Conditions: Malignant Adrenal Gland Pheochromocytoma Malignant Paraganglioma Metastatic Adrenal Gland Pheochromocytoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This phase II trial studies how well lenvatinib works in treating patients with pheochromocytoma or paraganglioma that has spread to other places in the body or cannot be removed by surgery. Lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the anti-tumor activity of lenvatinib (overall response rate; \[ORR\]) in patients with metastatic or advanced unresectable pheochromocytomas and paragangliomas.

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS). II. To determine overall survival (OS). III. To determine duration of tumor response. IV. To determine safety and tolerability of lenvatinib. V. To assess patient reported quality of life using EuroQol Five-Dimensional Five Level Scale Questionnaire (EQ-5D-5L) and Functional Assessment of Cancer Therapy-General (FACT-G).

TERTIARY OBJECTIVES:

I. For patients with secretory tumors, to examine changes in plasma metanephrine levels and urinary catecholamine and/or metanephrine levels.

II. For patients with secretory tumors, to examine whether lenvatinib-induced changes in plasma metanephrines and urinary catecholamine and/or metanephrine levels during the first cycle of treatment may be associated with objective tumor response.

III. To examine associations between tumor response and somatic mutational status in archived tumors, or germline mutational status (presence of SDHD, SDHB, RET, VHL, neurofibromatosis type-1).

OUTLINE:

Patients receive lenvatinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 or 6 months for up to 5 years.

Arms:
arm 1: Patients receive lenvatinib PO once daily on days 1-28. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Lenvatinib intervention 3: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 




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Table of Contents 
Phase II Trial of Lenvatinib in Metastatic or Advanced Pheochromocytoma and Paraganglioma .............. 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
SCHEMA ...................................................................................................................................................... 4 
1.0 
BACKGROUND .......................................................................................................................... 5 
2.0 
OBJECTIVES ............................................................................................................................. 14 
3.0 
ELIGIBILITY ............................................................................................................................. 15 
4.0 
STUDY CALENDAR ................................................................................................................ 18 
5.0 
STRATIFICATION FACTORS: None ...................................................................................... 20 
6.0 
REGISTRATION PROCEDURES............................................................................................. 20 
7.0 
PROTOCOL TREATMENT ...................................................................................................... 22 
8.0 
DOSAGE MODIFICATIONS .................................................................................................... 24 
9.0 
ANCILLARY TREATMENT/SUPPORTIVE CARE ............................................................... 29 
10.0 
ADVERSE EVENT (AE) REPORTING AND MONITORING ............................................... 32 
11.0 
TREATMENT EVALUATION ................................................................................................. 40 
12.0 
DESCRIPTIVE FACTORS ........................................................................................................ 45 
13.0 
TREATMENT/FOLLOW–UP DECISION AT EVALUATION OF PATIENT ....................... 46 
14.0 
BODY FLUID BIOSPECIMENS ............................................................................................... 47 
15.0 
DRUG INFORMATION ............................................................................................................ 48 
16.0  
STATISTICAL CONSIDERATIONS AND METHODOLOGY .............................................. 52 
17.0 
PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS ............................................ 58 
18.0 
RECORDS AND DATA COLLECTION PROCEDURES ....................................................... 60 
19.0  
BUDGET .................................................................................................................................... 60 
20.0 
REFERENCES ........................................................................................................................... 61 
Appendix I 
ECOG Performance Status ............................................................................................... 66 
Appendix II 
Patient Medication Diary .................................................................................................. 67 
Appendix III 
Potential drugs that could interact with lenvatinib (via CYP 3A4) .................................. 69 
Appendix IV 
Hypertension Management Guidelines ............................................................................. 70 
Appendix V 
Drugs with Risk of Torsades De Pointes .......................................................................... 79 
Appendix VI 
Patient Blood Pressure Diary ............................................................................................ 80 
Appendix VII 
FACT-G (Version 4) ....................................................................................................... 82 
Appendix VIII 
EQ-5D-5L Questionnaire ................................................................................................ 84 
Appendix IX 
Patient Information Sheet ................................................................................................. 87 
 
.


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SCHEMA 
 
 
 
 
 
REGISTRATION 
 
 
 
↓ 
 
 
 
Lenvatinib daily 
 
 
 
↓ 
 
 
 
Disease progression 
 
 
 
↓ 
 
 
 
At any time: 
Disease Progression 
Intolerable adverse effects 
Alternate therapy 
Patient refusal 
 
 
 
↓ 
 
 
 
Event Monitoring 
 
 
 
 
 
Cycle = 28 days 
Generic name: lenvatinib 
Brand name(s): Lenvima® 
Mayo Abbreviation: LENVATINIB 
Availability: Eisai Inc 
 


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1.0 
BACKGROUND 
1.1 
Pheochromocytoma and Paraganglioma 
1.11 
Clinical epidemiology of pheochromocytomas and paragangliomas 
Pheochromocytomas are tumors arising from chromaffin cells of the adrenal 
medulla. Paragangliomas on the other hand are tumors arising from extra-adrenal 
chromaffin cells of the sympathetic ganglia. Although paragangliomas are 
classically present in the head and neck (e.g. carotid bodies) they are also seen in 
the abdomen and pelvis and also sometimes in the thorax. Since both 
pheochromocytomas and paragangliomas arise from chromaffin cells they share 
many common clinicopathologic characteristics and treatment strategies, and for 
that reason they have historically been grouped and studied together. 
Both pheochromocytomas and paragangliomas are rare tumors. The prevalence 
of adrenal pheochromocytomas is not precisely known and estimates range from 
1-2 per 100,000 patients to 1.9% depending on the method of detection (Beard, 
Sheps et al. 1983; Stenstrom and Svardsudd 1986; Smythe, Edwards et al. 1992; 
McNeil, Blok et al. 2000). In general 10% of pheochromocytomas are malignant 
(Sinclair, Isles et al. 1987; Anderson, Blakeman et al. 1994; Goldstein, O'Neill et 
al. 1999; Omura, Saito et al. 2004). Extra-adrenal paragangliomas 
(paragangliomas) are less frequent, comprising 10-23% of catecholamine 
secreting tumors. Paragangliomas may also have a higher chance of being 
malignant, estimated at 20% (O'Riordain, Young et al. 1996; Bravo and Tagle 
2003). Similarly, tumors with SDH-B mutation also have a higher probability of 
being malignant (Amar, Baudin et al. 2007). Histopathologically, however, it is 
impossible to distinguish benign from malignant pheochromocytomas or 
paragangliomas - and the diagnosis of malignant disease relies solely on the 
demonstration of tumors in non-chromaffin tissue (Eisenhofer, Bornstein et al. 
2004; Tischler, Kimura et al. 2006). 
 
1.12  
Presentation and clinical course 
The presentation of malignant pheochromocytomas and paragangliomas depends 
mainly on their location and their ability to secrete catecholamines. 
Pheochromocytomas generally have longer overall survival than paragangliomas. 
However, in patients with metastatic disease from either pheochromocytoma or 
paraganglioma, the overall survival appears similar (Ayala-Ramirez, Feng et al. 
2011).  
Adrenal or extra-adrenal tumors of the abdomen and thorax frequently secrete 
catecholamines. They present either as an intraabdominal or a thoracic mass, or 
they are discovered due to catecholamine secreting complications (i.e. secondary 
or malignant hypertension). On the contrary, paragangliomas arising in the head 
and neck sympathetic ganglia rarely secrete catecholamines. Their most frequent 
location is along the carotid body, but can also be seen in the middle ear, jugular 
bulb or along the vagus nerve.(Neumann, Bausch et al. 2002; Boedeker, Ridder 
et al. 2005). The clinical course of malignant pheochromocytomas is extremely 
heterogeneous (Sisson, Shulkin et al. 2006; Huang, Chung et al. 2007). While 
survival of patients with metastatic disease is approximately 5 years 
(Schlumberger, Gicquel et al. 1992; John, Ziegler et al. 1999; Eisenhofer, 
Bornstein et al. 2004); half the patients have an indolent course with survival up 


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to 20 years - while the other half presents with aggressive disease and survival 
limited to 1-3 years (Remine, Chong et al. 1974; Scott, Reynolds et al. 1982; van 
Heerden, Sheps et al. 1982; Lewi, Reid et al. 1985).  
 
1.13 
Surgical management of pheochromocytomas and paragangliomas  
Surgical management of the disease, which is most frequently located in the 
abdomen and thorax, is the mainstay of treatment. Pheochromocytomas and 
paragangliomas can metastasize to the lung, liver, bone, lymph nodes and other 
locations. While surgical resection of metastatic lesions is desirable, this is not 
always possible. External beam radiation therapy has been successfully utilized 
to treat skeletal metastasis and other symptomatic disease. Other local modality 
treatments that have been employed successfully include radiofrequency ablation 
and hepatic artery embolization (Pacak, Fojo et al. 2001; Bianchi, Marchetti et al. 
2009).  
Issues pertaining to peri-operative management of the catecholamine secreting 
syndrome, which is frequently encountered in intrathoracic and intra-abdominal 
disease, is of the utmost importance, as hypertensive crisis can be triggered by 
surgical intervention. The surgical management of head and neck paragangliomas 
is also challenging, not usually due to catecholamine secretion, since this is 
infrequently encountered, but due instead to the location of the tumors along the 
carotid artery or the base of the skull. Treatment of localized paragangliomas of 
the head and neck requires a multidisciplinary approach in experienced centers 
and frequently requires involvement of surgery, tumor embolization, radiation 
therapy, and aggressive postoperative rehabilitation. Postoperative 
cerebrovascular accidents and cranial nerve abnormalities are a significant risk.  
1.14 
Systemic management of pheochromocytomas and paragangliomas  
Metaiodobenzylguanidine (MIBG) is a norepinephrine analogue that 
concentrates in the adrenal medulla and some tumors of neuroectodermal origin. 
Tumor irradiation with therapeutic doses of 131I-MIBG has been used to treat 
non-head and neck paragangliomas and pheochromocytomas with partial and 
durable responses seen in a third of patients (Shapiro, Sisson et al. 1991; Loh, 
Fitzgerald et al. 1997; Rose, Matthay et al. 2003; Safford, Coleman et al. 2003). 
High dose 131I-MIBG with autologous stem cell rescue has also been used in 
selected patients with a tumor response rate of 22%, minor response of 34%, 
biochemical response rate up to 74% and 5 year OS of 64%, which is thought to 
be better than historical controls (Gonias, Goldsby et al. 2009). However, this 
approach can have significant hematologic and pulmonary toxicities - and 
responses are not durable. Consequently, radiotherapeutic MIBG is an option of 
last resort in many centers, especially as hematological toxicities can obviate or 
delay safe alternative administration of other proven-effective cytotoxic 
therapies. 
Chemotherapy is generally reserved for recurrent/refractory or surgically 
inoperable progressive and/or symptomatic disease. Traditionally, a combination 
of cyclophosphamide, vincristine, and dacarbazine (CVD) has been used to treat 
these patients. One study has reported a tumor response rate 57% and 
biochemical response rate of 79% (cyclophosphamide 750 mg/m2 and vincristine 
at 1.4 mg/m2 on Day 1, and dacarbazine 600 mg/m2 on Day 1 and 2, every 21 to 
28 days) (Averbuch, Steakley et al. 1988). A long term follow up of that study 


