defined as systolic blood pressure >150 mmHg or 
diastolic pressure >90 mmHg, despite optimal medical management. 
23. Thrombotic or embolic events such as a cerebrovascular accident including transient 
ischemic, attacks, DVT within the past 6 months  
24. Bleeding or thrombotic disorders or use of anticoagulants, such as warfarin, or similar 
agents 
requiring 
therapeutic 
international 
normalized 
ration 
(INR) 
monitoring.(Treatment with low molecular weight heparin (LMWH) is allowed) 
25. Marked baseline prolongation of QT/QTc interval (QTc interval ≥ 500 msec) using 
the Fridericia method (QTc = QT/RR0.33) for QTc analysis 
26. Clinically significant bleeding within 4 weeks 
27. Medical need for the continued use of potent inhibitors/inducers of CYP3A4  
28. Creatinine clearance <30 mL/min 
29. Any condition that impairs patient’s ability to swallow whole pills or gastrointestinal 
malabsorption that, in the investigator’s opinion, might affect absorption of lenvatinib 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Lenvatinib 
24mg 
QD 
PO 
Every day of each 3 
week cycle 
Experimental 


 
 
16                                                                                              v5 dated 10Dec2018  
 
 
Trial treatment should begin as close as possible to the date on which treatment is 
allocated/assigned. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab and lenvatinib are provided in 
the Pharmacy Manuals.   
5.2.1.2 Dose Delays and Discontinuation   
Pembrolizumab and lenvatinib may be interrupted for situations other than treatment-related 
AEs such as medical / surgical events or logistical reasons not related to study therapy. 
Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should 
be documented in the patient's study record.  
 
Patients may continue on study treatment with either drug as monotherapy should they 
require discontinuation of one of the study drugs due to unacceptable toxicity or intolerance. 
Patients will continue to follow the study schedule and procedures, per protocol until 
discontinuation criteria is met for the second drug.  


 
 
17                                                                                              v5 dated 10Dec2018  
 
5.2.1.3 Dose Modification and toxicity management for immune-related AEs 
associated with pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical 
to reduce complications.  Based on existing clinical trial data, most irAEs were reversible 
and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such 
as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based 
on the severity of irAEs, withhold or permanently discontinue pembrolizumab and 
administer corticosteroids. Dose modification and toxicity management guidelines for 
irAEs associated with pembrolizumab are provided in Table 3.  
 
Table 3 Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab  
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper 
over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management 
with 
corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer 
corticosteroids 
(initial dose of 
1-2mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
 
Monitor subjects for 
signs and symptoms 
of pneumonitis 
 
Evaluate subjects 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid 
Grade 3 or 4, or 
recurrent grade 2 
Permanently 
discontinue 


 
 
18                                                                                              v5 dated 10Dec2018  
 
 
treatment 
 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
Diarrhea / colitis  
Grade 2 or 3 
Withhold 
 Administer 
corticosteroids 
(initial dose of 
1-2mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
 
 
Monitor subjects for 
signs and symptoms 
of enterocolitis (i.e. 
diarrhea, abdominal 
pain, blood or mucus 
in stool with or 
without fever) and of 
bowel perforation 
(i.e. peritoneal signs 
and ileus). 
 
Subjects with ≥ 
Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing 
endoscopy to rule out 
colitis.  
 
Subjects 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. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 
Withhold 
 Administer 
corticosteroids 
(initial dose of 
0.5- 1mg/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 
 Administer 
corticosteroids 
(initial dose of 
1-2mg/kg 
prednisone or 
equivalent) 
followed by 
taper 


 
 
19                                                                                              v5 dated 10Dec2018  
 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold 
 Initiate insulin 
replacement 
therapy for 
subjects with 
T1DM  
 Administer anti-
hyperglycemic 
in subjects with 
hyperglycemia  
 
 
Monitor subjects 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 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
 Treat with non-
selective beta-
blockers (e.g. 
propranolol) or 
thionamides as 
appropriate  
 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
Permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 Initiate thyroid 
replacement 
hormones (e.g. 
levothyroxine 
or 
liothyroinine) 
per standard of 
care 
 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Nephritis and 
renal dysfunction 
Grade 2 
Withhold  
 Administer 
corticosteroids 
(prednisone 1-
2mg/kg or 
equivalent) 
followed by 
taper. 
 
