Conditions: Columnar Cell Variant Thyroid Gland Papillary Carcinoma Follicular Variant Thyroid Gland Papillary Carcinoma Metastatic Thyroid Gland Follicular Carcinoma Metastatic Thyroid Gland Papillary Carcinoma Poorly Differentiated Thyroid Gland Carcinoma Recurrent Differentiated Thyroid Gland Carcinoma Recurrent Thyroid Gland Follicular Carcinoma Recurrent Thyroid Gland Papillary Carcinoma Stage III Differentiated Thyroid Gland Carcinoma AJCC v7 Stage III Thyroid Gland Follicular Carcinoma AJCC v7 Stage III Thyroid Gland Papillary Carcinoma AJCC v7 Stage IV Thyroid Gland Follicular Carcinoma AJCC v7 Stage IV Thyroid Gland Papillary Carcinoma AJCC v7 Stage IVA Differentiated Thyroid Gland Carcinoma AJCC v7 Stage IVA Thyroid Gland Follicular Carcinoma AJCC v7 Stage IVA Thyroid Gland Papillary Carcinoma AJCC v7 Stage IVB Differentiated Thyroid Gland Carcinoma AJCC v7 Stage IVB Thyroid Gland Follicular Carcinoma AJCC v7 Stage IVB Thyroid Gland Papillary Carcinoma AJCC v7 Stage IVC Differentiated Thyroid Gland Carcinoma AJCC v7 Stage IVC Thyroid Gland Follicular Carcinoma AJCC v7 Stage IVC Thyroid Gland Papillary Carcinoma AJCC v7 Tall Cell Variant Thyroid Gland Papillary Carcinoma Thyroid Gland Hurthle Cell Carcinoma Unresectable Differentiated Thyroid Gland Carcinoma Unresectable Thyroid Gland Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 57
Healthy volunteers: no

Brief summary:
This phase II trial studies how well pembrolizumab and lenvatinib work in treating patients with differentiated thyroid cancer that has spread to other places in the body or has come back and cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed description:
PRIMARY OBJECTIVES:

I. To investigate the clinical efficacy, as indicated by the rate of complete response (CR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, of combination therapy with pembrolizumab and lenvatinib in lenvatinib-naive patients with progressive radioiodine-refractory differentiated thyroid cancers (DTC). (Cohort 1) II. To determine the overall response rate (ORR) by the addition of pembrolizumab to patients with radioiodine-refractory DTC who have progressive disease on lenvatinib alone. (Cohort 2)

SECONDARY OBJECTIVES:

I. To determine the safety profile and toxicity of combination therapy with pembrolizumab and lenvatinib in patients with progressive DTC. (Cohort 1 and cohort 2) II. To determine progression-free survival (PFS) and overall survival (OS). (Cohort 1 and cohort 2)

CORRELATIVE RESEARCH OBJECTIVES:

I. To correlate tumor response (RECIST 1.1) with pretreatment frequency of CD8+ T cells in the primary and/or metastatic tumor. (Cohort 1 and cohort 2) II. To correlate tumor response (RECIST 1.1) with pretreatment PD-L1 and PD-L2 levels in the primary and/or metastatic tumor. (Cohort 1 and cohort 2) III. To correlate tumor response (RECIST 1.1) with pretreatment frequency of lymphocytes expressing CD3, CD4, PD-1, FoxP3, or CD20, and of CD163+ macrophages. (Cohort 1 and cohort 2) IV. To correlate tumor response (RECIST 1.1) with the phenotype and frequency of key leukocyte subsets (i.e., PD-1+ T cells, regulatory T cells \[Tregs\], myeloid subsets) in the peripheral blood before, at 6 and 18 weeks on therapy, and at 54 weeks (study completion), progressive disease (PD), or study withdrawal. (Cohort 1) V. To correlate tumor response (RECIST 1.1) with PD-1+ T cell functional capacity. (Cohort 1) VI. To correlate tumor response (RECIST 1.1) with serum anti-thyroglobulin antibody levels assessed before, and at 18 weeks on therapy. (Cohort 1 and 2) VII. To correlate tumor response (RECIST 1.1) with tumor mutation status. (Cohort 1) VIII. To broadly investigate mechanisms of response and resistance to combination therapy, gene expression profiles will be generated from frozen biopsies for analysis by ribonucleic acid-sequencing (RNA-Seq). (Cohort 1)

OUTLINE:

Patients receive lenvatinib orally (PO) once daily (QD) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to 35 cycles.

After completion of study treatment, patients are followed up every 3 months for up to 3 years.

Arms:
arm 1: Patients receive lenvatinib PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to 35 cycles.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Lenvatinib intervention 3: Lenvatinib Mesylate intervention 4: Pembrolizumab
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Given PO intervention 4: Given IV

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
 
ACCRU-ITOG-1504 
 
 
 
Academic and Community Cancer Research United (ACCRU) 
 
Combination Targeted Therapy with Pembrolizumab and Lenvatinib in Progressive,  
Radioiodine-Refractory Differentiated Thyroid Cancers: A Phase II Study 
 
 
For any communications regarding this protocol, please contact the person listed on the Protocol 
Resource page. This is a stand-alone document found on the ACCRU web site (
).  
 
ACCRU:  
 
 
 
  
 
 
FDA IND  
Sponsor/Investigator: 
 
 
Study Co-chairs: 
  
 
 
 
Statistician:   
 
 
 
 
 
√ Study contributor(s) not responsible for patient care. 
 
Drug Availability 
Drug Company Supplied:  Lenvatinib and Pembrolizumab – IND #132069 
 
 
Research Coordinating Center 
 
 
 
 
Document History 
Effective Date 
Pre-activation ACCRU 
October 7, 2016 
Activation Addendum 1 
January 26, 2018 


ACCRU-ITOG-1504 
2  
Addendum 6 
 
  Addendum 2                           May 04, 2018 
  Addendum 3  
          July 06, 2018 
  Addendum 4  
         May 10, 2019 
  Addendum 5  
         October 25, 2019  
  Addendum 6  
         December 16, 2020 


ACCRU-ITOG-1504 
3  
Addendum 6 
 
Index 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Grouping Factor  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
Appendix I  
Consent Form 
Appendix II  
Blood Pressure Diary 
Appendix III  
Medication Diary 
 
 


ACCRU-ITOG-1504 
4  
Addendum 6 
 
Schema 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle length= 21 days 
 
Generic name:   Pembrolizumab  
Brand name(s):  Keytruda  
Availability:   Merck 
Generic name:  Lenvatinib 
 
Brand name(s):  Lenvima  
Availability:   Eisai 
Treatment 
Lenvatinib 20 mg PO daily + Pembrolizumab 
200 mg IV D1 every 21 days until disease 
progression (for a maximum of 2 years)1 
Treatment 
Lenvatinib daily dose at progression + 
Pembrolizumab 200 mg IV D1 every 21 days 
until disease progression                       
(for a maximum of 2 years)1 
Confirmed Progressive Disease 
(PD) (See Sections 11 and 13.7) 
unacceptable adverse events, 
patient refusal 
 
 
Event Monitoring 
Cohort 1 (n=30):  
(Lenvatinib-naïve patients)  
Registration 
Cohort 2 (n=30):  
(progressed on Lenvatinib 
alone)  
Observation  
Event Monitoring 


ACCRU-ITOG-1504 
5  
Addendum 6 
 
1.0 
Background   
 
1.1 
Thyroid Cancer – Incidence and Standard of Care  
 
More than 500,000 people in the United States have a diagnosis of thyroid cancer, and 
the incidence is steadily growing, with an estimated 62,000 new cases in 2014.  Thyroid 
cancer is the 5th most commonly diagnosed cancer in women.  Although localized 
differentiated thyroid cancer (DTC) is generally managed by surgery and radioactive 
iodine therapy, approximately 10% of patients develop progressive invasive primary 
disease and 5% develop distant metastases (Howlader N, et. al., 2010)1.  Many of these 
patients develop radioiodine-refractory disease, and their prognosis is only minimally 
improved with tyrosine kinase inhibitors (TKIs).  Treatment with sorafenib does provide 
some benefit, with an overall partial response (PR) rate of 12% and a 5-month increase in 
progression-free survival (PFS).  However, no complete response (CR) is observed and 
the partial responses are not durable (Brose MS, et. al., 2014)2.  Lenvatinib, which is now 
approved as standard of care for progressive DTC, achieved a 1.5% CR and a 63.2 % PR 
and extended PFS by 14.7 months (Schlumberger M, et. al., 2015)3.  While these data are 
encouraging, TKI monotherapies are not curative.   
 
1.2 
Rationale for Immune-based Therapies in Aggressive DTC 
 
The thyroid is one of the most immunogenic organs in the body.  The prevalence of 
autoimmune thyroiditis in the general population is approximately 5-10%, and nearly 
30% of patients with DTC have thyroid autoantibodies.  Furthermore, checkpoint 
blockade therapies (i.e., anti-CTLA-4 and anti-PD-1) commonly lead to thyroiditis.  As in 
other inflammation-associated cancers, thyroiditis may contribute to tumorigenesis, 
tumor elimination, and, at later stages, tumor progression.  It is likely that a subset of the 
autoimmune T cell response is capable of recognizing the thyroid tumor in many patients 
with DTC.   
 
A growing body of literature has described the tumor-associated immune response in 
thyroid cancers (French JD, 2013)4.  Similar to other types of cancer, the immune milieu 
in thyroid cancer includes immature dendritic cells, M2-polarized macrophages, and 
suppressive or dysfunctional T cells.  Despite these classic signs of immune 
dysregulation, most patients with thyroid cancer have relatively indolent disease.  
Patients with invasive primary disease progress slowly compared to other types of 
inoperable cancers, with an average survival rate of 70% at 5 years.  Lymph node (LN) 
metastasis, while common in patients with DTC, rarely lead to distant metastasis and can 
persist for years without evident progression.  Given the potential immunogenicity and 
relatively indolent nature of DTC, we hypothesize that DTC may be exceptionally 
sensitive to immune-targeted therapies. 
 
1.3 
Tregs and T Cell Exhaustion in DTC 
 
Our previous (French JD, Kotnis GR, et. al., 2012 and French JD, Weber ZJ, et. al., 
2010)5, 6 and ongoing studies suggest that T cell dysfunction plays a role in DTC 
progression.  Specifically, FoxP3+ regulatory CD4+ T cells (Tregs) were found at 
increased frequencies in both primary tumors (T1-T4) and tumor-involved lymph nodes 
(TILN) compared to blood and uninvolved lymph nodes (UILN), respectively.  Treg 
frequency in primary tumors correlated with lymph node metastasis, and increased levels 
of Tregs were found in TILN from patients with recurrent disease.  Programmed-death-1 


ACCRU-ITOG-1504 
6  
Addendum 6 
 
(PD-1)+ T cells were also enriched in primary tumors (T1-T4) and TILN. Although we 
have not yet shown disease significance in primary tumors, high frequencies of PD-1+ T 
cells in TILN were associated with extranodal invasion, a sign of more aggressive 
disease.  Ongoing studies using archived tissues from patients with inoperable, invasive 
T4 tumors and distant metastases revealed intratumoral CD8+ T cells and FoxP3+ Tregs 
in 14 of 15 primary T4 tumors and 1 of 4 metastases tested to date. PD-1+ T cells were 
present in peritumoral and more distal regions in a subset of patients (n=6). PD-L1 was 
expressed by the primary tumor and infiltrating leukocytes in 8 (53%) of 15 samples 
tested, respectively. Furthermore, preliminary studies in progressive DTC suggest that 
Tregs (9-14%) and PD-1+CD8+ (27-46%) T cell frequencies are elevated in peripheral 
blood in a subset of patients.   
   
To further investigate the phenotype and functional capacity of PD-1+ T cells in DTC, we 
isolated tumor-associated lymphocytes from grossly-involved lymph nodes (Severson JJ, 
et. al., 2015)7.  PD-1+CD8+ T cells were enriched (5-38% of CD8+) in 7 of 11 of TILNs 
and displayed an exhausted molecular phenotype (i.e., CD69hi, CD127+/-, CD27hi).  T cell 
immunoglobulin and mucin domain protein 3 (Tim-3) was co-expressed with PD-1.  Ex 
vivo functional studies of CD8+ T cells revealed that stimulated cytokine (IL-2, TNFα, 
and IFNγ) production was diminished to varying degrees. However, ex vivo proliferative 
potential remained largely intact.  Thus, PD-1 expression is a sign of T cell dysfunction 
in patients with persistent lymph node involvement.  However, exhaustion may be in the 
early stages and readily reversible.  Analysis of PD-L1 expression on fresh tumor 
samples from TILN revealed that the majority of tumors (8/11) express PD-L1 and may 
contribute directly to PD-1-mediated T cell dysfunction.  In line with our previous 
studies, Tregs were elevated (13-39% of CD4+) in TILN from all 11 patients, regardless 
of PD-1 phenotype.  We predict that Tregs may contribute to the development of T cell 
exhaustion; and, even in the absence of exhaustion, may pose a substantial barrier to the 
success of immune-targeted and tumor-targeted therapies. 
 
1.4 
Antiangiogenic Therapy 
 
Angiogenesis, the formation of new blood vessels from a preexisting vascular network, is 
essential for tumor growth and metastasis. Many molecules have been implicated as 
positive regulators of angiogenesis, including VEGF, acidic fibroblast growth factor 
(aFGF), basic FGF (bFGF), hepatocyte growth factor (HGF), interleukin (IL)-8, and 
platelet-derived growth factor (PDGF). (Kobayashi M, et. al., 2013)19 In adults, 
physiological angiogenesis occurs during the female reproductive cycle and in wound 
healing. In addition to tumor growth, abnormally enhanced neovascularization is also 
observed in rheumatoid arthritis, psoriasis, and diabetic retinopathy. Of the numerous 
molecules that have been shown to have angiogenic properties, VEGF has been identified 
as a crucial regulator of both physiologic and pathologic angiogenesis with increased 
expression being associated with a poor prognosis in many human tumor types. (Rizvi 
NA, et. al., 2015, Taube JM, et. al., 2014, Tumeh PC, et. al., 2014, Qing W, et. al., 2012) 
21-24 VEGF acts primarily on endothelial cells to promote their proliferation and three-
dimensional organization for tube formation and is thought to be the most potent and 
specific proangiogenic factor. VEGF exerts its effects through two cell membrane bound 
receptors, Flt-1 and KDR, of which KDR is thought to be more important. There is 
increasing evidence that KDR is the major mediator of endothelial cell proliferation and 
survival as well as tube formation and microvascular permeability. KDR undergoes 
dimerization and ligand-dependent tyrosine phosphorylation, producing a mitogenic,  
 


ACCRU-ITOG-1504 
7  
Addendum 6 
 
chemotactic and prosurvival signal. Consequently, a KDR TK inhibitor would be 
expected to exert a potent inhibitory effect on tumor growth and metastasis formation. 
 
1.5 
Pembrolizumab Mechanism of Action 
 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis 
in various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of 
CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2).  The structure of murine PD-1 has been resolved.  PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding 
of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, 
an 
immunoreceptor 
tyrosine-based 
inhibition 
motif 
(ITIM) 
and 
an 
immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, 
PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The 
mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct 
from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  
PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ 
and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as 
subsets of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) 
are constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors.  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular 
region and contain short cytoplasmic regions with no known signaling motifs.  Binding of 
either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  
 
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-
L1 serves to dampen unwarranted T-cell function in peripheral tissues.  Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-
specific T-cell expansion in subjects with melanoma (MEL).  This suggests that the PD-
1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered 
as an attractive target for therapeutic intervention. 
 
Pembrolizumab (MK-3475, KeytrudaTM) is a potent and highly selective humanized 


ACCRU-ITOG-1504 
8  
Addendum 6 
 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.   
 
Clinical Experience with Pembrolizumab 
 
Melanoma: Pembrolizumab has recently been approved in the United Stated for the 
treatment of patients with unresectable or metastatic melanoma. Approval was based on 
the results of a multicenter, open-label, randomized trial, P001. 173 patients with 
unresectable or metastatic melanoma with disease progression on ipilimumab and, if 
BRAF V600 mutation positive, prior treatment with a BRAF inhibitor, were randomized 
to receive pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84) intravenously once every 
3 weeks until disease progression or unacceptable toxicity. 
  
Key exclusion criteria were an autoimmune disease, a medical condition that required 
immunosuppression, and/or a history of severe immune-mediated adverse reactions from 
treatment with ipilimumab.  Severe immune-mediated adverse reactions were defined as 
any CTCAE Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity 
requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) 
for greater than 12 weeks. 
  
The ORR was 24% (95% CI: 15, 34) in the 2 mg/kg arm, consisting of one complete 
response and 20 partial responses.  Among the 21 patients with an objective response, 3 
(14%) had disease progression at 2.8, 2.9, and 8.2 months after initial response. The 
remaining 18 patients (86%) have ongoing responses, ranging from 1.4+ to 8.5+ 
months;  8 patients have ongoing responses of 6 months or longer.  Similar ORR results 
were observed in the 10 mg/kg arm.  
  
The most common (greater than or equal to 20%) adverse reactions among patients 
receiving pembrolizumab 2 mg/kg every 3 weeks were fatigue, cough, nausea, pruritus, 
rash, decreased appetite, constipation, arthralgia, and diarrhea. 
  
The most frequent (greater than or equal to 2%) serious adverse drug reactions observed 
with pembrolizumab were renal failure, dyspnea, pneumonia, and cellulitis.  Additional 
clinically significant immune-mediated adverse reactions included pneumonitis, colitis, 
hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. 
 
Pembrolizumab is now being studied extensively in multiple cancer types, and in 
combination multiple antineoplastic agents.  
 
Lung Cancer: The safety of pembrolizumab was studied in 550 patients with advanced 
NSCLC. The most common side effects of pembrolizumab included fatigue, decreased 
appetite, shortness of breath or impaired breathing (dyspnea) and cough. Pembrolizumab 
also has the potential to cause severe side effects that result from the immune system 
effect of pembrolizumab (known as “immune-mediated side effects”).  
 
The effectiveness of pembrolizumab for this use was demonstrated in a subgroup of 61 
patients enrolled within a larger multicenter, open-label, multi-part study. The subgroup 
consisted of patients with advanced NSCLC that progressed following platinum-based 
chemotherapy or, if appropriate, targeted therapy for certain genetic mutations (ALK or 
EGFR). This subgroup also had PD-L1 positive tumors based on the results of the 22C3 
pharmDx diagnostic test. Study participants received 10 mg/kg of pembrolizumab every 


ACCRU-ITOG-1504 
9  
Addendum 6 
 
two or three weeks. The major outcome measure was overall response rate (percentage of 
patients who experienced complete and partial shrinkage of their tumors). Tumors shrank 
in 41 percent of patients treated with pembrolizumab and the effect lasted between 2.1 
and 9.1 months.                                                                                                           
 
In the 550 study participants with advanced NSCLC, severe immune-mediated side 
effects occurred involving the lungs, colon and hormone-producing glands. Other 
uncommon immune-mediated side effects were rash and inflammation of blood vessels 
(vasculitis). Women who are pregnant or breastfeeding should not take pembrolizumab 
because it may cause harm to a developing fetus or newborn baby. Across clinical 
studies, a disorder in which the body's immune system attacks part of the peripheral 
nervous system (Guillain-Barre Syndrome) also occurred. 
 
The FDA granted pembrolizumab breakthrough therapy designation for this indication 
because Merck demonstrated through preliminary clinical evidence that the drug may 
offer a substantial improvement over available therapies. The drug also received priority 
review status, which is granted to drugs that, at the time the application was submitted, 
have the potential to be a significant improvement in safety or effectiveness in the 
treatment of a serious condition. 
 
Thyroid Cancer:  There is an ongoing basket trial (KEYNOTE-028 (NCT02054806)) 
which has enrolled patients with advanced thyroid cancer to a single agent 
pembrolizumab (200 mg iv every 3 weeks) study.  Preliminary data from the thyroid 
cohort in this trial was presented at the 2016 American Society for Clinical Oncology 
(Mehnert JM, et al, J Clin Oncol 34, 2016 (suppl; abstr 6091)).  The study enrolled 22 
patients with DTC, with a median duration of follow-up of 74 weeks (29-87 weeks).  No 
patients achieved a CR (0%) and 2 patients had a PR (9.1%), with 12 achieved SD (54%). 
 
1.6 
Lenvatinib Mechanism of Action 
 
VEGF is a crucial regulator of both physiologic and pathologic angiogenesis. Its 
increased expression is associated with a poor prognosis in many cancers. VEGF exerts 
its effects through two cell membrane receptors, fms-like tyrosine kinase 1/vascular 
endothelial growth factor receptor 1 (Flt-1/VEGFR-1) and kinase insert domain receptor 
(KDR/VEGFR-2). (Kobayashi M, et. al, 2013)19  Lenvatinib is an orally available potent 
inhibitor of the split-kinase family of transmembrane growth factor receptors including 
Flt-1/VEGFR-1 and KDR/VEGFR-2. Receptor tyrosine kinase cell free assays 
demonstrate IC50 values of 22 (Flt-1/VEGFR-1) and 4 nM (KDR/VEGFR-2). 
Additionally, lenvatinib potently inhibits vascular endothelial growth factor receptor 3 
(VEGFR-3, IC50 5nM), fibroblast growth factor receptor (FGFR)-1 (IC50 46 nM),2,3,4 
and platelet-derived growth factor receptor (PDGFR, IC50 39 nM) beta tyrosine kinases. 
Lenvatinib also inhibits (IC50 5.2 nM) SCF-driven tube formation of HUVEC, which 
express SCF receptor, KIT. 
 
 
 
Clinical Experience with Lenvatinib 
 
A global Phase 1 program in patients with solid tumors has been conducted with 
lenvatinib to determine the safety, tolerability and pharmacokinetics of three different 
regimens including continuous once daily dosing. Pharmacokinetic analysis has 


ACCRU-ITOG-1504 
10  
Addendum 6 
 
demonstrated that lenvatinib is rapidly absorbed with maximum concentrations observed 
from 1 to 3 hours post dose. Lenvatinib elimination occurs with a biexponential decline 
composed of an initial rapid decline followed by a slower decline. The terminal half-life 
is approximately 30 hours and steady state is achieved within 5 days. A dose dependent 
increase in soluble VEGF, consistent with an anti-angiogenic effect was observed during 
2 weeks of continuous dosing. 
 
Hypertension and proteinuria were the most common dose limiting toxicities (DLT). A 
dose of 25 mg once daily was found to be the maximum tolerated dose (MTD) for the 
once daily continuous dosing schedule. A cohort of 24 patients treated at this dose level 
established the safety and tolerability of the lenvatinib 25 mg dose for once daily 
continuous dosing. To simplify drug administration, a dose of 24 mg (two 10 mg capsules 
+ one 4 mg capsule) once daily was selected for ongoing lenvatinib development. 
 
Lenvatinib - Clinical Experience in Thyroid Cancer 
 
Phase II study of lenvatinib in radioiodine-refractory DTC led to the SELECT trial, a 
global, placebo-controlled randomized phase III trial of lenvatinib in radioiodine-
refractory progressive DTC. The primary endpoint was PFS, which was significantly 
prolonged with lenvatinib versus placebo (median 18.3 months versus 3.6 months, 
respectively; hazard ratio [HR] 0.21; 99% confidence interval 0.14–0.31, P<0.001). 
Lenvatinib PFS benefit was observed in all predefined subgroups, including patients who 
received 0 (n=299) or 1 (n=93) prior tyrosine-kinase inhibitor therapies (HR: 0.20 and 
0.22, respectively). Lenvatinib significantly improved ORR versus placebo (64.8% [4 
complete; 165 partial responses] versus 1.5%; P<0.001). Median overall survival has not 
been reached. For lenvatinib, treatment-related adverse effects (>40%, all grades) were 
hypertension (67.8%), diarrhea (59.4%), fatigue/asthenia (59.0%), decreased appetite 
(50.2%), decreased weight (46.4%), and nausea (41.0%); adverse effects were managed 
with dose reductions and standard interventions. Discontinuations due to adverse effects 
occurred in 37 (14.2%) lenvatinib-treated and 3 (2.3%) placebo-treated patients. In the 
lenvatinib arm, 6/20 treatment-emergent deaths were considered drug-related.  
 
1.7  
Rationale for Combination Therapy with Pembrolizumab (MK-3475) and Lenvatinib 
 
We predict that successful elimination of aggressive DTC will require both cessation of 
tumor growth and activation of the anti-tumor immune response. 
 
Based on preliminary data, we predict that release of the PD-1 checkpoint and 
simulanteous elimination of Treg suppressive activity will be essential for immune 
activation in patients with advanced DTC.  Disruption of PD-1/PD-L1 interactions with 
MK-3475 (Pembrolizumab) would release a major checkpoint blockade in patients with 
PD-1+ tumor-specific T cells, encouraging immune-mediated tumor destruction.  
Importantly, Tregs have been shown to express both PD-1 and PD-L1, and blockade of 
PD-1/PD-L1 interactions is thought to inhibit the induction, maintenance, and function of 
Tregs. (Amarnath S, et. al, 2011, Duraiswamy J, et. al., 2013, Francisco LM, et. al., 2009, 
Kitazawa Y, et. al., 2007)8-11  Thus, pembrolizumab may also inhibit the suppressive 
effects of tumor-associated Tregs. 
 
