Phase II Trial of Pembrolizumab and Lenvatinib in Advanced/Metastatic Neuroendocrine Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer Metastatic, Neuroendocrine Tumors
Sponsor: University of Michigan Rogel Cancer Center

UMCC 
2020.106 
     
 
 
 
Pembrolizumab and Lenvatinib in Advanced/Metastatic 
Neuroendocrine Prostate Cancer 
    NCT04848337 
 

Clinical Study Protocol 
HCRN GU19-385 
 
Phase II trial of Pembrolizumab and Lenvatinib in Advanced/metastatic Neuroendocrine 
Prostate Cancer [PLANE-PC] 
 
 
Sponsor Investigator 
Ulka Vaishampayan MD 
Professor, Internal Medicine 
Division of Hematology/ Oncology 
University of Michigan 
Chair, Phase I Therapeutics 
7217 Rogel Cancer Center, SPC5948 
1500 E. Medical Ctr Dr. |ANN ARBOR, MI 48109 
OFFICE: 734-936-7813 FAX: 734-647-9480 
Email: vaishamu@med.umich.edu 
 
Biostatistician 
Jeremy M.G. Taylor PhD 
University of Michigan 
 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
7676 Interactive way, Suite 120 
Indianapolis 46278 
 
 
Trial Supported by  
Merck Sharp & Dohme LLC (59089) 
 
 
IND Exemption by FDA 8/13/2020  
 
 
 
 
Initial Protocol Version Date: 04JUN2020  
Protocol Amendment Version Date:  
11DEC2020 
11MAR2022 
30JUN2022 
 
 
 

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PROTOCOL SIGNATURE PAGE 
 
Phase II trial of Pembrolizumab and Lenvatinib in Advanced/metastatic Neuroendocrine 
Prostate Cancer [PLANE-PC] 
 
VERSION DATE: 30JUN2022 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
 
 
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Date 
 
 
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SYNOPSIS 
TITLE 
Phase II trial of Pembrolizumab and Lenvatinib in 
Advanced/metastatic Neuroendocrine Prostate Cancer [PLANE-PC] 
SHORT TITLE 
Pembrolizumab and lenvatinib in neuroendocrine prostate cancer 
PHASE  
II 
OBJECTIVES 
Primary Objective 
Evaluate 6 month radiographic progression free survival (rPFS) rate 
with lenvatinib and pembrolizumab combination therapy in 
metastatic neuroendocrine prostate cancer (NEPC).  
 
Secondary Objectives 
 Assess the safety of pembrolizumab and lenvatinib combination 
therapy in metastatic neuroendocrine prostate cancer (NEPC).  
 Assess overall survival (OS). 
 Assess objective response rate (ORR). 
 Assess duration of response (DoR). 
STUDY DESIGN 
An open label phase II study design of lenvatinib and 
pembrolizumab in metastatic NEPC is planned with primary 
endpoint of 6- month radiologic progression-free survival (rPFS) 
rate. 
STATISTICAL 
CONSIDERATIONS 
A 2-stage Simon near optimal statistical study design will be used 
for the binary primary endpoint of 6-month rPFS (yes/no). The 
design uses these input parameters: p0 = 0.10; p1 = 0.25; alpha = 
0.125; and power = 0.90.  If there are at least 3 successes in the 27 
patients in Stage 1 the study will proceed to Stage 2, otherwise it 
will terminate early due to insufficient efficacy.  If there are at least 
7 successes in the final total of 40 patients, the treatment will be 
considered promising. To allow for up to 20% of registered patients 
becoming non evaluable, up to 50 patients will need to be enrolled to 
yield 40 evaluable patients. It may become necessary to temporarily 
suspend accrual at or near the completion of Stage 1 of the study in 
order to evaluate the 6-month rPFS (primary endpoint) of the last 
few Stage 1 patients.  
TOTAL  
NUMBER OF 
SUBJECTS 
N = 40 evaluable, Up to 50 total accrual 

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ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 38 months of accrual.  
ESTIMATED 
STUDY DURATION  
Estimated 44 months to meet primary endpoint.  
 
 

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TABLE OF CONTENTS 
 
 
Schema ............................................................................................................................... 8 
1. 
Background and Rationale ..................................................................................... 9 
1.1 
Disease Background........................................................................................................ 9 
1.2 
Current Standard of Care .............................................................................................. 10 
1.5 
Hypothesis..................................................................................................................... 13 
2. 
Study Objectives and Endpoints........................................................................... 14 
2.1 
Objectives ..................................................................................................................... 14 
2.1.1 Primary Objective ..................................................................................................... 14 
2.1.2 Secondary Objectives................................................................................................ 14 
2.1.3 Correlative/Exploratory Objectives .......................................................................... 14 
2.2 
Endpoints ...................................................................................................................... 14 
2.2.1 Primary Endpoint ...................................................................................................... 14 
2.2.2 Secondary Endpoints ................................................................................................ 14 
3. 
Eligibility Criteria .................................................................................................. 15 
3.1 
Inclusion Criteria .......................................................................................................... 15 
3.2 
Exclusion Criteria ......................................................................................................... 16 
4. 
Subject Registration............................................................................................... 18 
5. 
Treatment Plan....................................................................................................... 18 
5.1 
Study Treatment Administration................................................................................... 18 
5.2 
Lenvatinib ..................................................................................................................... 19 
5.3 
Pembrolizumab ............................................................................................................. 19 
5.4 
Concomitant Medications ............................................................................................. 19 
5.4.1 Allowed Concomitant Medications .......................................................................... 19 
5.4.2 Prohibited Concomitant Medications ....................................................................... 20 
5.5 
Supportive Care ............................................................................................................ 20 
6. 
Toxicities and Dose Delays/Dose Modifications .................................................. 21 
6.1 
Dose Modifications for Lenvatinib ............................................................................... 21 
6.1.1 Dose Levels for Dose Reductions of Lenvatinib .......................................................... 22 
6.2 
Dose Modifications for Pembrolizumab ....................................................................... 22 
6.3 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab ....................................................................................................................... 27 
6.4 
Protocol Therapy Discontinuation ................................................................................ 29 
6.5 
Protocol Discontinuation .............................................................................................. 30 
6.6 
Safety Follow Up .......................................................................................................... 30 
6.7 
Long Term Follow Up .................................................................................................. 30 
7. 
Study Calendar & Evaluations ............................................................................. 32 
8. 
Biospecimen Studies and Procedures ................................................................... 35 
8.1 
Tissue ............................................................................................................................ 35 
8.1.1 Archival Tissue ......................................................................................................... 35 
8.2 
Peripheral Blood Samples ............................................................................................. 35 
8.2.1 Plasma for Circulating Tumor DNA and miRNA .................................................... 35 
8.3 
Stool for Microbiome ................................................................................................ 35 
Stool for microbiome will be collected prior to Cycle 1 Day 1 treatment and stored for 
correlative analysis once funding is available. ..................................................................... 35 

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8.4 
Banking of Leftover Biospecimens .......................................................................... 35 
8.5 
Confidentiality of Biospecimens................................................................................... 35 
9. 
Criteria for Disease Evaluation ............................................................................ 36 
9.1 
Measurable Disease ...................................................................................................... 36 
9.1.1 Malignant Lymph Nodes .......................................................................................... 36 
9.2 
Non-measurable Lesions ............................................................................................... 36 
9.3 
Target Lesions ............................................................................................................... 36 
9.4 
Non-target Lesions ........................................................................................................ 37 
9.5 
Evaluation of Target Lesions ........................................................................................ 37 
9.6 
Evaluation of Non-Target Lesions ................................................................................ 37 
9.7 
Evaluation of Best Overall Response ........................................................................... 38 
9.8 
Definitions for Response and Survival Evaluation ....................................................... 38 
9.8.1 Time to Response (TTR) .......................................................................................... 38 
9.8.2 Radiologic Progression Free Survival (rPFS) ........................................................... 38 
9.8.4  Duration of Response (DoR) ................................................................................... 39 
10. DRUG INFORMATION ....................................................................................... 39 
10.1 
Pembrolizumab ............................................................................................................. 39 
10.1.1 
Supplier/How Supplied ........................................................................................... 39 
10.1.1 
Preparation ............................................................................................................ 39 
10.1.2 
Storage and Stability ............................................................................................. 39 
10.1.3 
Handling and Disposal .......................................................................................... 40 
10.1.4 
Dispensing............................................................................................................. 40 
10.1.5 
Adverse Events Associated with Pembrolizumab ................................................ 40 
10.2.1 
Supplier/How Supplied ............................................................................................. 41 
10.1.2 
Storage and Stability ............................................................................................. 41 
10.1.3 
Handling and Disposal .......................................................................................... 41 
10.1.4 
Dispensing............................................................................................................. 41 
10.1.5 
Adverse Events Associated with Lenvatinib ........................................................ 41 
11. Adverse Events ....................................................................................................... 42 
11.1 
Definitions..................................................................................................................... 42 
11.1.1 
Adverse Event (AE) .............................................................................................. 42 
11.1.2 
Serious Adverse Event (SAE) ............................................................................... 42 
11.1.3 
Unexpected Adverse Event ................................................................................... 43 
11.1.4 
Relatedness ........................................................................................................... 43 
11.1.5 
Definition and Reporting of a Pembrolizumab and Lenvatinib Overdose .... 43 
11.1.6 
Reporting of Pregnancy ...................................................................................... 43 
11.1.7 
Definition and Reporting of Events of Clinical Interest (ECI) ....................... 44 
11.2 
Reporting....................................................................................................................... 44 
11.2.1 
Adverse Events ..................................................................................................... 44 
11.2.2 
Serious Adverse Events (SAEs)............................................................................ 45 
11.3 
Sponsor-Investigator Responsibilities .......................................................................... 45 
11.4 
Michigan Institute for Clinical and Health Research (MICHR) IND/IDE Investigator 
Assistance Program (MIAP) Responsibilities for Reporting SAEs to FDA ................. Error! 
Bookmark not defined. 
11.5 
IND Safety Reports Unrelated to this Trial .................................................................. 45 
12. Statistical Methods ................................................................................................. 46 