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reported a median duration of response of 20 months, and a median overall 
survival of 3.3 years, broken down to 3.8 years for responders and 1.8 years for 
non-responders, a difference however which is not statistically significant likely 
due to the small number of patients (Huang, Abraham et al. 2008). Another 
single institution cohort with different chemotherapy regimens also showed 
similar results where median overall survival for responders was 6.4 years versus 
3.7 years for nonresponders (Ayala-Ramirez, Feng et al. 2012). While treatment 
with CVD is generally well tolerated and can be administered for long periods of 
time, (Averbuch, Steakley et al. 1988; Huang, Abraham et al. 2008; Ayala-
Ramirez, Feng et al. 2012) better systemic therapies are clearly needed, since the 
majority of patients ultimately succumb to their disease despite therapy.  
There is relatively little experience with other chemotherapeutic regiments, 
generally limited to case reports or small series and include the combination 
cisplatin and 5-FU (Srimuninnimit and Wampler 1991), lomustine and 5-FU or 
capecitabine (Chrisoulidou, Kaltsas et al. 2007), carboplatin (Cairnduff and 
Smith 1986), etoposide and cisplatin (Mertens, Grignon et al. 1993; 
Chrisoulidou, Kaltsas et al. 2007), etoposide, carboplatin, vincristine, 
cyclophosphamide and doxorubicin (Jirari, Charpentier et al. 1999), 
modifications of CVD with doxorubicin (Patel, Winchester et al. 1995; Nakane, 
Takahashi et al. 2003; Ayala-Ramirez, Feng et al. 2012), MAID (Fitoussi, 
Debled et al. 1999), gemcitabine (Pipas and Krywicki 2000), paclitaxel 
(Kruijtzer, Beijnen et al. 2000), and temozolomide and thalidomide (Kulke, 
Stuart et al. 2006). At least 2 case series have reported very poor results with 
various chemotherapeutic regiments including cisplatin, etoposide, doxorubicin, 
cyclophosphamide and dacarbazine (Massey and Wallner 1992; Schlumberger, 
Gicquel et al. 1992). Recently, temozolomide (an oral prodrug of dacarbazine, an 
agent used in the CVD regimen above) was reported to have 33% partial 
response rate in a single center case series (Hadoux, Favier et al. 2014). Some 
targeted therapies have also been tried with imatinib mesylate being ineffective 
in 2 patients (Gross, Munter et al. 2006) and everolimus (RAD001) being also 
ineffective (Chrisoulidou, Kaltsas et al. 2007; Oh, Kim et al. 2012). 
1.15 
Pathophysiology and molecular characteristics of pheochromocytomas and 
paragangliomas 
Pheochromocytomas and paragangliomas are highly hypervascular tumors as 
suggested by immunohistochemical studies of vascular density (Liu, Djuricin et 
al. 1996; Ohji, Sasagawa et al. 2001). Quantitative as well as architectural 
differences between benign and malignant tumors have been demonstrated (Liu, 
Djuricin et al. 1996; Favier, Plouin et al. 2002; Zielke, Middeke et al. 2002). In 
addition, several angiogenic growth factors and their receptors are overexpressed 
in malignant pheochromocytomas and paragangliomas (Zielke, Middeke et al. 
2002; Salmenkivi, Heikkila et al. 2003; Favier, Igaz et al. 2012). From these, 
vascular endothelium growth factor (VEGF), the most potent factor of vascular 
development, is the most studied, and consistent overexpression at both the 
genetic and protein expression level has been demonstrated (Favier, Plouin et al. 
2002; Zielke, Middeke et al. 2002; Salmenkivi, Heikkila et al. 2003). Several 
other key angiogenic factors are also overexpressed such as the hypoxia induced 
transcription factor EPAS1, and the endothelin receptors type A (ETA) and type 
B (ETB) (Favier, Plouin et al. 2002). Anti-VEGF antibodies have been shown to 


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inhibit angiogenesis in experimental pheochromocytomas (Zielke, Middeke et al. 
2002). 
The genetics of pheochromocytomas and paragangliomas are very complex 
(Dahia 2006). Adrenal pheochromocytoma is strongly associated with multiple 
endocrine neoplasia 2A and 2B, von Hippel-Lindau disease (VHL), and familial 
paraganglioma syndrome (Neumann, Bausch et al. 2002; Boedeker, Ridder et al. 
2005), and is less commonly seen with neurofibromatosis type 1 (NF 1) or MEN 
1. However, malignant adrenal pheochromocytoma is only infrequently seen in 
association with these genetic syndromes. On the contrary, extra-adrenal 
malignant paragangliomas are most frequently seen in association with familial 
paraganglioma syndrome (PGL), an autosomal dominant disorder presenting 
with paragangliomas in the head and neck, but also in the thorax, abdomen, and 
urinary bladder (Neumann, Bausch et al. 2002; Boedeker, Ridder et al. 2005). 
Most cases are caused by mutations in the succinate dehydrogenase gene (SDH) 
subunits B, C and D even in apparent “sporadic” cases. Extra-adrenal malignant 
paraganglioma is strongly associated with mutations of the B subunit of the gene 
(SDHB) (Amar, Baudin et al. 2007). 
 
Global gene expression profiles of large series of sporadic pheochromocytomas 
and paragangliomas have generated 2 unique transcription signatures 
(Eisenhofer, Bornstein et al. 2004; Dahia, Ross et al. 2005). In the first cluster are 
mutations of the VHL, SDHB and SDHD genes known to be associated to VHL 
and PGL syndromes; in the second cluster are mutations in the RET and NF1 
genes associated with the MEN syndromes. Both VHL and SDH mutations are 
known to dysregulate the hypoxia response (Dahia, Ross et al. 2005). VHL 
mutations lead to hypoxia inducible factor (HIF) mediated hypoxia response with 
activation of genes involved in angiogenesis, proliferation, cell survival and 
death (Semenza 2002; Semenza 2002). Mutations in the SDH gene, an intergral 
enzyme of the Krebs cycle, also lead to activation of HIF mediated hypoxia 
signals likely through accumulation of Krebs cycle intermediates, mitochondrial 
complex II inhibition, and HIF1a over-expression (Gimenez-Roqueplo, Favier et 
al. 2001; Gimenez-Roqueplo, Favier et al. 2002; Gottlieb and Tomlinson 2005; 
Pollard, Briere et al. 2005; Selak, Armour et al. 2005; Dahia 2006).  
1.2 
Kinase inhibitors as therapeutics in pheochromocytoma and paraganglioma 
1.21 
Sunitinib 
Sunitinib is an oral multikinase inhibitor of VEGFR1-3, platelet-derived growth 
factor receptor (PDGFR)-α and -β, stem cell factor receptor (c-Kit), FLT3, and 
RET. Case studies and a case series from MD Anderson suggested benefit from 
this agent in patients with advanced metastatic pheochromocytomas and 
paragangliomas (Jimenez, Cabanillas et al. 2009; Joshua, Ezzat et al. 2009; 
Ayala-Ramirez, Chougnet et al. 2012; Jimenez, Rohren et al. 2013). 
 
1.22 
Pazopanib 
A phase II trial was conducted at our institution (Bible, PI) to evaluate the effects 
of another oral multikinase inhibitor, pazopanib, in patients with metastatic 
pheochromocytomas and paragangliomas, initiated after observing promising 
results in patients with metastatic differentiated thyroid cancers including 




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survival was 18.3 months in the lenvatinib group and 3.6 months in the 
placebo group (hazard ratio for progression or death, 0.21; 99% 
confidence interval, 0.14 to 0.31; P<0.001). The overall response rate 
(ORR) was 64.8% in the lenvatinib group and 1.5% in the placebo 
group (P<0.001).  
A phase 2 trial with medullary thyroid cancer (MTC) patients also 
showed promising results (Schlumberger, Jarzab et al. 2016). Fifty-
nine patients with unresectable progressive MTC who demonstrated 
progressive disease within the prior 12 months received lenvatinib at 
24 mg daily dose. Prior anti-VEGFR therapy was permitted. The 
primary endpoint was ORR. Lenvatinib ORR was 36% [95% 
confidence interval (CI), 24%-49%]. ORR was comparable between 
patients with (35%) or without (36%) prior anti-VEGFR therapy. 
Among responders, median time to response (TTR) was 3.5 months 
(95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 
months (95% CI, 7.0-not evaluable). 
Lenvatinib has not been concertedly yet investigated in paraganglioma 
and pheochromocytoma. We have, however, recently observed a very 
promising response to lenvatinib therapy in a patient with widely 
metastatic malignant paraganglioma noted as soon as after only two 24 
mg doses of lenvatinib were administered (Jasim Sina 2016). In 
particular, clinical regression of adenopathy was observed beginning 
only 24h after initial dosing. Therapeutic response was so prompt and 
profound that it was associated with (easily remediable) features 
suggestive of early tumor lysis syndrome. Anatomical response in this 
patient is indicated in Figure 2 below. We have subsequently treated 3 
more patients who have tolerated therapy but who have not yet 
undergone response assessment. All of these patients required careful 
close monitoring for adverse events including hypertension, including 
daily supervision via phone calls to provide dose modification advice 
and to assist in remediation of induced adverse effects. 
There is no ongoing clinical trial assessing the efficacy of lenvatinib in 
patients with pheochromocytoma or paraganglioma. We now thus 
propose studying lenvatinib in these patient groups. 
 
 
 




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(41%), stomatitis (36%), palmo-plantar erythrodysesthesia (32%) and 
proteinuria (31%). With the limited experience of using lenvatinib in 
paraganglioma/pheochromocytoma patients, we postulate that some 
patients may experience profound and quick response to therapy that 
may result in mild tumor lysis-like syndrome (Jasim Sina 2016).  
1.234 Quality -of –Life (QOL) Measurements for use of Lenvatinib 
As described above kinase inhibitors have been used previously for the 
treatment of advanced paraganglioma and pheochromocytoma patients 
(Ayala-Ramirez, Chougnet et al. 2012). Ayala-Ramirez et al. have 
described the largest cohort of patients treated with sunitinib for 
advanced and progressive metastatic pheochromocytoma/ and 
paraganglioma, however, data on QOL was unfortunately missing 
Clinical efficacy data on lenvatinib are derived from phase III, 
randomized, double-blind, multicenter study involving patients with 
progressive thyroid cancer that was refractory to iodine-131 (SELECT 
study) described above (Schlumberger, Tahara et al. 2015). This study, 
however, lacked the data on patient reported QOL during and after 
therapy.  
Data on QOL with other kinase inhibitors are variable. For instance, 
there was no reported change in QOL in renal cell carcinoma treated 
with sorafenib (Bukowski, Cella et al. 2007). While mild but detectable 
impact on health-related quality of life was noticed in patients with 
thyroid cancer (Schlumberger 2013).  
1.3 
Rationale 
Based on information presented above, agents implicated in inhibition of angiogenesis 
have been for long postulated as possible therapies for pheochromocytomas and 
paragangliomas (Jimenez, Cabanillas et al. 2009; Joshua, Ezzat et al. 2009; Ayala-
Ramirez, Chougnet et al. 2012; Jimenez, Rohren et al. 2013). To date, however, no 
clinical trials of tyrosine kinase inhibitors have been undertaken in 
pheochromocytoma/paraganglioma. 
In order to more rigorously assess the efficacy of tyrosine kinase inhibition in 
pheochromocytoma/paraganglioma, we plan to evaluate the tyrosine kinase inhibitor 
lenvatinib in these diseases in a phase II trial. Both patients with secretory and non-
secretory pheochromocytoma or paraganglioma will be permitted in the study as there is 
no substantial evidence to suggest that these tumor types are expected to have a 
differential response to lenvatinib—but we will examine this possibility in exploratory 
analyses as feasible. 
It is also not known whether patients with prior exposure to tyrosine kinase inhibitors 
may a have differential rate of response to lenvatinib compared to patients without such 
prior exposure. However, accumulating clinical evidence and experience in renal cell 
carcinoma and in thyroid cancer would suggest that tyrosine kinase inhibitors in general 
appear active even after prior exposure to anti-angiogenic therapy. Moreover, the patient 
response described in Figure 2 was observed in a patient who had previously received 
both CVD, and later, pazopanib therapy. As a result, and in consideration of the rarity of 
pheochromocytoma and paraganglioma requiring therapy as outlined in the clinical trial, 
we feel that there is greater disadvantage than advantage to developing independent 
patient cohorts based upon presence/absence of prior tyroisine kinase inhibitor therapy. 


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In assessing safety and efficacy of lenvatinib in patients with pheochromocytoma or 
paraganglioma, and given the wide range and seriousness of reported side effects, we 
plan to incorporate QOL data while treating our patient cohort in correlation with 
response outcomes. QOL data will be collected at baseline and every two months on 
therapy. We propose to use EQ-5D-5L descriptive questionnaire system designed by 
EuroQol group as well as FACT-G (Functional Assessment of Cancer Therapy-General). 
The usual starting dose for Lenvatinib in DTC is 24 mg per day (Schlumberger, Tahara et 
al. 2015). Hypertension is one of the most common side effects seen with lenvatinib use. 
Hypertension and its complications are usual in catecholamine secreting tumors like 
paragangliomas and pheochromocytomas. Therefore, a reduced starting dose of 20 mg 
daily is being proposed for this trial.    
 
1.4 
Hypotheses 
Hypothesis 1: Lenvatinib treatment of patients with advanced malignant 
pheochromocytoma and paraganglioma may lead to attenuated tumor 
growth and/or tumor regression (as defined by RECIST criteria – see 
Section 11.0). 
Hypothesis 2: Lenvatinib-induced changes in plasma and urinary catecholamine and/or 
metanephrine levels in patients with advanced, catecholamine secreting 
pheochromocytoma and paraganglioma may be observed and be 
predictive of patient objective response to lenvatinib therapy (per RECIST 
criteria – see Section 11.0). 
Hypothesis 3: Somatic mutational status (presence of SDHD, SDHB, RET, VHL, 
neurofibromatosis type-1 in archival tumors) may predict response to 
lenvatinib therapy. 
Hypothesis 4: Germline mutational status (detection of SDHD, SDHB, RET, VHL, 
neurofibromatosis type-1 in patient’s PBMCs) may predict response to 
lenvatinib therapy. 
Hypothesis 5: There is no significant deleterious net change in patient reported quality of 
life during lenvatinib therapy.  
 
 
 
 


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2.0 
OBJECTIVES 
2.1 
Primary objective 
To determine the anti-tumor activity of lenvatinib (overall response rate; ORR) in 
patients with metastatic or advanced unresectable pheochromocytomas and 
paragangliomas  
2.2 
Secondary objectives 
2.21 
To determine progression-free survival (PFS) 
2.22 
To determine overall survival (OS) 
2.23 
To determine duration of tumor response 
2.24 
To determine safety and tolerability of lenvatinib  
2.25 
To assess patient reported quality of life using EQ-5D-5L and FACT-G 
2.3 
Correlative objectives 
2.31 
For patients with secretory tumors, 
2.311 
To examine changes in plasma metanephrine levels and urinary 
catecholamine and/or metanephrine levels.  
2.312 
To examine whether lenvatinib-induced changes in plasma 
metanephrines and urinary catecholamine and/or metanephrine levels 
during the first cycle of treatment may be associated with objective 
tumor response.  
2.32 
To examine associations between tumor response and somatic mutational status 
in archived tumors, or germline mutational status (presence of SDHD, SDHB, 
RET, VHL, neurofibromatosis type-1).  
 