A number of studies have investigated the effects of multi-target tyrosine kinase 
inhibitors on the immune system. Sorafenib was initially developed to target RAF, but it 
also inhibits VEGFR-2, VEGFR-3, PDGFR-β, c-kit and FLT3 (Adnane L, et. al., 2006, 


ACCRU-ITOG-1504 
11  
Addendum 6 
 
and Ahmad T, et. al., 2004)12, 13.  Of note, Tregs are known to express VEGFR-214. 
Inhibition of VEGF activity by anti-VEGFR-2 antibody treatment inhibits Treg 
proliferation (Terme M, et. al., 2013)14.  Sorafenib inhibited Treg suppression in vitro 
(Busse A, et. al., 2011 and Cabrera R, et. al., 2013)15, 16 and reduced the number of 
peripheral Tregs in cancer patients in 2 of 3 independent studies (Chen ML, et. al., 2014, 
Florcken A, et. al., 2012 and Kobayashi M, et. al., 2013)17-19.  We believe that 
lenvatinib may have a more potent effect on Treg function in patients with advanced 
thyroid cancer based on its more potent effects on VEGFR-2. 
 
We hypothesize that combination pembrolizumab and lenvatinib therapy will generate 
significantly 
improved 
CR 
compared 
to 
pembrolizumab 
alone 
(MK3475-
028/KEYNOTE-28, ongoing basket trial that includes DTC, that demonstrated a CR of 
0%) or the historical CR of lenvatinib alone (1.5%). 
 
 
1.8  
Rationale for Dose Selection/Regimen/Modification 
 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors.  All three dose levels were well tolerated 
and no dose-limiting toxicities were observed.  This first in human study of MK-3475 
showed evidence of target engagement and objective evidence of tumor size reduction at 
all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to 
date.  10.0 mg/kg Q2W, the highest dose tested in PN001, was the dose and schedule 
utilized in Cohorts A, B, C and D of this protocol to test for initial tumor activity.  Recent 
data from other clinical studies within the MK-3475 program has shown that a lower dose 
of MK-3475 and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement 
is durable (>21 days).  This early PK and pharmacodynamic data provides scientific 
rationale for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication.  The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 
5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed 
dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication 
settings. 


ACCRU-ITOG-1504 
12  
Addendum 6 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed 
at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 
mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on 
distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) 
the assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
 
The starting dose of lenvatinib 24 mg by mouth daily is the FDA-approved dose for 
radioiodine-refractory progressive differentiated thyroid carcinoma based upon the 
dosing used in the phase III SELECT trial that established the efficacy of lenvatinib in 
this setting. An ongoing phase Ib basket trial of lenvatinib plus pembrolizumab in solid 
tumors (thyroid was not included), showed good tolerability of the combination and 
recommends a starting dose of 20 mg daily lenvatinib in combination with 200 mg iv 
pembrolizumab every 3 weeks, which will be the staring doses in Cohort 1 (personal 
communication). Patients entering Cohort 2 will have progressed on lenvatinib. These 
patients will remain on the dose they are taking at the time of study entry, which may 
have been previously reduced for side effect management, and will not exceed 20 mg by 
mouth daily. 
 
1.9 
Rationale for Correlative Research 
 
1.91 
Recent 
successes 
of 
anti-PD-1/PD-L1 
checkpoint 
inhibitors 
(e.g., 
pembrolizumab, and nivolumab) have reinvigorated the field of cancer 
immunotherapy (Hamid O, et. al., 2013 and Rizvi NA, et. al., 2015)20, 21. 
Response rates have ranged from 13% to 37% in patients with progressive 
cancers that have failed multiple lines of therapy.  Post-trial analyses have 
attempted to define molecular markers that correlate with tumor regression.  
Response to nivolumab was associated most strongly with expression of PD-L1 
by the tumor and did not significantly correlate with infiltrating lymphocytes.  
PD-1 was expressed by tumor-infiltrating lymphocytes in 7/10 of responders and 
9/18 non-responders and did not significantly correlate with a clinical response 
(Taube JM et. al., 2014)22.  In contrast, response to pembrolizumab was strongly 
associated with a high frequency of CD8+ or PD-1+ T cells, either at the invasive 
margin or infiltrating the tumor, and, to a lesser degree, expression of PD-L1 
(Tumeh PC, et. al., 2014)23.  In the proposed correlative research studies, we will 
assess CD8+ and PD-1+ T cell frequency and expression of PD-L1 and PD-L2 by 
tumor and associated leukocytes in primary tumor samples and pre-treatment 


ACCRU-ITOG-1504 
13  
Addendum 6 
 
biopsies by immunohistochemistry. We will also assess PD-1 expression and its 
functional consequences in peripheral blood leukocytes before and throughout 
treatment using flow cytometry.  
 
1.92 
Tregs have been shown to express both PD-1 and PD-L1, and blockade of PD-
1/PD-L1 interactions is thought to inhibit the induction, maintenance, and 
function of Tregs (Duraiswamy J, et. al., 2013)9, 11. A number of studies have 
investigated the effects of multi-target tyrosine kinase inhibitors on the immune 
system. Inhibition of VEGF activity by anti-VEGFR-2 antibody treatment 
inhibits Treg proliferation (Terme M, et. al., 2013)14.  Sorafenib, a multikinase 
inhibitor that targets VEGFR-2, has been shown to inhibit Treg suppression in 
vitro and reduce the number of peripheral Tregs in cancer patients (Busse A, et. 
al., 2011 and Cabrera R, et. al., 2013)15, 16. Thus, both pembrolizumab and 
lenvatinib may inhibit the suppressive effects of tumor-associated Tregs. We plan 
to investigate whether the frequency of FoxP3+ Tregs in the primary tumor and 
pre-treatment biopsy, as determined by immunohistochemistry for FoxP3, 
correlates with response to treatment. We will also investigate the frequency and 
phenotype of Tregs in peripheral blood before and throughout treatment using 
flow cytometry. 
 
1.93 
Tumor associated macrophages (TAM) and immature dendritic cells (iDC) have 
been described in primary thyroid tumors. Increased frequencies of TAM were 
associated with lymph node metastasis in patients with DTC (Qing W, et. al., 
2012)24. TAM in DTC expressed CD163 and IL-10 and have been proposed to 
play a role in tumor progression (Qing W, et. al., 2012)24. CD1a+ iDCs were also 
found at high frequencies in DTC samples (Batistatou A, et. al, 2002, Ugolini C, 
et. al. 2007, and Scarpino S, et. al., 2000)25-27. We identified PD-L1+ TAM in 
12/15 pT4 DTC and PDTC samples. Pro-angiogenic VEGFA is well documented 
in its ability to inhibit DC maturation and support the generation of TAM and 
myeloid derived suppressor cells (MDSC) (Alfaro C, et. al., 2009, Almand B., et. 
al., 2000, Dikov MM, et. al., 2005, Gabrilovich D, et. al., 1998, Voron T, et. al., 
2014)28-32. This immunosuppressive cellular network likely supports induction 
and maintenance of Tregs within the tumor microenvironment through 
production of IL-10 and TGFβ (Coffelt SB, et. al., 2011, Ghiringhelli F, et. al., 
2005, and Huang B, et. al., 2006)33-35. We plan to investigate the frequency and 
phenotype of TAM and MDSC in tumor and blood samples, respectively. 
 
1.94 
Approximately 25% of patients with DTC produce thyroid-specific antibodies, 
most commonly against Tg and TPO (Fiore E, et. al., 2009 and Pacini F, et. al., 
1988)36, 37. We predict that titers of these autoantibodies may be surrogate 
markers for the anti-tumor response with pembrolizumab and lenvatinib therapy.  
 
1.95 
Recent analyses of patients with melanoma that underwent treatment with anti-
PD-1 (pembrolizumab, Merck) revealed a strong positive association between the 
number of mutations in the tumor and responsiveness to the checkpoint blockade 
therapy (Rizvi NA, et. al., 2015)38. While thyroid cancer, in general, is thought to 
be a have a low mutation burden, little is known about mutation frequency and 
antigenicity in more aggressive and metastatic cases. Here, we propose to 
investigate whether high frequency of mutations or type of mutation is associated 
with response to combination therapy. 
 


ACCRU-ITOG-1504 
14  
Addendum 6 
 
1.96 
It is likely that a subset of patients will not respond to treatment and will require 
alternative therapies. Numerous tumor-intrinsic and tumor-extrinsic factors will 
undoubtedly contribute to resistance (e.g., mutation load, MHCI expression, 
antigen presentation, immune suppressive factors). We plan to compare gene 
expression profiles by RNA-Seq from responders and non-responders using pre-
treatment frozen and FFPE biopsy samples. 
 
2.0 
Goals    
 
2.1 
Primary 
 
2.11 
To investigate the clinical efficacy, as indicated by the rate of complete response 
(CR) per RECIST 1.1, of combination therapy with pembrolizumab and 
lenvatinib in lenvatinib-naïve patients with progressive radioiodine-refractory 
DTC (Cohort 1). 
 
2.12   To determine the overall response rate (ORR) by the addition of pembrolizumab 
to patients with radioiodine-refractory DTC who have progressive disease on 
lenvatinib alone (Cohort 2). 
 
2.2 
Secondary  
 
2.21 
To determine the safety profile and toxicity of combination therapy with 
pembrolizumab and lenvatinib in patients with progressive DTC. (Cohort 1 and 
Cohort 2) 
 
2.22 
To determine progression-free survival (PFS) and overall survival (OS). (Cohort 
1 and Cohort 2) 
 
2.3 
Correlative Research   
 
2.31 
To correlate tumor response (RECIST 1.1) with pretreatment frequency of CD8+ 
T cells in the primary and/or metastatic tumor.  FFPE tumor samples will be 
evaluated for CD8+ T cells by immunohistochemistry.  Staining intensity is 
scored on a 1+ to 3+ scale, and the percentage of positive cells per total 
lymphocytes is estimated (1 = <1%, 2 = 1-10%, 3 = 11-33%, 4 = 34-66%, 5 = 
67-100%). Allred scores (intensity + percent positive) are generated for 
comparison between samples (Phillips T, et. al., 2007). Quantitation of the CD8+ 
cells will be performed using the Aperio Scanscope AT2 system (20X, 0.5 
μm/pixel resolution). Our collaborating pathologist will designate both 
peritumoral and intratumoral areas for differential quantitation using the Aperio 
ImageScope application, and annotated regions will be analyzed for positive 
staining using an Aperio colormetric thresholding algorithm. To extrapolate the 
number of positive cells per mm2, 15 random cells will be chosen to determine 
the average pixels per positive CD8 event. The average number of CD8 pixels 
will be divided by the total positive pixels to determine the number of positive 
CD8 cells in the annotated regions. The number of CD8 cells divided by the area 
will estimate the number of positive cells per mm2.  (Cohort 1 and 2) 
 
2.32 
To correlate tumor response (RECIST 1.1) with pretreatment PD-L1 and PD-L2 
levels in the primary and/or metastatic tumor.  Tumors will be will be evaluated 
for PD-L1 (by QualTek Clinical Laboratories) and anti-PD-L2 (Biolegend 
MIH18) by immunohistochemistry, as described above.  (Cohort 1 and 2) 
 
2.33 
To correlate tumor response (RECIST 1.1) with pretreatment frequency of 
lymphocytes expressing CD3, CD4, PD-1, FoxP3, or CD20, and of CD163+ 


ACCRU-ITOG-1504 
15  
Addendum 6 
 
macrophages.  Cells types will be detected in pretreatment FFPE tumor tissue by 
immunohistochemistry.  (Cohort 1 and 2) 
 
2.34 
To correlate tumor response (RECIST 1.1) with the phenotype and frequency of 
key leukocyte subsets (i.e., PD-1+ T cells, Tregs, myeloid subsets) in the 
peripheral blood before, at 6 and 18 weeks on therapy, and at 54 weeks (study 
completion), PD, or study withdrawal.  Peripheral blood mononuclear cells and 
neutrophils will be isolated concomitantly by density gradient from peripheral 
blood, cryopreserved, and analyzed by 10-color flow cytometry.  (Cohort 1) 
 
2.35 
To correlate tumor response (RECIST 1.1) with PD-1+ T cell functional 
capacity.  Stimulated cytokine assays will be performed on lymphocyte 
populations isolated from peripheral blood, as described in 2.34.  Briefly, cells 
will be stimulated with PMA/ionomycin or plate-bound anti-CD3 plus soluble 
anti-CD28 for 6 hours in the presence of brefeldin A and intracellular expression 
levels of IL-2, IFNγ, and TNFα will be determined by flow cytometry.  Normal 
peripheral blood will be used as a control for optimal cytokine production. 
Patient T cell function will be compared before and after treatment.  (Cohort 1) 
 
2.36 
To correlate tumor response (RECIST 1.1) with serum anti-thyroglobulin 
antibody levels assessed before, and at 18 weeks on therapy .  (Cohort 1 and 2) 
 
2.37 
To correlate tumor response (RECIST 1.1) with tumor mutation status.  Tumor 
mutation analysis will be performed by whole exome sequencing with DNA 
isolated from pre-treatment frozen biopsies and FFPE archival primary tumor for 
each patient where available, using patient-matched blood as a baseline control.  
(Cohort 1) 
 
2.38 
To broadly investigate mechanisms of response and resistance to combination 
therapy, gene expression profiles will be generated from frozen biopsies for 
analysis by RNA-Seq. Total RNA will be isolated with the RNeasy kit (Qiagen) 
and 500ng of RNA will be submitted mRNA-seq library construction (TruSeq 
Stranded mRNA Library Kit, Illumina). In parallel, FFPE primary tumor samples 
will be analyzed by RNA-Seq (Graw S, et. al., 2015)40.  (Cohort 1) 
 
3.0 
Patient Eligibility    
 
 
*No waivers of eligibility per ACCRU 
 
 
3.1 
Inclusion Criteria  
 
3.11 
Age ≥18 years. 
 
3.12 
Locally recurrent and unresectable and/or distant metastatic differentiated thyroid 
cancer (DTC), histologically or cytologically confirmed. The diagnosis of DTC 
includes the following subtypes: Papillary thyroid cancer (PTC) (including but 
not limited to variants such as follicular variant, tall cell, columnar cell, Hürthle 
cell variant of papillary carcinoma, and poorly differentiated), Follicular thyroid 
cancer (FTC), including Insular variant, Hürthle cell carcinoma and poorly 
differentiated thyroid cancer.  
 
3.13 
Measurable disease meeting the following criteria (see Section 11.0): 
 
3.13a 
At least 1 lesion of ≥ 1.0 cm in the longest diameter for a non-lymph 
node or ≥ 1.5 cm in the short-axis diameter for a lymph node which is 


ACCRU-ITOG-1504 
16  
Addendum 6 
 
serially measurable according to RECIST 1.1 using computerized 
tomography/magnetic resonance imaging (CT/MRI). If there is only one 
target lesion and it is a non-lymph node, it should have a longest 
diameter of ≥ 1.5 cm. 
 
3.13b. Lesions that have had external beam radiotherapy (EBRT) or loco-
regional therapies such as radiofrequency (RF) ablation must show 
evidence of progressive disease based on RECIST 1.1 to be deemed a 
target lesion. 
    
3.14 
For Cohort 1 Only: Evidence of disease progression ≤14 months prior to 
registration according to RECIST 1.1, as confirmed by the site study PI. 
 
3.15 
For Cohort 2 Only: Progressive disease (PD) on lenvatinib per RECIST 1.1 ≤60 
days prior to registration, as confirmed by the site study PI. Patients need to have 
documented imaging and measurement of RECIST target lesions within 30 days 
of starting pembrolizumab. 
3.16 
Radioiodine (RAI)-resistant disease as defined by one or more of the following 
criteria: 
a. One or more measurable lesions that do not demonstrate RAI uptake  
b. One or more measurable lesions progressive by RECIST 1.1 ≤14 
months of prior RAI therapy.  
c. One or more measurable lesions present after cumulative RAI dose of 
≥ 600 mCi. 
d.  One or more measurable lesions that are FDG-avid (>5 SUV), if 
PET/CT scan performed. These lesions may also be RAI-avid. 
 
3.17 
ECOG Performance Status (PS) 0 or 1.  (Form is available on the ACCRU web 
site)  
 
 


ACCRU-ITOG-1504 
17  
Addendum 6 
 
3.18 
The following laboratory values obtained ≤30 days prior to registration, unless 
otherwise specified:  
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin 
dependency (≤7 days prior to registration) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional 
ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 
ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy as 
long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
 
3.19a 
Adequately controlled blood pressure with or without antihypertensive 
medications defined as BP < 150/90 mmHg at screening. 
 
3.19b Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.19c 
Ability to complete Patient Medication and Blood Pressure diaries by themselves 
or with assistance.  
 
3.19d Willing and able to provide informed written consent. 
 
 
 


ACCRU-ITOG-1504 
18  
Addendum 6 
 
3.19e 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
Note:  During the Active Monitoring Phase of a study (i.e., active treatment and 
observation), participants must be willing to return to the consenting institution 
for follow-up. 
 
3.19f 
Willing to provide tissue and blood samples for correlative research 
purposes.(see Sections 6.12, 14.1 and 17.11).   
 
3.2 
Exclusion Criteria 
 
3.21 
Cohort 1 only: Prior treatment with previous VEGFR active multikinase 
inhibitor. 
 
3.22 
Cohort 2 only: Discontinued lenvatinib due to toxicity. 
 
3.23 
Pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
 
3.24  
Female subjects of childbearing potential: Unwilling or unable to use 2 methods 
of birth control or be surgically sterile, or abstain from heterosexual activity for 
the course of the study through 120 days after the last dose of study medication.  
NOTE: Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
 
3.25 
Male subjects: Unwilling or unable to use an adequate method of contraception 
starting with the first dose of study therapy through 120 days after the last dose 
of study therapy. 
 
3.26 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.27 
Immunocompromised patients and patients known to be HIV positive (HIV 1/2 
antibodies) and currently receiving antiretroviral therapy.   
  
3.28 
Currently participating and receiving study therapy (except lenvatinib for patients 
in Cohort 2) or has participated in a study of an investigational agent and 
received study therapy within 4 weeks prior to registration. 
 
3.29a 
Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy ≤7 days prior to the first dose of trial 
treatment. 
 
 
3.29b Known history of active TB   (Bacillus Tuberculosis) 
 
3.29c 
Hypersensitivity to pembrolizumab or any of its excipients. 


ACCRU-ITOG-1504 
19  
Addendum 6 
 
 
3.29d Prior anti-cancer monoclonal antibody (mAb) ≤4 weeks prior to registration or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered ≥4 weeks prior to registration. 
 
3.29e 
Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 (except lenvatinib for patients in Cohort 2) or who 
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent.  
 
NOTE:  
• 
Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
• 
If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to 
registration, as deemed by treating investigator or site PI.   
 
3.29f 
Known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma 
of the skin that has undergone potentially curative therapy or in situ cervical 
cancer. 
 
3.29g Known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  NOTE: Subjects with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by imaging 
for at least four weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for ≥7 days prior to trial treatment.  This 
exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability.   
 
3.29h 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). NOTE: Replacement therapy (eg., thyroxine, insulin, 
or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.  
 
3.29i 
Known history of, or any evidence of active, non-infectious pneumonitis that 
required steroids. 
 
3.29j 
Active infection requiring systemic therapy. 
 
3.29k History or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.   
 
3.29l 
Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
3.29m Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 


ACCRU-ITOG-1504 
20  
Addendum 6 
 
 
3.29n Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
3.29o Received a live vaccine ≤30 days of planned start of study therapy. NOTE: 
Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
 
3.29p Proteinuria >1+ on dipstick urinalysis. Patients with >1+ proteinuria on dipstick 
urinalysis will undergo 24-hour urine collection for quantitative assessment. 
NOTE: Patients with > 1 g/24 hours will be ineligible. 
 
3.29q  Clinically significant gastrointestinal malabsorption syndrome. 
 
3.29r 
New York Heart Association congestive heart failure of grade II or above, 
unstable angina, myocardial infarction within the past 6 months, or serious 
cardiac arrhythmia associated with significant cardiovascular impairment within 
the past 6 months. EF by MUGA or echo should not be less than the institutional 
lower limit of normal. 
 
3.29s 
QTc prolongation > 480 msec, as calculated by either the Bazett or Fridericia  
formula, as per institutional standard. 
 
3.29t 
Active hemoptysis (bright red blood > 1 teaspoon on more than one occasion) ≤3 
weeks prior to registration. 
 
3.29u Cohort 2 only: More than one prior treatment with VEGFR active multikinase 
inhibitor prior to original start of lenvatinib. 


ACCRU-ITOG-1504 
21 
Addendum 6 
 
 
 
 
4.0 
Test Schedule 
Additional testing and monitoring can be done as clinically indicated. 
 
 
 
Tests and Procedures 
 
Active Monitoring 
 Cycles = 21 days 
Study visits and tests may occur +/- 3 days  
 
 
≤30 
days 
prior 
to 
reg. 
 
Prior to 
treatment 
initiation 
 
 
 
 
 
Cycle 
1,   
Day 1 
 
Cycle 2,4, 6, 
8, 10, 12, 
14, 16, 18, 
20, 21, 22, 
24*, 26*, 
28*, 29*, 
30*, 32* 
and 34*  
Day 1 
 
 
Cycle 3, 
day 1 
Cycle 7, 
day 1, 
Cycle 
19 day 
1, ( or at 
PD or 
withdra
wal) 
 
 
 
 
 
Cycle 7 day 
1 
 
Cycles 5,7, 
11, 15 and 
19, 23,* 
27,* 31,* 
35,* Day 1 
Cycles 9, 13,  
17, 25* and 
33,* Day 1 
 
 
At PD, 
withdrawal
, removal,  
or study 
completion 
 
 
Observation
† every 3 
months for 3 
years or 
until PD  
History and exam, wt, BP1, 
ECOG PS  
X 
 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment10 
X  
 
 
X 
 
X 
 
 
X 
X 
X 
X 
Hematology: 
CBC/ differential, PT/INR2, 
PTT2 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
 
Chemistries:  SGOT (AST), 
SGPT (ALT), alb, alk phos, T. 
bili, D. bili, albumin, BUN, 
CL, CO2, creatinine, calcium, 
phos, glucose, Na, K, Mg 
X 
 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
X 
X 
 
X 
X 
TSH, free T4, thyroglobulin  
X4 
 
 
 
 
X4 
 
 
X4 
 
 
 
Urinalysis9  
X 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
Pregnancy test 
X3 
 
 
 
 
 
 
 
 
 
 


     
ACCRU-ITOG-1504                                                  22                                           
 Addendum 6 
MUGA or Echocardiogram 
X 
 
 
 
 
 
 
 
X 
 
 
EKG 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
Tumor measurement 
X 
 
 
 
 
X5 
 
 
 
X5 
 
 
X5 
Mandatory blood sample 
(Cohort 1; see Section 14.0) 
 
X R , 6 
 
 
 
 
    X R , 6 
X R , 6 
 
 
 
X R , 6 
 
Mandatory blood sample 
(Cohort 2) 
 
X12 
 
 
 
 
 
 
 
 
 
Mandatory serum sample 
(Cohorts 1 and 2; see Section 
14.0) 
 
X R , 6 
 
 
 
 
 
 
X R , 6 
 
 
 
 
Mandatory archival surgical 
tissue sample (Cohorts 1 and 
2; see Section 17.3) 
XR, 7 
 
 
 
 
 
 
 
 
 
 
Optional tissue biopsy (Cohort 
1; see Section 17.3)  
 
X R, 8 
 
 
 
 
 
 
 
 
 
Patient Medication Diary 
 
 
 
X11 
X11 
 
X11 
 
 
X11 
X11 
X11 
 
Patient Blood Pressure Diary 
 
 
 
X11 
X11 
 
X11 
 
 
X11 
X11 
X11 
 
 
 
† Observation Phase: Part of the Active Monitoring Phase of a study. The time period following the active treatment phase when the 
participant continues to receive cycles of evaluation in compliance with the Test Schedule. Participants will be required to return to the 
consenting site for follow-up. Time frame is +/- two weeks. 
 
* Cycles 23 – 35 apply only to those patients who extend treatment for up to an additional 12 months beyond the initial 54-week treatment 
period. 
 
1 Patients should be instructed to monitor BP at home three times/week at a minimum, and notify treating team if systolic BP ≥ 160 
mmHg and/or diastolic BP ≥ 100 mmHg.  
 
2 PT/INR and PTT are only necessary at baseline, and as clinically indicated. 
 


     
ACCRU-ITOG-1504                                                  23                                           
 Addendum 6 
3 For women of childbearing potential only.  Must be done ≤ 7 days prior to registration. This can be done by either blood or urine test, at 
the physician’s discretion. 
 