Monitor changes of 
renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
All Other 
immune-related 
AEs 
Grade 3, or 
intolerable/ 
persistent Grade 
2 
Withhold 
 Based on 
severity of AE 
administer 
corticosteroids  
 
Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes 
 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 


 
 
20                                                                                              v5 dated 10Dec2018  
 
NOTES:  
1. Withholding or permanently discontinuing pembrolizumab is at the discretion of the investigator or treating 
physician.   
2. For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM) 
 
5.2.1.3 Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4.  
 
Table 4 Pembrolizumab Infusion Reaction Dose modification and 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 


 
 
21                                                                                              v5 dated 10Dec2018  
 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
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 deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  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 drug 
treatment 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., 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 at the bedside and a physician readily available during the period of 
drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
 
 
5.2.1.3 Dose Modification and toxicity management for AEs associated with lenvatinib 


 
 
22                                                                                              v5 dated 10Dec2018  
 
Hypertension 
 Assess blood pressure prior to and periodically during treatment. Initiate or adjust 
medical management to control blood pressure prior to and during treatment. 
 Withhold lenvatinib for Grade 3 hypertension that persists despite optimal 
antihypertensive therapy; resume at a reduced dose (see Table 1) when hypertension is 
controlled at less than or equal to Grade 2. 
 Discontinue lenvatinib for life-threatening hypertension. 
Cardiac dysfunction or hemorrhage 
 Discontinue for a Grade 4 event. 
 Withhold lenvatinib for development of Grade 3 event until improved to Grade 0 or 1 
or baseline. 
 Either resume at a reduced dose (see Table 1) or discontinue lenvatinib depending on 
the severity and persistence of the adverse event. 
Arterial thrombotic event 
 Discontinue lenvatinib following an arterial thrombotic event. 
Renal failure and impairment or hepatotoxicity 
 Withhold lenvatinib for development of Grade 3 or 4 renal failure/impairment or 
hepatotoxicity until resolved to Grade 0 to 1 or baseline. 
 Either resume at a reduced dose (see Table 1) or discontinue lenvatinib depending on 
the severity and persistence of renal impairment or hepatotoxicity. 
 Discontinue lenvatinib for hepatic failure. 
Proteinuria 
 Withhold lenvatinib for ≥2 grams of proteinuria/24 hours. 
 Resume at a reduced dose (see Table 1) when proteinuria is <2 gm/24 hours. 
 Discontinue lenvatinib for nephrotic syndrome. 
Gastrointestinal perforation or fistula formation 


 
 
23                                                                                              v5 dated 10Dec2018  
 
 Discontinue lenvatinib in patients who develop gastrointestinal perforation or life- 
threatening fistula. 
QT prolongation 
 Withhold lenvatinib for the development of Grade 3 or greater QT interval 
prolongation. 
 Resume lenvatinib at a reduced dose (see Table 1) when QT prolongation resolves to 
Grade 0 or 1 or baseline. 
Reversible posterior leukoencephalopathy syndrome (RPLS) 
 Withhold for RPLS until fully resolved. 
 Upon resolution, resume at a reduced dose or discontinue lenvatinib depending on the 
severity and persistence of neurologic symptoms. 
 
Manage other adverse reactions according to the instructions in Table 5. Based on the 
absence of clinical experience, there are no recommendations on resumption of dosing in 
patients with Grade 4 clinical adverse reactions that resolve. 
 
 


 
 
24                                                                                              v5 dated 10Dec2018  
 
Table 4 Recommended Dose Modifications for Persistent and Intolerable Grade 2 or Grade 3 
Adverse Reactions or Grade 4 Laboratory Abnormalitiesa 
 
a. Initiate medical management for nausea, vomiting, or diarrhea prior to interruption or 
dose reduction of lenvatinib 
b. Reduce dose in succession based on the previous dose level (24 mg, 20 mg, or 14 mg per 
day) 
c. Refers to the same or a different adverse reaction that requires dose modification 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Lenvatinib 24 mg will be administered orally and provided in 10mg and 4mg capsules 
(supplied in cartons of 6 cards; each card is a 5-day blister card), taken daily with or without 
food. Lenvatinib should be taken at the same time each day. If a dose is missed and cannot be 
taken within 12 hours, patients should skip that dose and take the next dose at the usual time 
of administration. Patients will be required to maintain documentation of all dose 
administrations on a pill diary each cycle.  
Adverse Reaction 
Modification 
Adjusted Doseb 
First occurrence 
Interrupt until resolved to 
Grade 0-1 or baseline 
20 mg (two 10 mg capsules) 
orally once daily 
Second occurrencec 
Interrupt until resolved to 
Grade 0-1 or baseline 
14 mg (one 10 mg capsule plus 
one 4 mg capsule) orally once 
daily 
Third occurrencec 
Interrupt until resolved to 
Grade 0-1 or baseline 
10 mg (one 10 mg capsule) 
orally once daily 