 


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3.0 
ELIGIBILITY 
3.1 
Inclusion Criteria  
3.11 
Age ≥18 years. 
3.12 
Histologically or cytologically confirmed malignant secretory or non-secretory 
pheochromocytoma or paraganglioma that is unresectable and deemed 
inappropriate for alternative local regional therapeutic approaches. 
3.13 
Measurable disease as defined in Section 11.0. 
3.14 
ECOG Performance Status (PS) 0, 1, or 2 (Appendix I). 
3.15 
Life expectancy >24 weeks. 
3.16 
The following laboratory values obtained ≤14 days prior to registration. 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
White blood cell (WBC) count ≥3,000/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Hemoglobin ≥9.0 g/dL (5.6mmol/L) 
NOTE: Transfusions are not allowed ≤7 days prior to registration 
• 
Total bilirubin ≤1.5 X upper limit of normal (ULN) 
(or total bilirubin ≤3.0 X ULN with direct bilirubin ≤1.5 X ULN in patients 
with well-documented Gilbert’s Syndrome) 
• 
Aspartate transaminase (AST/SGOT) ≤2.5 X ULN 
• 
Creatinine ≤1.5 X ULN 
• 
Urine protein/creatinine ratio ≤1 OR 24-hour urine protein <1.5 gram 
3.17 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
3.18 
Blood pressure (BP) <150 mmHg (systolic) and <90 mmHg (diastolic). Initiation 
or adjustment of BP medication is permitted prior to registration provided that 
the average of three BP readings at a visit prior to registration is <150/90 mmHg.  
NOTE: All patients with secretory pheochromocytoma or paraganglioma are 
REQUIRED to: 1) be evaluated in consultation by a hypertension specialist with 
specific experience in the management of hypertension in the setting of 
catecholamine-secreting tumors (usually an endocrinologist, nephrologist, or a 
cardiologist), and in the setting of hormone-associated hypertension) receive α- 
and β-adrenergic blockade for at least 7-14 days prior to initiation of lenvatinib 
(see Appendix IV for guidelines regarding proper α- and β-blockade). The 
hypertension specialist of record for each patient should be committed to closely 
following the patient during the clinical study with evaluation by said specialist 
required at Cycle 1 and 2 and thereafter on an as needed basis. Please see 
Appendix IV for guidelines on hypertension evaluation, follow up and 
management.  
Please note that this is a critical patient safety issue and that no exceptions to 
this approach are permitted. 
3.19a 
Provide written informed consent. 


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3.19b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.19c 
Ability to complete questionnaire(s) by themselves or with assistance. 
3.2 
Exclusion Criteria  
3.21 
Any of the following because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
3.22 
Chemotherapy/systemic therapy, radiotherapy, immunotherapy or surgery 
≤21 days prior to registration or kinase inhibitor therapy ≤14 days prior to 
registration or failure to recover from toxicities (to Grade 1 or below) from 
treatment. 
NOTE: Concurrent therapy with octreotide is allowed providing that tumor 
progression on this therapy has been demonstrated. Concurrent therapy with 
bisphosphonates (e.g. zoledronic acid) or denosumab is also allowed. 
NOTE: An unlimited number of prior chemotherapeutic or biologic therapies for 
malignant pheochromocytoma or paraganglioma is permitted. This includes prior 
anti-angiogenesis therapies such as tyrosine kinase inhibitors. 
3.23 
Active or uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
3.24 
Receiving any other investigational agent  
3.25 
Current use of warfarin for any reason. 
NOTE: If patient can be safely transitioned to another anticoagulant, they may 
be eligible provided other criteria are satisfied.  
3.26 
Any of the following: 
• 
QTc prolongation (defined as a QTc interval ≥500 msecs) 
• 
LVEF < institutional LLN 
• 
frequent ventricular ectopy  
• 
evidence of ongoing myocardial ischemia 
3.27 
Receiving any medications or substances with risk of torsades de pointes (see 
Appendix V for partial list). 
NOTE: Medications or substances with known Risk of Torsades de Pointes are 
prohibited. Consult pharmacist for review if needed. 
3.28 
Known active and/or untreated brain metastases. 
3.29a 
Known severe allergic or other prohibitive reactions to other tyrosine kinase 
inhibitors (TKI). 
3.29b Prior treatment with lenvatinib. 
3.29c 
Any of the following conditions: 
• 
Active peptic ulcer disease 
• 
Inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease) or other 


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gastrointestinal conditions which increase the risk of perforation 
• 
History of new abdominal fistula, gastrointestinal perforation or intra-
abdominal abscess ≤84 days prior to registration  
NOTE: Enrollment of patients with chronic/canalized fistulous tracts (present 
for >84 days) is allowed. 
• 
Serious or non-healing wound, ulcer, or bone fracture 
• 
History of familial QTc prolongation syndrome 
 
3.29d Any of the following conditions ≤6 months prior to registration:  
• 
Cerebrovascular accident (CVA) or transient ischemic attack (TIA)  
• 
Serious or unstable cardiac arrhythmia 
• 
Admission for unstable angina or Myocardial infarction 
• 
Cardiac angioplasty or stenting  
• 
Coronary artery bypass graft surgery  
• 
Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT 
which has been treated with therapeutic anticoagulation ≤30 days 
• 
Arterial thrombosis  
• 
Symptomatic peripheral vascular disease 
 
3.29e 
Other active malignancy ≤2 years prior to registration.  
EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.  
NOTE: If there is a history of prior malignancy, they must not be receiving other 
specific treatment for their cancer.  
NOTE: Adjuvant anti-estrogen/hormonal therapy for breast cancer is allowed 
 
 
 






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5.0 
STRATIFICATION FACTORS: None 
6.0 
REGISTRATION PROCEDURES  
6.1 
Registration 
6.11 
Mayo Clinic Sites 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) 
web page and enter the remote 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 
MCCC Registration Office at 
 between the hours of 8 
a.m. and 5:00 p.m. Central Time (Monday through Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page
and detail the 
process for completing and confirming patient registration. Prior to initiation of 
protocol treatment, this process must be completed in its entirety and a MCCC 
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 MCCC Registration Office 
. If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.12 
Non-Mayo Clinic sites 
To register a patient, fax 
a completed eligibility checklist to the 
Mayo Clinic Cancer Center (MCCC) Registration Office between 8 a.m. and 
4:30 p.m. central time Monday through Friday. 
6.2 
Verification 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval of the study 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
 


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6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
. If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.4 
Correlative studies 
An optional correlative component is part of this study. There will be an option to select 
if the patient is to be registered onto this component (see Section17.2). 
• 
Patient has/has not given permission to use his/her tissue sample for research testing 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research of cancer at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
6.5 
Treatment on protocol 
Treatment on this protocol must commence at enrolling institution under the supervision 
of a medical oncologist or endocrinologist  
6.6 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
6.7 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.8 
Baseline symptoms 
All required baseline symptoms (see Section 10.0) must be documented and graded. 
6.9a 
Study drug availability 
Study drug is available on site for this patient. 
6.9b 
Booklet availability 
Patient questionnaire booklet is available on site for this patient; copies are not acceptable 
for this submission. 
6.9c 
Consultation with hypertension specialist 
A hypertension specialist (endocrinologist, or cardiologist, or nephrologist) at enrolling 
institution has seen this patient and confirms the patient is a suitable candidate for this 
study ≤14 days prior to registration. 
 
 


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7.0 
PROTOCOL TREATMENT 
7.1 
Treatment Schedule 
Treatment will be administered on an outpatient basis. Reported AEs and potential risks 
are described in Sections 9 and 10. No other investigational or commercial agents or 
therapies may be administered with the intent to treat the subject’s malignancy. 
Subjects will receive lenvatinib on an outpatient basis at a dose of 20 mg/day (two 10-mg 
capsules; dose modification will be accomplished by combining 10-mg and 4-mg 
capsules as necessary). Subjects are instructed to swallow capsules once a day (preferably 
in the morning) with or without food with about 1 cup (240 mL) water. Capsules should 
be swallowed whole; they must not be chewed, broken, or crushed. Treatment continues 
until progression, excessive toxicity, or patient refuses to continue study medication. 
Missed and/or withheld doses of lenvatinib (whether intentional or not) are to be reported 
in the Medication Diary, but not made up. 
• 
Patients will be provided with a Medication Diary for lenvatinib (Appendix II). 
Patient should bring the diary back at the end of each cycle of treatment. 
• 
Any blood pressure medications patients is already taking or started during the 
treatment period should be listed in the CRF. 
 
Study drug lenvatinib will be administered at a dose of 20 mg daily by mouth on a 28 day 
cycle for a maximum of 5 years. 
7.11 
Treatment medication table 
Agent 
Dose Level 
Route 
Day 
ReRx 
Lenvatinib 
20 mg daily 
oral 
1-28 
Q4w 
7.2 
Criteria for Continuing Treatment 
Subjects will be evaluated at each clinic visit during the treatment period to determine if 
continued treatment is appropriate. If, at any time during treatment the evaluation criteria 
are not met, lenvatinib will be held or the dose adjusted according to the dose 
modification criteria stated in Section 8. 
 
To continue therapy, subjects must meet the following criteria: 
• 
Absolute neutrophil count (ANC) ≥1,000/mm3 (1 X 109/L), 
• 
Platelet count ≥50,000/mm3 (50 X 109/L), 
• 
Blood pressure, if elevated, should be controlled with antihypertensive medication(s),  
• 
Grade ≤3 proteinuria or (urinary protein ≤3.5 g/24 hrs), 
• 
QTc interval <500 msec, 
• 
hypokalemia or hyperkalemia ≤Grade 1 or within institutional limits of normal, 
• 
hypocalcemia or hypercalcemia is ≤Grade 2,  
• 
hypomagnesemia or hypermagnesemia is ≤Grade 2; Medical judgment should be 
exercised in deciding whether an AE of greater than or equal to grade 2 requires dose 
interruption or modification (see Section 8.0 for Dose Modification guidelines). 
7.3 
Self-administration statement  
Patients can be instructed in administration techniques and granted treatment 
independence with nursing staff approval. 
 
 


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7.4 
Return to consenting institution  
For this protocol, the patient must return to the consenting institution for evaluation at 
least every 28 days during treatment. 
NOTE: If patient is tolerating treatment well, return visits to Mayo Clinic may be reduced 
to once every 56-60 days at PI discretion. Required laboratory testing may be done 
locally and transmitted to Mayo Clinic.  
7.5 
Treatment by local medical doctor 
Treatment by local medical doctor (LMD) is not allowed and patients will be treated only 
at Mayo clinic. 
NOTE: For patients who are tolerating treatment well, safety assessments including labs 
may be done locally and transmitted to Mayo Clinic at PI discretion. 
7.6 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s) or intolerable toxicity, 
treatment will continue for a maximum of 5 yearsor until one of the following criteria 
applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable AE(s), 
 
Subject decides to withdraw from the study, or 
 
General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 
 
Patients who discontinue treatment for any of above reasons will proceed to 
event monitoring. 
 
7.7 
Duration of follow up 
 
If a patient discontinues treatment due to progression within 5 years of registration, 
submission of an event monitoring form is required every 6 months thereafter until 
death or a maximum of 5 years post-registration. 
 
If a patient discontinues treatment due to reasons other than progression or death 
within 5 years of registration, submission of an event monitoring form is required 
every 3 months until progression then every 6 months thereafter until death or a 
maximum of 5 years post-registration. 
 
If a patient is deemed ineligible after receiving treatment, all study-related materials 
including biospecimen data up until the point of confirmation of ineligibility must be 
submitted. The patient will proceed to event monitoring phase per Section 4.2 of the 
protocol. 
 
If a patient does not receive treatment, On-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further follow-up 
information is necessary.  
 