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12.2 
Endpoints ...................................................................................................................... 46 
12.2.1 
Definition of Primary Endpoint ............................................................................ 46 
12.2.2 
Definition of Secondary Endpoints ....................................................................... 46 
12.3 
Study Design and Interim Analyses .............................................................................. 47 
12.4 
Analysis......................................................................................................................... 48 
12.5 
Assessment of Safety .................................................................................................... 49 
12.7 
Expected Accrual Rate, Accrual Duration, and Total Study Duration ......................... 49 
13. Trial Management ................................................................................................. 49 
13.1 
Data and Safety Monitoring Plan (DSMP) ................................................................... 49 
13.2 
University of Michigan Data and Safety Monitoring Committee ................................ 50 
13.4 
Data Quality Oversight Activities ................................................................................. 50 
13.4.1 
Onsite Monitoring ................................................................................................. 50 
13.5 
Compliance with Trial Registration and Results Posting Requirements ...................... 50 
14. Data Handling and Record Keeping .................................................................... 51 
14.1 
Data Management ......................................................................................................... 51 
14.2 
Case Report Forms and Submission ............................................................................. 51 
14.3 
Record Retention .......................................................................................................... 51 
14.4 
Confidentiality .............................................................................................................. 51 
15 
Ethics ....................................................................................................................... 52 
15.1 
Institutional Review Board (IRB) Approval ................................................................. 52 
15.2 
Ethical Conduct of the Study ........................................................................................ 52 
15.3 
Informed Consent Process ............................................................................................ 52 
16 
References ............................................................................................................... 53 
 
 
 
 
 

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SCHEMA  
 
 
 
 
 
 
 
 

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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
Metastatic prostate cancer remains an incurable, terminal prognosis and within this, small cell 
type is a particularly lethal and aggressive form with few therapeutic options [1]. Recent 
advances in advanced prostate adenocarcinoma have not benefitted patients with small 
cell/neuroendocrine prostate cancer (NEPC) whether de novo small cell or treatment induced. As 
resistance develops, the neuroendocrine component emerges as the predominant driver of 
metastases. Abiraterone or enzalutamide treatment induced neuroendocrine prostate cancer has 
been reported. The morphologic and molecular features of NEPC are quite distinct from 
adenocarcinoma of the prostate.  NMYC amplification can elicit transformation of the prostate 
epithelium to NEPC.  Aurora kinase overexpression is frequently noted, but an aurora kinase 
inhibitor that was evaluated revealed only modest efficacy [2]. Overall a critical unmet need 
exists for the development of effective therapies in NEPC. 
 
NEPC is typically resistant to hormone therapies and to standard taxane based chemotherapy 
regimens used in advanced prostate adenocarcinoma. One of the reasons is that lineage plasticity 
is noted with conversion from luminal epithelial cells to basal androgen independent cells. Sox 2 
overexpression and Rb and p53 loss have been reported to create this lineage plasticity. N-Myc 
overexpression has also been attributed to neuroendocrine differentiation of prostate cancer. A 
review of clinical characteristics and outcomes of either de novo small cell prostate cancer or 
high-grade neuroendocrine transformation from prostate adenocarcinoma are that prognosis is 
poor and median survival is about 15 months. The front line therapy is platinum and etoposide 
chemotherapy which was noted to have a 48% objective response rate and median PFS of 6.5 
months [3] The results of second line therapy demonstrated limited efficacy and clinical impact.   
 
Pembrolizumab has been evaluated in small cell lung cancer and demonstrated efficacy [4]. In a 
study conducted in 107 patients with extensive small cell lung cancer who had failed standard 
therapy, the overall response rate was 18.7% (20/107; 95% CI, 11.8–27.4) with 35.7% response 
rate in pts with PD-L1–positive tumors, and 6.0% (3/50; 95% CI, 1.3–16.5) in PD-L1–negative 
tumors. 77% had durable remissions at 9 months or greater.  
 
Lenvatinib is a multitargeted kinase that is currently FDA approved in hepatocellular cancer and 
advanced endometrial cancer. It is also approved in combination with everolimus for advanced 
kidney cancer. The agent has demonstrated promising tumor regression effects in a small cell 
lung cancer tumor model; H 146. The tumor shrinkage was affected through stem cell factor 
(SCF) induced angiogenesis inhibition. In a murine immunocompetent model of anaplastic 
thyroid cancer, lenvatinib monotherapy increased tumor-infiltrating macrophages, CD8+ T-cells, 
regulatory T-cells, and most notably, polymorphonuclear myeloid derived suppressor cells 
(PMN-MDSCs). While combination with other therapies led to increases in CD8+ T-cells, only 
the lenvatinib and anti-PD-1 combination decreased PMN-MDSCs [5]. Increased tumor 
shrinkage and longer survival was noted with the combination as compared to lenvatinib 
monotherapy. Similar results were noted in hepatocellular carcinoma xenograft model. 
Lenvatinib has immunomodulatory activity that contributes to the antitumor activity enhanced by 
treatment with anti-PD-1 antibody which results in increased CD8+ve lymphocytes and depleted 
monocytes and MDSC. Lenvatinib demonstrated single agent activity in pancreas and 

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gastrointestinal neuroendocrine tumors. The preliminary efficacy showed disease stabilization 
rates of 55.7% and 76% with median progression free survival of 16.5 months [6]. Phase I/II 
studies of lenvatinib and pembrolizumab have been conducted in multiple malignancies. The 
results revealed predominant toxicities of decreased appetite (67%), fatigue (62%), 
hypothyroidism (43%), diarrhea (43%), proteinuria (43%), arthralgia (33%) and hypertension 
(33%). Tolerability and promising efficacy were noted in metastatic melanoma, renal cancer and 
urothelial cancer cohorts regardless of PD-L1 status. A large randomized trial in advanced renal 
cancer contained the lenvatinib and pembrolizumab combination as one of the arms. Since this 
trial recently completed accrual without interruption, the tolerability of the combination is noted 
in a multicenter setting. These preclinical and clinical trial results provide robust rationale for the 
proposed phase II trial in NEPC. 
 
1.2 
Current Standard of Care 
No standard of care exists at present for this disease after platinum and etoposide combination.  
 
1.3 
Lenvatinib (E7080); LENVIMA; KISPLYX  
 
1.3.1 Therapeutic Indications 
Lenvatinib is indicated for the treatment of patients with progressive, RAI-RDTC and for the 
treatment of patients with HCC. Lenvatinib is indicated in combination with everolimus for the 
treatment of patients with advanced RCC in the EU following one prior anti-angiogenic therapy. 
It has also received recent FDA approval in combination with pembrolizumab for treatment of 
advanced endometrial cancer.  
 
Lenvatinib is a potent multiple RTK inhibitor that selectively inhibits VEGF receptors, VEGFR1 
(FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), FGFR1-4, PDGFRα, KIT, and RET. Co-crystal 
structural analysis demonstrated that lenvatinib has a distinct mode of the interaction with 
VEGFR2 or FGFR1, termed Type V, while most of the known kinase inhibitors on market are 
categorized as Type I or II (Okamoto, et al., 2015). Lenvatinib binds to ATP-binding site and the 
neighboring allosteric region in the kinase domain adopting the DFG-in conformation. Most of 
the known kinase inhibitors are categorized as Type I, binding these kinases in the DFG-in 
configuration and only binding to the ATP-binding site, or Type II binding to the kinase in the 
DFG-out conformation and binding to both the ATP-binding site and the neighboring regions. 
Among known kinase inhibitors in clinical use, lenvatinib is one of the only inhibitors currently 
labeled with a mechanism of action as an inhibitor of not only VEGFRs but also FGFRs, both of 
which are currently believed to very important for tumor angiogenesis. Lenvatinib inhibited cell 
free kinase activities for VEGFR1 – 3 and FGFR1 – 3 with Ki values around 1 nmol/L, and 8 – 
22 nmol/L, respectively. In cell based assays, lenvatinib inhibited VEGF-derived and FGF-
derived tube formation of HUVEC with IC50 values of 2.1 and 7.3 nmol/L, respectively. 
Analysis of the signal transduction molecules revealed that lenvatinib inhibited both the MAPK 
pathway and the mTOR-S6K-S6 pathway in HUVECs triggered by activated VEGFR and 
FGFR. Furthermore, lenvatinib (10, 30 mg/kg) significantly inhibited both VEGF- and FGF-
driven angiogenesis in a murine in vivo model (Yamamoto, et al., 2014). In vivo, lenvatinib 
exhibited antitumor activity against various human tumor xenografts in athymic mice including 5 
types of thyroid carcinomas (differentiated [papillary and follicular], anaplastic, squamous, and 
MTC), RCC, HCC, melanoma, gastric cancer, NSCLC, ovarian cancer, Ewing’s sarcoma, and 

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osteosarcoma. In addition, the antitumor activity of lenvatinib in combination with other 
anticancer agents in several xenograft models was greater than that of lenvatinib or the other 
agents alone. Therefore, lenvatinib is being developed as an anticancer therapy for use either as a 
single agent or in combination with other anticancer agents for the treatment of malignancies 
including thyroid cancer, RCC, HCC, and endometrial cancer. The results of the cell-based 
assays, as well as the results of various murine in vivo models (Yamamoto, et al., 2014; 
Tohyama et al., 2014) suggest that in most tumors, the mode of action for lenvatinib antitumor 
activity is primarily related to the inhibition of both VEGF and FGF- dependent angiogenesis. 
For several thyroid cancers where RET kinase is constitutively activated, direct antitumor 
activity of lenvatinib is postulated to be important in the model of action. In subjects with RCC, 
our Study E7080-G000-205 demonstrated that the combination of lenvatinib and everolimus, an 
mTOR targeting agent improved PFS compared to everolimus alone (Motzer, et al., 2015). This 
clinical evidence is supported by the nonclinical in vitro and in vivo studies, which suggested a 
dual targeting of mTOR-S6KS6 pathway by lenvatinib and everolimus. The malignancies for 
which treatment with lenvatinib will be investigated are those in which lenvatinib has 
demonstrated nonclinical or clinical antitumor activity. An effective oral, QD outpatient 
treatment regimen that is well tolerated, with toxicities that are easily managed with standard 
therapies or dose reduction/interruption, would be an important advancement in the treatment of 
patients with thyroid cancer (Schlumberger, et al., 2014; Dunn and Fagín, 2015; Cully, 2015), 
RCC (Motzer, et al., 2015), HCC, endometrial cancer, melanoma, glioblastoma, ovarian cancer, 
and nonsquamous NSCLC. 
 