4 Check TSH and free T4 at baseline, then every other cycle starting with Cycle 3 then cycles 5 & 7 (day 1), then every 4th cycle starting 
with Cycles 11, 15 and 19 (day 1)for up to 54 weeks for all patients. For those patients who continue treatment beyond 54 weeks (up to 
an additional 12 months), continue checking TSH and free T4 on cycle 23, 27, 31 and 35. For those patients who do NOT have anti-
thyroglobulin antibodies, check thyroglobulin at baseline, and then same time points as TSH and free T4.  
5 Imaging is to be performed day 1 for Cycles 3, 5, and 7, then every 4th cycle for Cycles 11, 15, and 19, up to 54 weeks. Scans can be 
done sooner than 18 weeks if clinically indicated. (See Section 13 for further details.) For those patients who continue treatment 
beyond 54 weeks (up to an additional 12 months), imaging should be done on Cycle 23, 27, 31 and 35. CT or MRI scans of the neck, 
chest, abdomen and pelvis, as determined by the investigator to assess response per RECIST v1.1. Imaging with IV contrast is 
encouraged but will be done per investigator’s discretion. If the abdomen-pelvic CT is negative at baseline, subsequent imaging of this 
site is required only if clinically indicated during the study period. NOTE: Use same imaging throughout the study as much as possible. 
PET scans are performed only as clinically indicated at pre-study, and for restaging as determined per investigator’s discretion. For 
those patients who have initial progression (PD) in the first 12 weeks post-registration, a confirmation scan will be required 4 weeks 
later to confirm PD. See 13.6 for further details. If progression is confirmed then the date of disease progression will be the first date 
the patient met the criteria for progression based on standard RECIST 1.1 criteria. 
 
6 Mandatory blood draws for research immunology studies should not be collected and submitted until after the patient is registered onto 
the study, but before beginning study treatment, Cycle 3, Cycle 7 and Cycle 19 or PD, withdrawal, removal, or study completion for 
peripheral blood mononuclear cells (PBMC) (4 times), and for serum before treatment and cycle 7 day 1 (2 times). See Section 14 and 
Laboratory Manual for detailed information regarding blood draws. 
 
7 ≤60 days from registration. NOTE: Receipt of archival tumor tissue is not required for study registration and initiation of therapy. 
(Cohort 1 and 2) 
 
8 CT-guided or ultrasound-guided tumor biopsy after the patient is registered onto the study, but before beginning study treatment. 
Collection of this tissue is optional for research purposes. If a patient is not willing to undergo this procedure, it does not cause the 
patient to be ineligible; however, collection of this tissue is strongly encouraged (Cohort 1; anticipate collecting samples from 20 of 
30 patients) 
 
9 Patients with >1+ proteinuria on dipstick urinalysis will undergo 24-hour urine collection for quantitative assessment. Patients with > 1 
g/24 hours on the baseline assessment will be ineligible. See Section 8.22 for management of proteinuria.  
 
10 Adverse events should be assessed at every cycle and are done prior to infusion of pembrolizumab. 


     
ACCRU-ITOG-1504                                                  24                                           
 Addendum 6 
 
11 Patients’ blood pressure diary and patient medication diary should be given to the patient on day 1 of each cycle. 
 
12 The mandatory blood sample for Cohort 2 can be drawn at any time after registration. For new patients, it must be drawn prior to the 
study treatment initiation. For patients who have started treatment, it must be drawn at the next treatment visit. Submit the Specimen 
Submission: Blood (PBMC for Cohort 2 only) Form in Rave via Add Event drop down box. 
R Research funded (see Section 19.0) 
 
 


     
ACCRU-ITOG-1504                                                  25                                           
 Addendum 6 
 
5.0 
Grouping Factor:  
• 
Cohort 1 vs. 2 
 
6.0  
Registration Procedures 
 
6.1 
Registration Procedures 
 
6.11 
To register a patient, access the ACCRU web page at 
 , go to 
the Application section and click on “Registration” and enter the 
registration/randomization application.  The registration/randomization 
application is available 24 hours a day, 7 days a week.  Back up and/or system 
support contact information is available on the Web site.  If unable to access the 
Web site, call the Academic and Community Cancer Research United (ACCRU) 
Registration Office at 
between the hours of 8 a.m. and 4:30 p.m. 
Central Time (Monday through Friday). 
 
Instructions for the registration/randomization application are available on the 
above web page under the Study Resources section, “Application Training.”   
 
Prior to initiation of protocol study intervention, this process must be completed 
in its entirety and an ACCRU subject ID number must be available as noted in 
the instructions.  It is the responsibility of the individual and institution 
registering the patient to confirm the process has been successfully completed 
prior to release of the study agent.  Patient registration via the 
registration/randomization application can be confirmed in any of the following 
ways: 
• 
Contact the ACCRU Registration Office 
  If the patient was 
fully registered, the ACCRU Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Application Training” at 
 click on “Registration, 
Installation & Entry Instructions”. 
 
6.12 
Correlative Research  
 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19f, 14.1 and 
17.11). 
 
Cohort 1 only: An optional correlative research component is part of this study, 
there will be an option to select if the patient is to be registered onto this 
component (see Section 17.11). 
 
• 
Patient has/has not given permission to give his/her tissue sample for 
optional correlative research testing planned as part of this study.  
 
6.13 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. Approvals should be uploaded using 
the online ACCRU Regulatory Management System (ARMS). 
 


     
ACCRU-ITOG-1504                                                  26                                           
 Addendum 6 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) with ACCRU. Approvals 
should be uploaded using the online ACCRU Regulatory Management System 
(ARMS).  If the necessary documentation is not submitted in advance of 
attempting patient registration, the randomization will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved.  
 
Submission of annual IRB approvals is required until the study has been closed 
through your IRB. 
 
6.14 
Prior to accepting the registration/randomization, the registration/randomization 
application will verify the following: 
 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information   
 
 
 
6.15  At the time of registration, the following will be recorded: 
 
• 
Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example:  diabetes, Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her tissue 
sample(s) to outside researchers. 
• 
Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example:  diabetes, Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her blood 
sample(s) to outside researchers. 
 
6.16 
Treatment cannot begin prior to registration and must begin ≤10 days after 
registration. 
 
6.17 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.18 
All required baseline symptoms (see Section 10.5) must be documented and 
graded. 
 
6.19a 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of the treating physician who is either study site’s principal 
investigator or co-investigator. 
 
6.19b Study drug is available on site. 
 


     
ACCRU-ITOG-1504                                                  27                                           
 Addendum 6 
 
 7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule  
 
Arm 
Agent 
Dose Level 
Route 
Day 
 
Lenvatinib 
20 mg  
PO 
Once daily 
Days 1 
through 21 of 
each 21-day 
cycle 
 
Pembrolizumab 200 mg  
IV 
Day 1 of 
each 21-day 
cycle 
 
7.11 
Cohort 1: Lenvatinib-naïve patients will be administered both study drugs 
(pembrolizumab and lenvatinib) as of Cycle 1 Day 1. Each cycle is 21 days. The 
starting dose of oral lenvatinib is 20 mg (two 10-mg capsules). 
 
7.12 
Cohort 2:  Pembrolizumab will be added to the treatment for patients who experience PD 
on lenvatinib alone. They will remain on or resume the dose of lenvatinib on which they 
experienced PD. Cycle 1 Day 1 will be the first day pembrolizumab is added to the treatment.  
Patients who have temporarily stopped lenvatinib dosing within 30 days of enrollment will restart 
lenvatinib at their prior dose along with pembrolizumab on Cycle 1 Day 1 of treatment.  
Patients entering Cohort 2 will have progressed on lenvatinib. These patients will remain on the 
dose they are taking at the time of study entry, which may have been previously reduced for side 
effect management, and will not exceed 20 mg by mouth daily. 
 
 
7.2 
Patients will be instructed on lenvatinib administration, to be taken with water orally once 
a day (with or without food) at approximately the same time each day, and granted 
treatment independence with nursing staff approval. If a patient misses a dose, and cannot 
be taken within 12 hours, then that dose should be omitted and the next dose should be 
taken at the usual time of administration. If a patient vomits after taking the daily dose of 
lenvatinib, DO NOT repeat dosing. Resume regular dosing the next day. NOTE: The 
patient will be requested to maintain a medication diary to document time and date when 
each dose of lenvatinib is taken. Patient will also document number of pills/dose of 
medication taken, and note any vomiting subsequent to dosing. The medication diary will 
be returned to clinic staff at each examination visit (see Section 4.0). 
 
7.3 
Pembrolizumab, 200 mg, will be administered as a 30-minute IV infusion every 21 days 
(treatment cycle intervals may be increased based on toxicities as described in section 
8.3). Sites should 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 and +10 minutes 
is permitted (i.e., infusions lasting between 25 minutes to 40 minutes are acceptable).  
 
7.4 
Study treatment with pembrolizumab may be administered up to 3 days before or after 
the scheduled Day 1 of each cycle due to administrative reasons. 
  
7.5 
For this protocol, the patient must return to the consenting ACCRU institution for 
evaluation day 1 of cycles 2, 3, 5, 7, 9, 11, 13, 15, 17 and 19 (see Section 4.0 Test 


     
ACCRU-ITOG-1504                                                  28                                           
 Addendum 6 
 
Schedule, Active Monitoring Phase). 
 
7.6 
Treatment with study-specific drugs by a local medical doctor (LMD) is not allowed. 
7.7  
Patients who develop PD in the CNS only may receive radiotherapy and continue 
treatment on study after completion of radiotherapy. Patient must be clinically stable and 
have been off systemic corticosteroids for at least 14 days at the time of 
recommencement of treatment. NOTE: Both lenvatinib and pembrolizumab should be 
withheld for a minimum of 3 days prior to radiation and for 3 weeks after radiation. 
 
7.8 
Accumulating evidence indicates a minority of patients treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. Patients receiving treatment in this 
study will be permitted to continue treatment beyond initial PD, if the initial PD happens 
in the first 12 weeks post-registration (by RECIST 1.1), as long as they meet the 
following criteria: 
• 
Investigator-assessed clinical benefit (e.g. absence of rapid disease progression and 
absence of progressive tumor at a critical anatomic site that requires urgent 
alternative intervention), and 
• 
The patient is tolerating study drug. 
• 
Patient does not continue to progress at 4 week follow-up imaging after PD first 
noted. 
 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained.  Thereafter, these modifications should be regarded as guidelines to 
address side effects.  If multiple adverse events are seen, administer dose based on greatest 
reduction required for any single adverse event observed.  Reductions or increases apply to 
treatment given in the preceding cycle and are based on adverse events observed since the prior 
dose. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1  
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
Dose 
Level 
Lenvatiniba 
Pembrolizumab 
0b 
 
20 mg orally once a day 
200 mg IV every 21 days 
-1 
 
14 mg orally once a day 
No dose reduction allowed 
-2 
 
10 mg orally once a day 
No dose reduction allowed 
-3 
4 mg orally once a day 
No dose reduction allowed 
a Once the dose has been reduced, it should not be increased at a later date. 
b Dose level 0 refers to the starting dose. 
 
 


     
ACCRU-ITOG-1504                                                  29                                           
 Addendum 6 
 
8.2  
Dose Modifications for Lenvatinib-Related Toxicities 
 
Treatment-Related Toxicitya, b 
including hepatic injury and 
venous thromboembolic events 
Management 
Dose Modification 
Grade 1 and Tolerable Grade 2 
 
Continue Treatment 
No change 
Intolerable Grade 2c or Grade 3d, e 
First occurrence          
Hold until resolved to   Grade 0-
1 or baselinef 
14 mg orally once a day 
Second occurrence              
(same toxicity or new toxicity) 
Hold until resolved to   Grade 0-
1 or baselinef 
10 mg orally once a day 
Third occurrence               
(same toxicity or new toxicity) 
Hold until resolved to   Grade 0-
1 or baselinef 
4 mg orally once a day 
Fourth occurrence               
(same toxicity or new toxicity) 
Hold until resolved to   Grade 0-
1 or baselinef 
Contact ACCRU Quality 
Assurance Specialist 
Grade 4g: Discontinue Study Treatment 
NOTE: See CTCAE v4 for grading: 
  
 
Collect all CTC grades of AEs, decreasing and increasing grade. 
 
a. A delay of study treatment for more than 28 days (due to treatment-related toxicities) will 
require a discussion with the ACCRU Quality Assurance Specialist before treatment can be 
resumed (see protocol resource page). 
 
b. Initiate optimal medical management for nausea, vomiting, and/or diarrhea prior to any study 
treatment, interruption, or dose reduction. 
 
c. Grade 2 toxicities will be determined to be tolerable or intolerable by both the subject and 
investigator.  If Grade 2 toxicity is determined to be intolerable, the dose of study drug will 
be reduced with or without dose interruption.  Interruption for Grade 3 toxicities is 
mandatory.  
 
d. Weight loss of any grade may not require dose reduction, but should be managed based on 
the judgment of the investigator. Subjects with weight loss requiring dose interruption and 
reduction do not need to return to baseline weight to restart lenvatinib.  Based on the 
judgment of the investigator, subjects may be restarted at a lower dose of lenvatinib for 
weight loss.  Consultation with a registered dietician may be helpful in managing weight loss.  
 
e. Not applicable to abnormal clinical laboratory values that are not clinically relevant based on 
the judgment of the investigator (e.g., ALT, AST, γ-GTP values < 10 × ULN, and Na). 
 
f. For hematology toxicities, restart treatment after toxicity resolves to Grade ≤ 2. 
 
g. Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage 
as Grade 3. 


     
ACCRU-ITOG-1504                                                  30                                           
 Addendum 6 
 
8.21 
Management of Hypertension 
 
Hypertension is a known and potentially serious adverse event associated with 
lenvatinib treatment.  Patients will be given a Blood Pressure Diary (Appendix 
III) on which to record their measurements.  They should be instructed to check 
their blood pressure at least three times each week, and notify the treating 
physician if systolic BP ≥160 mmHg and/or diastolic BP ≥ 100 mmHg. 
 
The following guidelines should be followed for the management of systolic 
BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg confirmed on repeat 
measurements after an hour: 
 
Continue lenvatinib and institute antihypertensive therapy for subjects not 
already receiving this. 
 
For those subjects already on antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or one or more agents of a different class 
of antihypertensive should be added. 
 
If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg persists despite 
maximal antihypertensive therapy, then lenvatinib administration should be 
interrupted and restarted at a dose of 14 mg once daily (or one dose level 
reduction) when systolic BP ≤ 150 mmHg and diastolic BP ≤ 95 mmHg and the 
subject has been on a stable dose of antihypertensive medication for at least 
48 hours.  
 
If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg recurs on the 20-mg 
once daily dose despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a 
different class of antihypertensive), then lenvatinib administration should be 
interrupted and restarted at a dose of 14 mg once daily (one dose level reduction) 
only when systolic BP ≤ 150 mmHg and diastolic BP ≤ 95 mmHg and the subject 
has been on a stable dose of antihypertensive medication for at least 48 hours.  
 
If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg recurs on the 14-mg 
once daily dose despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a 
different class of antihypertensive), then lenvatinib administration should be 
interrupted and restarted at a dose of 10 mg once daily (one dose level reduction) 
only when systolic BP ≤ 150 mmHg and diastolic BP ≤ 95 mmHg and the subject 
has been on a stable dose of antihypertensive medication for at least 48 hours. 
 
If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg recurs on the 10-mg 
once daily dose despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a 
different class of antihypertensive), then lenvatinib administration should be 
interrupted and restarted at a dose of 4 mg once daily (one dose level reduction) 
only when systolic BP ≤ 150 mmHg and diastolic BP ≤ 95 mmHg and the subject 
has been on a stable dose of antihypertensive medication for at least 48 hours. 
 
Additional dose reduction should be discussed with the ACCRU SAE 


     
ACCRU-ITOG-1504                                                  31                                           
 Addendum 6 
 
Coordinator (see protocol resource page). 
 
The following guidelines should be followed for the management of Grade 4 
hypertension (life-threatening consequences): 
• 
Institute appropriate medical management 
• 
Discontinue lenvatinib 
 
8.22 
Management of Proteinuria 
 
Regular assessment of proteinuria should be conducted as detailed in the Test 
Schedule (Section 4.0). 
 
Guidelines for assessment and management of proteinuria: 
 
A 24-hour urine collection for protein quantitation is required in the following 
situations:  
 
• 
The first (initial) occurrence of 2+, 3+, or 4+ proteinuria on urine dipstick while 
on study drug  
• 
A subsequent apparent increase in severity of urine dipstick proteinuria (from the 
prior measurement which was ≥2+) occurring on the same lenvatinib dose level  
• 
When there has been a lenvatinib dose reduction and on follow-up, the urine 
protein dipstick result is 2+, 3+, or 4+ (at the new dose level)  
 
The 24-hour urine collection is not required in the following situations:  
• 
Persistence of the same severity of proteinuria by urine dipstick at the same 
lenvatinib dose level (when a 24-hour urine collection has already been collected 
at that dose level)  
• 
Subsequent occurrences of 2+, 3+, or 4+ proteinuria by urine dipstick when the 
subject has been off study drug  
 
Grading of proteinuria should be performed according to CTCAE v4.03 (Appendix 3) 
BUT will be based on the 24-hour urine collection for total protein result, if a 24-hour 
urine was performed at that time point.  
 
For subjects with lenvatinib-related toxicity, the dose reduction and/or 
interruption instructions provided in Table 2 of the study protocol should be 
followed. 
 
8.23 
Management of Hepatotoxicity 
 
Regular monitoring of liver function tests (ALT, AST, bilirubin levels) should be 
conducted as clinically indicated.  If signs/symptoms indicating liver injury 
occur, instructions contained in Table 8.2, “Dose Modifications for Lenvatinib-
Related Toxicities” should be followed.  Appropriate supportive care should be 
provided together with close monitoring.  If hepatic failure occurs, lenvatinib 
must be discontinued. 
 
 
 


     
ACCRU-ITOG-1504                                                  32                                           
 Addendum 6 
 
8.24 
Management of Venous and Arterial Thromboembolic Events 
 
Subjects should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events, which include acute onset of shortness of breath, 
dyspnea, chest pain, cough, hemoptysis, tachypnea, tachycardia, cyanosis, signs 
of deep vein thrombosis including lower-extremity swelling, and warmth to 
touch or tenderness.  In case any of these symptoms appear, subjects should be 
instructed to report such symptoms promptly to the treating physician.  If a 
venous thromboembolic event is confirmed, instructions contained in Table 8.2, 
“Dose 
Modifications 
for 
Lenvatinib-Related 
Toxicities” 
should 
be 
followed.  Appropriate supportive care should be provided together with close 
monitoring.   
 
If a subject experiences any arterial thromboembolic event, lenvatinib must be 
discontinued. 
 
8.25 
Management of Posterior Reversible Encephalopathy Syndrome   
 
In clinical studies with lenvatinib, events of posterior reversible encephalopathy 
syndrome (PRES) were reported in less than 1% of lenvatinib-treated 
subjects.  PRES is a neurological disorder, which can present with headache, 
seizure, lethargy, confusion, altered mental function, blindness, and other visual 
or neurological disturbances.  Mild to severe hypertension may be present.  MRI 
is necessary to confirm the diagnosis of PRES.  Appropriate measures should be 
taken to control BP.  In subjects with signs or symptoms of PRES, dose 
interruptions, dose adjustments, or discontinuation may be required as per 
instructions included in Table 8.2. 
 
8.26 Management of Hypocalcemia 
 
Serum calcium should be monitored per the Test Schedule (Section 
4).  Hypocalcemia should be treated per institutional guidelines (eg, using 
appropriate calcium, magnesium, and Vitamin D supplementation) until 
resolution. 
 
8.27 Management of Myocarditis 
 
8.27a LVEF normal/nonmalignant rhythm- Obtain cardiology consultation, review case with 
overall study PI, and consider 1 gram IV solumedrol daily for 3-5 days (consider 
mycophenolate vs IVIG vs cyclosporine vs plasmapheresis for persistent myocarditis). 
 
8.27b LVEF reduced or patient is unstable- Obtain a cardiology consultation and review the 
case with overall study PI. 
 
 
 
 
 
 
 
 


     
ACCRU-ITOG-1504                                                  33                                           
 Addendum 6 
 
 
8.3  
Dose Modifications for Pembrolizumab-Related Toxicities 
 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Hold 
Treatment  
for Grade 
Timing for 
Restarting 
Treatment 
Treatment 
Discontinuation 
Gastrointestinal 
Disorders 
 
 
 Diarrhea/Colitis 
 
2-3 
Toxicity resolves 
to 
Grade 0-1 
Toxicity does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10mg or less of 
prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently 
discontinue 
Permanently discontinue 
Endocrine Disorders 
Other: 
Hypophysitis 
2-4 
Toxicity resolves 
to 
Grade 0-1. 
Therapy with 
pembrolizumab 
can be continued 
while endocrine 
replacement 
therapy is 
instituted. 
Toxicity does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10mg or less of 
prednisone or equivalent 
per day within 12 weeks. 
Immune System 
Disorders 
Infusion 
Reaction 
3-4 
Permanently 
discontinue 
Permanently discontinue 
Investigations  
AST, ALT or 
Increased 
Bilirubin 
2 
Toxicity resolves 
to 
Grade 0-1 
Toxicity does not resolve 
within 12 weeks of last 
dose. 
 
3-4 
 
Permanently 
discontinue (see 
exception below)a 
Permanently discontinue 
Metabolism and 
Nutrition Disorders 
Type 1 
Diabetes 
Mellitus (if 
new onset) or 
Hyperglycemia 
TIDM or 
3-4 
Hold 
pembrolizumab 
for new onset 
Type 1 diabetes 
mellitus or Grade 
3-4 
hyperglycemia 
associated with 
evidence of beta 
cell failure. 
Resume pembrolizumab 
when subject is clinically 
and metabolically stable. 
 
Hypercalcemia 
3-4 
Toxicity resolves 
to Grade 0-1 
Resume pembrolizumab 
when subject is clinically 
and metabolically stable. 
 
 


     
ACCRU-ITOG-1504                                                  34                                           
 Addendum 6 
 
 
 
 
 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Hold 
Treatment  
for Grade 
Timing for 
Restarting 
Treatment 
Treatment 
Discontinuation 
Renal and urinary 
disorders 
 
Renal Failure 
or Nephritis 
2 
Toxicity 
resolves to 
Grade 0-1 
Toxicity does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10mg or less of 
prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently 
discontinue 
Permanently discontinue 
Respiratory, thoracic 
and mediastinal 
disorders 
 
Pneumonitis 
2 
Toxicity 
resolves to 
Grade 0-1 
Toxicity does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10mg or less of 
prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently 
discontinue 
Permanently discontinue 
Myocarditis 
Grade 1 or 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 
 
All Other 
Drug-Related 
Toxicityb 
3 or Severe 
Toxicity 
resolves to 
Grade 0-1 
Toxicity does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10mg or less of 
prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently 
discontinue 
Permanently discontinue 
NOTE: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. 
 
a.  For subjects with liver metastasis who begin treatment with Grade 2 AST or ALT, if 
AST or ALT increases by greater than or equal to 50% relative to baseline and lasts 
for at least 1 week then subjects should be discontinued. 
b. Subjects with intolerable or persistent Grade 2 drug-related AE may hold study 
medication at physician discretion. Permanently discontinue study drug for persistent 
Grade 2 adverse reactions for which treatment with study drug has been held, that do 
not recover to Grade 0-1 within 12 weeks of the last dose. 


     
ACCRU-ITOG-1504                                                  35                                           
 Addendum 6 
 
 
 
 


     
ACCRU-ITOG-1504                                                  36                                           
 Addendum 6 
 
8.4 
Treatment Guidelines for Subjects Who Experience an Infusion Reaction Associated with 
the Administration of Pembrolizumab 
 
Infusion Reaction Treatment Guidelines for Pembrolizumab 
CTCAE Grade 
Treatment 
Premedication at    
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hours 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (e.g., from 100 mL/h to 50 mL/h). 
Otherwise dosing will be held until 
symptoms resolve and the subject should 
be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further study treatment administration. 
Subject may be premedicated 
1.5h (±30 minutes) prior to 
infusion of pembrolizumab 
with: 
 
• 
Diphenhydramine 50 
mg orally (or 
equivalent dose of 
antihistamine). 
• 
Acetaminophen 500-
1000 mg orally (or 
equivalent dose of 
antipyretic). 
 
 
 
 
 
 
 
 
 
 
 


     
ACCRU-ITOG-1504                                                  37                                           
 Addendum 6 
 
 
 
Infusion Reaction Treatment Guidelines for Pembrolizumab 
CTCAE Grade 
Treatment 
Premedication at    
subsequent dosing 
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 
ventilator support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
• 
Epinephrine 
 
 
 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.  
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further study treatment 
administration. 
 
No subsequent dosing. 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, subject vacation, 
and/or holidays). Subjects should be placed back on study treatment within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the subject's study record. 
  
9.0 
Additional Supportive Care 
 
9.1 
Antiemetics and intravenous fluids may be used at the discretion of the treating 
physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors should 
follow the published Recommendations for the Use of WBC Growth Factors:  American 
Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical 
Oncology 2015;33:3199-3212. 


