Conditions: Cancer Solid Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
The overall purpose of this study is to determine the overall response rate, efficacy and safety of the combination of eribulin and Lenvatinib.

Detailed description:
This is a phase II clinical trial of the combination of eribulin, and Lenvatinib. A cycle will be defined as 21 days. Eribulin will be given on days 1 and 8 of each cycle. Lenvatinib will be given daily during each cycle.

Arms:
arm 1: Eribulin will be given on days 1 and 8. Lenvatinib will be given daily in each 28 day cycle.

Interventions: intervention 1: Eribulin intervention 2: Lenvatinib
Intervention descriptions: intervention 1: Will be given by I.V. at 1.4 mg/m2 on day 1 and day 8. intervention 2: Will be taken orally at 20-24 mg daily in each 21 day cycle.

Protocol document:
Prot_SAP_000.pdf: 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
Official Study Title: 
 Phase II Trial of Eribulin and Lenvatinib in Advanced Solid Tumors 
(CTMS 15-2139) 
NCT number: NCT02640508 
IRB Approval Date: 03.01.2018 
Unique Protocol ID: CTMS 15-2139 


CTRC Protocol Number CTMS# 15-2139 
 Date: February 27, 2018 
Protocol Version 7.0 
STUDY TITLE:   
Phase II Trial of Eribulin and Lenvatinib in Advanced Solid Tumors (CTMS 15-2139) 
 
PRINCIPAL INVESTIGATOR: 
Virginia G. Kaklamani, MD 
Mays Cancer Center 
7979 Wurzbach Rd 
San Antonio, TX 78229 
 
PARTICIPATING SITES/SUB-INVESTIGATORS: 
 
Mays Cancer Center 
Richard Elledge M.D.                                           
Hematology/Oncology 
7979 Wurzbach Rd                                               
San Antonio, TX. 78229                                       
Elledge@uthscsa.edu                              
 
Andrew Brenner MD, PhD 
Hematology/Oncology 
7979 Wurzbach Rd 
San Antonio, TX 78229 
Brenner@uthscsa.edu 
 
Kate Lathrop M.D. 
Hematology/Oncology 
7979 Wurzbach Road 
San Antonio, Texas, 78229 
Lathrop@Uthscsa.edu 
 
Susan Moobery 
UT Health San Antonio  
7703 Floyd Curl Drive,  
Mail Code 7764, San Antonio, TX 78229-3900.  
Phone: 210-567-4788; 
Mooberry@uthscsa.edu 
 
Alexander Pertsemlidis, PhD 
Hematology/Oncology 
7979 Wurzbach Rd 
San Antonio, Texas, 78229 
Pertsemlidis@Uthscsa.edu 
 
Anand Karnad M.D. 
Hematology/Oncology 
7979 Wurzbach Rd 
San Antonio, Texas, 78229 
Karnad@Uthscsa.edu 


 
 
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Praveena Iruku. M.D.                                           
Hematology/Oncology                                           
7979 Wurzbach Rd                                                
San Antonio, TX. 78229                                        
Iruku@uthscsa.edu                                 
 
 
Robert Setlik, MD, PhD 
SAN ANTONIO MILITARY MEDICAL CENTER 
Dept. of Hematology and Oncology 
3551 Roger Brooke Drive 
Ft. Sam Houston, Tx 78253 
robert.f.setlik.mil@mail.mil 
 
STATISTICIAN 
Joel Michalek, PhD.  
Hematology/Oncology 
MichalekJ@Uthscsa.edu 
 
SUPPORTING AGENCY 
UT Health San Antonio 
 
Protocol Version: 7.0 
Protocol Date: February 27, 2018 
 
 


 
 
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ABBREVIATIONS 
  
AE 
 
 
 
Adverse Event 
AUC:  
 
 
Area under the Curve 
CAI 
 
 
 
Corrective Action Item  
 
DSB 
 
 
 
Double Strand Breaks 
DSM 
 
 
 
