A Multicenter, Open-Label Phase 2 Study to Evaluate the Safety and Efficacy of Lenvatinib in Combination With Pembrolizumab in Black Participants With Mismatch Repair-Proficient Recurrent Endometrial Cancer
Phase: PHASE2
Conditions: Endometrial Cancer, Mismatch Repair-Proficient, Recurrent Endometrial Cancer
Sponsor: Virginia Commonwealth University

MCC-21-18659
NCT05263492
Multicenter, Open-Label Phase 2 Study to Evaluate the Safety and Efficacy of Lenvatinib in 
Combination with Pembrolizumab in Black Participants with Mismatch Repair-Proficient 
Recurrent Endometrial Cancer
5/09/2024

 
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TABLE OF CONTENTS 
SCHEMA ................................................................................................................................... 2 
REVISION HISTORY ................................................................................................................. 3 
TABLE OF CONTENTS ............................................................................................................ 5 
LIST OF TABLES ...................................................................................................................... 8 
LIST OF ABBREVIATIONS ....................................................................................................... 9 
1 
BACKGROUND .........................................................................................................10 
1.1 
CANCER IMMUNOTHERAPY – PROMISE AND LIMITATIONS .................................................10 
1.2 
PROPOSED IMMUNOTHERAPY REGIMEN .........................................................................10 
1.3 
STUDY RATIONALE........................................................................................................12 
1.4 
CORRELATIVE STUDIES .................................................................................................13 
2 
OBJECTIVES .............................................................................................................15 
2.1 
PRIMARY OBJECTIVE ....................................................................................................15 
2.2 
SECONDARY OBJECTIVES .............................................................................................15 
2.3 
EXPLORATORY OBJECTIVES ..........................................................................................15 
3 
STUDY DESIGN .........................................................................................................16 
3.1 
GENERAL DESCRIPTION ................................................................................................16 
3.2 
PRIMARY ENDPOINT ......................................................................................................16 
3.3 
SECONDARY ENDPOINTS ...............................................................................................16 
3.4 
EXPLORATORY ENDPOINTS ...........................................................................................16 
3.5 
MULTICENTER SITE PARTICIPATION ...............................................................................16 
4 
PATIENT SELECTION ...............................................................................................17 
4.1 
INCLUSION CRITERIA .....................................................................................................17 
4.2 
EXCLUSION CRITERIA ...................................................................................................18 
5 
STUDY ENTRY AND WITHDRAWAL PROCEDURES ..............................................21 
5.1 
STUDY ENTRY PROCEDURES.........................................................................................21 
5.2 
STUDY WITHDRAWAL ....................................................................................................22 
5.3 
LOST TO FOLLOW-UP ....................................................................................................22 
6 
STUDY TREATMENT ................................................................................................22 
6.1 
BASELINE TESTS AND PROCEDURES ..............................................................................22 
6.2 
INVESTIGATIONAL AGENT ADMINISTRATION ....................................................................22 
6.3 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ....................25 
6.4 
DURATION OF THERAPY ................................................................................................25 
6.5 
DURATION OF FOLLOW-UP ............................................................................................26 
6.6 
STUDY POCKET CARD FOR PATIENTS ............................................................................26 
6.7 
MONITORING PATIENT ADHERENCE ...............................................................................26 
7 
DOSING DELAYS/DOSE MODIFICATIONS ..............................................................27 
7.1 
RECORDING DOSE DELAYS AND OMISSIONS ...................................................................27 
7.2 
TOXICITY GRADING .......................................................................................................27 
7.3 
LENVATINIB TREATMENT MODIFICATION .........................................................................27 
7.4 
PEMBROLIZUMAB TREATMENT MODIFICATION .................................................................29 

 
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ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS ..............31 
8.1 
DEFINITIONS .................................................................................................................31 
8.2 
KNOWN AES LIST .........................................................................................................32 
8.3 
TIME PERIOD AND GRADE OF AE CAPTURE ....................................................................33 
8.4 
PROCEDURES FOR RECORDING AES, SAES, AND UPS ...................................................33 
8.5 
EXPEDITED REPORTING PROCEDURES ...........................................................................33 
9 
PHARMACEUTICAL INFORMATION ........................................................................34 
9.1 
LENVATINIB (LENVIMA) ..................................................................................................34 
9.2 
PEMBROLIZUMAB (KEYTRUDA) .......................................................................................39 
10 
MEASUREMENT OF EFFECT ...................................................................................45 
10.1 
EVALUATION CRITERIA FOR TUMOR RESPONSE ..............................................................45 
10.2 
IMAGING .......................................................................................................................46 
10.3 
CENTRALIZED RADIOLOGY REVIEW ................................................................................46 
11 
CORRELATIVE STUDIES .........................................................................................46 
11.1 
PARTICIPATION IN CORRELATIVE STUDIES ......................................................................46 
11.2 
PARTICIPATION IN URINE, BLOOD, AND VAGINAL CORRELATIVE STUDIES AND PROS ........46 
11.3 
URINE AND VAGINAL SAMPLES FOR MICROBIOME ...........................................................46 
REFER TO THE MCC-21-18659 BIOSPECIMEN MANUAL .............................................................46 
11.4 
OPTIONAL GENETIC ANCESTRY ANALYSIS FROM DNA ....................................................46 
REFER TO THE MCC-21-18659 BIOSPECIMEN MANUAL .............................................................47 
11.5 
CORRELATIVE BLOOD SAMPLES ....................................................................................47 
11.6 
TRACKING AND COLLECTION OF SAMPLES ......................................................................47 
12 
STUDY CALENDAR ..................................................................................................48 
13 
STATISTICAL CONSIDERATIONS ...........................................................................50 
13.1 
STUDY DESIGN AND ANALYSIS .......................................................................................50 
13.2 
SAMPLE SIZE/ACCRUAL RATES .....................................................................................50 
14 
DATA AND SAFETY MONITORING PLAN (DSMP) ..................................................50 
14.1 
MONITORING AND AUDITING ..........................................................................................51 
15 
REGULATORY COMPLIANCE AND ETHICS ...........................................................51 
15.1 
ETHICAL STANDARD ......................................................................................................51 
15.2 
REGULATORY COMPLIANCE ...........................................................................................51 
15.3 
INSTITUTIONAL REVIEW BOARD .....................................................................................51 
15.4 
INFORMED CONSENT PROCESS .....................................................................................51 
15.5 
PATIENT CONFIDENTIALITY ............................................................................................52 
16 
DATA COLLECTION AND MANAGEMENT ..............................................................52 
16.1 
DATA MANAGEMENT RESPONSIBILITIES .........................................................................52 
16.2 
CASE REPORT FORMS AND DATA COLLECTION ...............................................................52 
16.3 
ONCORE DATA ENTRY ..................................................................................................53 
16.4 
STUDY RECORD RETENTION .........................................................................................53 
17 
REFERENCES ...........................................................................................................54 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ..............................................................58 

 
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APPENDIX 2. DOSE MODIFICATION AND TOXICITY MANAGEMENT FOR IMMUNE-
RELATED ADVERSE EVENTS (IRAES) ASSOCIATED WITH PEMBROLIZUMAB ...............69 

 
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LIST OF TABLES 
Table 1. Management of Pembrolizumab Infusion-related Reaction ..........................................24 
Table 2: Recommended Dosage Modifications for Lenvatinib ...................................................28 
Table 3: Recommended Dosage Reduction Steps for Lenvatinib ..............................................28 
Table 4: Recommended Dosage Modifications for Pembrolizumab ...........................................30 
Table 5. Expedited Reporting Requirements for Participating Sites...........................................33 
Table 6. Expedited Reporting Requirements for Coordinating Center .......................................34 
Table 7. Adverse Reactions Occurring in ≥20% of Patients with Endometrial Carcinoma in 
KEYNOTE-146..........................................................................................................................44 
Table 8. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) or 
≥3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-146 ..........................45 
 

 
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LIST OF ABBREVIATIONS 
AE 
 
adverse event 
CAR-T  
chimeric antigen receptor-modified T cells 
CTCAE 
common terminology criteria for adverse events 
CTLA-4 
cytotoxic T lymphocyte-associated protein 4 
CR 
 
complete response 
dMMR  
deficient mismatch repair 
DOR  
duration of response 
DSMC  
data and safety monitoring committee 
DSMP  
data and safety monitoring plan 
ECOG  
Eastern Cooperative Oncology Group 
EPD 
 