     
ACCRU-ITOG-1504                                                  38                                           
 Addendum 6 
 
9.3 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records and on the case report form (CRF). 
 
9.4 
Diarrhea/Colitis: 
 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). 
 
All subjects who experience 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. For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
 
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
 
For Grade 3 or 4 diarrhea/colitis that persists >1 week, treat with intravenous 
steroids followed by high dose oral steroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
9.5 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community 
standards of medical care.  All concomitant medication will be recorded in the medical 
record and 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. 
 
9.6 
Apart from the assigned study drugs, subjects are prohibited from receiving the 
following therapies during the Screening and Treatment Phase (including retreatment for 
post-complete response relapse) of this trial: 
 
9.61  
Antineoplastic systemic chemotherapy or biological therapy  
 
9.62 
Immunotherapy not specified in this protocol 
 
9.63 
Chemotherapy not specified in this protocol 
 
9.64 
Investigational agents other than pembrolizumab and lenvatinib 
 
9.65 
Radiation therapy. NOTE: Radiation therapy to a symptomatic solitary lesion or 
to the brain may be allowed at the investigator’s discretion.   
 
9.66 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 
BCG, and typhoid vaccine.  
 
 


     
ACCRU-ITOG-1504                                                  39                                           
 Addendum 6 
 
9.67 
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 
ACCRU Quality Assurance Specialist (see protocol resource page). 
 
9.68 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the 
trial.  Subjects may receive other medications that the investigator deems to be 
medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
9.7 
Pneumonitis: 
 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
 
For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional antiinflammatory measures, as needed. Add prophylactic antibiotics for 
opportunistic infections in the case of prolonged steroid administration. 
 
9.8 
Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis [DKA]) or Grade 
3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 
For T1DM or Grade 3-4 Hyperglycemia 
 
• 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
 
• 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
 
9.9 
Hypophysitis: 
 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
9.9a 
Additional Supportive Care Guidelines for Pembrolizumab 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 


     
ACCRU-ITOG-1504                                                  40                                           
 Addendum 6 
 
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. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event.  
 
9.9a1 
Hepatic: 
 
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
o Treat with IV or oral corticosteroids 
 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
 
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
9.9a2 
Renal Failure or Nephritis: 
 
For Grade 2 events, treat with corticosteroids. 
 
For Grade 3-4 events, treat with systemic corticosteroids. 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
9.9a3 
Management of Infusion Reactions: Signs and symptoms usually develop during 
or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure.  
 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following:  
 
• 
Any suspected adverse reaction that is both serious and unexpected.  
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  


     
ACCRU-ITOG-1504                                                  41                                           
 Addendum 6 
 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug.  
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB).  
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor).  
 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be used for AE reporting.  All appropriate treatment areas should have access to 
a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site: 
     
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial.   
b. Identify the grade and severity of the event using the CTCAE version 4.0.   
c. Determine whether the event is expected or unexpected (see Section 10.2).  
d. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  


     
ACCRU-ITOG-1504                                                  42                                           
 Addendum 6 
 
f. Determine if other reporting is required (see Section 10.5). 
g. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same as serious 
AE which is defined in the table in Section 10.4. 
 
 
10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
 


     
ACCRU-ITOG-1504                                                  43                                           
 Addendum 6 
 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug/device and the adverse event.  
. 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME (Combination)Arm 
When a commercial agent(s) is (are) used on the same treatment arm as the 
investigational agent/intervention (also, investigational drug, biologic, cellular 
product, or other investigational therapy under an IND), the entire combination 
(arm) is then considered an investigational intervention for reporting. These 
AEs should be assessed as specified in the appropriate IND/IDE reporting 
guidelines in Section 10.4 
 
10.32 Special Situations for Expedited Reporting 
EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting   
For this protocol only, the following Adverse Events/Grades are expected to 
occur within this population and do not require Expedited Reporting. These 
events must still be reported via Routine Reporting (see Section 10.5). * 
 
 
System Organ 
Class (SOC) 
 
Adverse event/ 
Symptoms 
 
CTCAE Grade at which 
the event will not be 
expeditedly reported. 
Generalized 
disorders and 
administration site 
conditions 
Fatigue 
<Grade 3 
Gastrointestinal 
disorders 
Diarrhea 
<Grade 3 
Abdominal pain 
<Grade 3 
Vomiting 
<Grade 3 
Constipation 
<Grade 3 
Mucositis oral 
<Grade 3 
Nausea 
<Grade 3 
Investigations 
Weight loss 
<Grade 3 
Increased AST 
<Grade 3 
Metabolism and 
nutrition disorders 
Loss of appetite 
<Grade 3 


     
ACCRU-ITOG-1504                                                  44                                           
 Addendum 6 
 
Musculoskeletal and 
connective tissue 
disorders 
Myalgia 
<Grade 3 
Nervous system 
disorders 
Headache 
<Grade 3 
Renal and urinary 
disorders 
Proteinuria 
<Grade 3 
Respiratory, thoracic 
and mediastinal 
disorders 
 
Cough 
<Grade 3 
Skin and 
subcutaneous tissue 
disorders 
Palmar-plantar 
erythrodysesthesia 
<Grade 3 
Pruritis 
<Grade 3 
Rash maculo-papular 
<Grade 3 
Vascular disorders 
Hypertension 
<Grade 3 
 
*These exclusions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed. 
 
*Report any clinically important increase in the rate of a serious suspected adverse 
reaction (at your study) site over that which is listed in the protocol or investigator 
brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected as an    
expedited event  
*An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent.  Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required.   
Efficacy endpoints as outlined in this section will not be reported to Merck or Eisai as 
described in Section 10.4 - Immediate Reporting of Adverse Events to the ACCRU and 
to Merck, unless there is evidence suggesting a causal relationship between the drug and 
the event. Any such event will be submitted to the ACCRU within 24 hours and to Merck 
Global Safety within 2 working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that 
is disease progression of the cancer under study. 
ACCRU will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review 
is not progression of the cancer under study will be forwarded to Merck Global Safety 


     
ACCRU-ITOG-1504                                                  45                                           
 Addendum 6 
 
 
 
as a SAE within 2 working days of determination that the event is 
not progression of the cancer under study 
Hospitalization related to convenience (e.g., transportation issues etc.) will not be 
considered a SAE. 
A list of known/expected AEs is reported in the investigator brochure, package insert or 
the literature, including AEs resulting from a drug overdose. 
 
10.321 Death 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
• 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
• 
Reportable categories of Death: Death attributable to a 
CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by cessation of 
life during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be attributed to 
a CTCAE term associated with Grade 5. 
 
• 
Sudden death NOS:  A sudden (defined as instant or within 
one hour of the onset of symptoms) or an unobserved 
cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
 
• 
Death due to progressive disease should be reported as 
Grade 5 “Neoplasms benign, malignant and unspecified 
(including cysts and polyps) – Other (Progressive 
Disease)” under the system organ class (SOC) of the same 
name.  Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
10.322 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not 
considered a metastasis of the initial neoplasm. 
 


     
ACCRU-ITOG-1504                                                  46                                           
 Addendum 6 
 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE to be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.323 Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting. 
 
10.324 Pregnancy  
 
Prior to obtaining private information about a pregnant woman and her 
infant, the investigator must obtain consent from the pregnant woman 
and the newborn infant’s parent or legal guardian before any data 
collection can occur.  A consent form will need to be submitted to the 
IRB for these subjects if a pregnancy occurs. If informed consent is not 
obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion the mother is the patient. 
In cases where the child/fetus experiences a serious adverse event other 
than fetal death, the child/fetus is the patient. 
 
Although pregnancy and lactation are not considered adverse events, it is 
the responsibility of investigators or their designees to report any 
pregnancy or lactation in a subject (spontaneously reported to them) that 
occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but 
before treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be excluded from the trial, or are 
the result of a protocol-specified intervention, including but not limited 
to washout or discontinuation of usual therapy, diet, placebo treatment or 
a procedure.   
Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of study 
drugs, or 30 days following cessation of treatment if the subject initiates 
new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, 


     
ACCRU-ITOG-1504                                                  47                                           
 Addendum 6 
 
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. 
If a subject inadvertently becomes pregnant while on treatment with 
pembrolizumab, the subject will immediately be removed from the study.  
The site will contact the subject at least monthly and document the 
subject’s status until the pregnancy has been completed or terminated.  
The outcome of the pregnancy will be reported to the Sponsor and to 
Merck without delay and within 24 hours to the Sponsor and within 2 
working days to Merck if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus 
or newborn to the Sponsor.   If a male subject impregnates his female 
partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Merck and followed as 
described above. 
Such events must be reported within 24 hours to the Sponsor and within 
2 business days to Merck Global Safety
 
Use the ACCRU Expedited Report Form, found on the ACCRU web site 
(
). NOTE: When submitting ACCRU Adverse Event 
Report reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, 
the potential risk of exposure of the fetus to the investigational agent(s) 
or chemotherapy agent(s) should be documented in the “Description of 
Event” section. Include any available medical documentation.  
 
 


     
ACCRU-ITOG-1504                                                  48                                           
 Addendum 6 
 
10.4 Expedited Adverse Event Reporting Requirements for IND/IDE Agents 
 
10.41  Phase 1 and Early Phase 2 Studies:  Expedited Reporting via the ACCRU Adverse 
Event Expedited Report Form for Adverse Events That Occur Within 30 Days1 of the 
Last Dose of the Investigational Agent 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
(FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour / 3 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour / 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Follow site-specific reporting guidelines. 
Submit the ACCRU Adverse Event Expedited Report Form to ACCRU Safety via email at: 
ACCRU Safety will forward to Merck
  


     
ACCRU-ITOG-1504                                                  49                                           
 Addendum 6 
 
 ACCRU Safety will forward to 
as appropriate. The ACCRU IND 
Coordinator will assist the sponsor-investigator in notifying the FDA if required.  
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in general, 
include any incident, experience, or outcome that meets all the following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved in the 
research); and 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the physical or 
psychological harm associated with adverse events.  In other cases, unanticipated 
problems place subjects or others at increased risk of harm, but no harm occurs. 
 
Note: If there is no language in the protocol indicating that pregnancy is not considered 
an adverse experience for this trial, and if the consent form does not indicate that subjects 
should not get pregnant/impregnate others, then any pregnancy in a subject/patient or a 
male patient’s partner (spontaneously reported) which occurs during the study or within 
120 days of completing the study should be reported as a UPIRTSO. 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required by your 
institutional policies.   
 
 


     
ACCRU-ITOG-1504                                                  50                                           
 Addendum 6 
 
10.52 Baseline and Adverse Events Evaluations 
 
 
Pre-treatment symptoms/conditions to be graded at baseline and adverse events to be 
graded at each evaluation.  (Grading is not necessary in the absence of these conditions.) 
This list includes but is not limited to the symptoms/conditions listed below. The CTCAE 
v4.0 grading should be used: 
 
 
System Organ 
Class (SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
Generalized 
Fatigue 
X 
X 
Gastrointestinal 
Diarrhea 
X 
X 
Cardiovascular 
Hypertension 
X 
X 
Renal 
Proteinuria 
X 
X 
Generalized 
Weight loss 
X 
X 
Renal 
Acute kidney injury 
X 
X 
Pulmonary 
Pneumonitis 
X 
X 
 
 
10.53 Case Report Forms - Academic and Community Cancer Research United (ACCRU) 
 
Submit the following AEs not specified in Section 10.5 (paper or electronic, as 
applicable). 
 
10.54   Submit via appropriate Academic and Community Cancer Research United (ACCRU) 
Case Report Forms (i.e., paper or electronic, as applicable) the following AEs 
experienced by a patient and not specified in Section 10.5: 
 
10.531 Grade 1 and 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.532 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure 
 
10.533 Grade 5 AEs (Deaths) 
 
10.5331 Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or procedure. 
 
10.5332 Any death more than 30 days after the patient’s last study treatment or 
procedure that is felt to be at least possibly treatment related must also be 
submitted as a Grade 5 AE, with a CTCAE type and attribution assigned. 
 
10.55   Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
10.56   Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 24 hours to the ACCRU SAE Coordinator 
using the ACCRU Adverse Event Expedited Report Form. Within 2 working days, the 
ACCRU SAE Coordinator will report to Merck Global Safety. 
 


     
ACCRU-ITOG-1504                                                  51                                           
 Addendum 6 
 
 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject 
must be reported within 24 hours to ACCRU and within 2 working days to Merck Global 
Safety if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an 
ECI, whether or not related to Merck product, must be reported within 24 hours to 
ACCRU and within 24 hours to Merck Global Safety. 
 
Events of clinical interest for this trial include: 
 
1.  An overdose of pembrolizumab, as defined below that is not associated with 
clinical symptoms or abnormal laboratory results.  
 
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as determined 
by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  
 
 
Overdose: For purposes of this trial, an overdose of pembrolizumab will be defined as 
any dose of 1,000 mg or greater (≥5 times the indicated dose).  No specific information is 
available on the treatment of overdose of pembrolizumab. Appropriate supportive 
treatment should be provided if clinically indicated. In the event of overdose, the subject 
should be observed closely for signs of toxicity.  Appropriate supportive treatment should 
be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported 
as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 
hours to the ACCRU SAE Coordinator using the ACCRU Adverse Event Expedited 


     
ACCRU-ITOG-1504                                                  52                                           
 Addendum 6 
 
Report Form.  Within 2 working days, the ACCRU SAE Coordinator will report to 
Merck Global Safety. 
 
 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
NOTE:  This study uses protocol RECIST v1.1 template dated 2/16/2011.  See the footnote for 
the table regarding measureable disease in Section 11.44, as it pertains to data collection and 
analysis. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1).  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the short axis measurements in the case of lymph nodes are used in the RECIST 
guideline. 
 
11.1 
Schedule of Evaluations:  For the purposes of this study, patients should be reevaluated 
every 6 weeks to 18 weeks after treatment initiation, then every 12 weeks until end of 
active study treatment (54 weeks).  In addition to a baseline scan, confirmatory scans 
should also be obtained at least 4 weeks following initial documentation of objective 
response. 
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21   Measurable Disease 
 
11.211 A non-nodal lesion is considered measurable if its longest diameter can 
be accurately measured as ≥1.0 cm with CT scan, CT component of a 
PET/CT, or MRI.  
 
11.212 A superficial non-nodal lesion is measurable if its longest diameter is ≥ 
1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or 
imaging.  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
11.213 A malignant lymph node is considered measurable if its short axis is >1.5 
cm when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).   
 
NOTE:  Tumor lesions in a previously irradiated area are not considered 
measurable disease.   
 
11.22 Non-Measurable Disease 
 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to 
<1.5 
cm). 
 
Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable as well. 


     
ACCRU-ITOG-1504                                                  53                                           
 Addendum 6 
 
 
Note:  ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions.  In addition, lymph nodes that have a short axis <1.0 cm are 
considered non- pathological (i.e., normal) and should not be recorded or 
followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:   
 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. For patients having only lesions measuring at least 1 cm to less 
than 2 cm must use CT imaging for both pre- and post-treatment tumor 
assessments.   
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
 
11.32 Acceptable Modalities for Measurable Disease:       
 
• 
Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
or less. If CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness.     
 
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease.  The lesions should be measured on the same pulse 
sequence.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
• 
PET-CT:  If the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.   
 
• 
FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' 
disease.  A ‘positive’ FDG-PET scanned lesion is defined as one which is 
FDG avid with an update greater than twice that of the surrounding tissue on 
the attenuation corrected image; otherwise, an FDG-PET scanned lesion is 


     
ACCRU-ITOG-1504                                                  54                                           
 Addendum 6 
 
considered ‘negative.’  New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is 
a sign of PD based on a new lesion. 
 
b.   No FDG-PET at baseline and a positive FDG-PET at follow-up:   
 
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.   
 
ii. If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT at the same evaluation, additional follow-up CT 
scans (i.e., additional follow-up scans at least 4 weeks later) are 
needed to determine if there is truly progression occurring at that 
site. In this situation, the date of PD will be the date of the initial 
abnormal PDG-PET scan.   
 
iii If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, it is not classified as PD. 
 
11.33 Measurement at Follow-up Evaluation:   
 
• 
A subsequent scan must be obtained ≥4 weeks following initial 
documentation of an objective status of either complete response (CR) or 
partial response (PR).  
 
• 
In the case of stable disease (SD), follow-up measurements must have met 
the SD criteria at least once after study entry at a minimum interval of 4 
weeks (see Section 11.44). 
 
• 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline.  These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  


     
ACCRU-ITOG-1504                                                  55                                           
 Addendum 6 
 
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.   
 
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.   
 
• 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD).  The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.   
 
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target 
lymph nodes will be calculated and reported as the post-baseline sum of 
dimensions (PBSD).  If the radiologist is able to provide an actual measure 
for the target lesion (or target lymph node), that should be recorded, even if it 
is below 0.5 cm.  If the target lesion (or target lymph node) is believed to be 
present and is  
faintly seen but too small to measure, a default value of 0.5 cm should be 
assigned.  If it is the opinion of the radiologist that the target lesion or target 
lymph node has likely disappeared, the measurement should be recorded as 0 
cm. 
 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
 
 
11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at   
baseline.  These lesions and lymph nodes should be followed in accord with 
11.433. 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by 
 
CT/MRI/PET-CT/Chest X-ray/physical examination must be measured 
on re-evaluation at evaluation times specified in Section 11.1.  
Specifically, a change in objective status to either a PR or CR cannot be 
done without re-measuring target lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be 


     
ACCRU-ITOG-1504                                                  56                                           
 Addendum 6 
 
evaluated at each assessment, especially in the case of first response or 
confirmation of response.  In selected circumstances, certain non-target 
organs may be evaluated less frequently.  For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
 
11.432 Evaluation of Target Lesions 
 
• Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have 
reduction in short axis to <1.0 cm. 
 
• Partial Response (PR): 
At least a 30% decrease in PBSD (sum of 
the longest diameter for all target lesions 
plus the sum of the short axis of all the 
target lymph nodes at current evaluation) 
taking as reference the BSD (see Section 
11.41). 
 
• Progression (PD): 
At least one of the following must be 
true: 
 
a. At least one new malignant lesion, 
which also includes any lymph node 
that was normal at baseline (< 1.0 cm 
short axis) and increased to ≥ 1.0 cm 
short axis during follow-up.  
 
b. At least a 20% increase in PBSD 
(sum of the longest diameter for all 
target lesions plus the sum of the 
short axis of all the target lymph 
nodes at current evaluation) taking as 
reference the MSD (Section 11.41).  
In addition, the PBSD must also 
demonstrate an absolute increase of 
at least 0.5 cm from the MSD.  
 
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
  
• Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR, nor sufficient increase to qualify for 
PD taking as reference the MSD. 
 
 


     
ACCRU-ITOG-1504                                                  57                                           
 Addendum 6 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance 
of 
all 
non-target 
lesions.  
 
b. Each non-target lymph node must 
have a reduction in short axis to <1.0 
cm. 
 
• Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
 
• Progression (PD): 
At least one of the following must be 
true: 
 
a. At least one new malignant lesion, 
 
which also includes  any lymph node 
 
that was normal at baseline (< 1.0 cm 
 
short axis) and increased to ≥ 
 
1.0 cm short axis during follow-up.   
 
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes.  (NOTE:  Unequivocal 
progression should not normally 
trump target lesion and target lymph 
node status.  It must be representative 
of overall disease status change.)  
   
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
 
 
 


     
ACCRU-ITOG-1504                                                  58                                           
 Addendum 6 
 
11.44 Overall Objective Status 
 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-
target lymph nodes, and new disease as defined in the following table:  
 
 
Target Lesions 
& 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated (NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE:  This study uses the protocol RECIST v1.1 template dated 2/16/2011.  For data 
collection and analysis purposes the objective status changed from SD to PR in the 
ACCRU protocol RECIST v1.1 template as of 2/16/2011 and to match RECIST v1.1 
requirements. 
 
 
Note:  For those patients who have initial PD in the first 12 weeks post-registration, a 
confirmation scan will be required 4 weeks later to confirm PD. See Section 13.7 for 
further details. If progression is confirmed then the date of disease progression will be the 
first date the patient met the criteria for progression based on standard RECIST 1.1 
criteria. 
  
11.45 Symptomatic Deterioration: Patients with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 
progression at that time, and not either related to study treatment or other medical 
conditions, should be reported as PD due to “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after 
discontinuation of treatment due to symptomatic deterioration.  A patient is 
classified as having PD due to “symptomatic deterioration” if any of the 
following occur that are not either related to study treatment or other medical 
conditions: 


     
ACCRU-ITOG-1504                                                  59                                           
 Addendum 6 
 
• Weight loss >10% of body weight. 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 
 
12.0 
Descriptive Factors   
 
12.1 
Region:  North America vs. Europe 
 
12.2 
Disease TNM stage at diagnosis: I vs. II vs. III vs. 4A vs. 4B vs. 4C 
 
12.3 
History of lymphocytic thyroiditis: Yes vs. No 
 
12.4 
Prior systemic VEGFR-active kinase inhibitor therapy:  Yes vs. No 
 
12.5 
Histologic subtype of primary tumor: papillary vs. follicular variant vs. follicular vs. 
Hurthle or poorly differentiated 
 
12.6 
Sites of metastatic lesions:  none vs. nodal vs. pulmonary vs. bone vs. liver vs. CNS/brain 
vs. subcutaneous tissue vs. other 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Patients who are CR, PR, or SD will continue treatment per protocol. 
 
13.2 
Patients who develop PD while receiving therapy or refuse treatment or choose 
alternative therapy will go to the event-monitoring phase per Section 18.0 and be 
followed every 180 days for a maximum of 3 years from study registration. (See 
exceptions in 13.5 and 13.6.) 
 
13.3 
Patients who go off protocol treatment for reasons other than those listed in Section 13.2 
above (e.g., adverse events, other complicating disease) will go to Observation and will 
follow the test schedule (Section 4.0) every 84 days for a maximum of 3 years from study 
registration. If they progress or choose alternative therapy while in Observation, they will 
go to the event-monitoring phase. 
 
13.4 
OBSERVATION:  The study treatment period is 54 weeks (19 cycles). Patients who are 
receiving clinical benefit (i.e., in CR or PR or SD) and who are tolerating treatment at the 
end of the study treatment period may continue on therapy for an additional 12 months.  
After study treatment has been discontinued, they should be observed every 12 weeks 
until PD or a maximum follow-up of 3 years from study registration.  Once the patient 
has PD during observation, they will be followed in the event-monitoring phase for a 
maximum follow-up of 3 years from study registration (see Section 18.0).  Subsequent 
treatment is at the discretion of their attending physician. NOTE: If the patient continues 
for an additional 12 months of treatment beyond the initial 54 weeks, the patient should 
follow the same test schedule, per protocol, as is done during the initial 54-week period. 
 
13.5 
Patients who develop PD in the CNS may receive radiotherapy and continue treatment on 
study after completion of  radiotherapy. NOTE: Both lenvatinib and pembrolizumab 
should be withheld for a minimum of 3 days prior to radiation and for 3 weeks after 
radiation. 
 


     
ACCRU-ITOG-1504                                                  60                                           
 Addendum 6 
 
13.6 
Accumulating evidence indicates a minority of patients treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. Patients receiving treatment in this 
study will be permitted to continue treatment beyond initial PD, if the initial PD happens 
in the first 12 weeks post-registration (by RECIST 1.1), as long as they meet the 
following criteria: 
 
• Investigator-assessed clinical benefit (e.g. absence of rapid disease progression 
and absence of progressive tumor at a critical anatomic site that requires urgent 
alternative intervention), and 
• The patient is tolerating study drug. 
• Patient does not continue to progress at 4 week follow-up imaging after PD first 
noted. 
 
Patients with initial  progression will be assessed with clinical judgment as to whether the 
patient is deriving clinical benefit from treatment and should continue study treatment or 
discontinue and enter the follow up/survival phase of the study. If progression is 
confirmed then the date of disease progression will be the first date the patient met the 
criteria for progression based on the standard RECIST 1.1 criteria. 
 
13.7 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol.  
 
13.8 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol. 
13.9 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and Off-Treatment Form must be 
submitted.  Event monitoring will be required per protocol (Section 18.0). 
 


     
ACCRU-ITOG-1504                                                  61                                           
 Addendum 6 
 
14.0 
Body Fluid Biospecimens   
 
14.1 
Summary Table of Research Blood/Blood Products to Be Collected for This Protocol 
NOTE:  Please refer to study specific Laboratory Manual. 
 