1.3.2 Lenvatinib (Lenvima) Dose Justification 
A variety of doses have been used for the different clinical uses of lenvatinib [7]. The starting 
dose utilized for single agent lenvatinib was 24 mg once daily in thyroid cancer trials and 12 mg 
and 8 mg once daily respectively for patients with advanced hepatic cancers with body weight 
>60 kg and < 60 kg. In renal cancer lenvatinib 18 mg oral daily dose in combination with 
everolimus 5 mg daily demonstrated improved efficacy and received FDA approval.  Keynote 
146 was a phase IB/II trial conducted in metastatic endometrial cancer that used a combination 
of lenvatinib 20 mg oral daily dose and pembrolizumab 200 mg IV every 21 days. The 
combination received accelerated FDA approval in 2019 and safety is well established in this 
trial. Since the same combination is being evaluated in the current proposed trial the starting dose 
of lenvatinib in this trial is 20 mg orally daily. 
 
1.4 
Pembrolizumab  
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD 1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure. 
 
 
 

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1.4.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010].  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes 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 (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such 
as melanoma [Dudley et al., 2005; Hunder et al., 2008]. 
 
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 immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD L1 and/or PD-L2) [Greenwald et al., 2005; 
Okazaki et al., 2001]. 
 
The structure of murine PD-1 has been resolved [Zhang et al., 2004].  PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV type) 
domain responsible for ligand binding and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch 
motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, 
to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade [Okazaki et al., 2001; Chemnitz et al., 2004; Sheppard et al., 2004; and Riley, 
2009].  The mechanism by which PD-1 down-modulates T cell responses is similar to, but 
distinct from, that of CTLA-4, because both molecules regulate an overlapping set of signaling 
proteins [Parry et al., 2005; Francisco, 2010].  As a consequence, the PD 1/PD-L1 pathway is an 
attractive target for therapeutic intervention in neuroendocrine metastatic prostate cancer. 
 
1.4.2 Justification for Dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.  
As outlined below, this dose is justified by: 
 Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 
mg/kg Q2W, representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2) 

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 Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 
 Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
 Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006).  All of these studies demonstrated flat dose- and exposure-
response relationships across the doses studied representing an approximate 5- to 7.5 fold 
difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to 
the highest doses studied.  Subsequently, flat dose-exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer and 
classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type.  These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
 
1.5 
Hypothesis 
The clinical hypothesis is that the combination of lenvatinib and pembrolizumab will provide at 
least an absolute 15% improvement in 6 month radiologic PFS as compared to historical controls 
or as noted in contemporary phase II studies conducted in this patient population. 
 
 
 

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2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
Evaluate 6 month radiographic progression free survival (rPFS) with lenvatinib and 
pembrolizumab combination therapy in metastatic neuroendocrine prostate cancer (NEPC).  
 
2.1.2 Secondary Objectives 
 Assess the safety of pembrolizumab and lenvatinib combination therapy in metastatic 
neuroendocrine prostate cancer (NEPC).  
 Assess overall survival (OS). 
 Assess objective response rate (ORR). 
 Assess duration of response (DoR). 
 
2.1.3 Correlative/Exploratory Objectives 
 Correlate genomic sequencing results with clinical outcomes in the study population. 
 Correlate PDL-1 status and tumor mutation burden with clinical outcomes. 
 Correlate gut microbiome data with clinical outcomes. 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
 Evaluate the clinical efficacy as defined by 6-month radiologic progression free survival 
rate (rPFS).  
o For soft tissue lesions, rPFS is defined as the date of Cycle 1 Day 1 to date of 
radiologic progression of soft tissue lesions per RECIST 1.1 or death whichever 
occurs first.  
o For bone lesions, rPFS is defined as the date of Cycle 1 Day 1 to date of 
progression of bone lesions per PCWG3 criteria or death whichever occurs first. 
NOTE: the “date of progression” is the earlier date of either of those two possible types 
of progression.   
 
2.2.2 Secondary Endpoints 
 Safety of the combination will be assessed based on Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. 
 Overall survival (OS) will be measured from date of registration to date of death from 
any cause.    
 ORR will be the proportion of patients achieving either a complete response or a partial 
response, among all patients meeting the criteria of Section 12.6, as well as among all 
patients enrolled. 
 DOR will be measured from the start date of the best response achieved until the date of 
relapse (i.e., progression). 
 
 
 

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3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. NOTE:  HIPAA authorization may be included in the 
informed consent or obtained separately. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days 
prior to the date of registration. 
 
4. The subject has histologically proven prostate cancer with radiologic evidence of 
metastases and at least one of the following:  
 Small-cell or NEPC morphology (determined by the enrolling center) on the basis 
of tissue sample. 
 Prostate adenocarcinoma with IHC staining for neuroendocrine markers (e.g., 
chromogranin and synaptophysin). 
 Presence of visceral metastases or high volume disease (> 4 sites of metastases)   
with a PSA ≤ 5.  
 Serum chromogranin A level ≥ 5× upper limit of normal (ULN) and/or serum 
neuron specific enolase (NSE) ≥ 2× ULN. 
 RB1 deletions or mutations noted on genomic testing  
 Trans-differentiated carcinoma or poorly-differentiated carcinoma 
 
5. Subject has adequate organ function as defined in the table below; all screening labs to be 
obtained within 10 days prior to Cycle 1 Day 1. 
 Absolute neutrophil count (ANC) ≥ 1500/mm3without colony stimulating factor 
support 
 Platelets ≥ 100,000/mm3 
 Hemoglobin ≥ 9 g/dL. Transfusions are allowed as needed. 
 Serum creatinine ≤ 1.5  ULN or creatinine clearance (CrCl) ≥ 30 mL/min. For 
creatinine clearance estimation, the Cockcroft and Gault equation should be used. 
 Bilirubin ≤ 1.5  the upper limit of normal (ULN) OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN. For subjects with known 
Gilbert’s disease, bilirubin ≤ 3.0 mg/dL 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5  ULN if no liver involvement, or ≤ 5  ULN with liver involvement 
 International normalized ratio (INR) OR prothrombin time (PT), Activated partial 
thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is within therapeutic range of 
intended use of anticoagulants 
 Urine protein < 2+ by urine dipstick 
 

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6. A male participant must agree to use of contraception during the treatment period and for 
at least 120 days after the last dose of study treatment and refrain from donating sperm 
during this period.  
 
7. Projected life expectancy of at least 6 months as determined by treating physician. 
 
8. As determined by the enrolling physician or protocol designee, ability of the subject to 
understand and comply with study procedures for the entire length of the study. 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Received prior therapy with VEGF-TKI, immune checkpoint inhibitor, an anti-PD-1, 
anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-
inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137). 
 
2. Received prior systemic anti-cancer therapy including investigational agents within 3 
weeks prior to registration. NOTE: Participants must have recovered from all AEs due to 
previous therapies to ≤ Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may 
be eligible. NOTE: If participant received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention prior to starting 
study treatment. 
 
3. Received more than two prior chemotherapy regimens for metastatic prostate cancer. 
Prior therapy with androgen receptor axis targeted agents is allowed but needs to be 
discontinued at least 2 weeks prior to study therapy. Prior therapy with Rad-223 or other 
radiopharmaceuticals is permitted but study therapy should be started at least 4 weeks 
after the last dose. 
 
4. Concurrent treatment with anti-androgen medications. NOTE: LHRH agonists and 
GNRH antagonists may be continued. All oral anti androgens should be discontinued.   
 
5. Received prior radiotherapy within 2 weeks of start of study treatment.  Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not 
have had radiation pneumonitis.  A 1-week washout is permitted for palliative radiation 
(≤ 2 weeks of radiotherapy) to non-CNS disease. 
 
6. Currently participating in or has participated in a study of an investigational agent or has 
used an investigational device within 3 weeks prior to the first dose of study treatment. 
NOTE:  Participants who have entered the follow-up phase of an investigational study 
may participate as long as it has been 3 weeks after the last dose of the previous 
investigational agent. 
 
7. Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) 
despite an optimized regimen of antihypertensive medication.  
 

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8. Presence of non-healing wounds after surgical procedures. 
9. Known active CNS metastases and/or carcinomatous meningitis.  Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note 
that the repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
treatment. 
 
10. Received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of 
study drug.  Administration of killed viruses are allowed. All COVID-19 vaccines are 
permitted at any time before or during the study. 
 
11. Significant cardiovascular impairment: history of congestive heart failure greater than 
New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or 
stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring 
medical treatment at Screening.  
 
12. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of 
tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be 
considered because of the potential risk of severe hemorrhage associated with tumor 
shrinkage/necrosis following lenvatinib therapy.   
 
13. Subjects having > 1+ proteinuria on urine dipstick testing unless a 24-hour urine 
collection for quantitative assessment indicates that the urine protein is <1 g/24 hours.   
 
14. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. 
 
15. Severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients. 
 
16. Severe hypersensitivity (≥ Grade 3) to lenvatinib and/or any of its excipients. 
 
17. 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. Replacement steroids for adrenal insufficiency or daily dose equivalent of 10 
mg prednisone are allowed. 
 
18. History of severe (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease. 
 
19. Active uncontrolled infection. 
 

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20. Known additional malignancy that is progressing or has required active treatment within 
the past 3 years.  NOTE:  Participants with basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin or carcinoma in situ (e.g. breast carcinoma, cervical cancer in 
situ) that have undergone potentially curative therapy are not excluded. Subjects with 
other solid tumors treated curatively and without evidence of recurrence for at least 2 
years prior to enrollment may be eligible for study after discussion with the sponsor-
investigator. 
 
21. Known history of Human Immunodeficiency Virus (HIV).  NOTE: HIV testing is not 
required unless mandated by a local health authority. 
 
22. Known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) 
or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) 
infection. NOTE: Hepatitis B and Hepatitis C testing is not required unless clinical 
history indicates that this is likely.  
 
23. Known history of active TB (Bacillus Tuberculosis). 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. A subject 
is considered registered when an “On Study” date is entered into the EDC system. Subjects must 
be registered prior to starting protocol therapy. Protocol therapy must begin within 5 business 
days of study registration. 
 
5. 
TREATMENT PLAN 
Eligible patients will be treated with the combination of lenvatinib and pembrolizumab. A cycle 
equals 21 days and therapy will continue until radiographic progression, intolerable toxicity, or 
patient/physician wishes to discontinue protocol therapy. A maximum of 35 cycles may be 
administered. On Day 1, when both pembrolizumab and lenvatinib are administered, patients 
should take the lenvatinib per their normal routine. 
 
If measurable disease is present, response will be assessed by RECIST 1.1 criteria. For bone only 
metastases at least 2 new areas of metastases will qualify as progression, and PSA response will 
be also reported per Prostate Cancer working Group 3 guidelines. Section 7 calendar outlines the 
schedule for assessments. 
 
5.1 
Study Treatment Administration 
 
Drug 
Dose 
Route 
Schedule 
Cycle 
Length 
Lenvatinib 
20 mg 
Orally 
Day 1-21 
3 weeks 
(21 days) 
Pembrolizumab 
200 mg 
Intravenously (IV) 
over 30 minutes 
Day 1  

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A window of ± 3 days may be applied to all study visits to accommodate observed holidays, inclement 
weather, scheduling conflicts etc. Date and time of each drug administration should be clearly 
documented in subject’s chart and electronic case report forms (eCRFs). 
 
5.2 
Lenvatinib 
Lenvatinib can be taken orally with or without food once daily. For subjects that cannot swallow 
the capsule: Use a medicine cup to measure about one tablespoon of water or apple juice and 
place into a small glass. Place the lenvatinib capsules into the small glass without breaking or 
crushing them. Leave the capsules in the liquid for at least 10 minutes. Stir the contents of the 
glass for at least 3 minutes. Drink the mixture. After drinking, rinse the glass with a small 
amount of additional water or apple juice and swallow the liquid. If a dose is missed and cannot 
be taken within 12 hours, then that dose should be skipped and the next dose should be taken at 
the usual time of administration.  
 
Optimal medical management for nausea, vomiting, and/or diarrhea should be initiated prior to 
any lenvatinib therapy interruption or dose reduction; however, gastrointestinal toxicity should 
be actively managed in order to reduce the risk of development of renal impairment or renal 
failure.  
 
NOTE: Diaries will be provided to subjects for completion of oral medication administration. 
Subjects will be asked to bring the diary and medication container to each clinic visit. Dose 
modification guidelines can be found in Section 6. 
 
5.3 
Pembrolizumab 
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). 
 
5.4 
Concomitant Medications 
 
5.4.1 Allowed Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  Bisphosphonate therapy can be continued. 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 if associated 
with SAEs and ECIs as defined in Section 11. 
 
 
 

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5.4.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab and lenvatinib 
 Radiation therapy  
 Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.  
 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-investigator. 
 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.   
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, the sponsor-
investigator and the participant. There are no prohibited therapies during the Post-Treatment 
Follow-up Phase. 
 
5.5 
Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines.  Where 
appropriate, these guidelines include the use of oral or IV treatment with corticosteroids, as well 
as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as symptoms may 
worsen when the steroid dose is decreased.  For each disorder, attempts should be made to rule 
out other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care.  The treatment guidelines are intended to be applied when the 
Investigator determines the events to be related to pembrolizumab.  
 

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NOTE: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to guidelines regarding 
dose modification and supportive care.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
 
5.6 
Reproductive Information 
 
5.6.1 Male Recipients 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to one of the following during the protocol defined time frame in section 3.1:  
 Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
 Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described above when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant. NOTE: Men with a pregnant or 
breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or 
use a male condom during each episode of penile penetration. 
 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade 
adverse events. Subjects enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this study as specified 
in Study Calendar & Evaluations. Subjects will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug interruption or discontinuation as 
specified in Study Calendar & Evaluations.   
 
6.1 
Dose Modifications for Lenvatinib 
Management of some adverse reactions may require dose interruption, adjustment, or 
discontinuation of lenvatinib therapy. Upon resolution/improvement of an adverse reaction, 
treatment should be resumed at a reduced dose. Mild to moderate adverse reactions (eg, Grade 1 
or 2) generally do not warrant interruption of lenvatinib or of the combination, unless intolerable 
to the patient despite optimal management. Severe and clinically relevant (eg, Grade 3 or 4) or 
intolerable adverse reactions that are considered to be possibly, probably or definitely related to 
lenvatinib, pembrolizumab or both require interruption of lenvatinib or the combination until 
improvement of the reaction to Grade 0-1 or baseline.  
 
For lenvatinib-related toxicities, upon resolution/improvement of an adverse reaction to Grade 0-
1 or baseline, treatment of lenvatinib should be resumed with one level dose reduction as 
outlined in the Table below. For patients deriving clinical benefit and persistent toxicities at the 
lowest (-3) dose of lenvatinib, please contact the sponsor-investigator and HCRN for 
consideration of lowering the dose further. No dose re-escalation is allowed unless discussion 
with the sponsor-investigator and HCRN occurs and approval is obtained.  
 

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Treatment should be discontinued in case of life-threatening reactions (e.g., Grade 4) with the 
exception of laboratory abnormality judged to be non-life-threatening, in which case they should 
be managed as severe reactions (e.g., Grade 3). 
 
6.1.1 Dose Levels for Dose Reductions of Lenvatinib 
 
Dose level 
Dose of Lenvatinib 
Starting Dose 
20 mg 
Dose level (-1) 
14 mg 
Dose level (-2) 
10 mg 
Dose level (-3) 
8 mg 
 
6.2 
Dose Modifications for Pembrolizumab 
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, 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/combination 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 study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab/combination treatment, 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.  Dose modification and 
toxicity management guidelines for irAEs associated with pembrolizumab are provided in Table 
1. 
 
 
 

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Table 1: Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
monotherapy and IO Combinations 
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤Grade 1 after corticosteroid taper.
 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
  Add prophylactic antibiotics for 
opportunistic infections 
  Monitor participants for signs and symptoms of 
pneumonitis 
  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis 
Grade 2 or 3 
Withhold 
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
 
  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus) 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis 
  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion 
AST or ALT 
Elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper 
  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure 
Withhold d 
  Initiate insulin replacement therapy for 
participants with T1DM 
  Administer antihyperglycemic in 
participants with hyperglycemia 
 
  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Hyperthyroidism
Grade 2 
Continue 
  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
  Monitor for signs and symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care 
  Monitor for signs and symptoms of thyroid 
disorders 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper 
  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
  Based on severity of AE administer 
corticosteroids 
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
  Based on severity of AE administer 
corticosteroids 
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or 
DRESS 
Withhold 
  Based on severity of AE administer 
corticosteroids 
  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, or 
DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 Withhold 
  Based on severity of AE administer 
corticosteroids 
  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Grade 3 
Withhold or 
discontinue based 
on the event e  
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
 
 
 
 

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6.3 
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 reactions are provided below.   
 
Table 2: 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 participant is 
deemed medically stable in the opinion of the investigator. 
None 
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 participant 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 participant should 
be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study drug treatment 
Participant 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 participant is 
deemed medically stable in the opinion of the investigator.
No subsequent dosing 

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Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug treatment. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
 
 
 
 
 

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6.3 
Dose Modifications for Overlapping Toxicities 
Based on the known toxicity profiles of pembrolizumab and lenvatinib, certain treatment-related 
AEs are uniquely associated with one drug versus the other. For example, hypertension, arterial 
thrombotic events, proteinuria, and hemorrhagic events are known risks for lenvatinib treatment, 
while immune-related AEs are risks for pembrolizumab treatment. However, certain AEs, such 
as such as diarrhea, hypothyroidism, and liver enzyme elevation, may be initially considered 
attributable to either study drug. Therefore, evaluation of attribution is important for determining 
the study drug most likely related to the AE, or an alternative etiology, and subsequently proper 
clinical management. The following aspects should be considered:  
 
1. Timing of AE onset  
Since lenvatinib is dosed daily and continuously due to a relatively short half-life 
(28 hours), and pembrolizumab is dosed Q3W due to a long half-life, lenvatinib can be 
interrupted to assess whether an AE improves/resolves with dechallenge (ie, interruption 
of treatment) based on the following two scenarios: 
o If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab 
doses), only lenvatinib dose interruption is needed.  
o If an AE is identified at the beginning of a treatment cycle, lenvatinib can be 
interrupted and dosing of pembrolizumab should be held. 
If the subject recovers from an AE in response to lenvatinib interruption (ie, positive 
dechallenge), the event is more likely to be related to lenvatinib. Otherwise, after 
excluding other alternative explanations, an immune-related AE should be considered.  
 