Early Phase Development  
eCRF  
electronic case report form 
FDA 
 
Food and Drug Administration 
HADS-D 
hospital anxiety and depression scale-depression subscale 
HADS-A 
hospital anxiety and depression scale-anxiety subscale 
HIV 
 
human immunodeficiency virus 
Ig 
 
immunoglobulin 
IHC 
 
immunohistochemistry 
irAE 
 
immune-related adverse event 
IRB 
 
Institutional Review Board 
ITIM 
 
immunoreceptor tyrosine-based inhibition motif 
ITSM  
immunoreceptor tyrosine-based switch motif 
IV 
 
intravenous 
LVEF  
left ventricular ejection fraction 
mAb 
 
monoclonal antibody 
MCC  
Massey Cancer Center 
MOE  
margin of errors 
MSI-H  
microsatellite instability-high 
MSS 
 
microsatellite stable 
NCI 
 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
NYHA  
New York Heart Association 
ORR  
objective response rate 
OS 
 
overall survival 
PD-1  
programmed cell death-1 
Pdcd1  
programmed cell death protein 1 
PD-L2  
programmed cell death ligand 2 
PFS 
 
progression-free survival 
PRO 
 
patient-reported outcomes 
PR 
 
partial response 
SD 
 
stable disease 
SAE 
 
serious adverse event 
UP 
 
unanticipated problem 
VCU 
 
Virginia Commonwealth University 
WCBP  
woman of child-bearing potential 

 
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1 BACKGROUND 
1.1 
Cancer Immunotherapy – Promise and Limitations 
Over the past 4 decades, the promise of immunotherapy for treating cancer has waxed 
and waned, but has recently enjoyed a dramatic renaissance of enthusiasm. For many 
years, the successes of manipulating the immune response to induce regression of 
cancers were largely limited to murine models, human melanoma, and renal cell 
carcinoma, with little cause for optimism in the treatment of epithelial malignancies, which 
are the most common causes of cancer death (1-3). 
Immunotherapeutic approaches can be roughly divided into 2 main categories—active and 
passive. Active immune therapies are aimed at stimulating and activating the host’s own 
immune system to recognize and destroy cancer cells. This category includes vaccines, 
infusion of immunologically active cytokines, and altering the tumor itself to make it more 
immunogenic. Passive immunotherapy refers to treatments that involve infusing antigen-
targeted molecules or cells into the host, which then attack the tumor directly, either 
causing tumor cell destruction or inhibition of tumor growth. These passive approaches 
include adoptive cellular therapy, such as infusion of T lymphocytes which have been 
removed from the patient, manipulated and expanded in vitro, and then reinfused into the 
host, sometimes in combination with recombinant cytokines that encourage expansion of 
the cells and increase their activity (4). For example, tumor-infiltrating lymphocytes grown 
from biopsy samples of melanoma tumors have induced dramatic regression in patients 
with metastatic disease. More recently, T cells genetically modified to express chimeric 
antigen receptors (CAR-T cells) created from antibody-antigen combining regions and T-
cell signaling molecules have been used successfully to treat hematologic malignancies (5-
7). Monoclonal antibodies, either alone or linked to cytotoxic molecules, are another 
example of passive immunotherapy that has had considerable success (8). To a varying 
degree, monoclonal antibodies that recognize cancer cell surface targets may be both 
passive and active, in the sense that antibodies bound to cancer cells can directly inhibit 
signaling by the target molecule and can also trigger host immune cells (e.g., natural killer 
[NK] cells) to attack and kill the cancer cells (9) (10). 
The most recent wave of excitement about immunotherapy has been generated by what 
may be considered a “hybrid” form of therapy that is both passive and active. This 
approach, termed “immune checkpoint inhibition”, uses monoclonal antibodies to inhibit 
mechanisms that suppress T-cell activation and function, and led to the 2018 Nobel Prize 
in Physiology or Medicine (11). 
1.2 
Proposed Immunotherapy Regimen 
 Pembrolizumab (Keytruda) 
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 

 
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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 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, Tregs, and NK 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 patients with melanoma. 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. Pembrolizumab is approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilumumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor. Examples of additional indications include non-small cell lung 
cancer (NSCLC), head and neck squamous cell carcinoma, classical Hodgkin 
lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, 
microsatellite instability-high cancer, and gastric/gastroesophageal junction cancer. 
 Lenvatinib (Lenvima, Eisai) 
Lenvatinib is an oral, multi–tyrosine kinase inhibitor active against RET, VEGFR1–3, 
FGFR1–3, KIT, and PDGFRα (12-16). It is approved in the US for the treatment of 
(1) patients with locally recurrent or metastatic, progressive, radioactive iodine 
refractory differentiated thyroid cancer, (2) in combination with everolimus for 
patients with advanced renal cell carcinoma following 1 prior antiangiogenic therapy, 
(3) for the first-line treatment of patients with unresectable hepatocellular carcinoma, 
and (4) in combination with pembrolizumab, for the treatment of patients with 
advanced endometrial carcinoma that is not MSI-H or dMMR who have disease 

 
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 Rationale for Version 3 Changes 
In patients with advanced or recurrent endometrial cancer, the addition of 
pembrolizumab to standard chemotherapy resulted in significantly longer 
progression-free survival than with chemotherapy alone. In the mismatch repair-
proficient cohort, median progression-free survival was 13.1 months with 
pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 
0.71; P<0.001 (17) 
Dostarlimab plus carboplatin–paclitaxel significantly increased progression-free 
survival among patients with primary advanced or recurrent endometrial cancer In 
the overall population, progression-free survival at 24 months was 36.1% (95% CI, 
29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the 
placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival 
at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% 
CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 
0.87).(18) 
1.4 
Correlative Studies  
 Patient-Reported Outcomes (PROs) 
PROs provide unique information on the impact of a medical condition and its 
treatment from the patient’s perspective and help ensure the impact of a trial 
intervention is comprehensively assessed. PROs to be measured include health 
related quality of life (HRQOL), financial toxicity and depression and anxiety.  
EORTC-QLQ-C30+EN24 is a PRO measurement system developed to assess the 
health related quality of life of cancer patients. It has been translated and validated 
(19) (into over 100 languages and is used each year in more than 5,000 studies 
worldwide. Subscales include assessments of physical, role, cognitive, emotional, 
and social function; physical symptoms; and overall QOL. Scores are linearly 
transformed to a 0-100 scale, where higher scores for the functional subscales 
represent healthier level of functioning. Higher scores on the symptom subscales 
represents higher level of symptomatology. Symptoms specific to endometrial 
cancer are assessed including lymphoedema, urological symptoms, gastrointestinal, 
body image, and sexual/vaginal symptoms; and single items assess back/pelvic 
pain, tingling/numbness, muscular/joint pain, hair loss, taste change, sexual interest, 
sexual activity, and sexual enjoyment. 
EQ-5D-5L is a self-assessed, health related, quality of life questionnaire. The 
scale measures quality of life on a 5-component scale including mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression. Each level is 
rated on scale that describes the degree of problems in that area (i.e. I have no 
problems walking about, slight problems, moderate problems, severe problems, 
or unable to walk). This tool also has an overall health scale where the rater 
selects a number between 1-100 to describe the condition of their health, 100 
being the best imaginable. Convergent validity was demonstrated by a 
correlation between EQ-5D-5L and the dimensions of WHO 5, (r=.43, P<.001) . 
(20).The EuroQuol approach is reliable, average test-re-test reliability using 
inter-class coefficients with mean of .78 and .73 (20-23).   