 
 


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8.0 
DOSAGE MODIFICATIONS 
Strictly follow the modifications in Table 8.1 for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, 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.  
8.1 
Dose Modification Table 
If patient is able to tolerate the starting dose of 20 mg daily for the first 2 cycles and if 
patient shows stable disease (SD) or objective response (OR) by RECIST 1.1 (see Section 
11.0), then dose can be escalated to 24 mg daily at the physician’s discretion. 
Otherwise follow the dose modifications below: 
Dose 
Level 
Lenvatinib 
+1 
24 mg daily 
0* 
20 mg daily 
-1 
14 mg daily 
-2 
10 mg daily 
*Dose level 0 refers to the starting dose. 
ALERT: ADR reporting may be required for some adverse events (See Section 10.0)  
8.2 
Dose Modifications Based on Adverse Events 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Blood and lymphatic 
system 
Anemia* 
Grade ≥3 
lenvatinib 
Hold treatment until event is ≤Grade 2; 
reduce one dose level 
If no recovery to ≤Grade 2 or recurrent 
Grade 3 or 4, discontinue lenvatinib and 
enter event monitoring. However, if the 
subject is benefiting from therapy, contact 
the PI to discuss course of action. 
Cardiac disorders 
Acute coronary 
syndrome  
Grade ≥3 
 
Discontinue lenvatinib and enter event 
monitoring 
Gastrointestinal 
disorders 
Diarrhea 
Grade ≥3 
 
Grade 3, hold lenvatinib until it resolves 
to Grade 1 or less and resume at one 
reduced dose level 
Grade 4, discontinue lenvatinib and enter 
event monitoring 
 
Nausea/vomiting 
Grade ≥3 despite 
antiemetics 
 
Grade 3, hold lenvatinib until it resolves 
to Grade 1 or less and resume at one 
reduced dose level 
Grade 4, discontinue lenvatinib and enter 
event monitoring 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Gastrointestinal 
disorders 
Weight loss 
Grade ≥3 
Discontinue lenvatinib and enter event 
monitoring 
However, if the subject is benefiting from 
therapy, contact the PI to discuss course of 
action 
General disorders and 
administration site 
conditions 
Fatigue  
Grade ≥2 
 
Grade 2, hold lenvatinib until it resolves 
to Grade 1 or less and resume at one 
reduced dose level 
Grade 3, discontinue lenvatinib and enter 
event monitoring 
Endocrine disorders 
Hypothyroidism 
Grade ≥3 
 
Grade 3 and 4, hold lenvatinib and replace 
with levothyroxine until TSH is 
normalized and resume lenvatinib at same 
dose 
Investigations 
Neutrophil count 
decreased 
Grade ≥3 
lenvatinib 
Hold treatment until event is ≤Grade 2; 
reduce one dose level 
If no recovery to ≤Grade 2 or recurrent 
Grade 3 or 4, discontinue lenvatinib and 
enter event monitoring  
However, if the subject is benefiting from 
therapy, contact the PI to discuss course of 
action 
 
Platelet count decreased 
Grade ≥3 
 
Hold treatment until event is ≤Grade 2; 
reduce one dose level 
If no recovery to ≤Grade 2 or recurrent 
Grade 3 or 4, discontinue lenvatinib and 
enter event monitoring 
However, if the subject is benefiting from 
therapy, contact the PI to discuss course of 
action 
Infections and 
infestations 
Any infection 
Grade ≥3 
 
Hold lenvatinib; resume when AE is 
Grade 1 or less 
Metabolism and 
nutrition disorders 
Tumor lysis Grade ≥3 
 
Hold lenvatinib until it resolves and 
resume at one reduced dose level 
Renal and urinary 
disorders 
Proteinuria Grade ≥3 
 
Grade 3, hold lenvatinib until it resolves 
to Grade 2 or less and resume at one 
reduced dose level (see Section 8.33) 
Grade 4, discontinue lenvatinib and enter 
event monitoring 
Skin and subcutaneous 
tissue disorders 
Palmoplantar 
erythrodysesthesia 
Grade ≥2 
 
Grade 2, hold lenvatinib until it resolves 
to Grade 1 or less and resume at one 
reduced dose level 
Grade 3, discontinue lenvatinib and enter 
event monitoring 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Skin and subcutaneous 
tissue disorders 
Maculopapular-rash 
Grade ≥2 
lenvatinib 
Grade 2, hold lenvatinib until it resolves 
to Grade 1 or less and resume at one 
reduced dose level 
Grade 3, discontinue lenvatinib and enter 
event monitoring 
Vascular disorders 
Hypertension 
Grade ≤3 
 
Dose adjust and/or hold lenvatinib and 
continue to manage per Appendix IV; 
consultation with expert recommended 
Grade 4, discontinue lenvatinib and enter 
event monitoring 
Other non-
hematologic adverse 
events  
(excluding alopecia) 
Grade ≥3 
 
Grade 3, hold lenvatinib until AE resolves 
to Grade 1 or less and resume at one 
reduced dose level  
Grade 4, discontinue lenvatinib and enter 
event monitoring 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the start of the 
next cycle, then the dose will remain lowered for that entire subsequent cycle. If that cycle is completed 
with no further adverse events >Grade 2, then the dose may be increased, at the investigator’s discretion, 
one level at a time, in the following cycles.  
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond the two dose-
reduction steps (levels –1 and –2) will be at the discretion of the treating physician, if the decision is made 
for the patient to be kept on study. These dose reductions must be clearly recorded in reported clinical 
data.  
8.3 
Management of Specific Adverse Events 
8.31 
Electrolyte abnormalities with or without tumor lysis syndrome 
Management of Grade 2 or higher hypokalemia and hyperkalemia, management 
of Grade 3 or higher hypomagnesemia and hypermagnesemia, Grade 3 or higher 
hypophosphatemia and Grade 3 or higher hypocalcemia and hypercalcemia. 
Management of Abnormal Laboratory Assessments 
Hypokalemia or hyperkalemia ≥Grade 2 
 
Hypocalcemia or hypercalcemia ≥Grade 3 
 
Hypophosphatemia ≥Grade 3 or 
 
Hypomagnesemia or hypermagnesemia 
≥Grade 3 
• Hold treatment and ECG must be performed 
• Laboratory values should be corrected as soon 
as possible in a manner consistent with good 
medical judgment 
• 
Lenvatinib may be re-administered when  
− hypokalemia or hyperkalemia is 
Grade 1 or within institutional 
normal limits 
− hypocalcemia or hypercalcemia is 
≤Grade 2 
− hypophosphatemia is ≤Grade 2 
− hypomagnesemia or 
hypermagnesemia is ≤Grade 2  


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8.32 
Management of QTc Prolongation 
Table below outlines the management of QTc prolongation of 500 msec and 
management of QTc prolongation of 60 msec or more from baseline. 
Management of QTc Prolongation 
If ECG reveals an increase in the QTc to >500 
msec or an increase in the QTc by at least 60 msec 
from baseline 
Hold lenvatinib and repeat ECG ≤7 days 
and before re-administration of lenvatinib 
If repeat ECG shows QTc interval is >500 msec 
Discontinue lenvatinib and patient enters 
the event monitoring  
If on repeat ECG, QTc remains at least 60 msec 
longer than baseline but is <500 msec  
Consider discontinuing lenvatinib or 
increase monitoring after discussion with PI 
8.33 
Management of Proteinuria 
If, at any time, a subject has a urine protein/creatinine ratio greater than 1, a 24 
hour urine collection must be performed. If a subject develops the nephrotic 
syndrome, treatment must be discontinued. 
Although subjects with ≥1+ proteinuria at entry are ineligible, increases in proteinuria 
may occur during treatment and should be managed as follows: 
Management of Proteinuria 
UPC >1and <3 
Obtain 24-hr urine protein and if <3.4 g, continue at current dose and 
monitor as clinically indicated 
UPC ≥3 or 24-h 
urine protein ≥3.5g 
Step 1: Hold lenvatinib 
Step 2: Weekly UPC or 24-hr urine protein monitoring until UPC is <3 or 
24-hr urine protein is <3 grams 
Then restart lenvatinib one dose level less 
Step 3: If UPC >3 or 24-h urine protein ≥3g recurs, repeat Steps 1 and 2 
Step 4: If UPC ≥3 or 24-hr urine protein ≥3 recurs and the lenvatinib dose 
can no longer be reduced, discontinue lenvatinib and remove 
subject from study 
 
8.34 
Management of Subjects with Elevations in AST, ALT and/or Bilirubin 
Management of AST, ALT and/or Bilirubin Elevations 
Isolated AST/ALT 
elevations between 
3X ULN and 8X 
ULN 
Continue lenvatinib, but monitor weekly until AST/ALT returns to ≤2.5 
or baseline 
AST/ALT >8 X 
ULN 
Hold lenvatinib until AST/ALT returns to ≤2.5 X ULN or baseline 
If the potential benefit of reinitiating lenvatinib treatment is considered 
to outweigh the risk for hepatotoxicity, then consider reintroducing 
lenvatinib at one dose level less and measure serum liver tests weekly 
for 8 weeks only after discussion with the PI 
If AST/ALT elevations >3 X ULN recur, then lenvatinib should be 
permanently discontinued and patient enters event monitoring phase 
AST/ALT >3 X 
ULN and 
Discontinue lenvatinib and enter event monitoring phase 


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concurrent direct 
bilirubin elevations 
>2 X ULN 
Mild indirect 
hyperbilirubinemia, 
known or suspected 
Gilbert’s syndrome, 
and elevation in 
ALT >3 X ULN 
Continue lenvatinib, but monitor weekly until ALT returns to Grade 1 
(NCI CTCAE v4) or baseline 
 
8.35 
Management of Other Adverse Events 
CTCAE 
SOC 
Adverse 
Event 
Grade 
Treatment Modification 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Broncho-
pulmonary 
hemorrhage 
Grade 1 
Hold therapy if hemoptysis is in excess of 2.5 mL 
(1/2 teaspoon) per day until resolved, otherwise 
maintain current dose. 
Grade 2 
Hold lenvatinib unless resolved to ≤Grade 1; reduce 
dose to next lower dose level, and continue 
treatment.  
If Grade 2 or greater hemorrhage/ bleeding recur 
following dose reduction, discontinue lenvatinib and 
patient enters event monitoring phase 
Grades 3 or 4 
Discontinue lenvatinib and patient enters event 
monitoring study phase 
 
 
Grade 1 
No interruption in treatment; maintain current dose 
Vascular 
disorders 
Thrombo-
embolic event Grade 2, 3 
Hold lenvatinib until subject is receiving a stable 
dose of Low Molecular Weight Heparin (LMWH). 
Concurrent warfarin will not be allowed, if patient 
needs warfarin, stop the study drug and enter event 
monitoring. 
Treatment may resume during the period of full-
dose anticoagulation if all of the following criteria 
are met: 
• The subject must be have been treated with an 
anticoagulant at the desired level for at least one 
week 
• The subject must not have had a Grade 3 or 4 or 
significant Grade 2 hemorrhagic event while on 
anticoagulant 
Subject should be monitored as clinically indicated 
during anticoagulation treatment and after resuming 
study treatment.  
 
 
Grade 4 
or pulmonary 
embolus 
Discontinue lenvatinib and patient enters event 
monitoring 
 
 


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9.0 
ANCILLARY TREATMENT/SUPPORTIVE CARE 
9.1 
Full supportive care  
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. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Vol 24, No 18 (June 
20), 2006: pp. 2932-2947. 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Diarrhea 
Diarrhea could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances. 
9.5 
Hypertension 
Please see Appendix IV for guidelines regarding management of hypertension. They 
should be seen by an expert in management of hypertension before they are started on the 
study drug. During the therapy patients will experience worsening of hypertension 
especially the secretory tumors and repeat consultation with the expert in recommended 
for concurrent management.  
9.6 
Tumor lysis syndrome 
Patients may experience tumor lysis-like syndrome if they get profound, rapid response 
to therapy. Tumor lysis is characterized by hyperkalemia, hypocalcemia, elevated uric 
acid, renal failure and ECG abnormalities. Please see Section 8.2 for dose modification. 
If there are changes in the electrolytes they should be managed as per the Section 8.31. If 
there is suspicion of tumor lysis or tumor lysis-like syndrome then therapy should be 
held, Allopurinol 300 mg daily should be instituted. EKG, laboratory examination, 
history and physical examination should be repeated in 1 week. If EKG and laboratory 
values have normalized, and patient is clinically stable then therapy can be re-instituted.  
9.7 
Precautions/Warnings  
9.71 
Drug-Drug Interactions 
There have been few completed human studies, at present, specifically evaluating 
drug-drug interactions with lenvatinib. The weak inhibitory effect on CYP P450 