Indicate if 
specimen 
is 
mandatory 
or optional 
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Volume 
to collect 
per tube 
(number 
of tubes 
to be 
collected) 
Blood 
product 
being 
processed 
and 
submitted 
by 
participating 
site 
Prior to 
Treatment 
Initiation3 
 
Cycle 3,    
Day 1,     
Cycle 7,    
Day 1, Cycle 
19 day 1,  and 
at PD, study 
completion,  
or time of 
withdrawal 
or removal  
Cycle 7, 
Day 1 
Additional 
processing 
required 
at site 
after blood 
draw? 
Storage 
/shipping 
conditions1 
Mandatory 
(Cohort 1) 
BD 
Vacutainer 
Cell 
Preparation 
Tube with 
sodium 
citrate 
(CPT; light 
blue/black)  
 
8 ml; up 
to 24 ml 
total (3) 
 
PBMC2 
X 
X 
 
Yes, 
Process 
within 2 
hours of 
collection 
Frozen/Dry Ice 
or 
Cryopreservation
/Liquid Nitrogen 
Mandatory 
(Cohort 2) 
BD 
Vacutainer 
Cell 
Preparation 
Tube 
with 
sodium 
citrate 
(CPT; light 
blue/black) 
8 ml; up 
to 24 ml 
total (3) 
PBMC2 
X 
 
 
Yes, 
Process 
within 2 
hours of 
collection 
Frozen/Dry Ice 
or 
Cryopreservation
/Liquid Nitrogen 
Mandatory 
(Cohorts 1 
BD 
Vacutainer 
7.5 ml (1) 
Serum 
X 
 
X 
Yes, 
Process 
Frozen/Dry ice 


     
ACCRU-ITOG-1504                                                  62                                           
 Addendum 6 
 
Indicate if 
specimen 
is 
mandatory 
or optional 
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Volume 
to collect 
per tube 
(number 
of tubes 
to be 
collected) 
Blood 
product 
being 
processed 
and 
submitted 
by 
participating 
site 
Prior to 
Treatment 
Initiation3 
 
Cycle 3,    
Day 1,     
Cycle 7,    
Day 1, Cycle 
19 day 1,  and 
at PD, study 
completion,  
or time of 
withdrawal 
or removal  
Cycle 7, 
Day 1 
Additional 
processing 
required 
at site 
after blood 
draw? 
Storage 
/shipping 
conditions1 
and 2) 
Serum 
Separator 
Tube (SST; 
red/gray) 
within 2 
hours of 
collection 
1. 
Kits should be ordered using the Biospecimen Kit Order Form found on the ACCRU web site.  After all samples 
have been processed according to kit instructions, ship all specimens according to shipping instructions (see 
Section 14.215 and Laboratory Manual for detailed shipping instructions.) 
2. 
Individual sites will run a density gradient with Ficoll-Hypaque gradient that is supplied in the Cell Preparation 
Tubes (CPT).  This will give a PBMC layer in each of the 3 tubes that can be combined in the same 
cryopreservation tubes. 
3. 
Mandatory blood draw is collected once any time after study registration. For new patients, it must be drawn prior 
to the study treatment initiation. For patients who have started treatment, it must be drawn at the next treatment 
visit. Submit the Specimen Submission: Blood (PBMC for Cohort 2 only) form for this blood draw in Rave via 
Add Event drop down box.  


     
ACCRU-ITOG-1504                                                  63                                           
 Addendum 6 
 
14.2 
Study Methodology and Storage Information 
 
14.21 Blood/blood product samples will be collected for the following research  
 
NOTE: research blood samples should not be collected and submitted until after 
the patient is registered onto the study, but prior to beginning study treatment. 
 
14.211 The peripheral blood mononuclear cells (PBMC) will be isolated by 
density gradient from approximately 24ml peripheral blood. In Cohort 1, 
Samples will be collected before treatment, Cycle 3 Day 1, Cycle 7 Day 
1 and Cycle 19 Day 1, or time of withdrawal or removal. In Cohort 2, a 
single blood draw will be performed pretreatment or at any point during 
the study in order to generate a source of normal DNA. PBMC will be 
washed and cryopreserved for later analysis by flow cytometry and as a 
source of normal control DNA.  Cells will be aliquoted in 
cryopreservation media, frozen at -80°C and shipped overnight on dry 
ice. For long-term storage, frozen cells will be stored in liquid nitrogen 
and shipped on liquid nitrogen.  (See Laboratory Manual, Cohort 1) 
 
14.212 Serum will be isolated from blood for analysis of TPO and Tg 
autoantibody levels. Samples will be collected before treatment and on 
Day 1 of Cycle 7. Autoantibody levels will be run at the University of 
Colorado Hospital (UCH) providing uniform testing in a CLIA 
accredited clinical laboratory. The Siemens ADVIA Centaur XP anti-
TPO assay at UCH has an analytical sensitivity of 28 U/mL and a 
dynamic range of 28–1300 U/mL. The Beckman Coulter Access 
Thyroglobulin Antibody II assay at UCH has an analytical sensitivity of 
0.9 IU/mL and a dynamic range of 0.9-2500 IU/mL. Baseline 
autoantibody status (positive or negative) and titer as well as 
autoantibody level changes over the treatment period will be correlated 
with response to therapy.  Serum will be isolated from 7.5 mL of blood, 
aliquoted into 4 cyrovials, and frozen at -80°C for 48 hours before 
shipping overnight on dry ice (See Laboratory Manual, Cohorts 1 and 2) 
 
14.213 DNA and RNA will be extracted from peripheral blood to generate a 
baseline control for the studies detailed in Section 17. Remaining DNA 
and RNA will be stored frozen at   -80ºC at the University of Colorado, 
according to patient consent information (see Section 6.12) until specific 
analyses are identified.    As protocols are developed, they will be 
presented for ACCRU, ITOG, and IRB review and approval.  (This 
collection is part of a general strategy of investigation for the majority of 
ACCRU studies.) 
 
14.214 As part of ongoing ACCRU research, remaining serum will be stored 
frozen at -80ºC at University of Colorado, according to patient consent 
information (See Section 6.15) for future studies until specific analyses 
are identified. As protocols are developed, they will be presented for 
ACCRU, ITOG and IRB review and approval. 
   
 
 


     
ACCRU-ITOG-1504                                                  64                                           
 Addendum 6 
 
14.215  Shipment of samples:  Please refer to the Laboratory Manual.  
 
 14.3 
Return of Genetic Testing Research Results 
 
 
Because the results generated by the genetic testing included in this section are not 
currently anticipated to have clinical relevance to the patient or their family members, the 
genetic results will not be disclosed to the patients or their physicians. 
 
 
If at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA-certified setting will be required.  Sharing of 
research data with individual patients should only occur when data have been validated 
by multiple studies and testing has been done in CLIA-approved laboratories. 
 
15.0 
Drug Information 
 
IND #132069 
 
15.1 
Lenvatinib   (LENVIMA®)  
• 
Investigator brochure is available on the ACCRU web site. 
 
 
15.11 Background: Lenvatinib is an oral, multiple receptor tyrosine kinase (RTK) 
inhibitor that selectively inhibits the kinase activities of vascular endothelial 
growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and 
VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-
related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, 
and 4; the platelet derived growth factor (PDGF) receptor PDGFRα; KIT; and 
RET.  
 
15.12 Formulation:  Lenvatinib is available as 1 mg, 4 mg and 10 mg capsules.  The 
following are inactive ingredients: Calcium Carbonate, USP; Mannitol, USP; 
Microcrystalline Cellulose, NF; Hydroxypropyl Cellulose, NF; Hydroxypropyl 
Cellulose (type H), NF; and Talc, USP. The hypromellose capsule shell contains 
titanium dioxide, ferric oxide yellow, and ferric oxide red. The printing ink 
contains shellac, black iron oxide, potassium hydroxide, and propylene glycol. 
 
15.13 Preparation and storage: Store at controlled room temperature, 25 degrees C 
(77 degrees F), with excursions permitted between 15 and 30 degrees C (59 and 
86 degrees F). 
 
15.14 Administration:  Take lenvatinib at the same time each day with or without 
food. The capsules should be swallowed whole with water. If a patient misses a 
dose, and it cannot be taken within 12 hours, then that dose should be omitted 
and the next dose should be taken at the usual time of administration. 
 
Alternatively, add the lenvatinib capsules to a tablespoon of water or apple juice 
in a small glass to produce a suspension. Leave the capsules in the liquid for at 
least 10 minutes. Stir for at least 3 minutes. Drink the mixture. After drinking, 
add the same amount (1 tablespoon) of water or apple juice to the glass. Swirl the 
contents a few times and swallow the additional liquid. 
 


     
ACCRU-ITOG-1504                                                  65                                           
 Addendum 6 
 
This can also be administered by gastric feeding tube. 
 
 
15.15 Pharmacokinetic information: 
 
Absorption:  Lenvatinib is rapidly absorbed after oral administration with tmax 
typically observed from 1 to 4 hours post dose. Food does not affect the extent of 
absorption, but slows the rate of absorption. When administered to healthy 
subjects with food, peak plasma concentrations are delayed by 2 hours.  
 
 
 
Distribution:  In vitro binding of lenvatinib to human plasma proteins is high 
and ranged from 98% to 99% (0.3 – 30 μg/mL, mesilate). This binding was 
mainly to albumin with minor binding to α1-acid glycoprotein and γ-globulin.  In 
vitro blood to plasma ratios of lenvatinib (0.1 - 10 μg/mL) remained constant in 
humans (0.589 – 0.608).  
 
 
 
Metabolism:  Lenvatinib is extensively metabolized in humans. The main 
metabolic pathways in humans were identified as oxidation by AO, 
demethylation via CYP3A4, glutathione conjugation with elimination of the O-
aryl group (chlorbenzyl moiety), and combinations of these pathways followed 
by further biotransformations (eg, glucuronidation, hydrolysis of the glutathione 
moiety, degradation of the cysteine moiety, and intramolecular rearrangement of 
the cysteinylglycine and cysteine conjugates with subsequent dimerization). 
 
 
 
Half-life elimination:  Plasma concentrations decline bi-exponentially following 
Cmax. The terminal exponential half-life of lenvatinib is about 28 hours. 
 
 
 
Excretion:  Following administration of radiolabeled lenvatinib to 6 subjects 
with solid tumors, approximately two-thirds and one-fourth of the radiolabel 
were eliminated in the feces and urine, respectively.  
 
 
Special populations: No dose adjustments are required on the basis of hepatic 
function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) 
hepatic impairment. In patients with severe (Child Pugh C) hepatic impairment, 
the starting dose should be lowered. No dose adjustments are required on the 
basis of renal function in patients with mild or moderate renal impairment. In 
patients with severe renal impairment, the starting dose should be lowered. 
Further dose adjustments may be necessary on the basis of individual tolerability. 
 
15.16 Potential Drug Interactions:  In vitro, cytochrome P450 3A4 was the 
predominant (>80%) cytochrome isoform involved in the P450-mediated 
metabolism of lenvatinib. In vivo, inducers and inhibitors of CYP3A4 had a 
minimal effect on lenvatinib exposure. Lenvatinib is not considered a strong 
inducer or inhibitor of cytochrome P450 or uridine 5´-diphospho-glucuronosyl 
transferase (UGT) enzymes.  Lenvatinib may be co-administered without dose 
adjustment with CYP3A, P-glycoprotein (P-gp), and BCRP inhibitors or CYP3A 
and P-gp inducers. 
 
15.17 Known potential toxicities:   
 
 
Common and less common known potential toxicities, ≥ 1% 
 
  


     
ACCRU-ITOG-1504                                                  66                                           
 Addendum 6 
 
 
Gastrointestinal: Abdominal pain, diarrhea, diarrhea nausea, vomiting,  
 
General and administrative site conditions:  Asthenia 
 
Metabolism and nutrition disorders: Decreased appetite, dehydration 
 
Renal and urinary disorders: Acute kidney injury 
 
Respiratory thoracic, and mediastinal disorders: Pulmonary embolism 
 
Vascular disorders: Hypertension, hypotension  
 
 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening): 
 
 
 
Blood and lymphatic disorders: Thrombocytopenia  
 
Cardiac disorders:  Acute myocardial infarction, cardiac failure, congestive 
cardiac failure, coronary artery occlusion, left ventricular dysfunction, 
myocardial infarction 
 
Endocrine disorders: hypothyroidism 
 
Gastrointestinal: Abdominal pain lower, abdominal pain upper, anal fistula, 
constipation, diverticular perforation, intestinal perforation, pancreatitis, acute 
pancreatitis, rectal hemorrhage, rectal perforation, stomatitis, upper 
gastrointestinal hemorrhage 
 
General disorders and administration site conditions: Fatigue, malaise, peripheral 
edema, impaired wound healing 
 
Hepatobiliary:  Cholecystitis, cholecystitis acute, hepatic failure, hepatic function 
abnormal, hepatitis acute, hyperbilirubinemia, liver injury 
 
Infections and infestations: Colonic abscess, perineal abscess, urinary tract 
infection, urosepsis 
 
Investigations: Alanine aminotransferase increased, aspartate aminotransferase 
increased, blood bilirubin increased, ejection fraction increased, lipase increased, 
weight decreased 
 
Metabolism and nutrition disorders: Hypocalcemia, hypokalemia, 
hypomagnesemia 
 
Musculoskeletal and connective tissue disorders: Arthralgia, back pain, 
musculoskeletal chest pain, musculoskeletal pain, pain in extremity 
 
Neoplasms benign, malignant and unspecified:  intracranial tumor hemorrhage, 
tumor hemorrhage 
 
Nervous system:  Cerebrovascular hemorrhage, cerebral infarction, 
cerebrovascular accident, dizziness, hemorrhage intracranial, headache, ischemic 
stroke, monoparesis,  posterior reversible encephalopathy syndrome, 
subarachnoid hemorrhage, transient ischemic attack  
 
Renal and urinary disorders: Hematuria, proteinuria, renal failure, renal 
impairment, renal tubular necrosis, nephrotic syndrome 
 
Reproductive system and breast disorders: female genital tract fistula, vaginal 
hemorrhage 
 
Respiratory, thoracic and mediastinal disorders: Epistaxis, hemoptysis, 
pulmonary hemorrhage, pneumothorax 
 
Vascular: Arterial hemorrhage, aortic dissection 
 
15.18 Drug procurement:  Investigational lenvatinib is provided free of charge to 
patients by Eisai. Each participating ACCRU membership will order a starter 
supply of lenvatinib from Eisai.    
 
E-mail the Lenvatinib Drug Order Request Form (found on the ACCRU web 


     
ACCRU-ITOG-1504                                                  67                                           
 Addendum 6 
 
site) to the following: 
 
   
  
 
Include amount of drug needed and date your site must receive drug.  
NOTE: drug shipments will take 3-4 days from receipt of drug order. No drug 
shipments are done on weekends or holidays. 
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of lenvatinib and will use the drug ordering instructions above to order 
additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
15.19 Nursing guidelines 
 
15.191 Hypertension is very common with agent. Monitor BP as per protocol 
and report BP elevations to the study team. 
 
15.192 Diarrhea is common.  This may be increased in patients who are 
undergoing simultaneous treatment with immunotherapy agents.  Instruct 
patients to report any diarrhea immediately and treat symptomatically per 
protocol instructions.  
 
15.193  Other GI side effects can occur, including decreased appetite, weight 
loss, and nausea/vomiting.  Manage patients symptomatically and 
monitor for effectiveness. 
 
15.194  Patients may experience fatigue. Instruct patients in energy conserving 
lifestyle. 
 
15.195 Dermatologic related side effects have been seen, including: hand-foot 
syndrome, rash, and alopecia. Instruct patients to report these signs and 
symptoms to the study team immediately. 
 
15.196 Patients may experience increased risk of bleeding. Instruct patients to 
report any unusual bruising or bleeding to the study team.  Patients 
should not undergo invasive procedures without first discussing with the 
study team. 
 
15.197 Monitor for proteinuria per protocol. 
 
15.198 Rarely agent may cause decreased LVEF.  Instruct patients to report any 
peripheral edema, DOE, chest pain or significant fatigue to the study 
team. 
 
15.199 Monitor LFT’s and renal function. Report any elevations to the provider. 
 
15.2 
Pembrolizumab (Keytruda®)  


     
ACCRU-ITOG-1504                                                  68                                           
 Addendum 6 
 
 
 
Investigator brochure is available on the ACCRU web site. 
 
15.21 Background:  Pembrolizumab is a potent humanized IgG4 monoclonal antibody 
with high specificity of binding to the PD-1 receptor, thus inhibiting its 
interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
 
15.22 Formulation:  Pembrolizumab is available as a liquid 25 mg/mL, 100 mg/vial.   
 
15.23 Preparation and storage: Vials should be stored in the refrigerator at 
temperatures between 2-8°C (36-46ºF).   
 
Drug concentrate is further diluted with normal saline (or 5% dextrose) in the 
concentration range of 1 to 10 mg/mL in IV containers made of polyvinyl 
chloride (PVC) or non-PVC material.  The infusion solution in the IV bag should 
be immediately administered.  Diluted pembrolizumab solutions may be stored at 
room temperature for a cumulative period of up to 4 hours. This includes room 
temperature storage of admixture solutions in the IV bags and the duration of 
infusion. The product can also be stored under refrigeration at 2°C to 8°C for no 
more than 96 hours from the time of dilution. If refrigerated, the diluted solution 
must be allowed to come to room temperature prior to administration. The 
solution must be discarded after 6 hours at room temperature or 96 hours under 
refrigeration.   
15.24 Administration:  Pembrolizumab is administered by intravenous infusion over 
30 minutes via a 0.22 micron in-line filter. The final infusion volume must be 
between 1 and 10 mg/mL. Maximum rate of infusion should not exceed 6.7 
mL/minute through a peripheral or indwelling catheter. Flush the line with 0.9% 
NaCL following the completion of the infusion. 
 
 
15.25 Pharmacokinetic information: 
 
a) Absorption –Because pembrolizumab is administered intravenously, it is 
immediately and completely bioavailable.  Steady-state concentrations of 
pembrolizumab are reached by 16 weeks of repeated dosing with a Q3W regimen 
and the systemic accumulation is 2.1-fold. The peak concentration, trough 
concentration, and area under the plasma concentration versus time curve at 
steady state of pembrolizumab increased dose proportionally in the dose range of 
2 to 10 mg/kg Q3W. 
 
b)  Distribution – Pembrolizumab has a limited volume of distribution.  
 
c)  Excretion – CL is approximately 23% lower after achieving maximal change 
at steady state compared with the first dose. The terminal elimination half-life 
(t½) is estimated to be 22 days at steady state. 
 
d)  Metabolism - Pembrolizumab is catabolized through non-specific pathways; 
metabolism does not contribute to its CL. 
 
 
 
There are no limited clinical studies on the subcutaneous formulation. 
Model-based analysis showed an estimated bioavailability of 64% (95% 
CI: 54% to 74%; variability, 128% CV). This is consistent with the 
reported bioavailability for other mAbs (range: 50% to 85%) given SC. 
Clearance was the same for the IV and SC formulations. The mean time to 
achieve maximum concentration (Tmax) with pembrolizumab SC was 


     
ACCRU-ITOG-1504                                                  69                                           
 Addendum 6 
 
estimated to be 5.5 days (range: 3 days to 14 days). 
 
 
 
 
 
 


     
ACCRU-ITOG-1504                                                  70                                           
 Addendum 6 
 
 
 
15.26 Potential Drug Interactions:  There are no known significant drug interactions.  
 
15.27 Known potential toxicities:   
 
Very common known potential toxicities, > 10%:   
Gastrointestinal: diarrhea nausea 
 
Skin and subcutaneous tissue disorders: rash, pruritus 
 
General disorders and administration site conditions: fatigue 
 
 
Common known potential toxicities, > 1% - 10%: 
 
Blood and lymphatic system disorders: anemia 
 
Immune system disorders: infusion related reaction  
 
Endocrine disorders: Hypothyroidism, hyperthyroidism 
 
Gastrointestinal disorders: colitis, vomiting, abdominal pain, constipation, dry 
mouth 
Metabolism and nutrition disorders: decreased appetite 
Musculoskeletal and connective tissue disorders: arthralgia, myositis, 
musculoskeletal pain, arthritis, pain in extremity 
Nervous system disorders: headache, dizziness, dysgeusia 
 
Respiratory thoracic, and mediastinal disorders:  pneumonitis, dyspnea, cough 
Skin and subcutaneous tissue disorders: severe skin reactions, vitiligo, dry skin, 
erythema 
General disorders and administration site conditions: asthenia, edema, pyrexia, 
influenza like illness, chills 
Investigations: alanine aminotransferase increased, aspartate aminotransferase 
increased, blood alkaline phosphatase increased, blood creatinine increased 
 
Uncommon known potential toxicities, ≥0.1% to <1%: 
Cardiac disorders: myocarditis 
Blood and lymphatic system disorders: neutropenia, thrombocytopenia, 
leukopenia, lymphopenia, eosinophilia 
Eye disorders: uveitis, dry eye 
Endocrine disorders: hypophysitis, adrenal insufficiency, thyroiditis 
Gastrointestinal disorders: pancreatitis, dysphagia 
Hepatobiliary disorders: hepatitis 
Infusion related reactions 
Metabolism and nutrition disorders: type I diabetes mellitus, hyponatremia, 
hypokalemia, hypocalcemia 
Musculoskeletal and connective tissue disorders: tenosynovitis 
Nervous system disorders: epilepsy, lethargy, peripheral neuropathy 
Psychiatric disorders: insomnia 
Renal and urinary disorders: nephritis, acute kidney injury 
Skin and subcutaneous tissue disorders: lichenoid keratosis, psoriasis, alopecia, 
dermatitis, dermatitis acneiform, eczema, hair color changes, papule 
Vascular disorders: hypertension  
Investigations: blood bilirubin increased, amylase increased, hypercalcemia 
Respiratory: aspiration pneumonia 
 
Rare known potential toxicities, <0.1% (Limited to important or life-
threatening): 
Blood and lymphatic system disorders: immune thrombocytopenic purpura, 


     
ACCRU-ITOG-1504                                                  71                                           
 Addendum 6 
 
hemolytic anemia 
Immune system disorders: sarcoidosis 
Nervous system disorders: Guillain-Barre syndrome, myasthenic syndrome 
Gastrointestinal disorders: small intestinal perforation 
Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, Stevens-
Johnson syndrome, erythema nodosum 
 
The risk profile for pembrolizumab also includes two important potential risks: a) 
myasthenic syndrome, and b) an increased risk of severe complications (such as 
early severe graft versus host disease and veno-occlusive disease) of allogeneic 
transplant in patients with hematologic malignancies who have previously been 
treated with PD-1 inhibitors.  
 
Patients with multiple myeloma who were treated with pembrolizumab in 
combination with either pomalidomide or lenalidomide and dexamethasone, had 
an increased number of serious side effects and deaths as compared to patients 
who received only dexamethasone and either pomalidomide or lenalidomide. The 
benefit-risk profile is unfavorable for the combination of pembrolizumab, 
pomalidomide, and dexamethasone in relapsed refractory multiple myeloma, and 
the combination of pembrolizumab, lenalidomide, and dexamethasone in newly 
diagnosed treatment-naive multiple myeloma. 
 
15.28 Drug procurement:  Investigational pembrolizumab is provided free of charge to 
patients by Merck. Each participating ACCRU membership will order a starter 
supply of pembrolizumab from Merck.   
 
E-mail the Pembrolizumab Drug Order Request Form (found on the ACCRU 
web site) to: 
 
Merck, Inc. 
 
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of pembrolizumab and will use the Drug Order Request Form to order 
additional supplies as needed. 
 
NOTE: in order to obtain a drug re-supply, Merck should be notified six months 
prior to study drug expiry. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
15.29 Nursing Guidelines:  
 
15.291 Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team immediately. 
Side effects may be immediate or delayed up to months after 
discontinuation of therapy. Most side effects are reversible with prompt 
intervention of corticosteroids. 
 


     
ACCRU-ITOG-1504                                                  72                                           
 Addendum 6 
 
15.292 Diarrhea can be seen, however, it is less common than what is seen with 
anti-CTLA-4 agents. It can occasionally be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to the 
study team immediately.  
 
15.293 Rash/pruritus/dermatitis is seen. Patients should report any rash to the 
study team. Treat per section 9.0 and monitor for effectiveness.  
 
15.294 Monitor LFT’s closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team immediately. 
 
15.295 Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any shortness of breath, 
dyspnea, cough, and/or chest pain to the study team immediately. 
Patients reporting these symptoms should have a pulse oximetry checked 
and consider immediate imaging per the treating physician. 
 
15.296 Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysitis, and adrenal insufficiency) are seen with this agent. Patients 
may present only with the vague sense of fatigue and “not feeling well.” 
Additional symptoms may be that of nausea, sweating and decreased 
activity tolerance. Instruct patients to report these signs or symptoms 
immediately and obtain appropriate labs as ordered by the treating 
physician.  
 
15.297 Patients who are started on steroid therapy for any side effects of 
pembrolizumab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and be 
severe. Patients may be on steroid therapy for weeks. Instruct patients to 
report any increase or change in side effects with any dosage decrease as 
patients may need a slower taper.  
 
15.298 Fatigue is common and may or may not be associated with immune- 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 
 
15.299a Patients should avoid receiving live vaccines within 30 days of study 
drug administration or per other study guidelines.  
 
15.299b Patients who have undergone an allogenic bone marrow transplant, have 
an increased risk of severe complications including early GVHD, and 
veno-occlusive disease, if they have previously been treated with 
pembrolizumab. 
 
15.299c Myocarditis has been reported and associated with pembrolizumab. 
Instruct patients to report chest pain, SOB, or dyspnea to study team 
immediately and/or seek emergency medical attention. 
 