Data Safety Monitoring 
DSMB  
 
 
Data Safety Monitoring Board 
DSMC  
 
 
Data Safety Monitoring Committee 
 
DSMP  
 
 
Data Safety and Monitoring Plan 
DQA 
 
 
 
Director of Quality Assurance 
FDA 
 
 
 
Food and Drug Administration  
GCP 
 
 
 
Good Clinical Practice 
GFR 
 
 
 
Glomerular Filtration Rate 
HRD   
 
 
Homologous recombination deficiency 
IDD 
 
 
 
Institute for Drug Development  
IDEAS  
 
 
Informatics Data Exchange Acquisition System 
IIS 
 
 
 
Investigator Initiated Protocol 
IND 
 
 
 
Investigational New Drug 
IRB 
 
 
 
Institutional Review Board 
MBC  
 
 
Metastatic Breast Cancer 
QAD 
 
 
 
Quality Assurance Division 
PI 
 
 
 
Principal Investigator 
PSD 
 
 
 
Pharmacokinetic Sampling Department  
SAE 
 
 
 
Serious Adverse Event 
SSB 
 
 
 
Single Strand Breaks 
UPIRSO 
 
 
Unanticipated Problem Involving Risks to Subjects or Others  
 
 


 
 
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Introduction – Background and Rationale ........................................................................ 8 
1.0 Eribulin .................................................................................................................... 9 
Overview ................................................................................................................................. 9 
1.1 Preclinical Studies with Eribulin ........................................................................................ 9 
1.2 Clinical Studies with Eribulin .......................................................................................... 10 
2.0 Lenvatinib ............................................................................................................... 11 
Overview ............................................................................................................................... 11 
2.1 Preclinical studies with Lenvatinib ................................................................................... 11 
2.2 Clinical studies with Lenvatinib ....................................................................................... 12 
2.3 Rationale for combining Lenvatinib and Eribulin. ........................................................... 15 
2.4 Rationale for patient population ....................................................................................... 15 
3.0 Objective ................................................................................................................. 16 
3.1 Selection of Patients ......................................................................................................... 16 
Inclusion Criteria................................................................................................................... 17 
Exclusion Criteria .................................................................................................................. 17 
4.0 Treatment plan ....................................................................................................... 18 
4.1 Overview .......................................................................................................................... 18 
4.2 Study Drug Administration .............................................................................................. 18 
Eribulin ................................................................................................................................. 18 
Lenvatinib ............................................................................................................................. 19 
4.3 Supportive Care Guidelines ............................................................................................. 19 
Eribulin Dose Modifications .................................................................................................. 23 
Lenvatinib Dose Modifications .............................................................................................. 23 
4.4 Concomitant medications ................................................................................................. 24 
4.5 Not Permitted ................................................................................................................... 24 
4.6 Permitted ......................................................................................................................... 24 
4.7 Duration of Therapy ........................................................................................................ 24 
4.8 Follow-up Post Therapy ................................................................................................... 24 
5.0 Response Assessment ............................................................................................... 25 
5.1 Definitions ........................................................................................................................ 25 
5.1.1 Measurable disease ........................................................................................................ 25 
5.1.2 Non measurable disease ................................................................................................. 25 
5.1.3 Target Lesions ............................................................................................................... 25 
5.1.4 Non-Target Lesions ....................................................................................................... 25 
5.2 Guidelines for Evaluation of Measureable Disease ........................................................... 25 
5. 3 Response Criteria ............................................................................................................ 26 
6.0 Study Parameters .................................................................................................... 28 
7.0 Drug formulation and Procurement ......................................................................... 30 
7.1 Eribulin ............................................................................................................................ 30 
7.2 Lenvatinib ........................................................................................................................ 31 
8.0 Statistical Considerations ........................................................................................ 33 
8.1 Proposed sample size ........................................................................................................ 33 
8.1.1 Safety run in phase ........................................................................................................ 33 


 
 