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enzymes (in vitro) exhibited by lenvatinib suggests a low risk of lenvatinib 
interference with the pharmacokinetics of other drugs coadministered in usual 
clinic practice (Shumaker, Aluri et al. 2015). However, preliminary preclinical 
studies identify CYP3A4 as an important enzyme responsible for human hepatic 
metabolism of lenvatinib. Caution should be exercised when administering drugs 
metabolized by CYP3A4 or drugs that are inhibitors or inducers of CYP3A4 
(including herbal supplements or grapefruit), as administration of such drugs 
could affect the metabolism of lenvatinib. Please refer to Appendix III. 
Other medications have potential to increment risks to patients when combined 
with lenvatinib. These include: i) agents that increase bleeding risks (Warfarin is 
specifically prohibited, whereas heparin and NSAIDS/anti-platelet agents should 
be used with caution), and ii) bisphosphonates and denosumab (as there is 
potential that combined therapy with lenvatinib may further increase the risks of 
jaw osteonecrosis and other bone liabilities due to combined antiangiogenic 
effects). 
9.72  
Hypertension 
Hypertension is an important AE associated with lenvatinib (Schlumberger, 
Tahara et al. 2015). Frequent blood pressure (BP) monitoring is important in 
subjects receiving lenvatinib. In addition patients with secretory 
pheochromocytomas and paragangliomas are at risk for hypertension and 
hypertensive crisis by virtue of disease. Patients will be provided with a diary in 
which to record their daily BP readings (see Appendix VI) for fist three cycles. 
Daily readings should be taken. If the systolic reading is >140 mmHg OR the 
diastolic reading is >90 mmHg OR any combination of elevated systolic and 
diastolic readings, patients will be instructed to retake their blood pressure within 
1-4 hours. If a second consecutive reading is elevated patient will be instructed to 
contact their physician as soon as possible. Patients should seek medical advice if 
their BP exceeds 180 mmHg (systolic) or 105 mmHg (diastolic) at any time and 
should also be encouraged to contact their physician if they are concerned about 
any symptoms that may be associated with high BP (e.g., headache). In addition, 
expert consultation and follow-up for patients with secretory tumors will be 
required prior to enrollment, and during the study. Experience to date suggests 
that increases in BP may occur following dosing with lenvatinib for a number of 
weeks and that these increases may occur relatively quickly. It is imperative that 
the investigator institute appropriate measures to control BP. This may 
necessitate changes to existing antihypertensive medication, addition of new 
medication(s) and/or holding therapy with lenvatinib. Considering the potential 
of this adverse event we will monitor patients closely in the initial weeks with 
frequent measurement of blood pressure in clinic on Day 1, 3 and 10. 
Recommendations for hypertension monitoring and management are presented in 
Appendix IV. 
9.73 
QTc prolongation and Torsades de Pointes 
QTc prolongation was not seen in the healthy volunteers studied with lenvatinib 
(Shumaker, Zhou et al. 2014). But QTc prolongation and Torsades de Pointes are 
rare but possible serious adverse event associated with tyrosine kinase inhibitors. 
Therefore, the following is required:  
- 
Intensive QTc monitoring. A baseline ECG is required prior to study 
registration, and subjects with QTc≥500 msec are excluded. Repeat ECG 


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performed at the completion of Cycle 1 and 2. See Section 8.32 for dose 
modification related to QTc prolongation.  
- 
Subjects must be questioned about family history of prolonged QTc, personal 
history of prolonged QTc, relevant cardiac disease, and concomitant 
medications which are associated with a high risk of causing QTc 
prolongation prior to study registration.  
- 
Potassium, calcium, phosphate, and magnesium levels must be obtained 
before administration of the first dose of lenvatinib and as described in the 
study calendar, thereafter. 
9.74 
Tumor Lysis Syndrome 
Tyrosine kinase inhibitors have been previously used in the treatment of 
paraganglioma and pheochromocytoma. Mayo Clinic Phase 2 Consortium (P2C) 
was conducting a phase 2 trial with pazopanib. Seven patients were enrolled 
before the trial was closed due to lack of funding by National Cancer Institute. 
Another case series of 17 patients was also (Ayala-Ramirez, Chougnet et al. 
2012) published by the MD Anderson group and treatment was well tolerated. 
There were no reported cases of tumor lysis syndrome in both cohorts. However, 
one patient that was treated at Mayo Clinic with lenvatinib experienced transient 
fever, and a mild elevation of uric acid. Other laboratory parameters including 
potassium and creatinine were normal. Considering the potential of this milder 
form a tumor lysis we will monitor patients closely in the initial week with 
frequent measurement of electrolytes and clinic visits on Day 1, 3 and 10.  
 
9.75 
Proteinuria 
Urinary protein/creatinine ratio should be frequently monitored to screen for 
proteinuria as it is a known adverse event associated with antiangiogenic agents 
including lenvatinib. Specific guidelines for management of proteinuria are 
presented in Section 8.2 and Section 8.33. 
 
 
 
 




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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).  
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 
10.1 
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 utilized 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: 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. 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). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined 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. 
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. 


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NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 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 10.6).* 
*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. 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be reported in an expedited 
manner1 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 4 
Investigations 
Lymphocyte count decreased 
≤Grade 4 
 
Neutrophil count decreased 
≤Grade 4 
 
Platelet count decreased 
≤Grade 4 
 
White blood cell count 
decreased 
≤Grade 4 
General disorders and 
administrations site 
conditions 
Fatigue  
≤Grade 3 
Malaise 
≤Grade 3 
Gastrointestinal disorders 
Nausea 
≤Grade 3 
Vomiting 
≤Grade 3 
Diarrhea 
≤Grade 3 
Renal and urinary 
disorders 
Proteinuria 
≤Grade 2 
Skin and subcutaneous 
tissue disorders 
Alopecia 
≤Grade 2 
Rash 
≤Grade 3 
Vascular disorders 
Hypertension 
≤Grade 3 
1 These exceptions 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.  
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 










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10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation.  
Grading is per CTCAE v4.0 unless alternate grading is indicated in the table 
below: 
System Organ Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Blood and lymphatic system 
disorders 
Anemia 
X 
X 
Gastrointestinal disorders 
No. of stools 
X 
 
 
Diarrhea 
 
X 
 
Mucositis oral 
 
X 
 
Nausea 
X 
X 
 
Oral dysesthesia 
 
X 
 
Vomiting 
 
X 
 
Weight loss 
 
X 
General disorders and 
administration site conditions 
Fatigue 
X 
X 
Renal and urinary disorders 
Proteinuria 
X 
X 
Respiratory, thoracic and 
mediastinal disorders 
Cough 
X 
X 
Skin and subcutaneous  
Rash maculo-papular 
X 
X 
disorders 
Palmar-plantar 
erythrodysesthesia syndrome 
X 
X 
Vascular disorders 
Hypertension 
X 
X 
10.62 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 


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10.6232 
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. 
10.7 
Late Occurring Adverse Events 
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). 
 
10.8 
[Insert industry partner name] Additional Event Reporting Instructions 
Insert any additional language requested by industry partners in this section. 
 
11.0 
TREATMENT EVALUATION 
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)(Eisenhauer, Therasse et al. 2009). 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 8 weeks for the first 
year and then every 12 weeks after Year 1. 
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 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 considered measurable disease 
under the following conditions:  
• 
If they have progressed at screening evaluation 
11.22 Non-Measurable Disease 
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. 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 


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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 
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.  


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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 8 
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.  
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.  


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• 
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/ 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 
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. 
c. Normalization of tumor biomarkers. 
• 
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 






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13.0 
TREATMENT/FOLLOW–UP DECISION AT EVALUATION OF PATIENT  
13.1 
Continuation of treatment 
Patients who are CR, PR, or SD will continue treatment per protocol. 
13.2 
Progressive disease (PD) 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
13.3 
Off protocol treatment 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 4. 
13.4 
Complete response 
If the patient has achieved CR then treatment will continue for a maximum of 5 years 
from time of registration.  
13.5 
Duration of therapy for PR or SD 
Patients who are in PR or SD will continue on therapy until PD or for maximum 5 years 
from registration date and then they will go to event monitoring. Subsequent treatment is 
at the discretion of their attending physician 
13.6 
Progressive Disease (PD) 
Patients who develop PD at any time should go to event monitoring.  
13.7 
Inevaluable patients 
If a patient fails to complete the first cycle of treatment for reasons other than toxicity, 
the patient will be regarded as inevaluable and will be replaced.  
13.8 
Ineligible 
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.  
13.9a Major violation 
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. 
 
 


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13.9b Cancel 
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 the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 
14.0 
BODY FLUID BIOSPECIMENS 
Optional blood and urine specimen for correlative studies will be collected from Mayo Clinic 
patients at baseline for Mayo Clinic biomarker study (IRB 13-005838) . Patient will be consented 
separately for the study and provided with study card for blood and urine collection. Collection, 
transport and processing should follow IRB 13-005838 instructions. 
 


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15.0 
DRUG INFORMATION 
15.1 
Lenvatinib (E7080, Lenvima®) 
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 4 mg and 10 mg capsules. The following 
are capsule 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. 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 of water or apple juice (one tablespoon) to the glass. Swirl the contents 
of the glass a few times and swallow the additional liquid. If a patient misses 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. 
15.15 Pharmacokinetic information: 
Absorption: Lenvatinib is rapidly absorbed after oral administration with tmax 
typically observed from 1 to 4 hours postdose. 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. 


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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 adverse events: 
Common known potential toxicities, >10%: 
Gastrointestinal disorders: Abdominal pain, diarrhea, nausea, vomiting 
General disorders and administrative site conditions: Asthenia 
Metabolism and nutrition disorders: Decreased appetite, dehydration 
Renal and urinary disorders: Acute kidney injury 
Vascular disorders: Hypertension 
 
Less common known potential toxicities, 1%-10%: 
Metabolism and nutrition disorders: dehydration 
Respiratory, thoracic, and mediastinal disorders: pulmonary embolism 
Vascular disorders: hypotension 
Rare known potential adverse events, <1% (Limited to important or life-
threatening): 
Blood and lymphatic disorders: Thrombocytopenia 
Cardiac disorders: Acute myocardial infarction, myocardial infarction, cardiac 
failure, congestive cardiac failure, coronary artery occlusion, left ventricular 
dysfunctioion 
Endocrine disorders: hypothyroidism 
Gastrointestinal disorders: abdominal pain lower, abdominal pain upper, anal 
fistula, constipation, diverticular perforation, intestinal perforation, pancreatitis, 
acute pancreatitis, rectal hemorrhage, rectal perforation, stomatitis, upper 
gastrointestinal hemorrhage 
Hepatobiliary disorders: Cholecystitis, cholecystitis acute, hepatic failure, 
hepatic function abnormal, hepatitis acute, hyperbilirubinemia, liver injury 
Infections and infestations: Colonic abscess, perineal abscess, urinary tract 
infection, urosepsis 


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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:  
Neoplasms benign, malignant and unspecified: Intracranial tumor hemorrhage, 
tumor hemorrhage 
Nervous system disorders: Cerebral hemorrhage, cerebral infarction, 
cerebrovascular accident, dizziness, hemorrhage intracranial, headache, ischemic 
stroke, monoparesis,, reversible posterior leukoencephalopathy syndrome, 
subarachnoid hemorrhage, transient ischemic attack 
Renal and urinary disorders: Hematuria, proteinuria, renal failure, renal 
impairment, renal tubular necrosis 
Reproductive system and breast disorders: Female genital tract fistula, vaginal 
hemorrhage 
Respiratory, thoracic, and mediastinal disorders: Epistaxis, hemoptysis, 
pulmonary hemorrhage 
Vascular disorders: Hypertensive crisis 
15.18 Drug procurement 
Each participating site will order/monitor drug supply through Eisai Inc. 
NOTE: Outdated or remaining drug is to be destroyed on-site 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 patient 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. 


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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 LFTs and renal function. Report any elevations to the 
provider. 
 


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16.0  
STATISTICAL CONSIDERATIONS AND METHODOLOGY  
16.1 
Statistical Design: 
A Simon two-stage, phase II optimal clinical trial design was chosen to examine anti-
tumor activity and safety profile of lenvatinib as a treatment for patients with progressive 
malignant pheochromocytoma or paraganglioma. 
16.11 Primary endpoint 
The primary endpoint is the confirmed tumor response rate defined as 100% 
times the number of eligible patients who has started lenvatinib and whose 
objective tumor status was a CR or PR on 2 consecutive evaluations at least 
4 weeks apart (using RECIST v1.1 criteria) divided by the number of eligible 
patients who has started lenvatinib.  
16.12 Operating Characteristics 
The largest tumor response rate for which there would be little interest in 
pursuing further studies of this lenvatinib regimen in patients with progressive 
malignant pheochromocytoma or paraganglioma is 10%. The smallest tumor 
response rate for which there would be interest in pursuing further studies of this 
lenvatinib regimen in patients with progressive malignant pheochromocytoma or 
paraganglioma is 30%. The study design proposed below yields a 85% chance of 
detecting that the true tumor response rate is at least 30% at a 0.15 significance 
level when the true tumor response rate is at least 10% 
16.121 
Stage 1: Enter 6 eligible patients. If no tumor responses are 
documented among these 6 patients within the first 6 cycle of 
treatment, we will consider the regimen lacking in sufficient antitumor 
activity to recommend further testing in this patient population and 
terminate further enrollment. If at least one response is observed 
among these 6 patients within the first 6 cycles of treatment, we will 
proceed to Stage 2.  
16.122 
Stage 2: Enter an additional 17 eligible patients. If three or fewer tumor 
responses are documented among all 23 eligible patients within the 
first 6 cycle of treatment, we will consider the regimen lacking in 
sufficient antitumor activity to recommend further testing in this 
patient population. If four or more tumor responses are documented 
among all 23 eligible patients within the first 6 cycle of treatment, this 
will be considered of the regimen to have promising antitumor activity 
in this patient population. 
We anticipate enrolling a minimum of 6 and a maximum 23 eligible. 
At the close of stage 1 or stage 2 enrollment, if more patients than 
planned have been enrolled only the first 6 eligible patients or the first 
23 eligible patients enrolled, respectively, will be used to evaluate the 
decision rule. We anticipate accruing 2 additional patients (25 total) to 
account for patients found to be ineligible after signing a consent or 
who refused to start study treatment after signing a consent form. 
16.13 Power and Significance Level 
Assuming that the number of tumor responses is binomially distributed, the 
probability of declaring that this regimen warrants further studies (i.e. statistical 
power) under various tumor response rates and the probability of stopping 


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accrual after the first stage can be tabulated as a function of the true tumor 
response rates as shown in the following table. 
 