 
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 Explore ancestral markers and microbiome and cytokine/growth factor levels in 
blood, urine, and vaginal samples  in Black patients with recurrent endometrial 
cancer undergoing treatment with lenvatinib and pembrolizumab 
3 STUDY DESIGN 
3.1 
General Description 
This study is a single-arm, open-label, multicenter phase 2 trial designed to prospectively 
evaluate the safety and efficacy of lenvatinib in combination with pembrolizumab for 
mismatch repair-proficient recurrent endometrial cancer in Black patients (a population 
under-represented on 2 FDA registration trials). Up to 100 patients will be treated at up to 
10 sites throughout the United States. All patients will receive lenvatinib and 
pembrolizumab while participating in the study. Patients will continue to receive lenvatinib 
and pembrolizumab until their disease progresses or they experience unacceptable 
toxicity. 
3.2 
Primary Endpoint 
ORR at 24 weeks in Black patients with recurrent endometrial cancer treated with 
lenvatinib 20 mg orally daily in combination with pembrolizumab 200 mg IV every 3 weeks 
3.3 
Secondary Endpoints 
 Proportion of patients who are alive and have not had disease progression or 
relapse following last dose of study treatment 
 Using criteria in the National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 5.0 (CTCAE v5.0), all AEs captured as described in 
Section 8.4. 
 Number of patients who discontinue treatment due to treatment-related AEs. 
3.4 
Exploratory Endpoints 
 Effects of lenvatinib and pembrolizumab on patient-reported outcomes of health 
related quality of life (EORTC-QLQ-C30+EN24), anxiety and depression (HADS), 
and financial toxicity (FACIT COST) in the study population 
 Genetic ancestry analysis, microbiome analysis, and levels of cytokines/growth 
factors in blood, and urine 
 Quantify patient-reported gendered racial microaggressions, in-group identification 
scale, and Africultural coping systems inventory and compare with allostatic load 
scores, inflammatory markers and treatment response. 
3.5 
Multicenter Site Participation 
This study will be conducted at up to 10 sites across the United States. The VCU MCC 
Early Phase Development Department serves as the Coordinating Team.  

 
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4 PATIENT SELECTION 
4.1 
Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible to participate in the 
study: 
 
Yes 
No 
N/A 
 Histologically and/or cytologically confirmed endometrioid, 
serous, clear cell, carcinosarcoma, or de-differentiated or 
undifferentiated endometrial cancer with radiographic and/or 
clinical evidence of disease progression 
 
 
 
 Documented microsatellite stable disease as tested by either 
MSI PCR or DNA mismatch repair (MMR) by IHC 
 
 
 
 Self-identify as being of predominantly (>50%) Black race, 
inclusive of Black, African-American, Black Hispanic (Afro-
Latinx), African, or Afro-Caribbean ancestry 
 
 
 
 Received, ineligible for (by investigator determination), or 
declined platinum containing chemotherapy 
 
 
 
 Received no greater than 2 prior lines of therapy. Maintenance 
therapies and hormonal therapies will NOT count as a line of 
therapy. Patients may have received prior immune checkpoint 
inhibitor therapy or bevacizumab in one of the 2 prior lines of 
therapy. 
 
 
 
 Measurable disease as determined by RECIST v1.1: 
● At least one lesion of ≥10 mm in the longest diameter for a 
non-lymph node, or ≥15 mm in the short-axis diameter for a 
lymph node that is serially measurable using computerized 
tomography/magnetic resonance imaging (CT/MRI) 
● Target lesions limited to a radiated field must show evidence 
of substantial size increase according to previous scans to 
be deemed a target lesion 
 
 
 
 Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 to 2 (see Appendix 1) 
 
 
 
 Age ≥ 18 years 
 
 
 
 Ability to swallow oral medications 
 
 
 

 
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Yes 
No 
N/A 
 Patients who are not postmenopausal or have not undergone 
hysterectomy must have a documented negative serum 
pregnancy test within 72 hours prior to initiating study treatment 
Note: Postmenopausal is defined as any of the following: 
• 
Age ≥ 60 years 
• 
Age < 60 years and amenorrheic for at least 1 year with 
follicle-stimulating hormone (FSH) and plasma estradiol 
levels in the postmenopausal range 
• 
Bilateral oophorectomy 
 
 
 
 Patients of child-bearing potential must agree to use a medically 
accepted method for preventing pregnancy during and for a 
minimum of 4 months following the last dose of lenvatinib or 
pembrolizumab 
 
 
 
 Patients with known brain metastases will be eligible if they have 
completed primary brain therapy (such as whole brain 
radiotherapy, stereotactic radiosurgery, or complete surgical 
resection) and if they have remained clinically stable, 
asymptomatic, and off of steroids for at least 28 days before 
starting study treatment 
 
 
 
 Toxicities from previous cancer therapies resolved to grade ≤1 
unless specified otherwise (exceptions: chronic residual 
toxicities that in the opinion of the investigator are not clinically 
relevant, given the known safety/toxicity profiles of Lenvatinib 
and pembrolizumab, such as alopecia, grade ≤2 anemia; 
neuropathy related to previous chemotherapy must be resolved 
to grade ≤2) 
 
 
 
 Ability to understand and the willingness to sign a written 
informed consent document 
 
 
 
 
4.2 
Exclusion Criteria 
A patient who meets any of the following exclusion criteria is ineligible to participate in the 
study: 
 
Yes 
No 
N/A 
 Endometrial leiomyosarcoma or endometrial stromal sarcoma 
 
 
 

 
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Yes 
No 
N/A 
 Unstable central nervous system (CNS) metastases 
 
 
 
 Gastrointestinal malabsorption, gastrointestinal anastomosis, 
or any other condition that might affect the absorption of 
lenvatinib 
 
 
 
 Pre-existing grade ≥3 gastrointestinal or non-gastrointestinal 
fistula 
 
 
 
 Radiographic 
evidence 
of 
major 
blood 
vessel 
invasion/infiltration 
 
 
 
 Clinically significant hemoptysis or tumor bleeding within 2 
weeks prior to the first dose of study treatment 
 
 
 
 History of congestive heart failure greater than New York Heart 
Association (NYHA) Class II, unstable angina, myocardial 
infarction, cerebrovascular accident, stroke, or cardiac 
arrhythmia associated with hemodynamic instability within 12 
months of the first dose of study treatment 
 
 
 
 Known history or evidence of interstitial lung disease or active, 
non-infectious pneumonitis 
 
 
 
 Administration of or condition requiring administration of 
systemic 
steroid 
therapy 
or 
any 
other 
form 
of 
immunosuppressive therapy within 7 days prior to initiating 
study treatment 
Exception: Patients with conditions that can be managed with 
steroids equivalent to or less than an oral prednisone dose of 
10 mg daily are not excluded from the study 
 
 
 
 Active autoimmune disease (with the exception of psoriasis) 
that has required systemic treatment in the past 2 years (ie, with 
use 
of 
disease-modifying 
agents, 
corticosteroids, 
or 
immunosuppressive drugs) or a documented history of clinically 
severe autoimmune disease or a syndrome that requires 
systemic steroids or immunosuppressive agents 
Note: Patients with the conditions or medical history listed below 
are not excluded from the study. 
• 
Vitiligo 
• 
Resolved childhood asthma/atopy 
• 
Requirement for intermittent use of bronchodilators or local 
steroid injections or topical steroids 
 
 
 

 
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Yes 
No 
N/A 
• 
Hypothyroidism stable on hormone replacement 
• 
Sjogren’s Syndrome 
 Has received >2 prior systemic chemotherapy regimen (other 
than adjuvant or neoadjuvant) for endometrial cancer; 
participants may receive up to 2 regimens of platinum-based 
chemotherapy in total, as long as one is given in the 
neoadjuvant or adjuvant treatment setting 
 
 
 
 Prior anticancer treatment within 28 14 days of study start 
 
 
 
 Has received prior treatment with an agent directed to a 
stimulatory or co-inhibitory T-cell receptor other than an anti-
PD-1, anti-PD-L1, or anti-PD-L2 agent, and who has 
discontinued from that treatment due to a grade 3 or higher 
immune-related adverse event (irAE) 
 
 
 
 Has received prior radiation therapy within 21 days of study start 
with the exception of palliative radiotherapy to bone lesions, 
which is allowed if completed 2 weeks before study start; 
participants must have recovered from all radiation-related 
toxicities and/or complications prior to randomization 
 
 
 
 Participants with urine protein ≥3.5 gram (g)/24 hour 
 
 
 
 Administration of a live vaccine within 30 days prior to initiating 
study treatment 
Note: Seasonal influenza vaccines for injection are generally 
inactivated flu vaccines and are permitted; however, intranasal 
influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, 
and are not allowed. COVID-19 vaccines are allowed and 
encouraged  
 
 
 
 Administration of any investigational agent within 4 weeks prior 
to initiating study treatment 
 
 
 
 History of solid organ or allogeneic stem cell transplant 
 
 
 
 Known intolerance to either of the study drugs (or any of the 
excipients) 
 
 
 
 Known immunodeficiency, eg, human immunodeficiency virus 
(HIV) 
Note: HIV testing is not required for eligibility screening 
 
 
 
 Known active hepatitis B or C 
 
 
 

 
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Yes 
No 
N/A 
Note: hepatitis B and C testing is not required for eligibility 
screening 
 Serious (ie, grade ≥3) uncontrolled infection 
 
 
 
 Pregnancy or breastfeeding 
 Diagnosis or treatment for another malignancy within 2 years 
prior to study registration, with the following exceptions: 
complete resection of basal cell carcinoma or squamous cell 
carcinoma of the skin,  and any in situ malignancy. 
 