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8.1.2 Phase II ......................................................................................................................... 33 
8.2 Data analysis .................................................................................................................... 33 
9.0 Adverse Events Reporting ....................................................................................... 34 
9.2.1Adverse event (AE) ......................................................................................................... 35 
9.2.2 Severity of AEs .............................................................................................................. 35 
9.2.3 Serious Adverse events .................................................................................................. 36 
9.2.4 Exceptions to the Definition of SAE ............................................................................... 36 
9.2.5 Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO) .................... 36 
10.0 Adverse event reporting .......................................................................................... 36 
10.1 Expedited Reporting of SAEs ......................................................................................... 37 
10.2 Routine Reporting .......................................................................................................... 38 
11.0 Study Management.................................................................................................. 38 
11.1 Institutional Review Board (IRB) Approval and Consent ............................................... 38 
11.1.1 Access to IDEAS .......................................................................................................... 39 
11.1.2 Registering a Patient for the Safety run in Portion of the Study .................................. 39 
11.1.3 Registering a Patient to the Phase II Portion of the Study ........................................... 40 
12.0 Data Management and Monitoring .......................................................................... 40 
13.0 Record Retention .................................................................................................... 41 
14.0 Obligations of Investigators ..................................................................................... 42 
15.0 Pathology Requirements .......................................................................................... 42 
I.     Appendix Lenvatinib Package Insert ....................................................................... 44 
II. Appendix – Common Toxicity Criteria for Adverse Events ...................................... 62 
III. Appendix – Data Safety & Monitoring Plan ............................................................. 62 
IV.  Appendix - Data Collection & Submission ................................................................ 68 
V. Appendix – Table of Assessments ............................................................................. 70 
VI. Appendix SAE Reporting Form ............................................................................... 71 
References ..................................................................................................................... 75 
 
 


 
 
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SYNOPSIS 
 
 
Title 
Phase II Clinical Trial on the Combination of Eribulin and Lenvatinib in 
patients with advanced solid cancers 
Design 
Non-randomized, open-label, multi-center, phase II, dose-escalation with a 
safety run-in phase. 
Objectives 
The overall purpose of this study is to determine the overall response rate, 
efficacy and safety of the combination of Eribulin and Lenvatinib. 
 
The primary objectives are: 
1. Overall Response rate of the combination at MTD (Phase II)  
Secondary objectives include: 
1. Determine the safety of Eribulin and Lenvatinib 
2. Define the progression free survival 
3. Expression profile of MicroRNA 
Patient Population 
The number of subjects in the safety run-in phase will be 10.  In the phase II 
trial the number of patients will be 30.   
Treatment Plan 
This is a phase II clinical trial of the combination of Eribulin, and Lenvatinib. 
A cycle will be defined as 21 days. Eribulin will be given on days 1 and 8 of 
each cycle. Lenvatinib will be given daily during each cycle. Eribulin will be 
given on day 1 and day 8 at 1.4 mg/m2 and lenvatinib at a dose of 20 mg will 
be started on day 2 for the first ten patients. At that time and based on 
tolerability the PI will have a teleconference with the EISAI medical team and 
decide whether to increase the lenvatinib dose to 24mg/day.  Then the dose of 
lenvatinib can increase to 24 mg/day for the remaining cycles.  
Efficacy Assessment 
Response rate will be measured by performance of imaging after every two 
cycles of therapy. 
 