 
 
25                                                                                              v5 dated 10Dec2018  
 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. Lenvatinib will be 
dispensed and handled according to the FDA approved package insert.  
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2.  Somatostatin analogs (octreotide and 
lanreotide) are rarely used in patients with poorly differentiated/high grade neuroendocrine 
cancers, but are allowed if needed for control of hormonal syndromes. 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 


 
 
26                                                                                              v5 dated 10Dec2018  
 
 Investigational agents other than pembrolizumab 
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
 Strong CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) 
inhibitors and CYP3A and P-gp inducers are not prohibited, but should be avoided 
while on study therapy.  
 Grapefruit, grapefruit juice, or Seville oranges 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.4 
Diet/Activity/Other Considerations 
5.4.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.4.2 Contraception 
The study drugs may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
these drugs havetransient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   


 
 
27                                                                                              v5 dated 10Dec2018  
 
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
  
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 


 
 
28                                                                                              v5 dated 10Dec2018  
 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
5.4.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on study treatment, the subject will 
immediately be removed from the study.  The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the Sponsor and to Merck without delay and 


 
 
29                                                                                              v5 dated 10Dec2018  
 
within 24 hours to the Sponsor and within 2 working days to Merck if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or 
life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 
5.4.4 Use in Nursing Women 
It is unknown whether pembrolizumab and/or lenvatinib are excreted in human milk.  Since 
many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment. 
5.5 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.3 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Confirmed radiographic disease progression 
 Unacceptable adverse experiences as described in Section 5.2.1.2 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 


 
 
30                                                                                              v5 dated 10Dec2018  
 
 Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.4 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
 
5.6 
Subject Replacement Strategy 
Subjects who enroll but do not receive first dose of trial drug will be replaced 
5.7 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drugs, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 


Product:  Pembrolizumab 
31 
Protocol/Amendment No.:   
 
 
 
 
 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visitsc 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-42 to -1 
-14 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 9 
weeks post 
discon 
Every 
12 
weeks  
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study drug Administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Full Physical Examination 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Directed Physical Examination 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Vital Signs and Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Electrocardiogram 
 
X 
 
 
 
Xa 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test –Serum -HCG 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Comprehensive Serum Chemistry Panel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


Product:  Pembrolizumab 
32 
Protocol/Amendment No.:   
 
 
 
 
 
 
Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visitsc 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-42 to -1 
-14 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 9 
weeks post 
discon 
Every 
12 
weeks  
Urinalysis 
 
Xc 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
T3, FT4 and TSH 
 
Xc 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Efficacy Measurements 
Tumor Imaging 
 
Xf 
 
 
Xd 
 
 
X 
 
 
 
 
X 
 
Archival Tissue Collection/Correlative Studies Blood 
Archival Tissue Collection 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
ECG at baseline and at each restaging assessment for patients that are symptomatic or have QTcF at baseline of >450ms 
b. 
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to first dose of trial treatment and repeated at each 
restaging assessment.   
c. 
Every other cycle (including beyond cycle 8). Add on 24-hour urine protein for any visit with urine protein 1+ (>30mg/dL) 
d. 
The first on-study imaging time point will be at 9 weeks (+/- 7 days) after the date of cycle 1 day 1, then every 9 weeks (+/- 7 days) thereafter.  After 12 
months, imaging frequency should be reduced to every 12 weeks (+/- 7 days).  Imaging timing should follow calendar days and should not be adjusted for 
delays in cycle starts.   
e. 
Archival tumor collection can be performed at any time during the study and is not a prerequisite for enrollment or initiation of treatment 
f. 
Tumor imaging for screening may be at day -28 to -1  
 
 
 
 
 


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative 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 trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 


Product:   Pembrolizumab 
34 
Protocol/Amendment No.:   
 
 
 
 
 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial during all visits.  All medications related to reportable SAEs and ECIs should 
be recorded as defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject 
will move into survival follow-up.  