If the true tumor response 
rate is 
10% 
15% 
20% 
25% 
30% 
Then the probability of 
declaring that the regimen 
warrants further study is… 
0.15 
0.37 
0.59 
0.75 
0.85 
And the probability of 
stopping at the completion 
of stage 1 
0.53 
0.38 
0.26 
0.18 
0.12 
16.14 Accrual Time and Study Duration:  
No similar studies have been conducted for comparison. Based on our anecdotal 
experience from referrals of patients from outside institutions who would 
otherwise fit eligibility criteria we believe we will be able to enroll 4 to 8 patients 
per year at our institution (Mayo clinic). We believe we can complete accrual 
within the proposed 3-year period. 
 
16.2 
Analysis Plan:  
16.21 Primary Endpoint:  
Ninety-five percent confidence intervals for the true response proportion will be 
calculated according to the approach of Duffy and Santner (Duffy and Santner 
1987). 
16.22 Definitions and analyses of secondary clinical endpoints 
• 
Safety profile of lenvatinib 
• 
Duration of tumor response 
• 
Progression-free survival time 
• 
Overall survival time 
• 
Patient reported quality of life (QOL) using EQ-5D, and FACT-G 
16.221 
Safety profile of lenvatinib 
All adverse events will be graded using the NCI CTCAE Version 4.0. 
For each type of adverse event classified as either possibly, probably, 
or definitely related to study treatment, the proportion of patients 
experiencing a severe (grade 3 or higher) adverse event will be noted 
per cycle. 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. 
16.222 
Time to event distributions 
Time to event distributions will be estimated using the Kaplan-Meier 
method 
16.2221 Duration of response 
Duration of response is defined for all patients whose tumor 
met the criteria of CR or PR (using the RECIST criteria) as 
the date at which the patient’s objective status is first noted 


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to be either a CR or PR to the date progression is 
documented. 
16.2223 Progression-free survival  
Progression-free survival is defined as the time from 
registration to documentation of disease progression. If a 
patient dies without a documentation of disease progression, 
the patient will be considered to have had tumor progression 
at the time of their death unless there is sufficient 
documented evidence to conclude no progression occurred 
prior to death. 
If the patient is declared to be a major treatment violation, 
the patient will be censored on the date the treatment 
violation was declared to have occurred. In the case of a 
patient starting treatment and then never returning for any 
evaluations, the patient will be censored for progression on 
Day 1 post treatment. 
16.2224 Overall survival time  
Overall survival time is defined as the time from registration 
to death due to any cause.  
16.2225 Patient reported quality of life (QOL) using EQ-5D, and/or 
FACT-G 
Descriptive statistics, and scatter plots will form the basis of 
presentation of these data both overall and by other 
outcomes (toxicity, response and survival measures). 
Correlations between the QOL outcomes and other outcome 
measures will be carried out by standard parametric and non-
parametric tests (e.g. Pearson’s and Spearman’s rho). 
Comparison between continuous variables will be made with 
Wilcoxon rank sum tests, Fisher’s exact tests will be used to 
determine differences between categorical variables, and 
Log-rank test will be used to test differences between time-
to-event outcomes. 
16.23 Correlative aims:  
16.231 
For patients with secretory tumors  
To examine changes in urinary catecholamine and metanephrine levels 
during treatment, time series plots of urinary catecholamines and 
metanephrines levels will be constructed (with patient whose tumor 
responded to treatment in red and patients whose tumor remained 
stable or progressed in blue) to visually assess trends prior to treatment 
discontinuation within and between chemistries as well as difference in 
trends between those whose tumor responded to treatment and those 
whose tumor did not.  
To examine whether lenvatinib-induced changes in urinary 
catecholamine and/or metanephrine levels during the first cycle of 
treatment may be associated with objective tumor response, the fold 
change from baseline levels for each biomarker will be determined. For 
each biomarker, a plot of the fold change versus response status will be 
constructed to visually assess differences between those whose tumor 


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responded to treatment and those whose tumor did not. If feasible, 
Wilcoxon rank sum tests will be used to examine whether fold changes 
in a given biomarker during the first cycle of treatment differs between 
whose tumor responded to treatment and those whose tumor did not.  
16.232 
To examine associations between tumor response and somatic 
mutational status in archived tumors, or germline mutational status in 
patient’s peripheral blood mononuclear cells, (presence of SDHD, 
SDHB, RET, VHL, neurofibromatosis type-1).  
For SDHD, SDHB, RET, VHL, neurofibromatosis type-1, a 95% 
confidence interval for the difference in proportion of patients who 
have a documented tumor response among those with that particular 
biomarker present and proportion of patients who have a documented 
tumor response among those without that particular biomarker present. 
16.3 
Reporting and Exclusions 
16.31 Evaluation of adverse events.  
All subjects will be evaluable for adverse events from the time of their first 
treatment with lenvatinib. 
16.32 Evaluation of response.  
All subjects included in the study must be assessed for response to treatment, 
even if there are major protocol treatment deviations or if they are ineligible. 
Each subject will be assigned one of the following categories: 1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early death because 
of other cause, or 9) unknown (not assessable, insufficient data). [Note: By 
arbitrary convention, category 9 usually designates the “unknown” status of any 
type of data in a clinical database.] 
All of the subjects who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main analysis 
of the response rate. Subjects in response categories 4-9 should be considered to 
have a treatment failure (disease progression). Thus, an incorrect treatment 
schedule or drug administration does not result in exclusion from the analysis of 
the response rate. Precise definitions for categories 4-9 will be protocol specific.  
All conclusions should be based on all eligible subjects. Subanalyses may then be 
performed on the basis of a subset of subjects, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.). However, 
these subanalyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding subjects from the analysis 
should be clearly reported. The 95% confidence intervals should also be 
provided. 
 
 


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16.4 
Monitoring 
The principal investigator and the study statistician will review the study periodically to 
identify accrual, toxicity, and any endpoint problems that might be developing. In 
addition, this study will be monitored according to the Mayo Clinic Cancer Center 
(MCCC) Data Safety Monitoring Plan that is currently in place. The MCCC Data Safety 
Monitoring Board (DSMB) is responsible for reviewing safety data for this trial at least 
twice a year, based on reports provided by the MCCC Statistical Office. 
16.41 Adverse Event Stopping Rules 
NOTE: NCI CTCAE v4.0 will be used to determine grading for adverse event 
stopping rules. 
If 2 or more of the first 5 patients enrolled or 30% or more of the patients 
enrolled thereafter develop a grade 4 or severer non-hematologic toxicity (except 
for hypertension) or grade 4 or severer hematologic toxicity that are considered 
possibly, probably, or definitely related to treatment, enrollment to the study will 
be suspended. The study team will review all adverse event data. A trial 
recommendation will be formulated and presented to the MCCC DSMB – the 
study may permanently close or may re-open to accrual after CTEP and IRB 
approvals of protocol/consent form modifications. 
16.5 
Results Reporting on ClinicalTrials.gov 
At study activation, this study will have been registered within the “ClincialTrails.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on www.ClinicalTrials.gov. For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 3 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 6 months. 
16.6 
Subset Analyses for Minorities:  
16.61 Study availability 
This study will be available to all eligible patients, regardless of gender, race or 
ethnic origin.  
16.62 Statistical analysis by subset 
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. Therefore, although the planned analyses will 
look for differences in treatment effect based on racial groupings, the sample size 
is not increased in order to provide additional power for subset analyses.  
16.63 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 33% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
 
 


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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
1 
1 
Not Hispanic or Latino 
12 
12 
24 
Ethnic Category: Total of all subjects 
12 
13 
25 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
1 
2 
Black or African American 
0 
1 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
11 
11 
22 
Racial Category: Total of all subjects 
12 
13 
25 
 
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. 




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paraganglioma is strongly associated with mutations of the B subunit of the gene 
(SDHB). 
Global expression profiles of large series of sporadic pheochromocytomas and 
paragangliomas have generated 2 unique transcription signatures (Eisenhofer, 
Bornstein et al. 2004; Dahia, Ross et al. 2005). In the first cluster belong 
mutations of the VHL, SDHB and SDHD genes known to be associated to VHL 
and PGL syndromes, while in the second cluster belong mutations in the RET 
and NF1 genes associated with the MEN syndromes. Both VHL and SDH 
mutations are known to dysregulate the hypoxia response (Dahia, Ross et al. 
2005). Mutations in the SDH gene, an enzyme of the Krebs cycle, also lead to 
activation of HIF mediated hypoxia signals likely through accumulation of Krebs 
cycle intermediates, mitochondrial complex II inhibition, and HIF1a over-
expression (Gimenez-Roqueplo, Favier et al. 2001; Gimenez-Roqueplo, Favier et 
al. 2002; Gottlieb and Tomlinson 2005; Pollard, Briere et al. 2005; Selak, 
Armour et al. 2005; Pollard, El-Bahrawy et al. 2006).  
17.32 Methodology 
We will investigate if the somatic mutations and germline mutations in 
paragangliomas and pheochromocytomas correlated with outcome data. FFPE 
collected at registration will be subjected to DNA extraction and analyzed for 
mutations in select genes using DNA sequencing.  
Ten 5-micron unstained slides and 1 hematoxylin and eosin (H&E) stained slide 
will be cut from fresh frozen paraffin embedded (FFPE) tissue block. Pathologist 
will review slides and circle areas with adequate tumor tissue (>20%-40%). 
Circled H&E slide will serve as template for microdissection (using razor blade 
or scalpel) of unstained slides for DNA extraction. DNA extraction will be 
performed using Qiagen FFPE kit as per manufacturer’s protocol. Approximately 
30 ng of input DNA will be placed into a polymerase chain reaction. The Ion 
Ampliseq Cancer Hotspot Panel v2 primers (Life technologies) and Illumina 
MiSeq instrument will be used for gene sequencing. The mutations and genetic 
alterations identified will be correlated with reference to clinical data obtained 
during the conduct of the trial. 
Germline mutation data will be collected from consenting patients and correlated 
with outcome data. If it is already performed we will obtain the report. If not 
performed, consulatation will be perfoemed with genetic counelsor and germline 
testing obtained if conseted and recommended. 
Both of the above components, somatic mutational profile and germline testing 
are optional correlatives. 
 


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18.0 
RECORDS AND DATA COLLECTION PROCEDURES  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission Schedule 
(in Medidata Rave®). 
18.2 
Event monitoring 
See Section 4.0 and Data Submission Schedule for the event monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for evidence of response to study therapy 
and progression after study therapy (CR, PR, PD).  
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any materials deemed incomplete by the MCCC Operations Office will be considered 
“not received” and will not be edited or otherwise processed until the missing 
information is received. A list of the missing documents will be made available to the 
appropriate co-sponsor/participant. 
18.8 
Overdue lists 
A list of overdue materials and forms for study patients will be generated monthly. The 
listings will be sorted by location and will include the patient study registration number. 
The appropriate co-sponsor/participant will be responsible to obtain the overdue material. 
18.9 
Corrections forms 
If a correction is necessary the QAS will query the site. The query will be sent to the 
appropriate site to make the correction and return the query and documentation of 
correction back to the QAS.  
 
19.0  
BUDGET 
19.1 
Costs charged to patient: routine clinical care 
19.2 
Tests to be research funded: 
19.3 
Other budget concerns: 
 
 


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20.0 
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metabolism 94(2): 386-391. 
Jimenez, C., E. Rohren, et al. (2013). "Current and future treatments for malignant pheochromocytoma 
and sympathetic paraganglioma." Current oncology reports 15(4): 356-371. 
Jirari, A., A. Charpentier, et al. (1999). "A malignant primary cardiac pheochromocytoma." The Annals 
of thoracic surgery 68(2): 565-566. 
John, H., W. H. Ziegler, et al. (1999). "Pheochromocytomas: can malignant potential be predicted?" 
Urology 53(4): 679-683. 


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Joshua, A. M., S. Ezzat, et al. (2009). "Rationale and evidence for sunitinib in the treatment of malignant 
paraganglioma/pheochromocytoma." The Journal of clinical endocrinology and metabolism 
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394-398. 
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Surgery 120(6): 938-942; discussion 942-933. 
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652. 
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Neumann, H. P., B. Bausch, et al. (2002). "Germ-line mutations in nonsyndromic pheochromocytoma." 
The New England journal of medicine 346(19): 1459-1466. 
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genetics 14(15): 2231-2239. 


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Pollard, P. J., M. El-Bahrawy, et al. (2006). "Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their 
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discussion 962-953. 
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Selak, M. A., S. M. Armour, et al. (2005). "Succinate links TCA cycle dysfunction to oncogenesis by 
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Sisson, J. C., B. L. Shulkin, et al. (2006). "Courses of malignant pheochromocytoma: implications for 
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486-492. 