15.299d Autoimmune hematologic disorders including ITP and hemolytic 


     
ACCRU-ITOG-1504                                                  73                                           
 Addendum 6 
 
anemia have been reported. Monitor blood counts closely and report any 
abnormalities to the study team. 
 
15.299e Rare neurologic disorders including Guillain-Barre syndrome and 
myasthenia gravis have been reported. Instruct patients to report any 
neurologic symptoms including weakness, paresthesia or numbness, 
tingling to the study team immediately. 
 
16.0  
Statistical Considerations and Methodology  
 
 
16.1 
Study Design/Endpoints 
 
 
16.11 
Background/Overview:  This novel study will be the first to assess 
pembrolizumab and lenvatinib combination therapy in advanced DTC (and in 
any cancer).  There is an ongoing basket trial (KEYNOTE-028 
(NCT02054806)) that has enrolled patients with advanced thyroid cancer to a 
single agent pembrolizumab (200 mg iv every 3 weeks) study.  Preliminary data 
from the thyroid cohort in this trial was presented at the 2016 American Society 
for Clinical Oncology (Mehnert JM, et al, J Clin Oncol 34, 2016 (suppl; abstr 
6091)).  The study enrolled 22 patients with DTC, with a median duration of 
follow-up of 74 weeks (29-87 weeks).  No patients achieved a CR (0%) and 2 
patients had a PR (9.1%), with 12 having SD (54%), which is why we will not 
have a pembrolizumab-only arm in this study.    Our study will be done for 2 
different cohorts (Cohort 1: Lenvatinib-naïve patients; Cohort 2: progressed on 
Lenvatinib alone).  Both cohorts will receive the same combination therapy.  
The primary endpoint is different for the 2 cohorts, as described below (16.12 
and 16.14).  This study will also assess many secondary endpoints as well, as 
explained in detail below (16.3).  Finally, this study will also assess important 
correlative science endpoints (16.4).           
 
16.12  Overview and Primary Endpoint for Cohort 1:  The complete response (CR)  rate 
for lenvatinib alone was around 2%.  The CR for patients with advanced DTC 
treated with pembrolizumab is 0% (see Section 16.11).  A CR rate of around 15% 
would be clinically significant and worthy of further study.  The primary 
endpoint for Cohort 1 is this CR rate (per RECIST 1.1 criteria).   All patients 
meeting the eligibility criteria who have signed a consent form and have begun 
treatment will be considered evaluable for the primary endpoint.  A patient that 
has a CR (Cohort 1) is considered a treatment “success”.  The following one-
stage binomial design (see below) requires 25 evaluable patients, and 
simultaneously discriminates between CR rates of 2% vs. 15%.   
 
 
  
16.13 
Decision Rules for Cohort 1: 
 
 
16.131 Final Analysis Decision Rule:  Enroll 25 total evaluable patients.  If at 
least 2 patients have a success (at least 8%) among the 25 evaluable 
patients, this combination therapy would be considered worthy of further 
testing in this disease.  If 0 or 1 patients have a success, this combination 
therapy will be considered negative and no further study would be 
warranted.  
 
 
16.132  Power and Significance Level:  This design has 91% power to detect a 


     
ACCRU-ITOG-1504                                                  74                                           
 Addendum 6 
 
true success rate of 15%, with a significance level of 0.09 if the true 
success rate is 2%. 
 
16.14  Overview and Primary Endpoint for Cohort 2:  It is expected that the confirmed 
response rate is around 5% in this disease population.  A confirmed response rate 
of around 25% would be clinically significant and worthy of further study.  The 
primary endpoint for Cohort 2 is this confirmed response rate (per RECIST 1.1 
criteria).   All patients meeting the eligibility criteria who have signed a consent 
form and have begun treatment will be considered evaluable for the primary 
endpoint.  A confirmed tumor response is defined to be a CR or PR noted as the 
objective status on 2 consecutive evaluations at least 4 weeks apart.  A patient 
that has a confirmed response (Cohort 2) is considered a treatment “success”.  
The following 2-stage Simon Optimal MinMax design (see below) requires a 
maximum of 25 evaluable patients, and simultaneously discriminates between 
confirmed response rates of 5% vs. 25%.   
 
 
  
16.15 Decision Rules for Cohort 2: 
 
16.151  Final Analysis Decision Rule:  Enroll 25 evaluable patients.  If at least 4 
patients have a success (at least 16%) among the 25 evaluable patients, 
this combination therapy would be considered worthy of further testing 
in this disease.  If 3 or fewer patients have a success, this combination 
therapy will be considered negative and no further study would be 
warranted.  
 
16.152  Stage 1 Decision Rule:  After the first 15 patients entered into the trial 
become evaluable for the primary endpoint, a stage 1 analysis will be 
performed.  If 1 or more patients have a success, the study will continue 
to full accrual.  Otherwise, if 0 successes are observed, the study will be 
stopped early and the treatment will be considered ineffective in this 
patient population.  Accrual will stop after we enroll the first 15 eligible 
patients to this cohort. 
 
 
16.153 Power and Significance Level:  This design has 90% power to detect a 
true success rate of 25%, with a significance level of 0.05 if the true 
success rate is 5%. 
 
 
  
16.16 Over Accrual:  If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making process.   
 
 
  
16.17 Other Considerations:  Toxicity, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
 
16.2 
Sample Size/Accrual Rate 
 
16.21 Sample Size:  A total of 25 evaluable Cohort 1 and 25 evaluable Cohort 2  
patients will be accrued per study design (50 evaluable total), unless one or both 
cohorts of the study are permanently closed at the stage 1 analysis or undue 


     
ACCRU-ITOG-1504                                                  75                                           
 Addendum 6 
 
toxicity is observed.  We anticipate accruing an additional 10 patients (5 Cohort 
1, 5 Cohort 2) in order to account for ineligibility, cancellation, major treatment 
violation, or other reasons.  Therefore, maximum accrual is 60 patients for this 
trial (30 for each Cohort). 
 
16.22 Accrual Time and Study Duration:  We expect to accrue about 3 patients per 
month to this trial.  Therefore, the accrual period for this Phase II study is 
expected to be about 20 months.  We anticipate that the study will take 
approximately 3 years to complete.  This allows a 6 month follow-up for the final 
patient enrolled, along with data entry, data clean-up, and analysis. 
 
 
16.3 
Analysis of Secondary Endpoints for both Cohorts. 
 
This study will assess multiple secondary endpoints, including adverse events, 
progression-free survival (PFS) and overall survival (OS).  All these analyses will be 
done for each cohort separately.    In addition, all primary/secondary data will be 
summarized by descriptive factors as well (i.e. prior treatment, etc.).    
 
16.31 Adverse Events: All patients that have initiated treatment will be considered 
evaluable for assessing adverse events. The maximum grade for each type of 
adverse event will be recorded for each patient, and frequency tables will be 
reviewed to determine adverse event patterns.  Only the grade 2+ adverse events 
will be assessed, regardless of relationship to the study treatment.  
 
16.32 Progression-Free Survival (PFS):  Defined as the time from registration to the 
first of either death due to any cause or progression.  The distribution of PFS will 
be estimated using the method of Kaplan-Meier. 
 
16.33 Overall Survival:  Defined as the time from registration to death due to any 
cause.  The distribution of survival time will be estimated using the method of 
Kaplan-Meier.  Special attention will be paid to any registered patient who dies 
early (i.e., within 60 days) of initiating their treatment.  Circumstances 
surrounding such early deaths will be classified as being either due to malignant 
disease, toxicity, other causes, or of unknown reasons. 
16.4 
Laboratory Correlative Studies (all done by Cohort):  All analyses with respect to the 
translational component of this study are intended to be hypothesis-generating and 
descriptive in manner.  Clinical data (i.e. CR rates confirmed response rates, PFS, OS, 
etc.) will be correlated with tumor marker data of interest (CD8+, PD-L1, PD-L2, T cell 
functional capacity markers, anti-thyroglobulin antibody levels, tumor mutation status, 
and other markers).  The Chi-Square (or Fisher’s Exact test) will be used to assess the 
association of categorical clinical data with categorical biomarker data.  Time-to-event 
clinical data (PFS, OS) will be correlated with biomarker data using Kaplan-Meier 
methodology and Cox regression models.  Logistic regression models will also be used to 
predict binary clinical data with baseline biomarker data.  Finally, graphical methods and 
descriptive statistics will be used to summarize the data as well.  Two-sided p-values < 
0.05 will be considered statistically significant.  
 
 
16.5 
Adverse Event Stopping Rule: 
 


     
ACCRU-ITOG-1504                                                  76                                           
 Addendum 6 
 
16.51 Monitoring: The principal investigator and the study statistician will review the 
study periodically (at least twice a year) to identify accrual, toxicity, and any 
endpoint problems that might be developing. The trial is monitored continually 
by the study team who are notified of every grade 4 and 5 event in real time. The 
Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring Board (DSMB) is 
responsible for reviewing accrual and safety data for this trial at least twice a 
year, based on reports provided by the MCCC Statistical Office. 
 
16.52 Adverse Event Stopping Rule:  The stopping rule specified below is based on the 
knowledge available at study development. We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual after any temporary suspension or (2) at any time during the conduct of 
the trial and in consideration of newly acquired information regarding the 
adverse event profile of the treatment(s) under investigation. The study team may 
also choose to suspend accrual because of unexpected adverse event profiles that 
have not crossed the specified rule below.  We expect approximately 10% of 
patients to experience grade 4+ adverse events (at least possibly related to study 
medication).  In this study, we will suspend accrual to allow for a full review of 
the data, if any of the following occur in each cohort separately: 
• 
If at any time, 3 of the initial 10 patients (or 30% of all patients when accrual 
is greater than 10) have experienced any grade 4 adverse event (at least 
possibly related to the study medication).  
 
• 
If at any time, 1 of the initial 10 patients (or 10% of all patients when accrual 
is greater than 10) have experienced any grade 5 adverse event (at least 
possibly related to the study medication).   
 
  
16.6  
Accrual Monitoring Stopping Rule 
Given the expected accrual rate is around 3 patients per month, it is expected that the 
study will take around 20 months to fully accrue.  We plan to monitor the accrual 
continually and if we only end up accruing 5 patients or less in the first year (after study 
activation), we will consider stopping the trial for slow accrual.   
 
  
16.7 
Primary Endpoint Completion Time Estimation (For clinicaltrails.gov reporting): 
The primary endpoint is the complete response (CR) rate for Cohort 1 and the confirmed 
response rate for Cohort 2. The final analysis is expected to take place around 36 months 
after the study begins, so we expect the primary endpoint completion time to be around 
36 months after study activation.    
 
 
16.8 
Inclusion of Women and Minorities 
 
This study will be available to all eligible patients, regardless of race, gender, or ethnic 
origin.  There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to expect 
such differences to exist.  Based on prior studies involving similar disease sites, we 
expect about 10% of patients will be classified as minorities by race and about 50% of 
patients to be women.  Expected sizes of racial by gender subsets are shown in the 
following table: 
 


     
ACCRU-ITOG-1504                                                  77                                           
 Addendum 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnic 
Categories: 
 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
 
Racial 
Categories: 
 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, 
Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have 
been recorded as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black 
racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in 
addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of 
the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 
 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
3 
6 
Not Hispanic or Latino 
27 
27 
54 
Ethnic Category: Total of all subjects 
30 
30 
60 
Racial Category 
American Indian or Alaskan Native 
1 
1 
2 
Asian 
0 
1 
1 
Black or African American 
2 
1 
3 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
27 
27 
54 
Racial Category: Total of all subjects 
30 
30 
60 


     
ACCRU-ITOG-1504                                                  78                                           
 Addendum 6 
 
17.0  
Pathology Considerations/Tissue Biospecimens  
 
17.1 
Tissue Biospecimen Submission  
NOTE: Patients must have consented to submission of the optional tissue(s) listed in the 
following table. 
 
NOTE:  Please refer to study specific Laboratory Manual. 
 
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
Type of tissue 
biospecimen to 
submit 
Mandatory 
or optional 
When to 
submit 
Reason for 
submission 
(background / 
methodology 
section) 
Where to find 
specific details 
for biospecimen 
submission 
Storage/Shipping 
conditions† 
Formalin-fixed 
paraffin-embedded 
(FFPE) primary tumor 
tissue blocks (blocks 
preferred, OR 30 
four-micron unstained 
slides; Cohorts 1 and 
2)  
Mandatory 
≤60 days 
after 
registration 
Correlative studies  
(Section 2.31-2.33) 
Section 17.3 
Room temperature 
/ Standard 
shipping 
Formalin-fixed 
paraffin-embedded 
(FFPE) involved 
lymph node tissue 
blocks (blocks 
preferred, OR 30 
four-micron unstained 
slides; Cohorts 1 and 
2)  
Mandatory 
(if available) 
≤60 days 
after 
registration 
Correlative studies  
(Section 2.31-2.33) 
Section 17.3 
Room temperature 
/ Standard 
shipping 
Formalin-fixed 
paraffin-embedded 
(FFPE) tissue blocks 
from biopsy of 
metastatic or 
locoregional tumor 
recurrence (Cohort 1) 
Optional*  
≤60 days 
after 
registration 
Correlative studies  
(Sections 2.31-2.33 
and 2.37-2.38) 
Section 17.3 
Room temperature 
/ Standard 
shipping 
RNAlater®-preserved 
tissue biopsy from 
metastatic or 
locoregional tumor 
recurrence (Cohort 1) 
Optional*  
≤60 days 
after 
registration 
Correlative studies  
(Section 2.37-2.38) 
Section 17.3 
Incubate the 
specimens in the 
RNAlater® 
reagent at 4°C 
overnight and ship 
on ice.  For long-
term storage, 
transfer to -20°C 
and ship on dry 
ice 


     
ACCRU-ITOG-1504                                                  79                                           
 Addendum 6 
 
* Collection of this tissue is optional for research purposes. If a patient is not willing to undergo this 
procedure, it does not cause the patient to be ineligible; however, collection of this tissue is strongly 
encouraged (anticipate collecting samples from 20 of 30 patients in Cohort 1). 
† See separate lab manual for detailed instructions. 
 
17.2 
Paraffin Embedded Tissue Blocks/Slides and Frozen Biopsy Samples 
 
17.21 Submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block with 
largest amount of invasive tumor (at least 1 cm of tumor for cases of surgical 
resection) from the original surgery (Cohorts 1 and 2).  In addition, if available, 
submit one FFPE block containing tumor-involved lymph node. Preferably, 
chose a lymph node with gross tumor involvement. An H&E slide will be 
generated from all FFPE samples at the lead study site, which is responsible for 
correlative studies, to permit quality assessment of each tissue block.  Once the 
QA is completed, and the necessary slides are cut, the tissue block will be 
returned. If tissue blocks cannot be released, prepare 30 slides for each tissue 
using the provided slides in the kit for each patient (See Laboratory Manual). 
Slides should not be baked since these tissues will be used for molecular studies.  
Slides should be shipped with 24 hours of tissue cutting.  
 
17.22 A core biopsy will be performed after the patient is registered onto the study, but 
prior to the start of treatment from 20 patients in Cohort 1(see separate lab 
manual). Four passes will be obtained from tumor tissue in, but not limited to the 
neck, chest abdomen, pelvis, bone or extremities. The first two passes will be 
formalin fixed and paraffin embedded (FFPE). The second two passes will be 
preserved in RNAlater® for future molecular analysis. An H&E slide will be 
generated from all samples at the University of Colorado, responsible for 
correlative studies, to permit quality assessment of the biopsies. (See Laboratory 
Manual) 
 
17.23 The following materials below are mandatory (unless indicated otherwise) and 
required for shipment: 
• Paraffin embedded tissue blocks preferred (OR 30 four-micron unstained 
slides from primary tumor and involved lymph node).  
• Specimen Submission: Tissue form 
• Surgical Pathology Report 
• Operative Report (optional) 
 
 
Note: Please include the ACCRU patient ID number on all materials listed 
above. 
 
17.24 The block/slides must be appropriately packed and shipped to prevent damage 
(see Appendix IV). 
 
17.25 Tissue specimens must be shipped ≤60 days after registration. 
 
17.26 Verify that the appropriate sections of the Archival FFPE Tissue Submission 
Form and/or Biopsy Specimen Acquisition Tracking Form are completed and 
filled in correctly. (These forms are located on the ACCRU web site in the 
“Manuals & Forms” folder.) 
 


     
ACCRU-ITOG-1504                                                  80                                           
 Addendum 6 
 
17.3 
Study Methodology and Storage Information 
 
17.31 Submitted tissue samples will be analyzed as detailed in Section 2.3. DNA 
extraction and storage of DNA for future pharmacogenetic assays (e.g., for 
genetic polymorphisms such as BRAFV600E, NRAS, HRAS, KRAS, mutation 
burden, etc., that may correlate with efficacy and tolerability.   DNA will be 
isolated from 30 FFPE primary tumor samples and 20 core biopsy frozen samples 
from progressive tumors (Cohort 1).  To broadly investigate mechanisms of 
response and resistance to combination therapy, we plan to generate gene 
expression profiles from the frozen biopsies (n=20) for analysis by RNA-Seq. 
Total RNA will be isolated with the RNeasy kit (Qiagen) and 500ng of RNA will 
be submitted to our Genomics and Microarray core facility for mRNA-seq library 
construction (TruSeq Stranded mRNA Library Kit, Illumina). We aim to collect 
at least 20 pre-treatment biopsies, depending upon tumor accessibility and patient 
consent. In parallel, we will also analyze the 30 FFPE primary tumor samples by 
RNA-Seq51. RNA will be generated from FFPE tissue sections (Qiagen FFPE 
All-Prep kit) and 100ng will be submitted for library construction (TruSeq 
Stranded RNA Access mRNA Library Kit, Illumina). We plan to sequence 60-80 
million 1x125bp (FFPE) or 2x125bp (frozen) reads per sample.  DNA and RNA 
will be analyzed for mutations using whole-exome sequencing technology in the 
University of Colorado Cancer Center Gene Expression Core facility led by 
 
  Remaining DNA and RNA will be stored frozen at   -80ºC at the 
University of Colorado, according to patient consent information (see Section 
6.12) until specific analyses are identified.  As protocols are developed, they will 
be presented for ACCRU, ITOG, and IRB review and approval.  (This collection 
is part of a general strategy of investigation for the majority of ACCRU studies. 
 
17.32 At the completion of the study, any unused/remaining material will be stored in 
the University of Colorado Anschutz Medical Campus for future research 
according to the patient consent permission (see Section 6.15).  Potential future 
research may include immunohistochemistry (IHC) analyses to analyze 
predictive biomarkers, changes in expression pattern with therapy, and 
correlation with response and/or adverse events.  When a protocol is developed, 
it will be presented for ACCRU, ITOG and IRB review and approval. 
 
17.4 
Return of Genetic Testing Research Results  
 
Because the results generated by the genetic testing included in this section are not 
currently anticipated to have clinical relevance to the patient or their family members, the 
genetic results will not be disclosed to the patients or their physicians. 
 
If, at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA certified setting will be required. Sharing of research 
data with individual patients should only occur when data have been validated by 
multiple studies and testing has been done in CLIA-approved laboratories. 
 
17.5 
Shipment of specimens and accompanying materials:  Please refer to the Laboratory 
Manual.  
 
 


     
ACCRU-ITOG-1504                                                  81                                           
 Addendum 6 
 
18.0 
Records and Data Collection Procedures 
 
Access the RAVE system through the iMedidata portal at 
All data 
must be entered by Remote Date Entry (RDE) and completed by qualified and authorized 
personnel. All data on the CRF must reflect the corresponding source document. Please refer to 
the ACCRU website for instructions
  
 
18.1 Submission Timetable 
 
Initial Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
Institutional Contacts 
≤2 weeks  after registration 
On-Study  
On-Study: Prior Surgery 
On-Study: Prior Radioactive Iodine  (RAI) 
Therapy 
On-Study: Prior Radiation 
On-Study: Prior VEGFR-Targeted Therapy  
(Cohort 2 Only) 
Adverse Event - Baseline  
Endocrine Laboratory Tests and Results:   
Baseline 
Concomitant Medications: Baseline 
RECIST Measurements: Baseline 
Supporting Documentation: Baseline (Op & 
Path reports - see Section 17)1 
Specimen Submission: Blood (Baseline – 
Cohort 1 Only (see Section 14)) 
Specimen Submission: Blood (Baseline – 
Cohorts 1 & 2 (see Section 14)) 
Patient Status: Baseline  
Specimen Submission: Tissue (Baseline, 
Cohort 1 Only – Optional (see Section 17)) 
≤60 days after registration 
Specimen Submission: Tissue (Baseline, 
Cohorts 1 and 2 –  (see Section 17)) 
Off Treatment 
Submit ≤2 weeks  after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
ACCRU Deviation Form2 
Submit only if applicable during all phases of the study  
(initial, active and observation)  
1. Upload Op and Path Reports via the Supporting Documentation: Baseline form.  This is in addition to the 
 
pathology material requirements for tissue submission (Section 17.0). 
2. All participating ACCRU member sites must submit deviations using the ACCRU Deviation Form in the 
forms packet. 
 
 
 


     
ACCRU-ITOG-1504                                                  82                                           
 Addendum 6 
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
Observation 
Treatment (Intervention) 
X1 
X1 
 
Treatment (Intervention): Dose Modifications, 
Omissions and Delays 
X2 
 
 
Patient Status: Treatment (Intervention) 
X 
X 
 
Patient Status: Clinical Follow-up/Observation 
 
 
X3 
Adverse Events: Solicited  
X 
X 
X 
Adverse Events: Other 
X 
X 
X 
RECIST Measurements  
X4 
X4 
X4 
Supporting Documentation 
X4 
X4 
X4 
Endocrine Laboratory Tests and Results 
X 
 
 
Concomitant Medications  
X 
X 
X 
Specimen Submission: Blood (Cohort 1 only) 
 
X 
(see section 14.0) 
 
 
Specimen Submission: Blood (Cohorts 1 and 2) 
 
X 
(see section 14.0) 
 
 
Consent Withdrawal (choose appropriate form)2  
• Consent Withdrawal: Specimens Only  
• Consent Withdrawal: Clinical Follow-Up Only  
• Consent Withdrawal: All Follow-Up 
X 
X 
X 
Off Treatment 
 
X 
 
ACCRU Deviation Form2 
X2 
X2 
X2 
1. Complete at each evaluation during Active Treatment (see Section 4.0). 
2. Submit only if applicable. 
3. Complete at each evaluation during Observation (see Section 4.0). 
4.    Upload a copy of documentation of progression in RAVE on the Supporting Documentation Form. 
 
 


     
ACCRU-ITOG-1504                                                  83                                           
 Addendum 6 
 
Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
 
 
 
At PD 
After 
PD q. 6 
mos. 
 
 
 
Death 
 
 
 
New Primary 
Patient Status: Survival and Disease 
Status Follow-up/Event Monitoring  
X 
X 
X 
At each occurrence 
Adverse Events: Late 
X 
X 
 
 
Notice of New Primary 
 
 
 
X 
Consent Withdrawal 
• Consent Withdrawal: Specimens 
Only  
• Consent Withdrawal: Clinical 
Follow-Up Only  
• Consent Withdrawal: All Follow-Up 
X2 
X2 
X2 
X3 
Lost to Follow-up 
X2 
X2 
X2 
 
ACCRU Deviation Form2 
X2 
X2 
X2 
 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
2. Submit only if applicable. 
 
19.0  
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and 
regional coverage policies, to determine which items are standard of care and which are 
research at their site.  Refer to the payment synopsis for funding provided per accrual for 
covering study costs, as well as any additional invoiceables that may be allowed. 
 
19.2 
Eisai will provide investigational lenvatinib free of charge to patients participating in this 
study. 
 
19.3 
Merck will provide investigational pembrolizumab free of charge to patients participating 
in this study. 
 
 
19.4 
Blood pressure monitors will be provided for patients who do not already have a blood 
pressure monitor. 
 
 
 
19.41 Sites may order blood pressure monitors by submitting the Blood Pressure 
Monitor Ordering Contact Sheet to ACCRU Regulatory 
ACCRU Regulatory will send 
the completed form to ITOG designated personnel who will then grant access to 
the blood pressure monitor ordering system.  Once site personnel are notified that 
they have received access to the system, they may order blood pressure monitors 
via the following link: 
  
 


     
ACCRU-ITOG-1504                                                  84                                           
 Addendum 6 
 
20.0 
References 
 
Adnane, L, Trail, PA, Taylor, I and Wilhelm, SM. Sorafenib (BAY 43-9006, Nexavar), a dual-action 
inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in 
tumor vasculature. Methods Enzymol 2006;407:597-612. 
 
Ahmad, T and Eisen, T. Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin Cancer Res 
2004;10:6388S-92S. 
 
Alfaro, C, Suarez, N, Gonzalez, A, Solano, S, Erro, L, Dubrot, J, et al. Influence of bevacizumab, 
sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human 
dendritic cell differentiation from monocytes. Br J Cancer 2009;100:1111-9. 
 