2. Severity of AE 
If an AE is suspected to be treatment related and is severe/life threatening at the time of 
onset or is rapidly worsened, action including interrupting both drugs and initiating 
treatment with a corticosteroid (with exception of hypothyroidism, TIDM) and other 
supportive care should be taken promptly. 
 
3. Participants receiving the combination therapy (pembrolizumab + lenvatinib) must 
discontinue study therapy if any of the following occur:  
 ALT or AST >5 X ULN for more than 2 weeks. 
Pembrolizumab will have already been permanently discontinued per the Table 
above, but lenvatinib may be administered at a reduced dose by the time this criterion 
is met and must be permanently discontinued immediately. 
 ALT or AST >3 X ULN and (TBL >2 X ULN or INR >1.5). 
Although the Table above advises pembrolizumab to be withheld (interrupted), and 
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, 
both drugs must be permanently discontinued immediately. 
 
 
 

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6.4 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined above, a subject will 
also be discontinued from protocol therapy and followed per protocol under the following 
circumstances outlined below.  The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF)   
 
Completion of maximum of 35 cycles of study treatment. 
 
Documented disease progression per RECIST 1.1 (subjects with measurable disease) or 
PCWG (subjects without measurable disease). If a subject is receiving clinical benefit (as 
determined by treating physician), treatment can continue after discussion with sponsor-
investigator. 
 
Site investigator determines a change of therapy would be in the best interest of the 
subject 
 
Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons 
o In a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted for further 
scheduled study assessments. The outcome of that discussion should be documented 
in both the medical records and in the eCRF. 
 If protocol therapy (both drugs) is interrupted for ≥ 42 days from the expected day of the 
next treatment. If one drug is permanently discontinued, treatment with the other drug 
may continue at investigator discretion. 
 
6.5 
Protocol Discontinuation  
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 
 
6.6 
Safety Follow Up 
The safety follow-up visit should only occur when subjects permanently stop study treatment for 
whatever reasons (toxicity, progression, or other reason) and should be performed 30 days (+ 7 
days) after the last dose of treatment. Participants 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-cancer 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. The Day 90 
assessment may be performed via phone call, email or other avenues as appropriate. 
 
6.7 
Long Term Follow Up 
For subjects who discontinue for reasons other than progressive disease, radiographic disease 
assessment should be performed per discretion of the site investigator per standard of care for 
disease assessment. The scan interval may be reset if scans were done sooner for clinical reasons 
and the type of scan may be left to discretion of the site investigator. This imaging may be done 
locally. Follow up for these subjects will occur every 6 months until progression. Once disease 
progression is documented, subjects will be followed for survival every 6 months for 5 years 
from the time of documented progression. Follow up may be accomplished via clinic visit, phone 

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call, or other avenues as appropriate. A window of ± 14 days will be applied to long term follow 
up. 

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7. 
STUDY CALENDAR & EVALUATIONS 
 
Study Evaluation  
Cycle = 21 days 
Screening10 
Cycle 1  
Cycle 2+ 
Safety follow up visit8 
Long-term Follow up9 
-28 days 
from C1D1 
Day 1 
± 3 days 
Day 1 
± 3 days 
30/90 days post last dose 
+ 7 days 
Every 6 months 
(±14 days) 
REQUIRED ASSESSMENTS 
Informed Consent
X
Medical History and Disease Staging1 
X
Physical Exam
X
X
X
D30
Vital signs and ECOG Performance Status2 
X
X2 
X2 
D30
ECG2 
X
X2 
X2 
AEs & concomitant medications
X
X
X
X
LABORATORY ASSESSMENTS 
Complete Blood Cell Count with diff (CBC)3 
X
X10 
X
D30
Comprehensive Metabolic Profile (CMP)3 
X
X10 
X3 
D30
PT/INR and aPTT3 
X
Thyroid Function Testing3 
X
X3 
Urine protein3 
X
X3 
Chromogranin A, neuron specific enolase and urine NTx4 
X 
X4 
D30
Prostate-specific antigen (PSA)4 
X
X
D30
X4 
Testosterone4 
X
D30
DISEASE ASSESSMENT 
CT of chest5 
X
X5 
D305
X5
CT or MRI of abdomen and pelvis5 
X
X5 
D305
X5
MRI Brain5 
X
X5 
D305
X5
Bone scan5 
X
X5 
D305
X5
TREATMENT EXPOSURE 
Lenvatinib
D1-21
D1-21
Pembrolizumab
X
X
SPECIMEN COLLECTION  
Archival Tumor Tissue6
X6 
 
Blood for somatic baseline
X
Blood for plasma7
X7 
D307 
 
Stool for microbiome7 
 
X7
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X

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Key to Footnotes  
 
1: Medical History; other data to obtained during this assessment includes a smoking history questionnaire and trial awareness question.  In 
addition, prior anti-cancer treatment should be documented including medications (chemotherapy, checkpoint inhibitors, etc) radiation or surgery.  
Prior genomic sequencing and PD-L1 results are required if available. Diagnosis and staging to include pathology report and imaging reports.  
 
2: Vital signs to include temperature, pulse, respirations, blood pressure, weight, and height (screening only) and ECOG performance status.  
Blood pressure should be monitored after 1 week of treatment with lenvatinib (around C1D7), then every 2 weeks for the first 2 months (C2D1 at 
clinic visit and C2D14) and Day 1 of every cycle thereafter while on treatment. If a subject develops systolic BP ≥140 mmHg or diastolic BP ≥ 90 
mmHg active management is indicated. Monitoring may be done locally by clinic visit, at home BP monitoring or similar. Subjects will be asked 
to maintain a record of BP readings and communicate results to research staff at timepoints as outlined above. ECG to be performed at screening 
then as clinically indicated during study treatment per investigator discretion. 
 
3: CBC with differential and platelet to include: WBC, ANC, Hgb, Hct, PLT. CMP to include sodium, potassium, chloride, creatinine, blood urea 
nitrogen; calcium, albumin, and liver function tests (LFTs). LFTs to include AST, ALT, total bilirubin, and alkaline phosphatase; LFTs will be 
monitored every 2 weeks for 2 months (C1D14, C2D1, C2D14, C3D1). PT/INR and PTT should be obtained at screening then at site investigator 
discretion. Thyroid Function testing should be performed at screening then every 4 cycles (12 weeks). TSH should be obtained. T4 and T3 
including free versus total testing is at the discretion of the site investigator. Urine protein should be obtained at screening then every 3 cycles (9 
weeks). If urine dipstick ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary.  
 
4: Chromogranin A, neuron specific enolase and urine NTx (optional) will be performed at screening/day 1 then prior to treatment every other 
Cycle starting at Cycle 3 Day 1 then at the D30 safety visit. PSA should be obtained at screening then prior to treatment every Cycle then at the 
D30 safety visit. Subjects that come off study without progression should have PSA obtained per investigator discretion. Testosterone will be 
performed at screening and at the D30 safety visit.  
 
5: Tumor response assessment will consist of evaluation by CT scans of chest and MRI or CT of abdomen and pelvis. If a PET/CT is done for 
tumor assessment and if tumor/s are visible on the CT, this may be used for tumor evaluation. A bone scan will be obtained at screening and with 
other radiology imaging at the frequency as outlined below. An MRI of the brain should be performed at screening if there is a concern for the 
presence of brain metastases. Tumor imaging will be done at screening and every 3 cycles (9 weeks) for the first 12 cycles (36 weeks) and then 
every 4 cycles (12 weeks) until the patient is off study therapy (window of ± 1 week). Tumor imaging should follow week intervals in the case of 
study treatment delays due to toxicities. During follow up after completion of study treatment, imaging frequency is at the discretion of the site 
investigator. Imaging selected for each subject should remain the same throughout the study. Tumor imaging to be done at treatment 
discontinuation/safety follow up visit is at discretion of site investigator. If tumor assessments are available for subjects who have not yet 
experienced progressive disease (PD) at the time treatment is discontinued, the follow-up tumor evaluations will be documented in the eCRF until 
PD or death is confirmed, or until another treatment is initiated.   
 

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6: Archival tissue obtained within 12 months of registration is required if available. Archival tissue should be identified at screening and shipped 
prior to Cycle 2 Day 1 treatment. If not available, the patient may still be eligible after discussion with the sponsor-investigator. These samples 
will be stored for correlative analysis which may include PD-1/PD-L1 expression, tumor mutation burden, and next generation sequencing to 
evaluate genomic markers once funding is available. Subjects will also be consented for optional storage of any remaining tissue/blood samples 
after protocol-specified studies are complete. These samples will be stored for future unspecified cancer-related research and are considered 
“banking samples”. See Correlative Laboratory Manual (CLM) for additional details regarding correlative samples.  
 
7: Peripheral blood samples will be collected prior to treatment (1) Cycle 1 Day 1, (2) Cycle 3 Day 1 (9 weeks) and (3) at progression. For subjects 
that discontinue treatment for progression, these samples may be collected at the D30 safety visit. Plasma will be stored for circulating tumor DNA 
(ctDNA) and miRNA analysis once funding is available. Whole blood samples will also be collected prior to treatment (1) Cycle 1 Day 1 and 
stored for somatic baseline testing once funding is available. Stool for microbiome will be collected prior to (1) Cycle 1 Day 1 treatment and 
stored for correlative analysis once funding is available. Subjects will be provided instructions after consent during screening and asked to bring 
the sample back prior to C1D1 treatment. Subjects will also be consented for optional storage of any remaining tissue/blood/stool samples after 
protocol-specified studies are complete. These samples will be stored for future unspecified cancer-related research and are considered “banking 
samples”. See Correlative Laboratory Manual (CLM) for additional details regarding correlative samples.  
 