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Srimuninnimit, V. and G. L. Wampler (1991). "Case report of metastatic familial pheochromocytoma 
treated with cisplatin and 5-fluorouracil." Cancer chemotherapy and pharmacology 28(3): 217-
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Stenstrom, G. and K. Svardsudd (1986). "Pheochromocytoma in Sweden 1958-1981. An analysis of the 
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Tischler, A. S., N. Kimura, et al. (2006). "Pathology of pheochromocytoma and extra-adrenal 
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Tohyama, O., J. Matsui, et al. (2014). "Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor 
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van Heerden, J. A., S. G. Sheps, et al. (1982). "Pheochromocytoma: current status and changing trends." 
Surgery 91(4): 367-373. 
Yamada, K., N. Yamamoto, et al. (2011). "Phase I dose-escalation study and biomarker analysis of E7080 
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Zielke, A., M. Middeke, et al. (2002). "VEGF-mediated angiogenesis of human pheochromocytomas is 
associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors." 
Surgery 132(6): 1056-1063; discussion 1063. 
 
 
 
 


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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf stat.html 
 
 


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Appendix II 
Patient Medication Diary 
Name  
 
Study ID Number  
 
 
Please complete this diary on a daily basis. Write in the amount of the dose of lenvatinib that you took in 
the appropriate “Day” box (for example: 20 mg). 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily dose, 
please write in “0”, but remember to take your prescribed dose at the next regularly scheduled time. 
If you experience any health/medical complaints or take any medication other than lenvatinib, please 
record this information. 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Lenvatinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Lenvatinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Lenvatinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Lenvatinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient signature: ___________________________________________ 
Health or medical complaints during this time: 
 
 
 
 
 
 
 
 
 




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Appendix III Potential drugs that could interact with lenvatinib (via CYP 3A4) 
Inhibitors and inducers of CYP3A are shown below. A comprehensive list of inhibitors can be found at 
the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx . The general categorization 
into strong, moderate, and weak inhibitors according to the website is displayed below.  
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
INDINAVIR 
NELFINAVIR 
RITONAVIR 
CLARITHROMYCIN 
ITRACONAZOLE 
KETOCONAZOLE 
NEFAZODONE 
Posaconazole 
SAQUINAVIR  
SUBOXONE 
TELITHROMYCIN 
Voriconazole 
Moderate inhibitors: 
Aprepitant 
Erythromycin 
Diltiazem 
Fluconazole 
grapefruit juice 
Seville orange juice 
Verapamil 
Weak inhibitors: 
Cimetidine 
All other inhibitors: 
Amiodarone 
NOT azithromycin 
Chloramphenicol 
Boceprevir 
Ciprofloxacin 
Delaviridine 
diethyl-dithiocarbamate 
Fluvoxamine 
Gestodene 
Imatinib 
Mibefradil 
Mifepristone 
Norfloxacin 
Norfluoxetine 
star fruit 
Telaprevir 
Troleandomycin 
Carbamazepine 
Efavirenz 
Nevirapine 
Barbiturates 
Glucocorticoids 
Modafinil 
Oxcarbarzepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s Wort 
Troglitazone 
 


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Appendix IV Hypertension Management Guidelines 
D.1. Guidelines for the management of lenvatinib-Induced Hypertension: 
Non-secretory tumors  
(For secretory tumors please see Section D.2.) 
Increases in blood pressure (BP) and cases of hypertension have been associated with many 
drugs acting on the VEGF pathway. The proposed mechanism for this increase is through 
inhibition of VEGF-induced peripheral vasodilation. Hypertension following lenvatinib is 
well documented in clinical trials. With secretory paraganglioma and pheochromocytoma this 
could be a major toxicity.  
NOTE: that hypertension management of secretory tumors is more complex due to the 
additional risk of hypertension issues in these patients and management is discussed 
separately below. For example consultation with HTN specialist is required in patients with 
secretory tumors prior to study initiation. 
• 
While subjects are receiving treatment with lenvatinib, the early initiation of 
antihypertensive treatment for grade 1 or 2 hypertension to minimize more severe or 
persistent hypertension is not considered a grade 3 AE. 
• 
Decisions to hold or decrease the lenvatinib dose during treatment must be based on BP 
readings taken in the clinic by a medical professional. 
Recommended Hypertension Monitoring and Management for non-
secretory tumors (BP in mmHg) 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Lenvatinib 
Dose Modification 
Persistent* Grade 1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-90  
 
Standard  
No Change 
Persistent Grade 2- 
Moderate 
Systolic 140-159  
Diastolic 90-99  
 
Protocol-specific 
guidance supersedes 
any other management 
guidelines, including 
CTCAE v4.  
Step 1) Initiate anti-
hypertensive treatment 
(calcium channel 
blocking agents, e.g. 
amlodipine, are generally 
the preferred agents) and 
if needed, after 24-48 hr 
Rx, increase dose in 
stepwise fashion every 
24-48 hours until BP is 
controlled or at max dose 
of Rx 
Step 2) If BP still not 
controlled, add another 
anti-hypertensive Rx, a 
LA DHP CCB, ACE1, 
ARB, or ABB; increase 
dose of this drug as 
described in Step 1  
Step 3) If BP still not 
controlled, add 3rd drug 
from the list of anti-
BP should be 
monitored as 
recommended by the 
treating physician  
No change except as 
described in Step 4 


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Recommended Hypertension Monitoring and Management for non-
secretory tumors (BP in mmHg) 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Lenvatinib 
Dose Modification 
hypertensives in Step 2; 
increase dose of this drug 
as described in Step 1 
Step 4) If BP still not 
controlled, discontinue 
lenvatinib until BP 
controlled, then resume 
NOTE: Stopping or 
reducing the dose of 
lenvatinib is expected to 
cause a decrease in BP. 
The treating physician 
should monitor the 
subject for hypotension 
and adjust the number 
and dose of anti-
hypertensive medic-
ation(s) accordingly 
Persistent Grade 3 
Severe  
Systolic ≥160 
Diastolic ≥100 
 
Protocol-specific 
guidance supersedes 
any other management 
guidelines, including 
CTCAE v4 
HOLD lenvatinib until 
systolic BP ≤159 and 
diastolic BP ≤99 
 
BP management is 
identical to that for 
Grade 2 (see Steps 1-4 
above) with 2 major 
exceptions:  
1) If systolic BP >180 or 
diastolic BP >110 and 
the subject is 
symptomatic: optimal 
management with 
intensive IV support in 
ICU; STOP lenvatinib 
and notify hospital staff 
that stopping drug may 
result in a decrease in 
BP 
 and  
2) If systolic BP >180 or 
diastolic BP >110 and 
the subject is 
asymptomatic, 
consideration to 
initiation of 2 new 
antihypertensives 
together should be given 
in step 1 (and dose 
escalated appropriately 
as in step 1). 
BP should be 
monitored as 
recommended by the 
treating physician 
unless the subject is 
symptomatic with  
systolic BP >180 or 
diastolic BP >110 in 
which case, 
monitoring should 
be intensive 
HOLD lenvatinib 
until systolic BP 
≤159 and diastolic 
BP ≤99. After this, 
lenvatinib may be re-
administered. If BP is 
still Grade 2, manage 
as described above 
for Grade 2 
hypertension.  
 
In most 
circumstances, if BP 
cannot be controlled 
after an optimal trial 
of antihypertensive 
medications, consider 
either 1 dose 
reduction of 
lenvatinib when 
systolic BP ≤159 and 
diastolic BP ≤99 or 
stopping lenvatinib. 
 
HOWEVER, 
If the subject 
requires 
hospitalization for 
management of 
symptomatic 
systolic BP >180 or 
diastolic BP >110, 


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Recommended Hypertension Monitoring and Management for non-
secretory tumors (BP in mmHg) 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Lenvatinib 
Dose Modification 
 
NOTE: Stopping or 
reducing the dose of 
lenvatinib is expected to 
cause a decrease in BP. 
The treating physician 
should monitor the 
subject for hypotension 
and adjust the number 
and dose of 
antihypertensive 
medication(s) accordingly 
permanently 
discontinue 
lenvatinib or if BP is 
controlled to systolic 
BP ≤159 and 
diastolic BP ≤99, 
consider re-starting 
lenvatinib at 1 lower 
dose level after 
consultation with the 
Principal Investigator 
Grade 4 
Life-threatening 
consequences of 
hypertension 
Optimal management 
with intensive IV 
support in ICU; STOP 
lenvatinib and notify 
hospital staff that 
stopping lenvatinib may 
result in a decrease in 
BP 
Intensive 
Permanently 
discontinue 
lenvatinib or if 
systolic BP ≤159 and 
diastolic BP ≤99, 
consider restarting 
lenvatinib at 1 lower 
dose level after 
consultation with the 
Principal Investigator 
Abbreviations: Dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), 
Angiotensin Converting Enzyme Inhibitors (ACEI), Angiotensin II Receptor Blockers (ARB), alpha beta 
blocker (ABB) 
• See table below for suggested antihypertensive medications by class 
• If subjects require a delay of >2 weeks for management of hypertension, discontinue protocol therapy 
• 24-48 hours should elapse between modifications of antihypertensive therapy 
• Hypertension should be graded using CTCAE v4 
*NOTE: For the purposes of dosage reductions related to hypertension, persistent 
hypertension is defined as blood pressure elevations that meet the grading criteria on 
at least 2 separate measurements 7 days or more apart. (For the purpose of AE 
grading standard CTCAE will be utilized.) 
 
In some instances of treatment for hypertension, a lower dose of the medication may be 
sufficient to provide the required antihypertensive control. In other instances, the standard 
dose of such a medication may be associated with AEs because of increased exposure. 
Alternatively, the investigator may choose to replace the medication with another in the 
same pharmacologic class that is less likely to interact with lenvatinib. If such a medication 
is discontinued and replaced, the transition period should occur no less than 7 days prior to 
the first dose of lenvatinib. Based on prior clinical experience with lenvatinib, the use of 
calcium channel blockers (dihydropyridine category) and ACE inhibitors as first-line and 
second-line therapy is recommended.  
 
 
 


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Oral Antihypertensive Medications for patients with non-secretory tumors 
Agent 
class 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
and inhibitor 
Selective 
β Blockers 
(BB) 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x daily 
50 mg 3x daily 
CYP 2D6 substrate 
enalapril 
5 mg daily 
10-20 mg daily 
40 mg daily 
CYP 3A4 substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used: 
perindopril 
4 mg daily 
none 
8 mg daily 
Yes, but not 
CYP450 
Rarely used: 
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin II 
Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not 
CYP450 
α and β 
Blocker 
labetolol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice 
daily 
CYP 2D6 substrate 
and inhibitor 
 
 
 


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D2. 
Management of Lenvatinib-Induced Hypertension: Secretory Tumors 
All patients with secretory pheochromocytomas or paragangliomas are required to: 1) be evaluated in 
consultation, and followed by, a hypertension specialization with experience in the management of 
hypertension in the setting of catecholamine-secreting tumors (usually an endocrinologist, nephrologist, 
or a cardiologist), and 2) receive α- and β-adrenergic blockade for at least 7-14 days prior to initiation of 
lenvatinib (see below for guidelines regarding proper α- and β-blockade). The hypertension specialist of 
record for each patient should be committed to following the patient during the clinical study on an as 
needed basis.  
Recommended Hypertension Monitoring and Management for 
Patients with Catecholamine-Secreting Tumors (BP in mmHg) 
(CTCAE SOC Vascular Disorders/Hypertension) 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood 
Pressure 
Monitoring 
Lenvatinib 
Dose Modification 
Persistent* 
Grade 1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-90  
 
Standard α- and β-adrenergic 
blockade 
Standard  
No Change 
Persistent*Grade 
2- Moderate 
Systolic 140-159  
Diastolic 90-99  
  
Protocol-specific 
guidance 
supersedes any 
other management 
guidelines. 
Step 1) Advance dose of α-
adrenergic blocker until BP is 
controlled or at max dose of Rx. 
The β-adrenergic blocker dosage 
should be advanced for a target 
heart rate of less than 80 bpm. 
Step 2) If BP still not controlled, 
add another anti-hypertensive Rx 
(usually best a calcium channel 
blocker such as amlodipine), in 
conjunction with the patient’s 
identified hypertension specialist, 
increasing dosage of this drug as 
described in step 1 or as suggested 
by patient’s identified 
hypertension specialist. 
Step 3) If BP is still not 
controlled, consider either 1 dose 
reduction of lenvatinib or 
withholding lenvatinib until BP is 
better controlled. 
NOTE: Stopping or reducing the 
dose of lenvatinib is expected to 
cause a decrease in BP. The 
treating physician must therefore 
monitor the subject for 
hypotension and adjust the 
number and dose of 
antihypertensive medication(s) 
accordingly 
BP should be 
monitored as 
recommended 
by the 
treating 
physician and 
patient’s 
identified 
hypertension 
specialist 
No change except as 
described in Step 4 


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Recommended Hypertension Monitoring and Management for 
Patients with Catecholamine-Secreting Tumors (BP in mmHg) 
(CTCAE SOC Vascular Disorders/Hypertension) 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood 
Pressure 
Monitoring 
Lenvatinib 
Dose Modification 
Persistent* 
Grade 3 Severe  
Systolic ≥160 
Diastolic ≥100  
 
Protocol-specific 
guidance 
supersedes any 
other management 
guidelines. 
HOLD lenvatinib until systolic BP 
≤159 and diastolic BP ≤99 
 
BP management is identical to 
that for Grade 2 (see steps 1-3 
above) with 2 major exceptions:  
1) If systolic BP >180 or 
diastolic BP >110 and the 
subject is symptomatic: optimal 
management is with intensive 
IV support in ICU; STOP 
lenvatinib and notify hospital 
staff that stopping lenvatinib 
may result in a decrease in BP 
 and  
2) If systolic BP >180 or 
diastolic BP >110 and the 
subject is asymptomatic, 
Consultation with patient’s 
identified hypertension 
specialist is required as to the 
proper medical therapy, 
addition of additional anti-
hypertensive medications and 
monitoring. 
 