 
 
 Medical, psychological, or social condition that, in the opinion of 
the investigator, may increase the patient’s risk or limit the 
patient’s adherence with study requirements 
 
 
 
 
5 STUDY ENTRY AND WITHDRAWAL PROCEDURES 
5.1 
Study Entry Procedures 
 Required Pre-Registration Screening Tests and Procedures 
Refer to the study calendar in Section 12 for the screening tests and procedures 
that are required prior to registration and for the timing of these events relative to the 
start of treatment. 
Screen failures are defined as patients who consent to participate in the clinical trial 
but are not subsequently registered in the study. Demographics and consent data 
for these patients are entered into OnCore. 
 Registration Process 
After informed consent has been obtained, the following documents are submitted to 
the VCU MCC Coordinating Center 
 for study registration: 
 
• 
Completed registration cover sheet or request form as provided by the 
coordinating center 
• 
Attestation of patient eligibility  
• 
Signed and dated consent form 
The Coordinating Center will complete the registration process by assigning a study 
identification (ID) number and returning a Confirmation of Registration to the registering 
study team. Study treatment may not begin until the Confirmation of Registration 

 
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assigning a study ID number has been received from the registrar. The registering study 
team will enter the patient’s initial enrollment data (eg, demographics, consent, eligibility, 
on-study, treatment assignment) into the OnCore database within 24 hours following 
study registration (before treatment begins). 
 
5.2 
Study Withdrawal 
A patient may decide to withdraw from the study at any time. Patients must be withdrawn 
from the study when any of the following occurs:  
• The patient has withdrawn consent for study treatment and study procedures. 
• If, in the investigator's opinion, continuation of the study requirements would be harmful 
to the patient's well-being. 
• The patient is lost to follow-up. (See Sction 5.3) 
The reason for withdrawal from the study and the date the patient was removed from the 
study must be documented in the source documents and OnCore database. 
5.3 
Lost to Follow-Up 
A participant is identified as lost-to-follow-up (LTFU) if all of the following criteria are met:  
• The last contact date for a participant has exceeded 2 consecutive years.  
• Since the last contact date, documentation of at least 3 attempts to contact the 
participant by telephone and a certified letter to the last known address has either been 
returned or not answered within 7 days of confirmation that the letter was received or 
undeliverable.  
• A Social Security Death Index (SSDI) search has been completed with negative results. 
If a participant is determined to be LTFU, the certified letter receipt will be filed in the 
participant’s research record with a copy of the letter sent, a thorough explanation of the 
contact attempts will be documented in the participant’s research record, and the 
participant’s status will be changed/confirmed in OnCore. 
6 STUDY TREATMENT 
6.1 
Baseline Tests and Procedures 
Refer to the study calendar in Section 12 for requirements prior to initiation of therapy. 
6.2 
Investigational Agent Administration 
Participants will receive pembrolizumab 200 mg administered by IV infusion on day 1 of 
each 21-day cycle plus lenvatinib 20 mg administered orally (PO) once daily (QD) during 
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 Premedications for Pembrolizumab 
• 
Patients may be premedicated for nausea and vomiting. Choice of antiemetic is 
at the treating physician’sdiscretion with the exception that steroids are NOT 
permitted for this purpose. 
• 
Refer to Table 1 for management of infusion reactions. 
 Administration of Pembrolizumab 
Refer to Section 9.2.5 for preparation instructions. 
• 
Administer reconstituted pembrolizumab in intravenous infusion bag of either 
0.9% Sodium Chloride Injection or 5% Dextrose Injection. 
• 
Administer infusion solution over 30 minutes through an IV line containing a 
sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-
on filter. (Do not co-administer other drugs through the same infusion line.) 
• 
Every effort should be made to plan for administration as close to 30 minutes as 
possible. However, a window of -5 minutes and +10 minutes is permitted. 
 Pembrolizumab Infusion Reaction Treatment Guidelines 
Severe infusion reactions have been reported in 2 (0.1%) of 1562 patients receiving 
pembrolizumab in clinical trials. Management of a pembrolizumab infusion reaction 
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6.3 
General Concomitant Medication and Supportive Care Guidelines 
• 
Patients should receive appropriate supportive care measures as deemed necessary 
by the treating physician  and according to the current prescribing information for each 
agent. 
• 
Patients may be premedicated for nausea and vomiting. Choice of antiemetic is at the 
treating physician’s discretion with the exception that steroids are NOT permitted. 
• 
Refer to Table 1 for management of infusion reactions. 
 Supportive Care 
• 
Patients should receive appropriate supportive care measures as deemed 
necessary by the treating physician   
• 
Supportive care measures for the management of AEs with potential 
immunologic etiology, ie, irAEs, are outlined in Appendix 2. 
 Prohibited Medications and Treatments 
6.3.2.1 Cancer Treatment 
Cancer treatment (e.g., chemotherapy, biological therapy, immunotherapy, 
radiation therapy) other than the treatment specified in the protocol for this 
study is not permitted during study treatment.  
6.3.2.2 Other Medications 
• 
Live vaccines (examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, 
rabies, BCG, and typhoid vaccine) are prohibited. 
• 
Systemic glucocorticoids for any purpose other than to modulate 
symptoms from an event of suspected immunologic etiology are 
prohibited. Exception: Steroids equivalent to or less than an oral 
prednisone dose of 10 mg daily are permitted and steroids are allowed 
without limitation 
• 
Any investigational agent not specified in the protocol for this study is 
not permitted. 
6.4 
Duration of Therapy 
Study treatment will be administered per schema unless one of the following occurs (also 
see study withdrawal criteria in Section 5.2): 
• 
AE that requires discontinuation of study treatment (see Section 8) 
• 
Pregnancy 
• 
Determination by the investigator that discontinuation is in the patient’s best medical 
interest 

 
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• 
Patient decision to discontinue study treatment 
• 
Withdrawal of study sponsor support 
The reason for discontinuation of study treatment must be documented in the source 
documents and in the OnCore database. 
6.5 
Duration of Follow-Up 
 Initial AE Evaluation Period after Discontinuation of Treatment 
Patients who discontinue treatment for any reason other than death or their 
choice to withdraw from all study follow-up remain on study in follow-up status 
for an initial 30-day AE evaluation period following the last dose of study treatment. 
This 30-day post-treatment follow-up period is meant to capture resolution or 
stabilization of ongoing treatment-related AEs or evolution of new treatment-related 
AEs.  
The initial AE follow-up period may be extended if new or worsening treatment-
related AEs require longer observation. Similarly, the initial AE follow-up period may 
end early in the event of death, patient request to withdraw from follow-up, or 
initiation of new anticancer therapy. 
 Ongoing Follow-up 
Patients who discontinue treatment with ongoing SD, PR, or CR (see Section 10) 
remain in follow-up status for PFS by reported clinical status every 3 months until 
one of the following occurs: disease progression, relapse, or death. 
All patients will be followed for OS status every 3 months, until death or off-study.  
The primary reason(s) for a patient’s discontinuation from study treatment and from 
follow-up status are to be recorded in the source documents and the OnCore 
database. 
6.6 
Study Pocket Card for Patients 
A pocket card identifying the name of the study, the names of the study medications, and 
contact information including the study team and a 24-hour on-call study physician will be 
provided to each patient. The purpose of this card is to facilitate communication between 
the study team and the patient’s health care providers not involved with the study. Patients 
will be encouraged to carry the card with them at all times and to show it to their health 
care providers so that potential interactions with the study medications can be identified 
before initiating new medications. 
6.7 
Monitoring Patient Adherence  
Patients will be instructed to record their lenvatinib doses in the drug diary that will be 
provided.  
Adherence will be assessed at time points per Study Calendar. Patient reports of self-
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assess the patient’s adherence with the oral study treatment regimen. Adherence is 
defined as taking ≥ 80% of planned lenvatinib doses in a cycle. Doses omitted due to AE 
management will not count towards nonadherence. Patients who are not adherent will be 
re-instructed.  
7 DOSING DELAYS/DOSE MODIFICATIONS 
7.1 
Recording Dose Delays and Omissions 
All dosing delays and omissions will be recorded in the source documents and captured in 
the OnCore database. 
7.2 
Toxicity Grading 
AEs will be characterized and graded according to NCI CTCAE v5.0. 
7.3 
Lenvatinib Treatment Modification  
Dose modifications for lenvatinib are based on current prescribing information. 
Recommendations for lenvatinib dose interruption, reduction and discontinuation for 
adverse reactions are listed in Table 2. Table 3 lists the recommended dosage reductions 
of lenvatinib for adverse reactions. 