8: Safety Follow Up: The safety follow-up visit should only occur when subjects permanently stop study treatment for whatever reasons (toxicity, 
progression, or other reason) and should be performed 30 days (+ 7 days) after the last dose of treatment. Participants 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-cancer 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. The Day 90 
assessment may be performed via phone call, email or other avenues as appropriate. 
 
9: Long Term Follow Up: For subjects who discontinue for reasons other than progressive disease, radiographic disease assessment should be 
performed per discretion of the site investigator per standard of care for disease assessment. The scan interval may be reset if scans were done 
sooner for clinical reasons and the type of scan may be left to discretion of the site investigator. This imaging may be done locally. Follow up for 
these subjects will occur every 6 months until progression. Once disease progression is documented, subjects will be followed for survival every 6 
months for 5 years from the time of documented progression. Follow up may be accomplished via clinic visit, phone call, or other avenues as 
appropriate. A window of ± 14 days will be applied to long term follow up. 
 
10: Screening labs as outlined in Section 3 of the inclusion criteria must be performed within 10 days of C1D1. If screening (baseline) CBC and 
CMP were performed within 7 days of Day 1 of treatment, these do not need to be repeated.  All laboratory assessments should be done prior to 
treatment. 

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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
Please refer to the Correlative Laboratory Manual (CLM) for all sample collection, processing, 
labeling, and shipping instructions of samples outlined below. 
 
8.1 
Tissue 
Tissue samples will be stored for future correlative analysis which may include PD-1/PD-L1 
expression, tumor mutation burden, RNA and next generation sequencing to evaluate genomic 
markers once funding is available. 
 
8.1.1 Archival Tissue 
Archival tissue is required if available. Archival tissue should be identified at screening and 
shipped prior to Cycle 2 Day 1 treatment.  
 
8.2 
Peripheral Blood Samples 
 
8.2.1 Plasma for Circulating Tumor DNA and miRNA 
Peripheral blood samples will be collected prior to treatment Cycle 1 Day 1, prior to Cycle 3 Day 
1 and at progression. For subjects that discontinue treatment for progression, these samples may 
be collected at the D30 safety visit. Plasma will be stored for possible ctDNA and miRNA 
analysis once funding is available.  
 
8.2.2 Whole Blood for Somatic Baseline 
Whole blood samples will be collected prior to treatment Cycle 1 Day 1 and stored for future 
correlative analysis once funding is available. 
 
8.3 
Stool for Microbiome 
Stool for microbiome will be collected prior to Cycle 1 Day 1 treatment and stored for 
correlative analysis once funding is available. 
 
8.4 
Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples collected for study-specific 
correlative research. Hoosier Cancer Research Network (HCRN) will manage the banked 
samples. Samples will be coded and banked indefinitely in the Hoosier Cancer Research 
Network Biorepository and used for future unspecified cancer-related research.  
 
8.5 
Confidentiality of Biospecimens 
Samples will be identified by the subject’s study number assigned at the time of registration to 
the trial. Any material issued to collaborating researchers will be anonymized and only identified 
by the subject’s study number. 
 
 
 

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9. 
CRITERIA FOR DISEASE EVALUATION 
RECIST 1.1 criteria will apply to subjects with measurable disease. For patients with non-
measurable disease the PCWG3 criteria will be utilized for response assessment. PSA response 
and progression will also be evaluated per PCWG3 criteria. [9]  
 
9.1 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
9.1.1 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
9.2 
Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable.  
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
9.3 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement, in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 

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9.4 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
9.5 
Evaluation of Target Lesions 
NOTE: In addition to the information below, also see the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1[8] (Eur J 
Cancer 45;2009:228-247) for special notes on the assessment of target lesions.  
 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm.
Partial Response 
(PR)
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note:  the 
appearance of one or more new lesions is also considered 
progressions).
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study
 
 
9.6 
Evaluation of Non-Target Lesions 
 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes 
must be non-pathological in size (<10 mm short axis) 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a subject to be 
considered in complete clinical response.
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of 
overall disease status change, not a single lesion 
increase.

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Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator. 
 
9.7 
Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions
Overall 
Response 
CR
CR
No
CR
CR
Non-CR/ Non-PD
No
PR
CR
Not evaluated
No
PR
PR 
Non-PD/ or not all 
evaluated
No 
PR 
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
Non-evaluable
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
9.8 
Definitions for Response and Survival Evaluation  
 
9.8.1 Time to Response (TTR) 
The time between initiation of therapy and first documentation of PR or CR. 
 
9.8.2 Radiologic Progression Free Survival (rPFS) 
rPFS has two components to its definition.  For soft tissue lesions, rPFS will be measured from 
Cycle 1 Day 1 to date of radiologic progression per RECIST 1.1 or death from any cause, 
whichever occurs first.  For bone lesions (non-measurable disease), rPFS will be measured from 
Cycle 1 Day 1 to date of progression per PCWG3 criteria [9] or death from any cause, whichever 
occurs first.  Thus, the “date of progression” is the earlier date of either of those two possible 
types of progression.  Subjects who have not progressed will be right-censored at the date of the 
last disease evaluation.  
 
9.8.3 Overall survival  
Overall survival (OS) will be measured from Cycle 1 Day 1 to date of death from any cause.   
Patients still alive will be right-censored as of the most recent date on which they were last 
confirmed (by any of the methods listed) to be alive. 
 
 

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9.8.4  Duration of Response (DoR) 
DOR will be measured from the start date of the best response achieved until the date of relapse 
(i.e., progression).   Continuing responders will be right-censored as of the most recent date on 
which their response status had been assessed.  DoR applies to only the patients who achieve 
either a complete response (CR) or a partial response (PR). 
 
10. 
DRUG INFORMATION 
 
10.1 
Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure. 
 
10.1.1 Supplier/How Supplied 
Merck will supply pembrolizumab from commercial stock at no charge to subjects participating 
in this clinical trial.  
 
The investigator at each site 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. 
 
10.1.1 Preparation 
The product after reconstitution with sterile water for injection and the liquid drug product is a 
clear to opalescent solution, which may contain extraneous and proteinaceous particulates. The 
reconstituted product and liquid product is intended for IV administration. The reconstituted drug 
product solution and liquid drug product can be further diluted with normal saline in IV 
containers made of polyvinyl chloride (PVC) or non-PVC material. Reconstituted vials should be 
immediately used to prepare the infusion solution in the IV bag and the infusion solution should 
be immediately administered. If not used immediately, vials and/or IV bags may be stored at 2-8 
°C for up to a cumulative time of 24 hours from time of dilution. If refrigerated, the vials and/or 
IV bags should be allowed to equilibrate to room temperature prior to subsequent use. 
Pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 6 
hours. This includes room temperature storage of reconstituted drug product solution and liquid 
drug product in vials, room temperature storage of infusion solution in the IV bag and the 
duration of infusion. Please refer to the investigator’s brochure for additional information. 
 
10.1.2 Storage and Stability 
Clinical supplies must be stored in a secure, limited-access location. Store vials under 
refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. 
Do not shake. Receipt and dispensing of trial medication must be recorded by an authorized 

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person at the trial site. Clinical supplies may not be used for any purpose other than that stated in 
the protocol. 
 
10.1.3 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
After final drug reconciliation, unused pembrolizumab vials should be disposed at the site 
following procedures for the disposal of anticancer drugs. 
 
10.1.4 Dispensing 
Pembrolizumab must be dispensed only from official study sites and to eligible subjects under 
the supervision of the site investigator. Pembrolizumab should be stored in a secure area 
according to local regulations.  It is the responsibility of the site investigator to ensure that study 
drug is only dispensed to subjects. 
 
10.1.5 Adverse Events Associated with Pembrolizumab 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this 
mechanism of action, immune mediated adverse events are of primary concern. Important 
identified risks for pembrolizumab are of an immune mediate nature, including: pneumonitis, 
colitis, hepatitis, nephritis, endocrinopathies that include hypophysitis (including hypopituitarism 
and secondary adrenal insufficiency), thyroid disorder (hypothyroidism, hyperthyroidism, 
thyroiditis), Type I diabetes mellitis, uveitis, myositis, Guillain-Barré syndrome, pancreatitis, 
myocarditis, myasthenic syndrome, encephalitis, sarcoidosis, severe skin reactions including 
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal 
outcome; and “solid organ transplant rejection following pembrolizumab treatment in donor 
organ recipients” (risk applicable primarily to post-marketing setting only, as such patients are 
currently excluded from Merck-sponsored clinical studies with pembrolizumab). 
 
The majority of immune-mediated adverse events were mild to moderate in severity, were 
manageable with appropriate care, and rarely required discontinuation of therapy.  
 
Further details regarding immune-related adverse events (irAEs) can be found in the current 
version of the Investigator’s Brochure.  
 
10.2 
Lenvatinib 
Lenvatinib (lenvatinib mesilate) is an oral, potent multiple receptor tyrosine kinase (RTK) 
inhibitor that selectively inhibits vascular endothelial growth factor (VEGF) receptors, VEGFR1 
(FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other pro-angiogenic and 
oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptor FGFR1-4, 
platelet-derived growth factor (PDGF) receptor PDGFRα, KIT, and RET. Nonclinical studies 
showed lenvatinib to be a potent antiangiogenesis agent with antitumor activity versus various 
human cancer xenograft models in athymic mice.  
 

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10.2.1 Supplier/How Supplied 
Lenvatinib may be supplied in a 8 mg, 10 mg, 14 mg or 20 mg capsule. Lenvatinib drug 
substance is a white to pale yellow powder that is being used in the capsule formulation for the 
clinical studies evaluating lenvatinib. It is slightly soluble in water and has a molecular weight of 
522.96 and a pKa of 5.27 (mesilate salt). 
 