 
 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
Safety 
Run- in 
Phase 
First ten patients treated with Lenvatinib at 20 mg qd 
(starting day 2) and eribulin at 1.4 mg/m2 day 1 and day  
  8 of a 21 day cycle 
Based on toxicity data Lenvatinib 
dose may increase to 24 mg daily 
and Eribulin at 1.4 mg/m2 day 1 
and day 8 of a 21 day cycle 
PHASE 
II 
TRIAL 
(30 
patients) 


 
 
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Introduction – Background and Rationale  
 
Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation and is key to tumor 
angiogenesis and growth.1 Targeting VEGF or its receptor (VEGFR) may limit tumor induced 
angiogenesis, vascular supply to the tumor and halt tumor growth. The therapeutic benefits of this 
strategy have been proven in several solid tumors including non-small cell lung cancer, colon cancer, and 
renal cell carcinoma.2 3 
The VEGF pathway can be inhibited with monoclonal antibodies against VEGF (e.g. bevacizumab) or the 
extracellular domain of the VEGFR (e.g. ramucirumab), as well as by several small molecule tyrosine 
kinase inhibitors targeting VEGFR (e.g. sorafenib, lenvatinib, sunitinib, pazopanib ) among others. 
The recombinant humanized monoclonal antibody bevacizumab is directed against the pro-angiogenic 
VEGF subgroup A. One explanation for the failure of bevacizumab monotherapy to induce enduring 
clinical responses may be the fact that bevacizumab targets VEGF-A exclusively, thus only one member 
of a large family of pro-angiogenic growth factors inducing angiogenesis is targeted. This would suggest 
that the blockage of the interaction of multiple growth factors with their receptors might improve 
therapeutic efficacy.4 
Lenvatinib (LEN) is an oral tyrosine kinase inhibitor of the VEGFR1-3, FGFR1-4, PDGFRβ, RET, and 
KIT signaling networks. It has shown activity in many solid tumors, such as NSCLC and thyroid cancer.  
Data on xenograft models have shown activity of lenvatinib in breast cancer5. When compared with 
bevacizumab in breast cancer xenograft models lenvatinib provided better antitumor activity6. Lenvatinib 
is approved for use in thyroid cancer at a dose of 24 mg p.o. per day. Clinical trials are currently under 
way evaluating lenvatinib in patients with hepatocellular, lung and other cancers. 
Phase I studies identified the maximum tolerated dose to be 25 mg daily that, in fasting treated patients, is 
rapidly absorbed with maximum concentrations achieved within 3 h of administration. In these studies, 
lenvatinib showed activity in solid tumors.  
Chemotherapy agents acting on microtubules have demonstrated activity against multiple cancers, 
including breast cancer. Microtubules form an integral part of many intracellular processes, including 
maintenance of cell structure, transport of intracellular components, cell signaling, and mitosis7. These 
structures are tube-shaped filaments composed of α-tubulin and β-tubulin heterodimers, which form 
highly dynamic polymers. Exploitation of their vital importance in mitosis and cell division has led to 
development of some of the most effective systemic chemotherapy drugs, with the taxanes and vinca 
alkaloids being the most widely studied. 
Eribulin is a microtubule inhibitor was derived from halichondrin B, a large polyether macrolide found in 
marine sponges including Halichondria okadai and is shown to improve overall survival (OS) in breast 
cancer and with activity is other solid tumors such as NSCLC8 9. Eribulin has a unique mechanism of 
action, with a tubulin binding site that appears to be different from the taxane and vinca binding sites on 


 
 