Product:   Pembrolizumab 
35 
Protocol/Amendment No.:   
 
 
 
 
 
 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 5.0 (see Section 11.2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
Tumor imaging of the chest, abdomen and pelvis should be performed by computed 
tomography (CT) with iv contrast.  An alternative is an MRI of the abdomen/pelvis with iv 
contrast and a chest CT (with or without iv contrast).  


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
7.1.2.7 Initial Tumor Imaging  
Initial tumor imaging must be performed within 28 days prior to the first dose of trial 
treatment.  Scans performed as part of routine clinical management are acceptable for use as 
the screening scan if they are of diagnostic quality and performed within 28 days prior to the 
first dose of trial treatment. The same imaging technique should be used for a given subject 
throughout the trial. 
7.1.2.8 Tumor imaging During Trial 
The first imaging assessment during treatment should be performed at 9 weeks (63 ±7 days) 
from Cycle 1, Day 1. Subsequent imaging should initially be performed every 9 weeks (63 
±7 days) or more frequently, if clinically indicated. After the first 12 months on trial therapy, 
the imaging interval should be increased to every 12 weeks (84 ±7 days). Imaging timing 
should follow calendar days and should not be adjusted for delays in cycle starts. Imaging 
should continue to be performed until disease progression, the start of new anti-cancer 
treatment, withdrawal of consent, death, or notification by the Sponsor, whichever occurs 
first.  
Per RECIST 1.1, PRs and CRs should be confirmed by a repeat tumor imaging assessment 
not less than 4 weeks from the date the response was first documented. The tumor imaging 
for confirmation of response may be performed at the earliest 4 weeks after the first 
indication of response, or at the next scheduled scan (i.e., 9 weeks later). Subjects will then 
return to regular scheduled imaging every 9 weeks, starting with the next scheduled imaging 
time point. Subjects who obtain a confirmation scan do not need to undergo the next 
scheduled tumor imaging if it is < 4 weeks later; tumor imaging may resume at the 
subsequent scheduled imaging time point. 
7.1.2.9 Tumor Tissue Collection 
Archival tissue will be obtained, if available, to assess for PD-L1 expression and MMR 
status.  Availability of archival tissue will not be required for trial enrollment. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below (Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.   


Product:   Pembrolizumab 
37 
Protocol/Amendment No.:   
 
 
 
 
 
 
Table 6:  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Carbon Dioxide 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
  (CO2 or biocarbonate) 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
Calcium 
 
Thyroid stimulating hormone (TSH) 
 
Chloride 
 
 
 
Glucose 
 
 
 
Potassium   
 
 
 
Sodium 
 
  
 
Total Bilirubin 
 
  
 
Total protein 
 
  
 
Blood Urea Nitrogen 
 
  
 
 
 
 
† Perform on women of childbearing potential only.  
 
 
 


Product:   Pembrolizumab 
38 
Protocol/Amendment No.:   
 
 
 
 
 
 
Laboratory tests for screening should be performed within 28 days prior to the first dose of 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing.  Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of trial treatment.  
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.5.5.  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4). 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
Within 42 days prior to enrollment, potential subjects will be evaluated to determine if they 
fulfill the entry requirements as set forth in section 5.1.  Screening procedures may be 
repeated.   
Imaging for baseline tumor assessment, laboratory tests and ECOG status are to be 
performed within 28 days prior to the first dose of trial treatment 
For women of reproductive potential, a serum pregnancy test will be performed 72 hours 
prior to the first dose of trial treatment.   
7.1.5.2 Treatment Period 
Visit requirements are outlined in section 6.0 – Trial Flow Chart.  A window of +/- 3 days is 
permitted for tests and trial drug infusion 
7.1.5.3 Post-Treatment Visits 
7.1.5.3.1  Safety Follow-Up Visit 


Product:   Pembrolizumab 
39 
Protocol/Amendment No.:   
 
 
 
 
 
 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  Subjects who are eligible for retreatment 
with pembrolizumab (as described in Section 7.1.5.5) may have up to two safety follow-up 
visits, one after the Treatment Period and one after the Second Course Phase. 
 