Merck will supply lenvatinib from clinical lots at no charge to subjects participating in this 
clinical trial.  
 
The investigator at each site 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. 
 
10.1.2 Storage and Stability 
Lenvatinib capsules are packaged in cold form blisters or high-density polyethylene (HDPE) 
bottles with a polypropylene cap and desiccant. The blisters and bottles should be stored under 
room temperature. 
 
10.1.3 Handling and Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. Do not open the capsule. Avoid repeat exposure to contents of the capsule. 
 
10.1.4 Dispensing 
Lenvatinib must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Lenvatinib should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects. 
 
10.1.5 Adverse Events Associated with Lenvatinib 
The most common adverse reactions include fatigue, arthralgia/myalgia, vomiting, nausea, 
stomatitis/oral inflammation, hypertension, headache, decreased appetite, stomach pain, 
hoarseness and rash, redness, itching or peeling of your skin on your hands and feet. 
 
Further details around frequency, reporting, and management of adverse events (AEs) can be 
found in the current version of the Investigator’s Brochure. 
 
 
 

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11. 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v5 will be utilized for AE 
assessment. A copy of the CTCAE v5 can be downloaded from the CTEP website at 
http://ctep.cancer.gov. All forms for AE/SAE recording and reporting can be found in the EDC 
system (Documents and Information Tab). 
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
 Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 

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11.1.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.   
 
11.1.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
11.1.5 Definition and Reporting of a Pembrolizumab and Lenvatinib Overdose 
For purposes of this trial, an overdose will be defined as any dose of 1,000 mg or greater (≥ 5 
times the indicated dose). No specific information is available on the treatment of overdose of 
pembrolizumab or lenvatinib. In the event of overdose, subject should be observed closely for 
signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated.  
If an AE (s) is associated with (“results from”) the overdose of pembrolizumab or lenvatinib, the 
AE(s) is reported as a SAE, even if no other seriousness criteria are met. 
 
If a dose of pembrolizumab or lenvatinib 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 ECI, using the terminology “accidental or intentional overdose without 
adverse effect.” 
 
All reports of overdose with and without an AE (and other Reportable Events) must be reported 
on a HCRN Serious Adverse Event Submission Form within 1 business day to HCRN safety via 
email: safety@Hoosiercancer.org. HCRN will report the event within 1 business day to Merck 
Global Safety (Attn: Worldwide Product Safety; FAX 215-661-6229). 
 
11.1.6 Reporting of Pregnancy  
Although pregnancy is not considered an adverse event, it is the responsibility of investigators or 
their designees to report any pregnancy of a participant’s partner (spontaneously reported to 
them) that occurs from the time of treatment initiation through 120 days following cessation of 
study drugs. 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. 

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All reports of pregnancy with and without an AE must be reported within 1 business day to 
SAFETY@hoosiercancer.org on appropriate Pregnancy Reporting form.. HCRN will report the 
event within 1 business day to Merck Global Safety (Attn: Worldwide Product Safety; FAX 
215-661-6229). 
 
11.1.7 Definition and Reporting of Events of Clinical Interest (ECI)  
Selected non-serious and SAEs are also known as ECI and must be recorded as such on the 
Adverse Event case report forms/worksheets and reported to HCRN within 1 business day of 
the event. 
 
ECI for this trial include: 
1. An overdose of pembrolizumab or lenvatinib, as defined above, 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 3 × the upper limit of 
normal, and an elevated total bilirubin lab value that is greater than or equal to 2 × the 
upper limit of normal, and, at the same time, an alkaline phosphatase lab value that is 
less than 2 × 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.  
 
ECIs that occur in any subject from the date of first dose through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates a new anticancer 
therapy, whichever is earlier, whether or not related to pembrolizumab or lenvatinib, must be 
reported within 1 business day to SAFETY@hoosiercancer.org. HCRN will report the event 
within 1 business day to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215-661-
6229). 
 
11.2 
Reporting 
 
11.2.1 Adverse Events  
 AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
 
 
 

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11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 
Site Requirements for Reporting SAEs to HCRN 
 SAEs will be reported from time of signed informed consent until 90 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
 SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event.   
 All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form will be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.   
 
The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site. 
 
Once the SAE has resolved, sites must submit a follow-up SAE Submission Form within a 
reasonable timeframe to HCRN electronically to safety@hoosiercancer.org.   
 
11.2.2.2 
HCRN Requirements for Reporting SAEs to Merck  
HCRN will report all SAEs to Merck within 1 business day of receipt of the SAE Submission 
Form from a site. Follow-up information will be provided to Merck as it is received from site.  
 
11.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.4 
IND Exempted Protocols 
For protocols exempt from the requirements of an IND, HCRN will continue to facilitate 
compliance of applicable requirements for the sponsor-investigator in relation to this study. This 
includes but is not limited to 21 CFR 50.20 informed consent, 21 CFR Part 56 IRB, and pertinent 
sections of the Public Health Service Act and FDAAA. 
 
11.5 
IND Safety Reports Unrelated to this Trial 
Merck will provide to HCRN IND safety reports from external studies that involve the study 
drug(s) per their guidelines.  HCRN will forward safety reports to the sponsor-investigator who 
will review these reports and determine if revisions are needed to the protocol or consent. HCRN 
will forward these reports to participating sites within 1 business day of receiving the sponsor-
investigator’s review.  Based on the sponsor-investigator’s review, applicable changes will be 
made to the protocol and informed consent document (if required).  Any changes made to the 
protocol and/or informed consent document will be submitted to the FDA by MICHR-MIAP. All 
IND safety reports will also be made available to sites via the EDC system.    

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Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
12. 
STATISTICAL METHODS 
 
12.1 
Objectives 
 
12.1.1 Primary Objective 
Evaluate 6 month radiographic progression free survival (rPFS) rate with lenvatinib and 
pembrolizumab combination therapy in metastatic NEPC.  
 
12.1.2 Secondary Objectives 
 Assess the safety of pembrolizumab and lenvatinib combination therapy in metastatic 
neuroendocrine prostate cancer (NEPC).  
 Assess overall survival (OS). 
 Assess objective response rate (ORR). 
 Assess duration of response (DoR). 
 
12.1.3 Correlative / Exploratory Objectives 
 Correlate genomic sequencing results with clinical outcomes in the study population. 
 Correlate PDL-1 status and tumor mutation burden with clinical outcomes. 
 Correlate gut microbiome data with clinical outcomes. 
 
12.2 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
rPFS is defined as the date of Cycle 1 Day 1 to date of radiologic progression of soft tissue 
lesions per RECIST 1.1 or death whichever occurs first. rPFS is defined as the date of Cycle 1 
Day 1 to date of progression of bone lesions (non-measurable disease) per PCWG3 criteria or 
death whichever occurs first. Censoring of rPFS is described in Section 9.8.2. 
 
12.2.2 Definition of Secondary Endpoints 
 Safety of the combination will be assessed based on NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. 
 Overall survival (OS) will be measured from Cycle 1 Day 1 to date of death from any 
cause. OS is further defined (including its censoring) in Section 9.8.3. 
 ORR will be the proportion of patients achieving either a complete response (CR) or a 
partial response (PR), among all patients meeting the criteria of Section 12.6, as well as 
among all patients enrolled. 
 DoR will be measured from the start date of the best response achieved until the date of 
relapse (i.e., progression).  DoR is further defined (including its censoring) in Section 
9.8.4.  DoR applies to only the CR or PR patients. 
 
 
 

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12.2.3 Correlative/Exploratory Endpoints 
 Genomic sequencing results will be either categorical variables (e.g, if from DNA 
sequencing), or continuous variables (e.g., if from RNA sequencing). 
 PDL-1 status will be a binary variable (either positive or negative).  Tumor mutation 
burden (TMB) is a continuous variable (e.g., the number of mutations per megabase [Mb] 
of the genome coding area (as per the Caris Life Sciences website). 
 Gut microbiome data will consist of continuous variables (i.e., diversity measures and 
composition measures).  Common diversity measures are the α-diversity and the Shannon 
diversity index.  One composition measure is the between-community diversity (the β-
diversity). 
 
12.3 
Study Design and Interim Analyses 
An open label phase II study design of lenvatinib and pembrolizumab in metastatic NEPC is 
planned with primary endpoint of 6- month radiologic progression-free survival (rPFS), yes/no.  
For this binary endpoint, a 2-stage Simon near optimal design will be used, with these input 
parameters: p0 = 0.10; p1 = 0.25; alpha = 0.125; and power = 0.90. This results in the following 
design features:  N1 = 27; R1 = 2; N = 40; R = 6; PET = 0.485; and ASN = 33.70.  
 
Hence, if there are at least 3 successes (patients who have had ≥ 6.00 months of rPFS) in the 27 
patients in Stage 1 then the study will proceed to Stage 2, otherwise it will terminate early.  If 
there are at least 7 successes in the final total of 40 patients, then the treatment will be considered 
promising. To allow for up to 20% of registered patients becoming non evaluable, up to 50 
patients will need to be enrolled to yield 40 evaluable patients. 
 
It may become necessary to temporarily suspend accrual at or near the completion of Stage 1 of 
the study in order to evaluate the 6-month rPFS (primary endpoint) of the last few Stage 1 
patients. If Stage 1 accrual is at say, 24 patients and there have been no successes (i.e., no 
patients who have had ≥ 6.00 months of rPFS), then Stage 2 of accrual could not begin until up 
to 3 more patients are enrolled in Stage 1 and their rPFS outcome (success or not) has been 
determined. 
 
Conversely, if ≥ 3 successes have been observed within the first 24 or fewer patients, then the 
interim analysis can be omitted, and accrual could continue into Stage 2 without interruption.   
There would be no need for a temporary suspension of accrual. 
 