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the positive end of the microtubule. In practical terms, Eribulin exerts its cytotoxic effect by inhibiting 
microtubule growth and sequestering tubulin, ultimately causing G2-M cell cycle arrest and cell death 
through apoptosis. Eribulin has shown preclinical activity against a number of human cancer cell lines 
and xenografts with a wide therapeutic index, making it attractive for clinical development. 
Recently data from Study 309 showed an improvement in OS in patients with advanced sarcoma with 
Eribulin compared with dacarbazine, a standard treatment in sarcoma (data not published yet). We 
propose a phase II clinical trial of the combination of Eribulin and lenvatinib in breast cancer, non-small 
cell lung cancer (NSCLC) and sarcoma. 
Primary objective will be response rate with secondary objectives being toxicity, progression free 
survival, and overall survival. If the combination is deemed safe future randomized phase II trials will be 
designed. 
1.0 
Eribulin 
Overview 
The search for active agents for the treatment of metastatic breast cancer (MBC) has included a 
meticulous assessment of naturally occurring compounds from the oceans. One such agent is halichondrin 
B, a large polyether macrolide, which is derived from the marine sponge Halichondria okadai found off 
the coast of Japan10. Halichondrins are potent antimicrotubule cytotoxic agents with activity against a 
variety of tumor cells in vitro11. However, a major limitation to the use of many naturally occurring 
substances as anticancer agents is the availability of adequate quantities of the naturally occurring 
compound. Hence, the synthesis of eribulin mesylate, formerly E7389, a synthetic halichondrin analog, 
was a major step in the investigation of these substances as possible anticancer agents.12 
1.1 Preclinical Studies with Eribulin 
Preclinical studies showed that the cytotoxic effect of Eribulin was maintained in paclitaxel-resistant cell 
lines, including those with mutations in b-tubulin. 13 Furthermore, Eribulin inhibited the growth of human 
tumor xenografts, including breast cancer14.This notable activity may be related to a somewhat novel 
mechanism of action. Similar to other microtubule agents, Eribulin seems to bind to a single site on 
tubulin, close to the vinca-binding site, and exerts a cytotoxic effect by blocking cell cycle progression at 
the G2–M phase, leading to apoptosis and ultimately resulting in tumor growth suppression.  However, 
unlike other microtubule agents such as taxanes, vinca alkaloids, and epothilones, Eribulin seems to have 
no effect on tubule shortening and causes sequestration of tubulin into nonfunctional aggregates15. Taken 
together, these attributes make Eribulin an exciting compound for investigation in clinical studies. 
1.2 Clinical Studies with Eribulin 
Phase III trials 
These encouraging results in heavily pretreated patients led to randomized phase III trials of Eribulin for 
MBC. As noted, anthracyclines and taxanes are the most active chemotherapy agents in breast cancer. For 
patients who experience disease progression despite these agents, numerous other active cytotoxic agents 


 
 
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have been investigated including gemcitabine, vinorelbine, capecitabine, and ixabepilone. However, for 
patients with heavily pretreated MBC, no standard of care exists and no individual agent has shown an 
OS benefit in clinical trials in this setting. Against this background, the Eisai Metastatic Breast Cancer 
Study Assessing Physician’s Choice versus Eribulin (EMBRACE) (305) study was conducted to compare 
single-agent Eribulin with standard chemotherapy for patients with heavily pretreated disease16. This was 
a large international phase III study comparing Eribulin with the ‘treatment of physician’s choice’ (TPC). 
Eligible patients had received two to five prior chemotherapy regimens, at least two of which must have 
been for MBC. In addition, the patients were required to have received both anthracyclines and taxanes, 
to have progressed within 6 months of past chemotherapy, have baseline neuropathy less than or equal to 
grade 2, and Eastern Cooperative Oncology Group performance status less than or equal to 2. Patients 
were randomized 2 : 1 to intravenous Eribulin of 1.4mg/m2 given over 2–5 min on days 1 and 8 of a 21-
day cycle or TPC, consisting of any monotherapy (cytotoxic chemotherapy/hormonal therapy/biologic 
therapy) or supportive care only. Baseline characteristics in the EMBRACE study were well matched 
between the treatment arms. In total, 762 patients were treated (508 with Eribulin and 254 with TPC) who 
were of a median age of 55.2 years (range: 27–85 years). Patients had received a median of four earlier 
chemotherapy regimens (range: 1–7). No patients randomized to the TPC arm received best supportive 
care or biological therapy alone. Furthermore, 96% of the patients in this arm received chemotherapy, 
consisting of vinorelbine (25%), gemcitabine (19%), capecitabine (18%), taxane (15%), and 
anthracyclines (10%) in decreasing frequency. The study met its primary endpoint; treatment with 
Eribulin was associated with an improvement in the median OS from 10.65 months to 13.12 months; 
hazard ratio 0.81 (95% CI, 0.66–0.99), P=0.041. In addition, the 1-year survival of patients treated with 
Eribulin was 53.9% as compared with 43.7% for patients who received TPC. In terms of secondary 
endpoints, on independent review of the intention to treat population, Eribulin showed a trend to 
improvement in median PFS from 2.2 months to 3.7 months (hazard ratio 0.87, 95% CI, 0.71–1.05), 
although this result was not statistically significant (P=0.14). However, Eribulin was associated with an 
increased response rate (12.2%) over TPC (4.7%) P=0.002, and the clinical benefit rate (response+stable 
disease >6 months) was 22.6% as compared with 16.8%. Furthermore, the toxicity profile seemed 
manageable and consistent with the earlier studies of Eribulin. For example, 25% of patients treated with 
Eribulin had a serious adverse event as compared with 25.9% of patients treated with TPC. Although 
Eribulin treatment was commonly associated with neutropenia (45.2% of patients grade 3), as reported 
earlier, this did not translate into a high rate of febrile neutropenia. Furthermore, as predicted from earlier 
clinical studies, the incidence of neuropathy was low (8.2% of patients >grade 3). This does not seem 
excessive considering that the patients were heavily pretreated and were eligible with less than or equal to 
grade 2 neuropathy at baseline. Therefore, this study shows that for patients with heavily pretreated MBC, 
Eribulin is associated with improved OS over standard chemotherapy and a manageable toxicity profile. 
Potential Risks of Eribulin 
Eribulin seems to have a manageable side-effect profile. In the Phase I study by Goel et al., the most 
common adverse events included fatigue, nausea and anorexia, seen in 53, 41 and 38% of patients, 
respectively. Most of these toxicities were grade 1 or 2, and none was grade 4. Grade 3 or 4 neutropenia 
occurred in six patents and fatigue in four patients. Grade 1 neuropathy was reported in eight patients, and 