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 9 (+/- 7 days) weeks with 
radiologic imaging to monitor disease status. Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, end of the study or if the subject begins retreatment with pembrolizumab 
as detailed in Section 7.1.5.5.  Information regarding post-study anti-neoplastic treatment 
will be collected if new treatment is initiated. 
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.  
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 


Product:   Pembrolizumab 
40 
Protocol/Amendment No.:   
 
 
 
 
 
 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome. 
Laboratory tests and vital signs which fall out of normal range will only be reported as 
adverse events if considered clinically significant by the investigator. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  An overdose of lenvatinib will be defined as any 
dose of 120 mg or greater (≥5 times the indicated dose). No specific information is available 
on the treatment of overdose of pembrolizumab or lenvatinib. Appropriate supportive 
treatment should be provided if clinically indicated. In the event of overdose, the subject 
should be observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 


Product:   Pembrolizumab 
41 
Protocol/Amendment No.:   
 
 
 
 
 
 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation 
of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is another important medical event  
 Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 


Product:   Pembrolizumab 
42 
Protocol/Amendment No.:   
 
 
 
 
 
 
● 
Is associated with an overdose. 
 
Refer to Table 6.5for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details) that occurs to any subject must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety if it causes the 
subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Merck product, must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to Merck product, must be reported within 24 hours to the Sponsor and 
within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, 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.  
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE. 
 


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 5.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
Laboratory tests and vital signs which fall out of normal range will only be reported as 
adverse events if considered clinically significant by the investigator. 


45 
 
  
 
 
 
Table 6.5  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days.. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 


46 
 
  
 
 
 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event will be provided by an investigator 
who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures 
that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 


47 
 
  
 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is 
reasonable.  The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck  product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated 
AE.) 


48 
 
  
 
 
 
 
7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
Simon two-stage single-arm phase II study 
8.2 
Statistical Analysis Plan 
This will be a standard phase II study.  The sample size calculation is based on the 
assumption that a true response of >38% would generate interest in a larger randomized 
study.  With 35 patients we will be able to test the hypothesis that the true response rate is 
38% versus 18% (null) with a power of 90% and a type 1 error of 8%.  Patients will be 
accrued to the protocol according to a Simon’s two-stage minimax design.  20 patients will 
be enrolled in stage 1.  If 4 or more responses are observed, than another 15 subjects will be 
enrolled into stage 2.  At the completion of the study, if 10 or more responses out of N=35 
are observed, significance at 8% is reached.  Under this design, if the true response rate is 
≥38%, then the probability of observing ≥1 response in stage 1 is 95%.   
The progression-free survival (PFS) estimates will be shown by Kaplan-Meier curve, and 
noted at landmark times: 3, 6, and 12 months.  For patients with a response, the duration of 
response will be plotted using a Kaplan-Meier curve and the median survival obtained from 
it.  The progression-free survival estimates will be shown by Kaplan-Meier curve, and noted 
at landmark times: 3, 6, and 12 months.  The overall survival (OS) estimates will be shown 
by Kaplan-Meier curve, and noted at landmark times, such as: median and 12 months.  
Overall safety will be assessed by identifying the highest toxicity grade for each patient; this 
will also be done for selected key toxicities. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 


49 
 
  
 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
Lenvatinib 10 mg  
Hard hypromellose capsules 
Lenvatinib 4mg 
Hard hypromellose capsules 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 


50 
 
  
 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.     
10.2 Data Management 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. 
This information enables the study to be fully documented and the study data to be 
subsequently verified. 
Original source documents supporting entries in the case report forms include but are not 
limited to hospital records, clinical charts, laboratory and pharmacy records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays. 
 
The trial will be monitored per Moffitt Cancer Center policy MRI-P.PSO.03, Monitoring of 
Investigator Initiated Clinical Research. Data will be captured in Oncore, Moffitt’s Clinical 
Trials Database, Regulatory documents and case report forms will be monitored internally 
according to Moffitt Cancer Center Monitoring Policies. Monitoring will be performed 
regularly to verify data is accurate, complete and verifiable from source documents; and the 
conduct of the trial is in compliance with the currently approved protocol/amendments, Good 
Clinical Practice, and applicable regulatory requirements 
Retained records will include all documentation of adverse events, records of study drug 
receipt and dispensation, and all IRB correspondence for at least 5 years after the 
investigation is completed. 
 
 
 


51 
 
  
 
 
11.0 APPENDICES 
11.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 


52 
 
  
 
 
 
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