Almand, B, Resser, JR, Lindman, B, Nadaf, S, Clark, JI, Kwon, ED, et al. Clinical significance of 
defective dendritic cell differentiation in cancer. Clin Cancer Res 2000;6:1755-66. 
 
Amarnath, S, Mangus, CW, Wang, JC, Wei, F, He, A, Kapoor, V, et al. The PDL1-PD1 axis converts 
human TH1 cells into regulatory T cells. Sci Transl Med 2011;3:111ra120. 
 
Batistatou, A, Zolota, V and Scopa, CD. S-100 protein+ dendritic cells and CD34+ dendritic interstitial 
cells in thyroid lesions. Endocr Pathol 2002;13:111-5. 
 
Brose, MS, Nutting, CM, Jarzab, B, Elisei, R, Siena, S, Bastholt, L, et al. Sorafenib in radioactive iodine-
refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 
3 trial. Lancet 2014; 
 
Busse, A, Asemissen, AM, Nonnenmacher, A, Braun, F, Ochsenreither, S, Stather, D, et al. 
Immunomodulatory effects of sorafenib on peripheral immune effector cells in metastatic renal cell 
carcinoma. Eur J Cancer 2011;47:690-6. 
 
Cabrera, R, Ararat, M, Xu, Y, Brusko, T, Wasserfall, C, Atkinson, MA, et al. Immune modulation of 
effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma. 
Cancer Immunol Immunother 2013;62:737-46. 
 
Chen, ML, Yan, BS, Lu, WC, Chen, MH, Yu, SL, Yang, PC, et al. Sorafenib relieves cell-intrinsic and 
cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. 
Int J Cancer 2014;134:319-31. 
 
Coffelt, SB, Chen, YY, Muthana, M, Welford, AF, Tal, AO, Scholz, A, et al. Angiopoietin 2 stimulates 
TIE2-expressing monocytes to suppress T cell activation and to promote regulatory T cell expansion. J 
Immunol 2011;186:4183-90. 
 
Dikov, MM, Ohm, JE, Ray, N, Tchekneva, EE, Burlison, J, Moghanaki, D, et al. Differential roles of 
vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 
2005;174:215-22. 
 
Duraiswamy, J, Freeman, GJ and Coukos, G. Therapeutic PD-1 pathway blockade augments with other 
modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res 
2013;73:6900-12. 
 


     
ACCRU-ITOG-1504                                                  85                                           
 Addendum 6 
 
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J.  New response 
evaluation criteria in solid tumors:  revised RECIST guideline (version 1.1).  Eur J Cancer 45(2):  228-
247, 2009. 
 
Fiore, E, Rago, T, Scutari, M, Ugolini, C, Proietti, A, Di Coscio, G, et al. Papillary thyroid cancer, 
although strongly associated with lymphocytic infiltration on histology, is only weakly predicted by 
serum thyroid auto-antibodies in patients with nodular thyroid diseases. J Endocrinol Invest 2009;32:344-
51. 
 
Florcken, A, Takvorian, A, Van Lessen, A, Singh, A, Hopfenmuller, W, Dorken, B, et al. Sorafenib, but 
not sunitinib, induces regulatory T cells in the peripheral blood of patients with metastatic renal cell 
carcinoma. Anticancer Drugs 2012;23:298-302. 
 
Francisco, LM, Salinas, VH, Brown, KE, Vanguri, VK, Freeman, GJ, Kuchroo, VK, et al. PD-L1 
regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 
2009;206:3015-29. 
 
French, JD. Revisiting immune-based therapies for aggressive follicular cell-derived thyroid cancers. 
Thyroid 2013;23:529-42. 
 
French, JD, Kotnis, GR, Said, S, Raeburn, CD, McIntyre, RC, Jr., Klopper, JP, et al. Programmed death-
1+ T cells and regulatory T cells are enriched in tumor-involved lymph nodes and associated with 
aggressive features in papillary thyroid cancer. J Clin Endocrinol Metab 2012;97:E934-43. 
 
French, JD, Weber, ZJ, Fretwell, DL, Said, S, Klopper, JP and Haugen, BR. Tumor-associated 
lymphocytes and increased FoxP3+ regulatory T cell frequency correlate with more aggressive papillary 
thyroid cancer. J Clin Endocrinol Metab 2010;95:2325-33. 
 
Gabrilovich, D, Ishida, T, Oyama, T, Ran, S, Kravtsov, V, Nadaf, S, et al. Vascular endothelial growth 
factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple 
hematopoietic lineages in vivo. Blood 1998;92:4150-66. 
 
Graw, S, Meier, R, Minn, K, Bloomer, C, Godwin, AK, Fridley, B, et al. Robust gene expression and 
mutation analyses of RNA-sequencing of formalin-fixed diagnostic tumor samples. Sci Rep 
2015;5:12335. 
 
Ghiringhelli, F, Puig, PE, Roux, S, Parcellier, A, Schmitt, E, Solary, E, et al. Tumor cells convert 
immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell 
proliferation. J Exp Med 2005;202:919-29. 
 
Hamid, O, Robert, C, Daud, A, Hodi, FS, Hwu, WJ, Kefford, R, et al. Safety and tumor responses with 
lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369:134-44. 
 
Huang, B, Pan, PY, Li, Q, Sato, AI, Levy, DE, Bromberg, J, et al. Gr-1+CD115+ immature myeloid 
suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-
bearing host. Cancer Res 2006;66:1123-31. 
 
Howlader N, NA, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, 
Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK 
(eds). Surveillance Epidemiology and End Results (SEER): Cancer Statistics Review 1975-2008, 


     
ACCRU-ITOG-1504                                                  86                                           
 Addendum 6 
 
National Cancer Institute Bethesda, MD, http://seer.cancer.gov/csr/1975_2008, based on November 2010 
SEER data submission, posted to the SEER web site, 2011. 
 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 1958; 53: 
457-481. 
Kitazawa, Y, Fujino, M, Wang, Q, Kimura, H, Azuma, M, Kubo, M, et al. Involvement of the 
programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to 
suppress alloimmune responses. Transplantation 2007;83:774-82. 
Kobayashi, M, Kubo, T, Komatsu, K, Fujisaki, A, Terauchi, F, Natsui, S, et al. Changes in peripheral 
blood immune cells: their prognostic significance in metastatic renal cell carcinoma patients treated with 
molecular targeted therapy. Med Oncol 2013;30:556. 
 
Pacini, F, Mariotti, S, Formica, N, Elisei, R, Anelli, S, Capotorti, E, et al. Thyroid autoantibodies in 
thyroid cancer: incidence and relationship with tumour outcome. Acta Endocrinol (Copenh) 
1988;119:373-80. 
 
Phillips T, Murray G, Wakamiya K, et al. Development of standard estrogen and progesterone receptor 
immunohistochemical assays for selection of patients for antihormonal therapy. Appl Immunohistochem 
Mol Morphol 2007;15:325-31. 
 
Qing, W, Fang, WY, Ye, L, Shen, LY, Zhang, XF, Fei, XC, et al. Density of tumor-associated 
macrophages correlates with lymph node metastasis in papillary thyroid carcinoma. Thyroid 2012;22:905-
10. 
 
Rizvi, NA, Hellmann, MD, Snyder, A, Kvistborg, P, Makarov, V, Havel, JJ, et al. Cancer immunology. 
Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 
2015;348:124-8. 
 
Rizvi, NA, Mazieres, J, Planchard, D, Stinchcombe, TE, Dy, GK, Antonia, SJ, et al. Activity and safety 
of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory 
squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 
2015;16:257-65. 
 
Scarpino, S, Stoppacciaro, A, Ballerini, F, Marchesi, M, Prat, M, Stella, MC, et al. Papillary carcinoma of 
the thyroid: hepatocyte growth factor (HGF) stimulates tumor cells to release chemokines active in 
recruiting dendritic cells. Am J Pathol 2000;156:831-7. 
 
Schlumberger, M, Tahara, M, Wirth, LJ, Robinson, B, Brose, MS, Elisei, R, et al. Lenvatinib versus 
placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621-30. 
 
Severson, JJ, Serracino, HS, Mateescu, V, Raeburn, CD, McIntyre, RC, Jr., Sams, SB, et al. PD-1+Tim-
3+ CD8+ T Lymphocytes Display Varied Degrees of Functional Exhaustion in Patients with Regionally 
Metastatic Differentiated Thyroid Cancer. Cancer Immunol Res 2015;3:620-30. 
 
Taube, JM, Klein, A, Brahmer, JR, Xu, H, Pan, X, Kim, JH, et al. Association of PD-1, PD-1 ligands, and 
other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer 
Res 2014;20:5064-74. 
 


     
ACCRU-ITOG-1504                                                  87                                           
 Addendum 6 
 
Terme, M, Pernot, S, Marcheteau, E, Sandoval, F, Benhamouda, N, Colussi, O, et al. VEGFA-VEGFR 
pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 
2013;73:539-49. 
Tumeh, PC, Harview, CL, Yearley, JH, Shintaku, IP, Taylor, EJ, Robert, L, et al. PD-1 blockade induces 
responses by inhibiting adaptive immune resistance. Nature 2014;515:568-71. 
Ugolini, C, Basolo, F, Proietti, A, Vitti, P, Elisei, R, Miccoli, P, et al. Lymphocyte and immature 
dendritic cell infiltrates in differentiated, poorly differentiated, and undifferentiated thyroid carcinoma. 
Thyroid 2007;17:389-93. 
Voron, T, Marcheteau, E, Pernot, S, Colussi, O, Tartour, E, Taieb, J, et al. Control of the immune 
response by pro-angiogenic factors. Front Oncol 2014;4:70. 
 


 
 
Appendix I 
 
 
Addendum6 
 
 
ACCRU Informed Consent Template for Cancer Treatment 
Trials 
(English Language) 
 
*NOTES FOR LOCAL INVESTIGATORS: [NOTE: Retain this section and asterisk item 
below for ACCRU model consents] 
• 
The goal of the informed consent process is to provide people with sufficient information 
for making informed choices.   The informed consent form provides a summary of the 
clinical study and the individual's rights as a research participant.  It serves as a starting 
point for the necessary exchange of information between the investigator and potential 
research participant.  This template for the informed consent form is only one part of the 
larger process of informed consent. For more information about informed consent, 
review the "Recommendations for the Development of Informed Consent Documents for 
Cancer Clinical Trials" prepared by the Comprehensive Working Group on Informed 
Consent in Cancer Clinical Trials for the National Cancer Institute.  The Web site 
address for this document is 
 
• A blank line, __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective research 
participant.  
• Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is 
available for your patients.  The pamphlet is entitled: "If You Have Cancer…What You 
Should Know about Clinical Trials".  This pamphlet may be ordered on the NCI Web site 
at 
or call 
to 
request a free copy.  
• Optional feature for Local Investigators: Reference and attach drug sheets, 
pharmaceutical information for the public, or other material on risks.  Check with your 
local IRB regarding review of additional materials. 
 
*These notes for {authors and} investigators are instructional and should not be included in the 
informed consent form given to the prospective research participant.  
 
 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 2 of 28 
 
 
Addendum 6 
 
Combination Targeted Therapy with Pembrolizumab 
and Lenvatinib in Progressive, Radioiodine-Refractory 
Differentiated Thyroid Cancers: A Phase II Study 
 
This is an important form.  Please read it carefully.  It tells you what you need to know about this 
research study.  If you agree to take part in this study, you need to sign this form.  Your signature 
means that you have been told about the study and what the risks are.  Your signature on this 
form also means that you want to take part in this study. 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.   Clinical trials include only people who choose to take part. Please take your time to 
make your decision about taking part.  You may discuss your decision with your friends and 
family.  You can also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation.  
 
You are being asked to take part in this research study because you have differentiated thyroid 
cancer that has spread and has not responded to treatment with radioactive iodine. 
 
Why is this research study being done? 
 
The purpose of this research study is to determine any good and bad effects of using lenvatinib 
alone, or lenvatinib along with pembrolizumab. The study will allow researchers to see if there is 
any benefit to adding pembrolizumab to the standard treatment (lenvatinib).  
 
How many people will take part in the research study? 
 
This study has two study groups, and each group will have about 25 patients. 
 
Group 1 includes people who have never received treatment with lenvatinib. These people will 
take 20 mg of lenvatinib by mouth, and receive 200 mg of pembrolizumab through an IV once 
every 21 days. 
 
Group 2 includes people who are already taking lenvatinib but their cancer has continued to 
spread.  These people will continue taking (or re-start) the lenvatinib at the same dose they had 
been taking, and will be given 200 mg of pembrolizumab through a needle in your arm (IV 
infusion) once every 21 days in addition to lenvatinib. 
 
What will happen if I take part in this research study? 
 
Before you begin the study …  
 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor. 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 3 of 28 
 
 
Addendum 6 
 
 
• Medical history and physical exam, including  pulse, blood pressure, height, weight and 
an assessment of how well you perform routine activities of daily living. 
• Routine blood tests. About 2 teaspoons of blood will be drawn. 
• A blood sample for research tests is required for this study. Before treatment starts, the 
research blood sample will be taken at the same time as the routine blood samples by 
drawing some blood from a vein. About 3 additional teaspoons of blood will be drawn. 
• Urine test 
• A pregnancy test done either by providing a urine sample or by taking a blood sample 
from a vein in your arm within 7 days of being registered on the study (if you are a 
woman of childbearing potential). Your study doctor will discuss these options with you. 
• A measurement and evaluation of your tumor by MRI and/or CT scan.  
• An echocardiogram and electrocardiogram to look at your heart and heart valves to see 
how well they are working. 
• A check to see if any of the side effects that may be caused by the study drugs are already 
present. 
 
During the study  
 
If the exams, tests and procedures show that you can be in the study, and you choose to 
take part, then you will need the following tests and procedures.  They are part of regular 
cancer care.  
 
• Medical history and physical exam, including  pulse, blood pressure, height, weight and 
an assessment of how well you perform activities of daily living. 
• Routine blood tests. About 2 teaspoons of blood will be drawn. 
• Urine test.  
• A MRI and/or CT scan to measure and evaluate your tumor, and to find out if your 
disease is progressing. 
• An echocardiogram and electrocardiogram to look at your heart and heart valves to see 
how well they are working. 
 
You will need these tests and procedures that are part of regular cancer care.   They are 
being done more often because you are in this study.   
 
• A check to see if you are having any of the side effects that may be caused by the study 
drugs. 
• Routine blood tests. About 2 teaspoons of blood will be drawn. 
• Urine test. 
• An echocardiogram and electrocardiogram to look at your heart and heart valves to see 
how well they are working. 
 
 
 
 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 4 of 28 
 
 
Addendum 6 
 
You will need these tests and procedures that are either being tested in this study or being 
done to see how the study is affecting your body. 
 
• A blood sample for research tests is required for this study. Before treatment starts, the 
research blood sample will be taken at the same time as the routine blood samples by 
drawing some blood from a vein. About 3 additional teaspoons of blood will be drawn. 
• Mandatory tumor tissue submission: This study also includes research tests that will be 
performed on tumor tissue samples that you will provide. These samples should be 
tissues that were obtained from previous surgeries or biopsies; no additional tumor tissue 
will be taken from you during this study.  
• A check to see if you are having any of the side effects that may be caused by the study 
drugs. 
• Routine blood tests. About 2 teaspoons of blood will be drawn. 
• Urine test. 
• An echocardiogram and electrocardiogram to look at your heart and heart valves to see 
how well they are working. 
• If you are in Group 1: An additional optional biopsy of your current tumor tissue may 
be performed.  The biopsies will be performed by specialists at your facility who are 
trained to do these biopsies. The specific procedure to be performed will depend on the 
site of your tumor.  The specific details and risks of the specific procedures will be 
explained to you by the specialist who will perform the biopsy. The specialist will use an 
ultrasound or CT scan to help them take the biopsy. Before the sample is taken, you will 
be given some medicine to numb the area.  A small cut will be made in your skin and the 
sample will be taken by pressing a hollow needle into your tumor.  When we take the 
needle out, it will remove a small circle of tumor tissue called a “plug.”  A total of four 
“plugs” will be taken. 
 
Some of the research tests done on the research blood and tissue samples are genetic tests. 
Because these genetic tests are not used for regular medical care, neither you nor your doctor 
will be told the results of the test(s).  The test results will not be put in your medical record 
either. 
 
There is more information about these research tests near the end of this form. 
 
You will be asked to keep a daily record of when you take the study medication (Patient 
Medication Diary), and every day write down the day and time you take the medication. If you 
notice any side effects, you can include this information in the Comments section of the diary. 
You will be asked to bring the medication diary each time you see your doctor. 
 
You will also be asked to check your blood pressure three times every week, and record it on the 
Blood Pressure Diary. If you do not already have a blood pressure monitor, one will be provided 
to you.  You will be asked to bring the Blood Pressure Diary each time you see your doctor. 
 
 
 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 5 of 28 
 
 
Addendum 6 
 
Study Calendar 
 
You will take lenvatinib every day. Every 21 days you will go to your treating facility to receive 
pembrolizumab by IV. This 21-day period of time is called a cycle.  The cycle will be repeated 
until your disease gets worse.  The chart below shows what will happen to you during the entire 
54-week treatment period (19 cycles).  
 
The left-hand column shows the day in the cycle and the right-hand column tells you what to do 
on that day.  Patients in both groups will do everything listed in the “What you do” column, 
unless otherwise specified.  
 
Groups 1 and 2 
Day 
What you do 
Up to 30 days 
before 
starting study 
• Medical history and physical exam, including pulse, blood pressure, height, 
weight and an assessment of how well you perform activities of daily living 
• Routine blood tests 
• Mandatory research blood samples 
• Pregnancy test (if applicable) 
• Urine test 
• MRI and/or CT scan for tumor measurement 
• Echocardiogram or multigated acquisition (MUGA) scan 
• Electrocardiogram 
• GROUP 1 ONLY: Optional tumor biopsy. 
Cycle 1,  
Day 1  
• Medical history and physical exam, weight, and blood pressure. 
• Routine blood tests 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. This infusion will take approximately 25-40 minutes. (This 
can be done 3 days before or after the scheduled day if your treating facility 
is closed on the scheduled day). 
• Begin taking 20 mg of lenvatinib once each day. Lenvatinib is in capsule 
form and you will need to two 10-mg capsules, for a total of 20mg. The 
capsules should be taken with water at about the same time each day, and 
can be taken with or without food, and should be taken every day that you 
are in the study.  
• Each day, in the Patient Medication Diary, write down when you take the 
study medication and any side effects you notice. 
• Three times each week during treatment, check your blood pressure and 
record it on the Blood Pressure Diary.  
Within 60 
days after 
starting study 
• Mandatory archival tissue collection. (NOTE: Receipt of archival tumor 
tissue is not required for study registration or initiation of therapy.) 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 6 of 28 
 
 
Addendum 6 
 
Cycle 2,    
Day 1 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• Medical history and physical exam, including  blood pressure, weight and 
an assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 3,    
Day 1 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• Medical history and physical exam, including  blood pressure, weight and 
an assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Electrocardiogram 
• Routine blood tests 
• GROUP 1 ONLY: Mandatory research blood sample 
• Urine test 
• MRI and/or CT scan for tumor measurement 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 4,    
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• Routine blood tests 
• Urine test 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 5,    
Day 1 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• Medical history and physical exam, including  blood pressure, weight and 
an assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• MRI and/or CT scan for tumor measurement 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 6,    
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• Routine blood tests 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 7 of 28 
 
 
Addendum 6 
 
• Urine test 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab.  
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 7,    
Day 1 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• Medical history and physical exam, including blood pressure, weight and 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• MRI and/or CT scan for tumor measurement 
• Mandatory research serum sample  
• Mandatory research blood sample 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 8,    
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• Routine blood tests 
• Urine test 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab.  
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 9,    
Day 1 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• Echocardiogram or multigated acquisition (MUGA) scan 
• Electrocardiogram  
• Routine blood tests 
• Urine test 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 10,    
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• Routine blood tests 
• Urine test 
• Go to your treating facility to receive the IV infusion of 200 mg of 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 8 of 28 
 
 
Addendum 6 
 
pembrolizumab.  
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 11,    
Day 1 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• Medical history and physical exam, including  blood pressure, weight and 
an assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• MRI and/or CT scan for tumor measurement 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 12,    
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• Routine blood tests 
• Urine test 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab.  
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 13,    
Day 1 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• Echocardiogram or multigated acquisition (MUGA) scan 
• Electrocardiogram  
• Routine blood tests 
• Urine test 
• Medical history and physical exam, including  blood pressure, weight and 
assessment of how well you perform activities of daily livingA check to see 
if you are having any of the side effects that may be caused by the study 
drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 14,    
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• Routine blood tests 
• Urine test 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• A check to see if you are having any of the side effects that may be caused 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 9 of 28 
 
 
Addendum 6 
 
by the study drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 15,    
Day 1 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• Medical history and physical exam, including  blood pressure, weight and 
an assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• MRI and/or CT scan for tumor measurement 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 16,    
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• Routine blood tests 
• Urine test 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab.  
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 17,    
Day 1 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
• Echocardiogram or multigated acquisition (MUGA) scan 
• Electrocardiogram  
• Routine blood tests 
• Urine test 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 
Cycle 18,    
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• Routine blood tests 
• Urine test 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab.  
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Review your Patient Medication and Blood Pressure diaries with study staff 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 10 of 28 
 
 
Addendum 6 
 
Cycle 19,    
Day 1 
 
• Medical history and physical exam, including  blood pressure, weight and 
an assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Group 1 ONLY: Mandatory research blood sample 
• Urine test 
• MRI and/or CT scan for tumor measurement 
• Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
Cycle 20, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• 
Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of pembrolizumab.  
Cycle 21, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• 
Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of pembrolizumab. 
Cycle 22, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• 
Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of pembrolizumab. 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 11 of 28 
 
 
Addendum 6 
 
Cycle 23,  
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• MRI and/or CT scan for tumor measurement 
• Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
Cycle 24,  
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
Cycle 25, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• Echocardiogram or multigated acquisition (MUGA) scan 
• 
Electrocardiogram 
• 
Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of pembrolizumab. 
Cycle 26, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 12 of 28 
 
 
Addendum 6 
 
Cycle 27, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• MRI and/or CT scan for tumor measurement 
• Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
Cycle 28, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and 
an assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• 
Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of pembrolizumab. 
Cycle 29, 
Day 1 
• 
Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• 
Routine blood tests 
• 
Urine test 
• 
Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of pembrolizumab. 
Cycle 30, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and 
an assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• 
Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of pembrolizumab. 
Cycle 31, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• MRI and/or CT scan for tumor measurement 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 13 of 28 
 
 
Addendum 6 
 
• Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
Cycle 32, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and 
an assessment of how well you perform activities of daily living 
• 
A check to see if you are having any of the side effects that may be caused by the 
study drugs. 
• 
Routine blood tests 
• 
Urine test 
• 
Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of pembrolizumab. 
Cycle 33, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• 
Routine blood tests 
• 
Urine test 
• 
Echocardiogram or multigated acquisition (MUGA) scan 
• 
Electrocardiogram  
• 
Review your Patient Medication and Blood Pressure diaries with study staff 
• 
Go to your treating facility to receive the IV infusion of 200 mg of pembrolizumab 
Cycle 34, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused 
by the study drugs. 
• Routine blood tests 
• Urine test 
• Review your Patient Medication and Blood Pressure diaries with study staff 
• Go to your treating facility to receive the IV infusion of 200 mg of 
pembrolizumab. 
Cycle 35, 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• 
A check to see if you are having any of the side effects that may be caused by the 
study drugs. 
• Routine blood tests 
• Urine test 
• 
MRI and/or CT scan for tumor measurement 
• Review your Patient Medication and Blood Pressure diaries with study staff 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 14 of 28 
 
 
Addendum 6 
 
• 
Go to your treating facility to receive the IV infusion of 200 mg of pembrolizumab 
 
You will continue the schedule above until your disease gets worse or you stop 
treatment for any reason. 
 
 
When I am finished with treatment  
 
When you finish treatment, you will need the following tests and procedures that are part of 
regular cancer care. They are being done more often because you are in this study. 
 
Study Calendar Following Completion of Therapy 
 
Day 
 
What you do 
Day 1 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused by the 
study drugs. 
• Routine blood tests 
• GROUP 1 ONLY: Mandatory research blood sample 
• 
Urine testMRI and/or CT scan for tumor measurement  
• Review your Patient Medication and Blood Pressure diaries with study staff 
 
Every 12 
weeks 
• Medical history and physical exam, including  blood pressure, weight and an 
assessment of how well you perform activities of daily living 
• A check to see if you are having any of the side effects that may be caused by the 
study drugs. 
• Routine blood tests 
• Urine test 
• MRI and/or CT scan for tumor measurement, per treating physician as clinically 
indicated 
 
 
 
 
How long will I be in the research study? 
 
You will be asked to take the combination of lenvatinib and pembrolizumab until your disease 
gets worse, you choose to withdraw from the study, or your doctor  indicates you should 
discontinue the study, for a maximum of 24 months (on treatment) .  After you are finished 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 15 of 28 
 
 
Addendum 6 
 
taking the combination of  lenvatinib and pembrolizumab, the study doctor will ask you to visit 
the office for follow-up exams every 12 weeks unless and until your disease gets worse, for a 
maximum of  up to5 years.    
 