 
 
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two patients experienced grade 2 neuropathy. There were no reports of grade 3 or 4 neuropathy. The most 
frequent adverse effects seen in the Phase I study by Tan et al. were neutropenia, fatigue and alopecia, in 
38, 33 and 33% of patients, respectively. Seven patients experienced nine serious adverse effects that 
were considered to be related to treatment. These adverse effects included one case of hyponatremia, six 
cases of grade 4 neutropenia and one grade 3 infection. One patient on study died of progressive disease. 
Fatigue and alopecia were all of either grade 1 or 2. Grade 1 nausea was seen in 19% of patients. Of note, 
neuropathy was seen as a grade 1 toxicity in one patient at a dose higher than the MTD as per Tan et al. 
Eribulin remained well tolerated in the Phase II studies among women with metastatic breast cancer 
(MBC). In the Phase II study of 291 women by Vahdat et al., the most common grade 3/4 toxicities were 
neutropenia, febrile neutropenia, leucopenia and fatigue, seen in 54, 5.5, 14- and 10% of women, 
respectively. There were no cases of grade 4 neuropathy, and grade 3 peripheral neuropathy was noted in 
5.5% of patients as referred in Vahdat et al. Similarly, results from the second Phase II study of 103 
women by Vahdat et al., demonstrate the most common grade 3/4 toxicities of Eribulin to be neutropenia, 
leucopenia, fatigue, peripheral neuropathy and febrile neutropenia, seen in 64, 18, 5, 5 and 4% of women, 
respectively. There was no incidence of grade 4 neuropathy. Nineteen per cent of patients received 
granulocyte growth factors during the first cycle of drug. Alopecia was reported in 41% of patients, but 
the presence of alopecia at baseline was not recorded. The 21-day cohort seemed to be better tolerated, 
with less anemia, thrombocytopenia and anorexia. 
2.0 
Lenvatinib 
 