 
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bleeding. Needle biopsies (fine needle aspirations and core needle aspiration) are 
usually considered minor procedures. 
For major procedures, lenvatinib should be stopped 1 week (5 half-lives) before the 
procedure and then restarted once there is clear wound healing and no risk of 
bleeding, but at least 1 week after the procedure. It is up to the investigator to 
determine if it is a major or minor procedure. Usually a major procedure implies 
general anesthesia. 
7.4 
Pembrolizumab Treatment Modification  
Dose modifications for pembrolizumab are based on current prescribing information. 
No dose reduction for pembrolizumab is recommended. In general, withhold 
pembrolizumab for severe (grade 3) immune-mediated adverse reactions. Permanently 
discontinue pembrolizumab for life-threatening (grade 4) immune-mediated adverse 
reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic 
immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or 
less of prednisone or equivalent per day within 12 weeks of initiating steroids. 
Dosage modifications for pembrolizumab for adverse reactions that require management 
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† Resume in patients with complete or partial resolution (grades 0 to 1) after corticosteroid taper. 
Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or 
inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating 
steroids. 
‡ If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue 
pembrolizumab based on recommendations for hepatitis with no liver involvement. 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with 
Eosinophilia and Systemic Symptoms, SJS = Stevens-Johnson Syndrome, TEN = toxic epidermal 
necrolysis, ULN = upper limit normal 
8 ADVERSE EVENTS: DEFINITIONS AND REPORTING 
REQUIREMENTS 
8.1 
Definitions 
 Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 Serious AE (SAE)  
An AE is considered “serious” if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 
• 
death, 
• 
a life-threatening AE (An AE is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death.), 
• 
inpatient hospitalization or prolongation of existing hospitalization, 
• 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
• 
a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
 Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets all 
of the following criteria: 
• 
unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 

 
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IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• 
related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 AE Description and Grade 
The descriptions and grading scales found in the revised Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
 AE Expectedness 
AEs can be ‘Unexpected’ or ‘Expected’. 
Expected AEs are listed in Section 8.2 below. 
Unexpected AEs are those AEs occurring in one or more subjects participating in 
the research protocol, the nature, severity, or frequency of which is not consistent 
with either: 
• 
The known or foreseeable risk of AEs associated with the procedures involved 
in the research that are described in (a) the protocol-related document, such as 
the IRB-approved research protocol, any applicable investigator brochure, and 
the current IRB-approved informed consent document, and other relevant 
sources of information, such as product labeling and package inserts; or 
• 
The expected natural progression of any underlying disease, disorder, or 
condition of the subject(s) experiencing the AE and the subject’s predisposing 
risk factor profile for the AE. 
 AE Attribution 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is doubtfully related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.2 
Known AEs List 
See Section 9.2.11 

 
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VEGFR3 (FLT4). Lenvatinib inhibits other kinases 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; platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. 
Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell 
lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-
receptor substrate 2α (FRS2α) phosphorylation. 
In syngeneic mouse tumor models, lenvatinib decreased tumor-associated 
macrophages, increased activated cytotoxic T cells, and demonstrated greater 
antitumor activity in combination with an anti-PD-1 monoclonal antibody compared 
to either treatment alone. 
 Storage and Handling Requirements 
Lenvatinib 4-mg capsules are supplied as hard hypromellose capsules with 
yellowish-red body and yellowish-red cap, marked in black ink with “Є” on the cap 
and “LENV 4 mg” on the body. 
Lenvatinib 10 mg capsules are supplied as hard hypromellose capsules with yellow 
body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 10 
mg” on the body. 
Lenvatinib capsules are supplied in cartons of 6 cards. 
Store at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F) 
 Administration 
Oral. 
Reduce the dose for certain patients with renal or hepatic impairment. 
Take lenvatinib once daily, with or without food, at the same time each day. If a 
dose is missed and cannot be taken within 12 hours, skip that dose and take the 
next dose at the usual time of administration.  
The recommended dosage of lenvatinib is 20 mg orally once daily, in combination 
with pembrolizumab 200 mg administered as an intravenous infusion over 30 
minutes every 3 weeks, until unacceptable toxicity or disease progression. 
 Availability and Ordering 
Lenvatinib is commercially available and administration is standard of care for 
patients with endometrial cancer. The costs of lenvatinib and its administration will 
be the responsibility of the patient and/or the patient’s 3rd party payor. 
 Contraindications 
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 Pharmacokinetics 
In patients with solid tumors administered single and multiple doses of lenvatinib 
once daily, the maximum lenvatinib plasma concentration (Cmax) and the area 
under the concentration-time curve (AUC) increased proportionally over the dose 
range of 3.2 mg (0.1 times the recommended clinical dose of 24 mg) to 32 mg (1.33 
times the recommended clinical dose of 24 mg) with a median accumulation index 
of 0.96 (20 mg) to 1.54 (6.4 mg). 
Absorption 
The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours 
post-dose. 
Food Effect: Administration with a high fat meal (approximately 900 calories of 
which approximately 55% were from fat, 15% from protein, and 30% from 
carbohydrates) did not affect the extent of absorption, but decreased the rate of 
absorption and delayed the median Tmax from 2 hours to 4 hours. 
Distribution 
In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99% at 
concentrations of 0.3 to 30 μg/mL. The blood-to-plasmconcentration ratio ranged 
from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro. 
Elimination 
The terminal elimination half-life of lenvatinib was approximately 28 hours. 
Metabolism: The main metabolic pathways for lenvatinib in humans were identified 
as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. 
Excretion: Ten days after a single administration of radiolabeled lenvatinib, 
approximately 64% and 25% of the radiolabel were eliminated in the feces and 
urine, respectively. 
 Drug Interactions 
Effect of Other Drugs on Lenvatinib 
CYP3A, P-gp, and BCRP Inhibitors: Ketoconazole (400 mg daily for 18 days) 
increased lenvatinib (administered as a single 5 mg dose on Day 5) AUC by 15% 
and Cmax by 19%. P-gp Inhibitor: Rifampicin (600 mg as a single dose) increased 
lenvatinib (24 mg as a single dose) AUC by 31% and Cmax by 33%. 
CYP3A and P-gp Inducers: Rifampicin (600 mg daily for 21 days) decreased 
lenvatinib (24 mg as a single dose on Day 15) AUC by 18%. The Cmax was 
unchanged. 
In Vitro Studies with Transporters: Lenvatinib is a substrate of P-gp and BCRP but 
not a substrate for organic anion transporter (OAT) 1, OAT3, organic anion 
transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 
1, OCT2, multidrug and toxin extrusion (MATE) 1, MATE2-K, or the bile salt export 
pump (BSEP). 