The study design operational characteristics were calculated using the “Two Stage Phase II 
Clinical Trials” program in the PASS (2019) software [10].  PET is the probability of early 
termination under the null hypothesis that p = 0.10.  ASN is the average sample number, which 
is what is minimized in a Simon optimal (or near optimal) design.  ASN is the mean number of 
patients required to complete a given Simon optimal (or near optimal) design after many 
hypothetical replications of the trial, wherein some trials terminated early (i.e., after Stage 1, 
with only N1 patients) and the others did not (i.e., went on to Stage 2, using a total of N 
patients). 
 
 
 

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12.4 
Analysis 
 
12.4.1 Primary Objective 
For the Primary objective (efficacy assessment), the binary endpoint (rPFS ≥ 6.00 months, 
yes/no) will be summarized with its point estimate (an occurrence rate), and 2-sided Wilson type 
95% confidence interval (CI). 
 
The duration of censored rPFS will be estimated with standard Kaplan-Meier (K-M) 
methodology.  Point and CI estimates of the median and various timepoint-specific rPFS rates 
will be derived from the K-M life table (e.g., 6 month rate, 12 month rate, etc.), each with its 
own respective CI.  A graph of the K-M curve for rPFS will be generated along with the Hall-
Wellner 95% confidence band, and a display of the number of patients at risk at several time 
points, below the X-axis.    
 
12.4.2 Secondary Objective 
For the first Secondary objective (safety assessment), the analysis of toxicity rates will be 
performed using only the toxicity-evaluable (t-e) patients.  All patients receiving at least one 
dose of study medication will be t-e.    
 
The grade of each type of toxicity (an ordinal categorical variable) will be summarized with 1-
way frequency distributions.  Dichotomized versions (e.g., the occurrence rate of Grade 3-4 
fatigue) will be summarized as described in Section 12.4.1 for a binary endpoint. 
 
For the second Secondary objective (follow up for survival), OS will be analyzed in the same 
fashion as rPFS.  See Section 12.4.1. 
 
For the third Secondary objective (ORR assessment), ORR will be analyzed in the same fashion 
as 6-month rPFS rate.  See Section 12.4.1, first paragraph.   
For the fourth Secondary objective (DoR assessment), DoR will be analyzed in the same fashion 
as rPFS.  See Section 12.4.1, second paragraph. 
 
12.4.3 Exploratory Objectives 
For the Exploratory objectives, all categorical variables will be summarized as described in 
Section 12.4.1.  All continuous variables (e.g., number of mutations, or TMB, or gut microbiome 
diversity or composition measures) will be summarized with descriptive statistics including the 
point estimate of the mean, its associated 95% CI, standard deviation, median, inter-quartile 
range (IQR), minimum, and maximum.  
 
The association of Exploratory correlative markers (whether binary, or ordinal categorical, or 
continuous) with a binary clinical outcome (e.g., the primary endpoint of achievement of rPFS ≥ 
6.00 months, yes/no) will be explored using logistic regression models. Point and CI estimates of 
the odds ratio (OR) will be calculated, but the statistical interpretation will be limited to only the 
direction, magnitude, and precision of the association (i.e., the OR) as these are only exploratory 
analyses. 
 
 
 

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The same approach will be used to model clinical response (defined in Section 9.0) as a function 
of a given Exploratory correlative marker (e.g, TMB). 
 
The association of Exploratory correlative markers (whether binary, or ordinal categorical, or 
continuous) with rPFS (or OS) will be explored using Cox proportional hazards (PH) regression 
models.  Point and CI estimates of the hazard ratio (HR) will be calculated, but the statistical 
interpretation will be limited to only the direction, magnitude, and precision of the association 
(i.e., the HR) as these are only exploratory analyses. 
 
12.5 
Assessment of Safety 
All patients receiving one dose of study medication (lenvatinib or pembrolizumab) will be 
evaluable for safety assessment.  National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE 5.0 will be used to evaluate toxicity.   
 
12.6 
Assessment of Efficacy 
All patients receiving 1 cycle of study treatment (any amount of pembrolizumab and lenvatinib) 
and having had radiology imaging for disease assessment will be evaluable for efficacy. 
 
12.7 
Expected Accrual Rate, Accrual Duration, and Total Study Duration 
The expected combined accrual rate for this multi-center trial would be 16-30 patients per year.  
Thus, to enroll up to 50 patients is expected to take 24-38 months of accrual. Allowing another 6 
months to obtain the primary endpoint (6-month rPFS), all biomarkers, and all genomic 
endpoints on all patients, the expected total study duration is 30-44 months. 
 
Patients who discontinue study treatment for reasons other than progression, should have disease 
assessment performed per investigator discretion. Follow up for these subjects will be every 6 
months until progression. Once disease progression is documented, patients will be followed for 
survival every 6 months for 5 years from the time of documented progression. 
 
13. 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
This study will be monitored in accordance with the NCI approved University of Michigan 
Rogel Cancer Center Data and Safety Monitoring Plan, with oversight by HCRN and the Rogel 
Cancer Center Data and Safety Monitoring Committee (DSMC). 
 
HCRN oversight activities include: 
 Review and process all adverse events requiring expedited reporting as defined in the 
protocol 
 Notify participating sites of adverse events requiring expedited reporting 
 Provide trial accrual progress, safety information, and data summary reports to the 
sponsor-investigator 
 Coordinate monthly study team meetings that include each accruing site’s principal 
investigator, clinical research specialist and/or research nurse (other members per site 
principal investigator’s discretion). On a quarterly basis, the study team meetings will 
also discuss matters related to:  

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o Enrollment rate relative to expectations, characteristics of participants 
o Safety of study participants (Serious Adverse Event reporting, 
unanticipated problems) 
o Adherence to protocol (protocol deviations) 
o Completeness, validity and integrity of study data 
o Retention of study participants 
 Submit a comprehensive Protocol Specific Data and Safety Monitoring Report 
(DSMR) form to the Rogel Cancer Center DSMC on a quarterly basis. The form will 
document the study team meeting and include data from all participating sites, signed 
by the sponsor-investigator. 
 
13.2 
University of Michigan Data and Safety Monitoring Committee  
The Rogel Cancer Center DSMC will review the information included on the DSMR from the 
first subject enrolled until the last subject has completed the study drug interventions and is 
outside the SAE reporting window. 
 
Documentation of DSMC reviews will be provided to the sponsor-investigator and HCRN. 
Issues of immediate concern by the DSMC will be brought to the attention of the sponsor-
investigator and other regulatory bodies as appropriate. The sponsor-investigator will work with 
HCRN to address the DSMC’s concerns. 
 
The DSMC will provide the sponsor-investigator and HCRN with evidence of its review. HCRN 
will distribute this information to the participating sites for submission to their respective IRB 
per the local IRB’s policies and procedures. 
 
13.4 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study. Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel.  
 
13.4.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause visits may occur as necessary. Selected source documents 
will be reviewed for verification of agreement with data entered into the EDC system.  It is 
important for the site investigator and their relevant personnel to be available for a sufficient 
amount of time during the monitoring visits or audit, if applicable. The site investigator and 
institution guarantee access to source documents by HCRN or its designee. 
 
Participating sites may also be subject to quality assurance audits by Merck or its designee as 
well as inspection by appropriate regulatory agencies. 
 
13.5 
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-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 

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requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. MICHR-MIAP will be responsible for 
submitting FDA Form 3674 to the FDA.  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 study site 
contact information.   
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform (EDC system), a system compliant with Good 
Clinical Practices and Federal Rules and Regulations.  HCRN personnel will coordinate and 
manage data for quality control assurance and integrity. Select data will be collected and entered 
into the EDC system by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in EDC system or other secure database(s). If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Merck, IRB, or government agencies, like the FDA, may 

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inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.  
 
 
 

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16 REFERENCES 
 
1. Aggarwal R, Zhang T, Small EJ, Armstrong AJ. Neuroendocrine prostate cancer: 
subtypes, biology, and clinical outcomes. J Natl Compr Cancer Netw 2014 
2. Beltran H, Oromendia C, Danila DC, et al. A Phase II Trial of the Aurora Kinase A 
Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate 
Cancer: Efficacy and Biomarkers. Clin Cancer Res. 2019 Jan 1;25(1):43-51. 
3. Apostolidis L, Nientiedt C, Winkler EC, et al. Clinical characteristics, treatment 
outcomes and potential novel therapeutic options for patients with neuroendocrine 
carcinoma of the prostate. Oncotarget. 2019 Jan 1;10(1):17-29.  
4. Calles A, Aguado G, Sandoval C, Álvarez R. The role of immunotherapy in small cell 
lung cancer. Clin Transl Oncol. 2019 Aug;21(8):961-976. 
5. Gunda V, Gigliotti B, Ashry T, et al. Anti-PD-1/PD-L1 therapy augments lenvatinib's 
efficacy by favorably altering the immune microenvironment of murine anaplastic 
thyroid cancer. Int J Cancer. 2019 May 1;144(9):2266-2278. 
6. Castillon JC, Fazio N, Lopez C, et al. Efficacy of Lenvatinib in patients with advanced 
pancreatic (panNETs) and gastrointestinal (giNETs) grade 1/2 (G1/G2) neuroendocrine 
tumors: Results of a trial. NCT02678780. Annals of Oncology (2018) 29 (suppl_8): 
viii467-viii478. 10.1093/annonc/mdy293 
7. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf 
8. Eisenhauer EA, Therasse P, Bogaerts, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1).Eur J Cancer 45;2009:228-247. 
9. Scher H, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-
Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical 
Trials Working Group 3. J Clin Oncol. 2016; 34(12): 1402–1418. 
10. Two Stage Phase II Clinical Trials” program in the PASS (2019) software. 
PASS 2019 Power Analysis and Sample Size Software (2019).   NCSS, LLC. Kaysville, 
Utah, USA, ncss.com/software/pass.