NOTE: Stopping or reducing 
the dose of lenvatinib is 
expected to cause a decrease in 
BP. The treating physician 
should monitor the subject for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly 
BP should be 
monitored as 
recommended 
by the 
treating 
physician and 
patient’s 
identified 
hypertension 
specialist 
unless the 
subject is 
symptomatic 
with  
systolic BP 
>180 or 
diastolic BP 
>110 in 
which case, 
monitoring 
should be 
intensive. 
HOLD lenvatinib until 
systolic BP ≤159 and 
diastolic BP ≤99. After 
this, lenvatinib may be re-
administered. If BP is still 
grade 2, manage as 
described above for grade 
2 hypertension.  
 
In most circumstances, if 
BP cannot be controlled 
after an optimal trial of 
antihypertensive 
medications, consider 
either 1 dose reduction of 
lenvatinib when systolic 
BP ≤159 and diastolic BP 
≤99 or stopping 
lenvatinib. 
 
HOWEVER, 
If the subject requires 
hospitalization for 
management of 
symptomatic systolic BP 
>180 or diastolic BP 
>110, permanently 
discontinue lenvatinib or 
if BP is controlled to 
systolic BP ≤159 and 
diastolic BP ≤99, 
consider re-starting 
lenvatinib at 1 lower dose 
level after consultation 
with the study Principal 
Investigator 
 
Grade 4 
Life-threatening 
consequences of 
hypertension 
 
Optimal management with 
intensive IV support in ICU; 
Contact of patient’s identified 
hypertension specialist. STOP 
lenvatinib and notify hospital 
staff that stopping lenvatinib 
may result in a decrease in BP 
Intensive 
Permanently discontinue 
lenvatinib or if systolic 
BP ≤159 and diastolic BP 
≤99, consider re-starting 
lenvatinib at 1 lower dose 
level after consultation 
with the study Principal 
Investigator 
Abbreviations: Dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), 
Angiotensin Converting Enzyme Inhibitors (ACEI), Angiotensin II Receptor Blockers (ARB), alpha beta 
blocker (ABB) 


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Recommended Hypertension Monitoring and Management for 
Patients with Catecholamine-Secreting Tumors (BP in mmHg) 
(CTCAE SOC Vascular Disorders/Hypertension) 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood 
Pressure 
Monitoring 
Lenvatinib 
Dose Modification 
• 
See table below for suggested antihypertensive medications by class 
• 
If subjects require a delay of >2 weeks for management of hypertension, discontinue protocol therapy 
• 
24-48 hours should elapse between modifications of antihypertensive therapy 
• 
Hypertension should be graded using CTCAE v4 
* NOTE: For the purposes of dosage reductions related to hypertension, persistent 
hypertension is defined as blood pressure elevations that meet the grading criteria on 
at least 2 separate measurements 7 days or more apart. (For the purpose of AE 
grading standard CTCAE will be utilized.) 
 
Oral Antihypertensive Medications for patients with secretory tumors 
(Decisions about changes in antihypertensive medications in this group of patients are best 
made with communication between patient’s primary oncologists and identified 
hypertension specialist). 
 
Agent 
class 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
and inhibitor 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
captopril 
12.5 mg 3x 
daily 
25 mg 3x daily 
50 mg 3x daily 
CYP 2D6 substrate 
enalapril 
5 mg daily 
10-20 mg daily 
40 mg daily 
CYP 3A4 substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used: 
perindopril 
4 mg daily 
none 
8 mg daily 
Yes, but not 
CYP450 
Rarely used: 
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin II 
Receptor 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 substrate 


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Agent 
class 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Blockers 
(ARBs) 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not 
CYP450 
 
In some instances of treatment for hypertension, a lower dose of the medication may be sufficient 
to provide the required antihypertensive control. In other instances, the standard dose of such a 
medication may be associated with AEs because of increased exposure. Alternatively, the 
investigator may choose to replace the medication with another in the same pharmacologic class 
that is less likely to interact with lenvatinib. If such a medication is discontinued and replaced, the 
transition period should occur no less than 7 days prior to the first dose of lenvatinib. Based on 
prior clinical experience with lenvatinib, the use of calcium channel blockers (dihydropyridine 
category) and ACE inhibitors as first-line and second-line therapy is recommended. 
 
D.3. Guidelines Regarding Proper α- and β-Adrenergic Blockade 
α-Adrenergic blockade should be started first, under the care of a hypertension specialist, to 
normalize blood pressure and expand the contracted blood volume. On the second or third day of 
α-adrenergic blockade, patients are encouraged to start a diet high in sodium content (≥5,000 mg 
daily) because of the catecholamine-induced volume contraction and the orthostasis associated 
with α-adrenergic blockade. This degree of volume expansion may be contraindicated in patients 
with congestive heart failure or renal insufficiency. After adequate α-adrenergic blockade has 
been achieved (typically 5 to 7 days), β-adrenergic blockade is initiated. The whole process 
should take place at least 1-2 week prior to initiation of lenvatinib.  
For α-adrenergic blockade phenoxybenzamine is the preferred drug. The initial dosage is 10 mg 
once or twice daily, and the dose is increased by 10 to 20 mg in divided doses every 2 to 3 days 
as needed to control blood pressure. The final dosage of phenoxybenzamine is typically between 
20 and 100 mg daily. The patient should be warned about the orthostasis, nasal stuffiness, and 
fatigue that occur in almost all patients. With their more favorable side-effect profiles and cost-
effectiveness, selective α1-adrenergic blocking agents (e.g., prazosin, terazosin, or doxazosin) 
may be used for those patients who are intolerant of the side effects of phenoxybenzamine or 
cannot afford phenoxybenzamine. Ultimately, the choice of the agents is at the discretion of the 
hypertension specialist. 
The β-adrenergic antagonist should be administered only after α-adrenergic blockade is 
effective (with near-normal BP) because with β -adrenergic blockade alone hypertension 
may be more severe from the unopposed α-adrenergic stimulation. β-adrenergic blockade is 
indicated to control the tachycardia associated with both the high concentrations of circulating 
catecholamines and the α-adrenergic blockade. The clinician should exercise caution if the patient 
is asthmatic or has congestive heart failure. Chronic catecholamine excess can produce a 
myocardiopathy that may become evident with the initiation of β -adrenergic blockade, resulting 
in acute pulmonary edema. Therefore, when the β -adrenergic blocker is administered, it should 
be used cautiously and at a low dose. For example, a patient is usually given 10 mg of 
propranolol every 6 hours to start. On the second day of treatment, the β-adrenergic blockade 
(assuming the patient tolerates the drug) is converted to a single long-acting dose of a 


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cardioselective β-blocker. The dose is then increased as necessary to control the tachycardia (goal 
heart rate is 60-80 beats per minute).  
Metyrosine, a catecholamine synthesis inhibitor, may be used in patients with particularly high 
metanephrines/normetanephrines and/or for difficult to control hypertension prior to initiation of 
lenvatinib. Typical doses may be up to 1-2 grams per day, but dose escalation is often limited by 
sedation.  
Metyrosine may also be used if there is significant concern for lenvatinib-induced catecholamine 
release following initiation of therapy. 
Orally Administered Drugs for Initial α- and β-Adrenergic Blockade 
Drug  
Dosage, mg/day* 
Initial (maximum) 
Side effects 
α-Adrenergic Blocking Agents   
Phenoxybenzamine 
10† (100)† 
Postural hypotension, tachycardia, miosis, 
nasal congestion, diarrhea, inhibition of 
ejaculation, fatigue 
Prazosin 
1 (20)‡ 
First-dose effect, dizziness, drowsiness, 
headache, fatigue, palpitations, nausea 
Terazosin 
1 (20)†  
First-dose effect, asthenia, blurred vision, 
dizziness, nasal congestion, nausea, 
peripheral edema, palpitations, 
somnolence 
Doxazosin 
1 (20) 
First-dose effect, orthostasis, peripheral 
edema, fatigue, somnolence 
Combined α- and β-Adrenergic 
Blocking Agent 
  
Labetalol 
200† (1,200)† 
Dizziness, fatigue, nausea, nasal congestion, 
impotence 
Calcium channel blocker   
Nicardipine sustained 
release 
30† (120)† 
Edema, dizziness, headache, flushing, 
nausea, dyspepsia 
Catecholamine synthesis inhibitor   
α-Methyl-ρ-L-tyrosine 
(Metyrosine) 
1,000‡ (4,000)‡  
Sedation, diarrhea, anxiety, nightmares, 
crystalluria, galactorrhea, extrapyramidal 
symptoms 
*Given once daily unless otherwise indicated 
†Given in two doses daily 
‡Given in three or four doses daily 
 
 


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Appendix V 
Drugs with Risk of Torsades De Pointes 
The following list contains medications that are generally accepted as having an increased risk of QT 
prolongation and/or torsades de pointes. Concomitant administration of lenvatinib and a medication 
on this list is prohibited.  
Generic Name 
Brand Name 
Comments 
Amiodarone 
Cordarone®, Pacerone® 
Low risk torsades de pointes 
Arsenic trioxide 
Trisenox® 
Torsades de pointes 
Bepridil 
Vasocor® 
 
Chloroquine 
Aralen® 
 
Chlorpromazine 
Thorazine® 
 
Cisapride 
Propulsid® 
Restricted availability in U.S. 
Clarithromycin 
Biaxin® 
 
Disopyramide 
Norpace® 
Torsades de pointes 
Dofetilide 
Tikosyn® 
Torsades de pointes 
Dolasetron 
Anzemet® 
 
Droperidol 
Inapsine® 
Torsades de pointes 
Erythromycin 
Erythrocin®, E.E.S. ® 
IV > PO 
Halofantrine 
Halfan® 
 
Haloperidol 
Haldol® 
IV > PO, high doses increase QT 
prolongation and torsades de pointes 
Ibutilide 
Corvert® 
Torsades de pointes, female > male, non-
Caucasian > Caucasian 
Levomethadyl 
Orlaam® 
 
Mesoridazine 
Serentil® 
 
Methadone 
Dolophine®, Methadose® 
 
Pentamidine 
Pentam®, Nebupent® 
 
Pimozide 
Orap® 
 
Procainamide 
Pronestyl®, Procan®, 
Procanbid® 
N-acetylprocainamide causes torsade de 
pointes, not parent compound 
Quinidine 
Cardioquin®, Quinaglute® 
Torsades de pointes 
Sotalol 
Betapace® 
Torsade de pointes female > male 
Sparfloxacin 
Zagam® 
 
Thioridazine 
Mellaril® 
 
Note: The above list is not all-inclusive. Consult your local pharmacist for any questions. 
 
 


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Appendix VI Patient Blood Pressure Diary 
Today’s date ________________________________ 
Patient Initials ________________________________  
Patient Study ID ________________________________ 
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 once daily: 
3. If you take your blood pressure at other times of the day, please record the numbers and 
time under “Other readings”. 
4. Normal blood pressure is usually considered to be 120/80 mmHg. If your systolic pressure 
is greater than 140 or your diastolic blood pressure is greater than 90 when you measure 
your blood pressure. Repeat your blood pressure within 1-4 hours. If your blood pressure is 
still elevated please contact your doctor’s office at 
 for instructions. Also, 
you should contact your doctor’s office at any time your blood pressure exceeds 180 
mmHg (systolic) or 105 mmHg (diastolic), or at any time you have symptoms that you 
think may be related to hi blood pressure (examples include headache, nausea, vomiting, 
confusion, anxiety, restlessness). If you need to call after business hours or during holidays 
or weekends, please call 
 and ask for the Medical Oncologist on call. 
5. Please bring this form to your visit at the end of Cycle 1, 2 and 3. 
Date 
Blood Pressure 
readings 
Other readings 
(include time of 
day) 
Date 
Blood Pressure 
readings 
Other readings 
(include time of 
day) 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 
 
/ 
 








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Appendix VIII 
EQ-5D-5L Questionnaire 
 
 
 


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Appendix IX 
Patient Information Sheet 
You have been given a booklet to complete for this study. The booklet contains some 
questions about your health as a patient receiving treatment for cancer. Your answers will 
help us to better understand how the treatment you are receiving is affecting the way you 
feel. 
 
1. The booklet contains two sets of questions: 
EQ-5D-5L questionnaire (6 questions) 
FACT-G questionnaire (27 questions) 
 
2. Please select one answer for each question. 
 
3. Please complete the booklet during your scheduled clinical visit and return it to your 
nurse or your physician 
 
 
 
Thank you for taking the time to help us!