 
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Effect of Lenvatinib on Other Drugs 
Clinical Studies with Substrates of CYP3A4 or CYP2C8: There is no projected 
significant drug-drug interaction risk between lenvatinib and midazolam (a CYP3A4 
substrate) or repaglinide (a CYP2C8 substrate). 
In Vitro Studies with Substrates of CYP or UDP-glucuronosyltransferase (UGT): 
Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and 
CYP3A. Lenvatinib does not inhibit CYP2A6 and CYP2E1. Lenvatinib induces 
CYP3A, but it does not induce CYP1A1, CYP1A2, CYP2B6, and CYP2C9. 
Lenvatinib inhibits UGT1A1, UGT1A4, and UGT1A9 in vitro, but likely only inhibits 
UGT1A1 in vivo in the gastrointestinal tract based on the expression of the enzyme 
in tissues. Lenvatinib does not inhibit UGT1A6, UGT2B7 or aldehyde oxidase. 
Lenvatinib does not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7. 
In Vitro Studies with Substrates of Transporters: Lenvatinib does not have the 
potential to inhibit MATE1, MATE2-K, OCT1, OCT2, OAT1, OAT3, BSEP, 
OATP1B1, or OATP1B3 in vivo. 
Lenvatinib has been reported to prolong the QT/QTc interval. Avoid coadministration 
of lenvatinib with medicinal products with a known potential to prolong the QT/QTc 
interval. 
 Warnings and Precautions 
Hypertension: Serious complications of poorly controlled hypertension have been 
reported. Control blood pressure prior to initiating lenvatinib. Monitor blood pressure 
after 1 week, then every 2 weeks for the first 2 months, and then at least monthly 
thereafter during treatment. Withhold or discontinue for grade 3 hypertension 
despite optimal antihypertensive therapy. At treating physician’s discretion, resume 
at a reduced dose when hypertension is controlled or permanently discontinue 
lenvatinib based on severity. Discontinue for grade 4 hypertension.  
Cardiac Dysfunction: Serious and fatal cardiac dysfunction can occur with lenvatinib. 
Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold or 
discontinue for grade 3 cardiac dysfunction. At treating physician’s discretion, 
resume at a reduced dose upon recovery. Discontinue for grade 4 cardiac 
dysfunction. 
Arterial Thromboembolic Events: Discontinue following an arterial thromboembolic 
event. 
Hepatotoxicity: Monitor liver function prior to treatment and periodically (every 2 
weeks for the first 2 months, and at least monthly thereafter) during treatment. 
Withhold or discontinue for grade 3 or 4 hepatotoxicity. Discontinue for hepatic 
failure. 
Renal Failure or Impairment Serious including fatal renal failure or impairment can 
occur with lenvatinib. Initiate prompt management of diarrhea or 
dehydration/hypovolemia. Withhold and resume at a reduced dose upon recovery or 
permanently discontinue lenvatinib for renal failure or impairment based on severity. 
Proteinuria: Monitor for proteinuria prior to treatment and periodically during 
treatment. Withhold for 2 or more grams of proteinuria per 24 hours. Discontinue for 
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Diarrhea: May be severe and recurrent. Promptly initiate management for severe 
diarrhea. Withhold and resume at a reduced dose upon recovery or permanently 
discontinue based on severity. 
Fistula Formation and Gastrointestinal Perforation: Permanently discontinue in 
patients who develop grade 3 or 4 fistula or any grade gastrointestinal perforation. 
QT Interval Prolongation: Monitor and correct electrolyte abnormalities. Withhold 
and resume at reduced dose of lenvatinib upon recovery based on severity for QT 
interval greater than 500 ms or for 60 ms or greater increase in baseline QT interval.  
Hypocalcemia: Monitor blood calcium levels at least monthly and replace calcium as 
necessary. Withhold and resume at reduced dose upon recovery or permanently 
discontinue lenvatinib depending on severity. 
Reversible Posterior Leukoencephalopathy Syndrome: Withhold and resume at a 
reduced dose upon recovery or permanently discontinue lenvatinib depending on 
severity and persistence of neurologic symptoms.  
Hemorrhagic Events: Serious including fatal hemorrhagic events can occur with 
lenvatinib. Consider the risk of severe or fatal hemorrhage associated with tumor 
invasion or infiltration of major blood vessels (e.g., carotid artery). Withhold and 
resume at reduced dose upon recovery or permanently discontinue lenvatinib based 
on the severity.  
Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: 
Lenvatinib impairs exogenous thyroid suppression. Monitor thyroid function prior to 
initiating lenvatinib and at least monthly during treatment. Treat hypothyroidism 
according to standard medical practice.  
Impaired Wound Healing: Impaired wound healing has been reported in patients 
who received lenvatinib. Withhold lenvatinib for at least 1 week prior to elective 
surgery. Do not administer for at least 2 weeks following major surgery and until 
adequate wound healing. The safety of resumption of lenvatinib after resolution of 
wound healing complications has not been established. 
Osteonecrosis of the Jaw Osteonecrosis of the Jaw (ONJ): ONJ has been reported 
in patients receiving lenvatinib. Perform an oral examination prior to treatment with 
lenvatinib and periodically during lenvatinib treatment. Consider preventive dentistry 
prior to treatment with lenvatinib. Avoid invasive dental procedures, if possible, 
particularly in patients at higher risk. Withhold lenvatinib for at least 1 week prior to 
scheduled dental surgery or invasive dental procedures, if possible. Withhold 
lenvatinib if ONJ develops and restart based on clinical judgment of adequate 
resolution. 
Embryofetal Toxicity: Lenvatinib can cause fetal harm. Advise of potential risk to a 
fetus and use of effective contraception during treatment and for at least 30 days 
after the last dose. 
 Adverse Events 
See Section 9.2.11 

 
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9.2 
Pembrolizumab (Keytruda) 
The following information is based on the Prescribing Information for Keytruda 
(pembrolizumab; MK-3475) dated July 2021. 
 Product Description 
Pembrolizumab is a programmed death-receptor-1 (PD 1)-blocking antibody. 
Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an 
approximate molecular weight of 149 kDa. Pembrolizumab is produced in 
recombinant Chinese hamster ovary (CHO) cells.  
KEYTRUDA (pembrolizumab) injection is a sterile, preservative-free, clear to slightly 
opalescent, colorless to slightly yellow solution for intravenous use. Each vial 
contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution 
contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), 
polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.  
 Mechanism of Action 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T 
cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 
ligands occurs in some tumors and signaling through this pathway can contribute to 
inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a 
monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with 
PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune 
response, including the antitumor immune response. In syngeneic mouse tumor 
models, blocking PD-1 activity resulted in decreased tumor growth. 
 Storage and Handling Requirements 
Store vials of solution under refrigeration at 2-8°C (36-46°F) in original carton to 
protect from light. Do not freeze. Do not shake. 
 Administration 
Pembrolizumab is administered by intravenous infusion over 30 minutes through an 
intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron 
to 5 micron in-line or add-on filter.  
No other drugs should be co-administered through the same infusion line. 
 Preparation and Storage Following Dilution 
Preparation for Intravenous Infusion  
• 
Visually inspect the solution for particulate matter and discoloration. The solution 
is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if 
visible particles are observed.  
• 
Dilute pembrolizumab (solution) prior to intravenous administration.  

 
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• 
Withdraw the required volume from the vial(s) of pembrolizumab and transfer 
into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 
5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not 
shake. The final concentration of the diluted solution should be between 1 
mg/mL to 10 mg/mL. 
• 
Discard any unused portion left in the vial. 
Storage of Diluted Solution  
The product does not contain a preservative. Store the diluted solution from the 
KEYTRUDA 100 mg/4 mL vial either:  
• 
At room temperature for no more than 6 hours from the time of dilution. This 
includes room temperature storage of the diluted solution, and the duration of 
infusion. 
• 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 96 hours from 
the time of dilution. If refrigerated, allow the diluted solution to come to room 
temperature prior to administration. Do not shake.  
Discard after 6 hours at room temperature or after 96 hours under refrigeration.  
Do not freeze. 
 Availability and Ordering 
Pembrolizumab is commercially available and administration is standard of care for 
patients with endometrial cancer. The costs of pembrolizumab and its administration 
will be the responsibility of the patient and/or the patient’s 3rd party payor. 
 Contraindications 
No contraindications have been identified. 
 Pharmacokinetics 
The pharmacokinetics (PK) of pembrolizumab was characterized using a population 
PK analysis with concentration data collected from 2993 patients with various 
cancers who received pembrolizumab doses of 1 to 10 mg/kg every 2 weeks, 2 to 
10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Steady-state concentrations of 
pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week 
regimen and the systemic accumulation was 2.1-fold. The peak concentration 
(Cmax), trough concentration (Cmin), and area under the plasma concentration 
versus time curve at steady state (AUCss) of pembrolizumab increased dose 
proportionally in the dose range of 2 to 10 mg/kg every 3 weeks. 
 Drug Interactions 
As pembrolizumab is an IgG4 antibody that is administered parentally and cleared 
by catabolism, food and drug-drug interactions are not anticipated to affect 
exposure. Therefore, no dedicated drug-drug interaction studies have been 
performed. However, as systemic corticosteroids may be used to treat immune-