Can I stop being in the research study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from taking 
the combination of lenvatinib and pembrolizumab can be evaluated by your doctor.  Another 
reason to tell your doctor that you are thinking about stopping is to discuss what follow-up care 
and testing could be most helpful for you.  The study doctor may stop you from taking part in 
this study at any time if he/she believes it is in your best interest, if you do not follow the study 
rules, or if the study is stopped. 
What side effects or risks can I expect from being in the research study? 
 
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen.  
Side effects may be mild or very serious.  Your health care team may give you medicines to help 
lessen side effects.  Many side effects go away soon after you stop taking the combination of 
lenvatinib and pembrolizumab. In some cases, side effects can be serious, long lasting, or may 
never go away.   
 
There also is a risk of death. 
 
You should talk to your study doctor about any side effects that you have while taking part 
in the study.    
 
Risks and side effects related to Pembrolizumab include those which are: 
 
Very common side effects (seen in more than 10% of people taking pembrolizumab): 
• Feeling tired  
• Itching of the skin  
• Rash 
• Frequent or excessive bowel movements or diarrhea 
• Fever 
• Shortness of breath 
• Decreased appetite 
• Cough 
• Nausea and vomiting 
• Decreased in red blood cells that may result in patients feeling tired or short of breath  
• Pain in a joint 
• Headache 
• Swelling of the legs 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 16 of 28 
 
 
Addendum 6 
 
• Muscle weakness or lack of energy 
• 
Bowel movements occurring less often than usual (Constipation) 
 
Common side effects (seen in 1-10% of people taking pembrolizumab) include the 
following:   
• Pain or cramping in a muscle or group of muscles 
• Decreased release of thyroid hormone. Symptoms may include feeling tired, feeling cold 
easily, weight gain, or bowel movements occurring less often than usual 
• Abnormal laboratory result of liver test by blood that occasionally indicates liver failure, 
may have yellowing of the skin or whites of the eyes, fatigue, or leg swelling 
• Feeling cold or sick 
• Loss of skin color 
• Pain or uncomfortable feeling in the belly 
• Bowel movements occurring less often than usual  
• Momentary feeling of whole body warmth possibly along with sweating 
• Sweating a lot while sleeping such that clothes and sheets are wet (“night sweats”) 
• Feeling dizzy or unsteady when walking or standing 
• Weight loss 
• Pain in the back, arms, or legs 
• Swelling of the legs 
• Decreased platelets that may cause you to bruise or bleed easily  
• Dry eyes 
• Blurred or changed vision 
• Dry mouth 
• Feeling of pain, pins & needles, or burning, usually in the fingers or toes 
• Back pain 
• Irritated or swollen lungs 
• Change of blood cholesterol or triglyceride level 
• Change of blood sugar or albumin level 
• Change of blood electrolytes, e.g. sodium, potassium, or magnesium 
• Loss of body fluid may feel tired, confused, have a dry mouth, or feel thirsty 
• Lung infection 
• Fluid around the lung 
• Blood clot developed in lung 
• Inflammation of the large intestine (colon) that may lead to frequent or excessive watery 
bowel movements 
 
 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 17 of 28 
 
 
Addendum 6 
 
Serious Adverse Events (No event occurred in more than 2% of people taking 
pembrolizumab): 
 
Please note that some of these events have been previously stated above, so some have occurred 
more frequently but with less severity. Serious adverse events seen in people taking 
pembrolizumab include the following: 
 
• Trouble thinking clearly or easily confused 
• Decreased white blood cells, red blood cells, and platelets which may cause fever, feeling 
cold, infections, shortness of breath, feeling tired, a tendency to bruise easily, or a 
tendency to bleed easily 
• Increased release of thyroid hormone which may cause anxiety, irritability, or trouble 
sleeping, weakness, trembling, sweating, feeling uncomfortable in warm weather, fast or 
uneven heartbeats, feeling tired, weight loss, and frequent or excessive bowel 
movements. 
• Infection throughout the body by a fungus or bacteria or others that may cause fever, 
feeling tired, feeling cold, and that does not respond to most antibiotics. This is serious 
and can be life-threatening. 
• Inflammation of the lining around the heart which may cause sharp chest pain and/or 
fever. 
• Inflammation of the pancreas. Symptoms may include abdominal pain that radiates to the 
back, swollen or tender abdomen, fever, nausea and/or vomiting. 
• Inflammation of the muscles. Symptoms may include weakness or pain in the muscles. 
• Inflammation of the kidneys causing them not to work as well, which may cause swelling 
of the legs and possibly a need for dialysis. 
• Inflammation of the pituitary gland, which may cause headache, nausea, a sensation of 
the room spinning around you, changes in behavior, double vision, or weakness 
• Irritation of body systems that may cause feeling sick to your stomach, high body 
temperature, chills, low blood pressure, increased heart rate, weakness, headache, rash, 
and/or difficulty breathing (Cytokine Release Syndrome).   
• Change of blood pressure or body fluid level that may cause you to feel dizzy. 
• Failure of liver or lung function that may cause yellowing of the skin or eyes, or 
difficulty breathing 
• Damage of the peripheral nerves that may cause weakness  
• Cancer of the skin 
• Inflammation of the heart muscle which can cause shortness of breath or heart rhythm 
problems. May be serious and require hospitalization. (Immune-mediated myocarditis) 
• Severe skin and digestive tract reaction that may include rash and sloughing or 
breakdown of tissue. This may manifest as various blisters, hives, and other lesions in 
various locations on the body including palms and soles, face and other extremities. This 
is serious and may be life threatening. [Stevens-Johnson Syndrome (SJS)] or Toxic 
Epidermal Necrolysis (TEN).  
• Myasthenic Syndrome (causes muscle weakness)  
• Guillain-Barre Syndrome (damage to the nervous system (causing numbness and/or 
paralysis) ) 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 18 of 28 
 
 
Addendum 6 
 
• High blood calcium (can cause fatigue, weakness, confusion, kidney stones, kidney 
damage) 
Other less common side effects have been reported.  The study doctor or staff can discuss these 
with you. 
 
There may be other side effects or risks that are not known at this time. 
 
There is also a risk of death.  
 
Risks and side effects related to Lenvatinib include those which are: 
 
Likely (events occurring greater than 20% of the time) 
• High blood pressure 
• Diarrhea 
• Decreased Appetite 
• Weight loss 
• Nausea 
• Mouth sores 
• Fatigue 
• Headache 
• Vomiting 
• Loss of protein into the urine 
• Bleeding 
• Sensitivity and irritation/rash, palms and soles (potentially severe) 
• Abdominal pain 
• Voice changes 
• Mouth pain 
• Cough 
• Arm and/or leg swelling (Edema) 
• Pain in the joints, back, muscles and/or limbs (Myalgias/arthralgias) 
• Nose bleeds 
• Dry mouth 
• Problems swallowing 
• Lack of energy (Asthenia) 
 
Less likely (events occurring less than or equal to 20% of the time) 
• Skin Rash or growths 
• Indigestion/heartburn (Gastrointestinal reflux, GERD) 
• Hair loss (Alopecia) 
• Change in taste sensation (Dysgeusia) 
• Dizziness 
• Low platelet count (blood cells responsible for blood clotting; thrombocytopenia) 
• Low lymphocyte count (blood cells responsible for fighting some infections including 
fungal infections; lymphopenia) 
• Anemia 
• Sleep difficulties (Insomnia) 
• Urinary tract infection 
• Dehydration 
• Shortness of breath (Dyspnea) 
• Low blood pressure (Hypotension) 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 19 of 28 
 
 
Addendum 6 
 
• Low blood level of potassium (Hypokalemia) 
• Low blood level of sodium (Hyponatremia) 
• Low blood level calcium (Hypocalcemia) 
• Low blood level of proteins (Hypoproteinemia) 
• Low blood level of magnesium (Hypomagnesemia) 
• Altered heart electrical conduction (ECG changes) 
• Increased liver tests/worsened liver function (Hepatitis) 
• Worsening kidney function 
• Low thyroid function/altered thyroid function tests 
• Decreased heart pumping function (Decreased cardiac ejection fraction) 
• High cholesterol (hyperlipidemia/cholesterolemia) 
• Increased passing gas (Flatulence) 
• Fever (pyrexia) 
• Gall bladder inflammation (Cholecystitis) 
• Upper respiratory or lung infection (Bronchitis, Pneumonia) 
• Pain or bleeding at sites of cancer 
• Headache 
• Fainting (Syncope) 
• Depression/altered mental status/anxiety (may be severe) 
• Muscle spasms 
• Itching 
• Tongue pain 
• High blood sugar (Hyperglycemia) 
 
Rare but serious risks (events occurring less than 2-3% of the time) 
• Stroke (Cerebrovascular accident) 
• Weakness of one limb 
• Seizure (Epilepsy) 
• Temporary brain inflammation (Reversible posterior leukoencephalopathy) 
• Chest pain from heart blockage (Angina) 
• Heart attack (myocardial infarction) 
• Heart failure (Congestive heart failure) 
• Irregular heart rhythm (Atrial fibrillation, tachycardia) 
• Blood clots in veins and/or in lungs (Deep venous thrombosis or/and pulmonary 
embolism) 
• Bleeding (in bowel movements/rectal bleeding, urine, coughing up blood) 
• Inflammation of the pancreas (Pancreatitis) 
• Liver inflammation or failure (Hepatitis) 
• Kidney failure (Renal failure) 
• Infection pocket in groin/around anus (Abscess) 
• Injury to spleen (splenic infarction) 
• Fluid build-up in abdomen (Ascites) 
• Fluid build-up around the lungs (Pleural effusions) 
• Yellowing of the skin/jaundice (Hyperbilirubinemia) 
• Intestinal break/leakage (perforation) 
• Infection in the appendix (Appendicitis) 
• Inflammation of the gall bladder (Cholecystitis) 
• Skin infection (Cellulitis) 
• Infection in bloodstream (Sepsis) 
• Suicidal thoughts 
• Breathing failure (Respiratory failure) 
• Abnormal connections between organs (Fistulas, including between bowel and skin, 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 20 of 28 
 
 
Addendum 6 
 
bladder and/or vagina) 
• Air leakage around lungs (Pneumothorax) 
• Intestinal blockage (Bowel obstruction) 
As with any medication, allergic reactions are a possibility. 
 
The risks of drawing blood include pain, bruising or rarely infection at the needle site. 
 
Group 1 only – if you agree to the optional tumor biopsy: Risks and side effects of the needle 
biopsy of tumor tissue are: 
 
• 
Small chance of infection at the needle site 
• 
Bleeding or bruising at the needle site or along the needle path to the tumor 
• 
Small scar at the needle site 
• 
Small chance of an allergic reaction to the numbing medicine 
• 
For biopsies of lung tumors and some liver and kidney tumors, there is a small risk of 
a pneumothorax.  A pneumothorax is introduction of air around the lung that can 
partially collapse the lung and make breathing difficult.  Some patients with 
pneumothorax will need a chest tube, which is a plastic tube inserted into the chest to 
remove the air and allow the lung to expand again.  This requires hospitalization 
usually for 2-5 days.   
• 
The specialist performing the biopsy will perform a full consent at the time of your 
procedure 
 
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby 
while on this study.  It is important you understand that you need to use birth control while on 
this study.  Check with your health care provider about what kind of birth control methods to use 
and how long to use them.  Some methods might not be approved for use in this study.  
 
[Note to Local Investigators: Include a statement about possible sterility when appropriate.  For 
example, “Some of the drugs used in the study may make you unable to have children in the 
future.”  If appropriate include a statement that pregnancy testing may be required.] 
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the research study? 
 
Taking part in this study may or may not make your health better.  While doctors hope the 
combination of lenvatinib and pembrolizumab will be more useful against cancer compared to 
the usual treatment, there is no proof of this yet.  We do know that the information from this 
study will help doctors learn more about the combination of lenvatinib and pembrolizumab as a 
treatment for cancer.  This information could help future cancer patients. 
 
What other choices do I have if I do not take part in this research study? 
 
You do not have to be in this study to receive treatment for your cancer. 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 21 of 28 
 
 
Addendum 6 
 
 
Your other choices may include: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study, if one is available 
• Getting no treatment 
• 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible.   
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private? 
 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• Government agencies, like the Food and Drug Administration (FDA), Office for Human 
Research Protections or other federal, state, or international regulatory agencies involved 
in keeping research safe for people; 
• Local Institutional Review Boards; 
• Pharmaceutical companies supporting the study (Merck and Eisai); 
• Your insurance company (if charges are billed to insurance); 
• International Thyroid Oncology Group (ITOG); 
• Academic and Community Cancer Research United (ACCRU) Coordinating Center. 
 
A description of this clinical trial will be available on 
as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of study results.  You can search this Web site at any time. 
 
[Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation 
found at 21 CFR 50.25(c) and must be included verbatim in all informed consent documents. The 
text in this paragraph cannot be revised.] 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.] 
 
What are the costs of taking part in this research study? 
 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 22 of 28 
 
 
Addendum 6 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
 
You WILL have to pay for: 
 
• All doctor’s visits, including physical exams, and medical histories 
• Review of your tumor tissue (Pathology review) 
• Routine blood test to check your health 
• Pregnancy test 
• Urine test 
• All standard imaging done while on the study (CT scans, MRI scans, echocardiograms, 
electrocardiograms, etc.)  
 
You will NOT have to pay for: 
 
• Lenvatinib or pembrolizumab. Merck is supplying pembrolizumab, and Eisai is supplying 
lenvatinib at no cost to you.  However, you or your health plan may need to pay for costs 
of the supplies and personnel who give you lenvatinib and pembrolizumab. NOTE: if you 
should need to take the study agents much longer than usual, the stock of free study 
agents could run out.  If this happens, your study doctor will discuss with you how to get 
more of the study agents from the manufacturer, and you may be asked to pay for them. 
• Mandatory serum samples for research purposes 
• Mandatory blood samples for research purposes 
• Costs to submit mandatory tumor tissue for research purposes (this is tissue from your 
original tumor obtained from previous surgery) 
• Optional tissue biopsy for research purposes 
• Blood pressure monitor if you do not already have one as a result of current or prior 
therapy with lenvatinib.  
 
You will not be paid for taking part in this study. 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at 
You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 
and ask them 
to send you a free copy. 
What happens if I am injured because I took part in this research study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 23 of 28 
 
 
Addendum 6 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.   The study will not pay for medical 
treatment.   
 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 24 of 28 
 
 
Addendum 6 
 
What are my rights if I take part in this research study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.    
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
Who can answer my questions about the research study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone number).   
[Note to Local Investigator: Contact information for patient representatives or other individuals 
in a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can be listed here.]    
 
PLEASE NOTE:  This section of the informed consent form is about additional research studies 
that are being done with people who are taking part in the main study.   You may take part in 
these additional studies if you want to.  You can still be a part of the main study even if you say 
‘no’ to taking part in any of these additional studies. 
 
You can say “yes” or “no” to each of the following studies.  Please mark your choice for each 
study.   
 
About Using Biological Samples for Research 
This study also has optional laboratory tests that will be performed to study small samples of 
tissue from patients in Group 1.  Should you choose to participate in this portion of the study, 
you will have a biopsy (or surgery) so your doctor can remove some body tissue to do some 
additional tests.  
The tissue will be sent to the Division of Endocrinology, Metabolism, and Diabetes Research 
Unit at the University of Colorado, School of Medicine where the tests will be done.  These tests 
will be done in order to understand how your cancer responds to treatment.  It is hoped that this 
will help investigators better understand your type of cancer.  The results of these tests will not 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 25 of 28 
 
 
Addendum 6 
 
be sent to you or your study doctor and will not be used in planning your care.  These tests are 
for research purposes only and you will not have to pay for them.   
You can take part in the treatment portion of this study without taking part in these research 
laboratory tests. 
Please read the following statements and mark your choice: 
 
1. Group 1 patients only: I agree to provide tissue to University of Colorado, School of 
Medicine laboratories associated with ACCRU/ITOG for research testing planned as part of 
this study. 
 
 
  Yes 
 
  No  
Please initial here: ________  Date: ________ 
 
We would also like to keep some of the tissue and blood that is leftover for future research.  If 
you agree, this leftover tissue and blood will be kept and may be used in research to learn more 
about cancer and other diseases.  Please read the online booklet called "Providing Your Tissue 
for Research: What You Need To Know," to learn more about tissue research: 
  
Your leftover tissue and blood may be helpful for research whether you do or do not have cancer.  
The research that may be done with your leftover tissue and blood is not designed specifically to 
help you.  It might help people who have cancer and other diseases in the future.  
Reports about research done with your leftover tissue and blood will not be given to you or your 
doctor.  These reports will not be put in your health record.  The research will not have an effect 
on your care.  
Things to Think About  
The choice to let us keep the leftover tissue and/or blood for future research is up to you.  No 
matter what you decide to do, it will not affect your care.  
If you decide now that your leftover tissue and/or blood can be kept for research, you can change 
your mind at any time.  Just contact us and let us know that you do not want us to use your tissue 
and/or blood; then any tissue and/or blood that remains will no longer be used for research.  
In the future, people who do research may need to know more about your health.  While 
ACCRU/ITOG may give them reports about your health, it will not give them your name, 
address, phone number, or any other information that will let the researchers know who you are.  
Sometimes tissue and/or blood are used for genetic research (about diseases that are passed on in 
families).  Even if your tissue and/or blood is used for this kind of research, the results will not 
be put in your health records.  


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 26 of 28 
 
 
Addendum 6 
 
Your leftover tissue and/or blood will be used only for research and will not be sold.  The 
research done with your leftover tissue and/or blood may help to develop new products in the 
future.  
Benefits  
The benefits of research using tissue and blood include learning more about what causes cancer 
and other diseases, how to prevent them, and how to treat them.  
Risks  
The greatest risk to you is the release of information from your health records.  We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
Making Your Choice  
Please read each sentence below and think about your choice.  After reading each sentence, 
circle "Yes" or "No".  If you have any questions, please talk to your doctor or nurse, or call our 
research review board at the IRB's phone number.  
No matter what you decide to do, it will not affect your care. 
 
1. My tissue sample(s) may be kept for use in future research to learn about, prevent, or treat 
cancer.  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
2. My tissue sample(s) may be kept for use in future research to learn about, prevent or treat 
other health problems (for example: diabetes, Alzheimer's disease, or heart disease).  
 
 
  Yes 
 
  No  
Please initial here: ________  Date: ________ 
 
3. My blood sample(s) may be kept for use in future research to learn about, prevent, or treat 
cancer.  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
4. My blood sample(s) may be kept for use in future research to learn about, prevent or treat 
other health problems (for example: diabetes, Alzheimer's disease, or heart disease).  
 
 
  Yes 
 
  No  
Please initial here: ________  Date: ________ 
 
 
If you want your sample(s) destroyed at any time, write to the Secretary of the 
___________________ Institutional Review Board 
____________________________________________.   
 
ACCRU/ITOG has the right to end storage of the sample(s) without telling you.  
 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 27 of 28 
 
 
Addendum 6 
 
The sample(s) will be the property of ACCRU/ITOG.  Outside researchers may one day ask for a 
part of your sample(s) for studies now or future studies. 
 
How do outside researchers get the sample? 
Researchers from universities, hospitals, and other health organizations do research using blood 
and tissue.  They may call ACCRU and ask for samples for their studies.  ACCRU looks at the 
way that these studies will be done, and decides if any of the samples can be used.  ACCRU 
sends the samples and some information about you to the researcher.  ACCRU will not send your 
name, address, phone number, social security number, or any other identifying information to the 
researcher.  If you allow your sample(s) to be given to outside researchers, it will be given to 
them with a code number.  If researchers outside ACCRU use the sample(s) for future research, 
they will decide if you will be contacted and, if so, they would have to contact the researchers at 
ACCRU.  Then ACCRU will contact the clinic where you registered for this study, who will 
contact you. 
 
Please read the following statements and mark your choice: 
 
I permit ACCRU/ITOG to give my tissue sample(s) to outside researchers: 
 
  Yes 
 
  No  
Please initial here: 
 
 
Date:  
 
 
 
I permit ACCRU/ITOG to give my tissue sample(s) to outside researchers: 
 
  Yes 
 
  No  
Please initial here: 
 
 
Date:  
 
 
 
 
 
 
 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
  
 
You may also visit the NCI Web site at 
 
 
• For NCI’s clinical trials information, go to: 
 
 
• For NCI’s general information about cancer, go to 
 
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor. 


ACCRU-ITOG-1504 
 
Appendix I 
 
 
Page 28 of 28 
 
 
Addendum 6 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my 
questions answered.  I agree to take part in this study. 
 
 
Printed Participant Name: __________________________________________ 
 
 
Participant Signature: ______________________________________________ 
 
 
Date: _____________________________________ 
 
 
Printed name of person obtaining informed consent:  
 
__________________________________________ 
 
 
Signature of person obtaining informed consent: 
 
___________________________________________ 
 
 
Date _____________________________________ 
 
 
 
This model informed consent form has been reviewed by the ACCRU and is the official 
consent document for this study.  Local IRB changes to this document are allowed.  
Sections “What are the risks of the research study” or “What other choices do I have if I 
don’t take part in this research study?” should always be used in their entirety if possible.  
Editorial changes to these sections may be made as long as they do not change information 
or intent.  If the institutional IRB insists on making deletions or more substantive 
modifications to these sections, they may be justified in writing by the investigator and 
approved by the IRB.  Under these circumstances, the revised language and justification 
must be forwarded to the Academic and Community Cancer Research United (ACCRU) 
Operations Office for approval before a patient may be registered to this study. 
 
Consent forms will have to be modified for each institution as it relates to where 
information may be obtained on the conduct of the study or research subject.  This 
information should be specific for each institution. 


 
 
Appendix II 
 
 
 
Page 1 of 1 
 
 
Addendum 6 
 
PATIENT’S BLOOD PRESSURE DIARY 
Today’s date ________________________________ 
Patient Name___________________________(initials acceptable)   Study Number __________________ 
INSTRUCTIONS TO THE PATIENT: 
 
1.   Your blood pressure readings have two numbers.  The first number is the pressure in your blood vessels during a 
heartbeat (systolic), and the second number is the pressure in the vessels when the heart rests in between beats 
(diastolic).  These numbers are usually written with a slash in between them (for example, 110/85). 
2. 
Record the date, then record your blood pressure.  Your blood pressure should be monitored and recorded at least 
three times every week during therapy (for example, Mondays, Wednesdays, and Fridays). You should take your 
blood pressure after you have been sitting at rest for 5 minutes.  Do not cross your legs. 
3. Normal blood pressure is usually about 120/80 mmHg.  If your systolic pressure is greater than 160 and/or your 
diastolic blood pressure is greater than 100 please rest for 15 - 20 minutes and then recheck your blood pressure.  
After resting, if your systolic pressure is still greater than 160 and/or your diastolic blood pressure is still greater 
than 100, please contact your doctor’s office at _______________________________ for instructions. 
4. 
Please bring this form to every clinic visit or appointment. 
Date 
Blood Pressure 
Reading 
 
Other readings 
(include time of day) 
Date 
Blood Pressure 
Reading 
 
Other readings 
(include time of day) 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
Patient’s Signature: _____________________________________________  Date: __________________________ 
This Section to be Completed by Study Staff Only  
 _________________________________ 
_______________________________________________________ 
 
Date of this clinic visit 
Physician/Nurse/Data Manager’s Signature    


 
 
 
Appendix III 
 
 
 
 
Page 1 of 1 
 
 
 
Addendum 6 
 
 
 
 
 
 
 
 
 
PATIENT MEDICATION DIARY 
(Lenvatinib) 
Today’s date ______________________ 
Patient Name___________________________(initials acceptable)   Study Number __________________ 
INSTRUCTIONS TO THE PATIENT: 
1. You will take two 10-mg capsules each day , for a total dose of 20 mg).  It is recommended that you take the capsules 
with water at about the same time each day, with or without food. 
2. Every day, in the table below, write the date, time you took the lenvatinib, and the amount (e.g., 20 mg). 
3. If you miss a dose, and it 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.. Place a “0” under “Dose”, but remember to take your prescribed dose at the 
next regularly scheduled time. NOTE: If you vomit after taking the daily dose of Lenvatinib, DO NOT repeat dosing. 
Resume dosing on the morning of the next day. Remember to write a comment on your diary if this happens. 
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Contact your physician and study coordinator any time you go into the hospital.  Your study doctor can advise if you 
should stop taking lenvatinib or continue it.   
6. Please bring your pill bottle, including any unused medication, and this form to your study doctor when you go for your 
next appointment. 
7. Store your study drug at normal room temperature and keep out of the reach of children and pets. 
Day 
Date & Time 
Dose  
Comments 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
Patient’s Signature: _______________________________                        _Date:___________________________ 
This Section to be Completed by Study Staff Only 
1. Patient’s planned daily dose: ________________________     
2. Total number of pills taken this month: ____________________ 
3. Number of pills returned: __________  Study Coordinator Signature: _____________________