 
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mediated adverse reactions concomitant with pembrolizumab, the potential for a PK 
drug-drug interaction with pembrolizumab as a victim was assessed. No relationship 
was observed between prolonged use of systemic corticosteroids and 
pembrolizumab exposure. Similarly, the potential of drug-drug interaction between 
pembrolizumab and chemotherapy agents as well as other small molecules is 
expected to be low.  
 Warnings and Precautions 
Severe and Fatal Immune-Mediated Adverse Reactions 
Pembrolizumab is a monoclonal antibody that belongs to a class of drugs that bind 
to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), 
blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune 
response, potentially breaking peripheral tolerance and inducing immune-mediated 
adverse reactions. Important immune-mediated adverse reactions listed may not 
include all possible severe and fatal immune-mediated adverse reactions.  
Immune-mediated adverse reactions, which may be severe or fatal, can occur in 
any organ system or tissue and can affect more than one body system 
simultaneously. Immune-mediated adverse reactions can occur at any time after 
starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated 
adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking 
antibodies, immune-mediated adverse reactions can also manifest after 
discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and 
management of immune-mediated adverse reactions are essential to ensure safe 
use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and 
signs that may be clinical manifestations of underlying immune-mediated adverse 
reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and 
periodically during treatment. In cases of suspected immune-mediated adverse 
reactions, initiate appropriate workup to exclude alternative etiologies, including 
infection. Institute medical management promptly, including specialty consultation 
as appropriate.  
Withhold or permanently discontinue pembrolizumab depending on severity. In 
general, if pembrolizumab requires interruption or discontinuation, administer 
systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until 
improvement to grade 1 or less. Upon improvement to grade 1 or less, initiate 
corticosteroid taper and continue to taper over at least 1 month. Consider 
administration of other systemic immunosuppressants in patients whose immune-
mediated adverse reactions are not controlled with corticosteroid therapy.  
• 
Immune-mediated adverse reactions, including severe and fatal cases, have 
occurred in patients receiving pembrolizumab. Immune-mediated adverse 
reactions can occur after discontinuation of treatment. In clinical trials, most 
immune-mediated adverse reactions were reversible and managed with 
interruptions in pembrolizumab, administration of corticosteroids and/or 
supportive care. For additional information, refer to the current version of the 
Prescribing Information for pembrolizumab. 
− Immune-mediated pneumonitis 

 
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− Immune-mediated colitis 
− Immune-mediated hepatitis 
− Immune-mediated hypophysitis 
− Adrenal insufficiency 
− Immune-mediated hyperthyroidism and hypothyroidism 
− Renal failure and immune-mediated nephritis 
− Immune-mediated Type 1 diabetes mellitus 
− The following additional clinically significant, immune-mediated adverse 
reactions occurred: severe skin reactions (including exfoliative dermatitis, 
Stevens-Johnson Syndrome, toxic epidermal necrolysis), uveitis, arthritis, 
myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient 
with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic 
syndrome, optic neuritis, rhabdomyolysis, myocarditis, and myelitis 
• 
Other immune-mediated adverse reactions:  
The following clinically significant immune-mediated adverse reactions occurred 
at an incidence of <1% (unless otherwise noted) in patients who received 
pembrolizumab or were reported with the use of other PD 1/PD-L1 blocking 
antibodies. Severe or fatal cases have been reported for some of these adverse 
reactions.  
− Cardiac/Vascular: Myocarditis, pericarditis, vasculitis . 
− Nervous System: Meningitis, encephalitis, myelitis and demyelination, 
myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-
Barré syndrome, nerve paresis, autoimmune neuropathy.  
− Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some 
cases can be associated with retinal detachment. Various grades of visual 
impairment, including blindness, can occur. If uveitis occurs in combination 
with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-
Harada-like syndrome, as this may require treatment with systemic steroids 
to reduce the risk of permanent vision loss.  
− Gastrointestinal: Pancreatitis, to include increases in serum amylase and 
lipase levels, gastritis, duodenitis. 
− Musculoskeletal and Connective Tissue: Myositis/polymyositis, 
rhabdomyolysis (and associated sequelae, including renal failure), arthritis 
(1.5%), polymyalgia rheumatica. 
− Endocrine: Hypoparathyroidism Hematologic/Immune: Hemolytic anemia, 
aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory 
response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi 
lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ 
transplant rejection. 

 
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• 
Transplant-related adverse reactions 
− Solid organ transplant rejection 
− Acute graft versus host disease (GVHD), including fatal GVHD, in patients 
with history of allogeneic hematopoietic stem cell transplant 
• 
Increased mortality in patients with multiple myeloma when pembrolizumab is 
added to a thalidomide analogue and dexamethasone 
• 
Infusion-related reactions, including hypersensitivity and anaphylaxis 
• 
Embryofetal toxicity: 
Pembrolizumab may cause fetal harm when administered to a pregnant woman. 
Highly effective contraception must be used during treatment with 
pembrolizumab and for 4 months after the last dose.  
 Adverse Events 
The safety of pembrolizumab in combination with lenvatinib (20 mg orally once 
daily) was investigated in KEYNOTE-146, a single-arm, multicenter, open-label trial 
in 94 patients with endometrial carcinoma whose tumors had progressed following 
one line of systemic therapy and were not MSI-H or dMMR. The median duration of 
study treatment was 7 months (range: 0.03 to 37.8 months). The median duration of 
exposure to pembrolizumab was 6 months (range: 0.03 to 23.8 months). 
Pembrolizumab was continued for a maximum of 24 months; however, treatment 
with lenvatinib could be continued beyond 24 months. Fatal adverse reactions 
occurred in 3% of patients receiving pembrolizumab and lenvatinib, including 
gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome 
(RPLS) with intraventricular hemorrhage, and intracranial hemorrhage. Serious 
adverse reactions occurred in 52% of patients receiving pembrolizumab and 
lenvatinib.  
Serious adverse reactions in ≥ 3% of patients were hypertension (9%), abdominal 
pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), 
confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis 
(3%), dyspnea (3%), and pyrexia (3%). Pembrolizumab was discontinued for 
adverse reactions (grade 1-4) in 19% of patients, regardless of action taken with 
lenvatinib.  
The most common adverse reactions (≥ 2%) leading to discontinuation of 
pembrolizumab were adrenal insufficiency (2%), colitis (2%), pancreatitis (2%), and 
muscular weakness (2%).  
Adverse reactions leading to interruption of pembrolizumab occurred in 49% of 
patients; the most common adverse reactions leading to interruption of 
pembrolizumab (≥2%) were: fatigue (14%), diarrhea (6%), decreased appetite (6%), 
rash (5%), renal impairment (4%), vomiting (4%), increased lipase (4%), weight loss 
(4%), nausea (3%), increased blood alkaline phosphatase (3%), skin ulcer (3%), 
adrenal insufficiency (2%), increased amylase (2%), hypocalcemia (2%), 
hypomagnesemia (2%), hyponatremia (2%), peripheral edema (2%), 
musculoskeletal pain (2%), pancreatitis (2%), and syncope (2%). Table 7 and  

 
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A. Unless otherwise noted, eligibility evaluations within 28 days prior to initiation of study treatment 
B. Day 1 assessments do not need to be repeated if done within 72 hours prior to initiation of study 
treatment. Assessments are to be completed every 21 ±3 days even if study drug is held. 
C. See Section 6.5. All patients who initiate treatment on study will proceed to 30-day follow-up and 
extended follow-up after the initial 30-day period.  
D. If a patient has been consented but not registered within 4 weeks, reconsenting is not required unless 
a new IRB-approved version of the consent form is available. 
E. See Appendix 1 for ECOG criteria. 
F. Include over-the-counter medications. 
G. Assessment and reporting based on the NCI CTCAE v5.0. Refer to Section 8 regarding expedited 
reporting. Assessment will be performed by the study team using telemedicine when treatment is 
received at a non-study site. 
H. Chemistry includes the following: basic metabolic panel (sodium, potassium, carbonate, chloride, 
glucose, calcium, BUN, creatinine) and hepatic panel (ALT, AST, ALP, total bilirubin, direct bilirubin, 
albumin, total protein). 
I. 
Every 6 weeks (± 1 week). 
J. Only required for WCBP (see SectionInclusion Criteria for definitions and related requirements). In 
addition, review pregnancy risks and offer pregnancy test as clinically indicated. 
K. Brain imaging only required for patients with brain metastasis diagnosed and treated prior to initiation 
of study treatment. The imaging used at baseline should be used at each subsequent imaging time 
point.  
L. Counting from C1D1, for the first 24 weeks, during Week 6, 12, 18, and 24 (±1 week), or sooner, if 
clinically indicated, until documentation of confirmed progression. After 24 weeks, tumor assessments 
must be performed every 9 weeks counting from C1D1 (during Week 33, 42, 51, 60, etc.) (±1 week), 
or sooner if clinically indicated, until documentation of confirmed PD. Responses and PD must be 
confirmed at least 4 weeks later (usually at the next tumor assessment). 
M. PROs will be administered every day 1 of every cycle starting at C1D1 and 30 days after last dose of 
study drug until patient enters the extended follow-up period. During the extended follow-up period 
PROs will be administered every 3 months (see Section 1.4.1). 
N. FACIT/HADS questionnaire will be administered at baseline, C1D1, C2D1, C3D1, then every other 
cycle beginning at C5 and beyond, end of study, and the first extended follow-up visit (see Section 
1.4.1).. 
O. Collect correlative whole blood urine, and vaginal swab samples any time after consent and before 
C1D1 prior to the initiation of any study treatment. See also Section 11.  
P. An optional additional blood sample will be collected for DNA ancestrial analysis. See Section 11.3.1 
Q. Collect correlative whole blood at the conclusion of therapy if prior to 90 days.  See also Section 11 
R. Capture survival status approximately every 3 months during the extended follow-up period. During 
the extended follow-up period, data may be obtained by record review or patients may be contacted 
by phone for report of disease status, new treatment and/or survival status approximately every 3 
months. 
S. Lenvatinib administered orally (PO) once daily (QD) during each 21-day cycle For lenvatinib 
instructions refer to Sections 6.2, 7.3, and 9.1.  
T. Pembrolizumab administered by IV infusion on day 1 of each 21-day cycle. For 
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13 STATISTICAL CONSIDERATIONS 
13.1 Study Design and Analysis 
Primary Analysis: The binary outcome ORR: will be estimated with a sample proportion 
and 95% Wilson confidence intervals. The ORR will be estimated in unadjusted and 
adjusted manners, where in the latter case we use logistic regressioin to model the 
outcome against fixed effects for patient characteristics and disease biomarkers, using a 
Bernoulli distribution and logit link function, including a set of measurements that minimize 
the Bayesian Information Criterion.  
Secondary Analyses: OS is calculated as the time between treatment start date until date 
of death from any cause or until censoring. PFS is calculated as the time between 
treatment start date until occurrence of disease progression or until censoring. The Kaplan-
Meier product limit approach will be used to estimate step functions for OS and PFS. 
Proportional hazard modeling will be used to estimate mean survival time  in both 
unadjusted and adjusted manners, where in the latter case we account for patient 
characteristics and disease biomarkers.  
Safety Analyses: Times to toxicity, dose reduction, or drug discontinuation will be used as 
safety outcomes. Each measure is calculated as the time between treatment start date 
until event occurrence or until censoring. These measures will be summarized using 
proportional hazards regression, and visually present the event curves with cumulative 
incidence curves.  
13.2 Sample Size/Accrual Rates 
As the goal of this proposal is to estimate ORR, we will not formally power for hypothesis 
testing. With 100 subjects (and conservativiely assuming a 0.5 ORR for maximum 
variability), we would be able to estimate the ORR with a margin of error of ±0.1.  
This study is expected to be open to accrual at a total of 10 sites across the US within 24 
months of its initial approval at the coordinating site, VCU Massey Cancer Center. Each 
site is anticipated to accrue an average of 1 patient every 2 to 3 months. The total period of 
study recruitment is therefore anticipated to occur over a period of 25 to 42 months, with 
recruitment complete by July 1, 2025. 
14 DATA AND SAFETY MONITORING PLAN (DSMP) 
While patients are on treatment, the principal investigator, study team members (e.g., site 
investigators, research nurses, clinical research associates) and Coordinating Center staff 
will meet at least monthly to review study status. The biostatistician will review data with 
the principal investigator and Coordinating Center staff at least quarterly. This review will 
include, but not be limited to, reportable events and an update of the ongoing study 
summary that describes study progress in terms of the study schema. All meetings, 
including attendance, are documented. 

 
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14.1 Monitoring and Auditing 
 MCC Compliance Office 
Compliance specialists in the MCC Compliance Office will provide monitoring and 
auditing for this study. 
 Data Safety and Monitoring Committee 
The study will be reviewed by the MCC DSMC initially according to the risk level 
specified by the MCC Protocol Review and Monitoring Committee (PRMC) and then 
according to a schedule based on study status and quality indicators. The DSMC 
will review reports provided by the principal investigator/study team and the MCC 
Compliance Office focusing on data integrity and patient safety. 
15 REGULATORY COMPLIANCE AND ETHICS 
15.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research (US National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research, April 18, 1979). 
15.2 Regulatory Compliance 
This study will be conducted in compliance with the clinical trial protocol and with federal 
regulations, as applicable, including: 21 CFR 50 (Protection of Human Patients/Informed 
Consent); 21 CFR 56 (Institutional Review Boards); 21 CFR 312 (IND Application); and 45 
CFR 46 Subparts A (Common Rule), B (Pregnant Women, Human Fetuses and 
Neonates), C (Prisoners), and D (Children). 
15.3 Institutional Review Board 
The VCU IRB, which is registered with the Office for Human Research Protections 
(OHRP), must review and approve the protocol, the associated informed consent 
document, and recruitment material (if any). Any amendments to the protocol or consent 
form must also be approved. 
15.4 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Discussion of risks and possible benefits of this therapy will be provided to patients and 
their families. Consent forms describing the study interventions, study procedures, and 
risks are given to the patient and written documentation of informed consent is required 
prior to starting intervention/administering study product. 
Consent forms will be IRB-approved and the patient will be asked to read and review the 
document. Upon reviewing the document, the investigator will explain the research study to 

 
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the patient and answer any questions that may arise. The patient will sign the informed 
consent document prior to any procedures being done specifically for the study. Patients 
should have the opportunity to discuss the study with their surrogates or think about it prior 
to agreeing to participate. Patients may withdraw consent at any time throughout the 
course of the trial. A copy of the informed consent document will be given to patients for 
their records; the original consent form will be maintained in the research records.  
15.5 Patient Confidentiality  
Patient confidentiality is strictly held in trust by the principal investigator, participating 
investigators, staff, and the sponsor and its agents. This confidentiality includes the clinical 
information relating to participating patients, as well as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the principal investigator. 
The participating site will allow access to all source data and documents for the purposes 
of monitoring, audits, IRB review, and regulatory inspections. Source documents provided 
to the Coordinating Center for the purpose of auditing or monitoring will be  
de-identified and labeled with the study number, patient ID number, and patient initials. 
The study monitor or other authorized representatives of the principal investigator may 
inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
patients in this study. The clinical study site will permit access to such records. 
16 DATA COLLECTION AND MANAGEMENT 
16.1 Data Management Responsibilities 
The principal investigator is responsible for: (i) the overall conduct of the investigation, (ii) 
ongoing review of trial data including all safety reports, and (iii) reporting SAEs and UPs as 
required in Section 8. 
16.2 Case Report Forms and Data Collection 
MCC will provide standard electronic CRFs (eCRFs) and create study-specific eCRFs to 
be able to capture all information required by the protocol. The eCRFs will be approved by 
the Coordinating Center to ensure the most effective data acquisition. 
The investigator(s) and study coordinator(s) must maintain source documents for each 
patient in the study. All information on eCRFs will be traceable to these source documents, 
which are generally maintained in the patient’s file. 
All eCRFs should be completed and available for collection within a timely manner, 
preferably no more than 5 days after the patient’s visit. 

 
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16.3 OnCore Data Entry 
Data will be entered into MCC’s OnCore database on an ongoing basis by all participating 
centers via remote access. Sites are responsible for updating data to allow for data 
compilation and review. Electronic data submissions will be reviewed periodically for data 
timeliness and accuracy. Sites will be queried periodically and significant problems with 
delinquency or accuracy may result in suspension of enrollment at a site. 
16.4 Study Record Retention 
As applicable, study records will be maintained a minimum of 5 years beyond the 
publication of any abstract or manuscript reporting the results of the protocol or submission 
of a final report to clinicaltrials.gov. 

 
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