Overview 
Lenvatinib  is a multitargeted receptor kinase inhibitor that inhibits the kinase activities of vascular 
endothelial-derived growth factor receptors 1, 2 and 3, fibroblast growth factor receptors 1, 2, 3 and 4, 
platelet-derived growth factor receptor α, RET and KIT. In addition to their role in normal cellular 
function, these kinases have been implicated in pathogenic angiogenesis, tumortumor growth and cancer 
progression. An improved understanding of molecular signaling pathways involved in normal 
physiological cellular functions and also implicated in the pathogenesis of tumortumor growth and cancer 
progression, has led to the investigation of targeted therapies, including multikinase inhibitors for the 
management of several solid tumors. 
2.1 Preclinical studies with Lenvatinib 
In preclinical in vitro studies in human cancer cell lines and in vivo studies involving a broad spectrum of 
human tumortumor xenograft models, including thyroid, melanoma and hepatocellular xenograft models 
and a RET gene fusion-driven tumortumor model (with RET gene fusions associated with thyroid and 
lung cancers), lenvatinib exhibited potent antitumortumor activity via inhibition of tyrosine kinase 
activities of VEGFR 1–3 and other pro-angiogenic and oncogenic pathway-related RTKs17 18. In an in 
vitro assay of angiogenesis, lenvatinib inhibited VEGFR- and FGFR-induced proliferation and tube 
formation of human umbilical vein endothelial cells.19 As described by Matsui et al, Inhibition of VEGF-
R3 kinase with Lenvatinib effectively decreased lymphatic vessel density within MDA-MB-231 tumors, 


 
 
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which express VEGF-C. Simultaneous inhibition of both VEGF-R2 and VEGF-R3 kinases by Lenvatinib 
may be a promising new strategy to control regional lymph node and distant lung metastases. 
2.2 Clinical studies with Lenvatinib 
 
Phase 1 trials 
In phase 1 and 2 studies, oral lenvatinib exhibited antitumor activity against a variety of tumor types.20 In 
a phase 1 trial conducted by Molina et al, with Lenvatinib and everolimus in the management of 
metastatic renal cell cancer, twenty patients (mean 58.4 years) received lenvatinib [12 mg (n = 7); 18 mg 
(n = 11); 24 mg (n = 2)] plus everolimus 5 mg. MTD was established as once daily lenvatinib 18 mg plus 
everolimus 5 mg. The most common treatment-related treatment-emergent adverse events (all dosing 
cohorts) were fatigue 60 % (Grade ≥3: 10 %), mucosal inflammation 50 %, proteinuria (Grade ≥3: 15 %), 
diarrhea (Grade ≥3: 10 %), vomiting (Grade ≥3: 5 %), hypertension, and nausea, each 40 %. In MTD and 
lowest-dose cohorts (n = 18), best responses of partial response and stable disease were achieved in 6 
(33 %) and 9 (50 %) patients, respectively. 
In a phase 1 study by Boss et al21, Eighty-two patients received Lenvatinib in dose cohorts from 0.2 to 
32 mg. Dose-limiting toxicities (DLTs) were grade 3 proteinuria (two patients) at 32 mg, and the MTD 
was defined as 25 mg. The most frequently observed cumulative toxicities (all grades) again noted were 
hypertension (40% of patients), diarrhea (45%), nausea (37%), stomatitis (32%) and vomiting (23%). 
Seven patients (9%) had a partial response and 38 patients (46%) had stable disease as best response. 
Lenvatinib has dose-linear kinetics with no drug accumulation after 4 weeks' administration. 
Another Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid 
tumors by Yamada et al22, twenty-seven patients (median age 53 years, performance status 0/1) were 
enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient 
cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 
AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg 
bid. The MTD of 13 mg bid was determined. After repeated doses, C(max) and area under the plasma 
concentration-time curve increased in a dose-dependent manner. After 14 days of treatment, c-kit(+) 
CEPs and CECs significantly decreased in cycle 1, but c-kit(-) CEPs and CECs did not. Change from 
baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio 
significantly correlated with the E7080 therapeutic effect. 
Phase II trials 
In a phase II trial by Schlumberger et al23 for the management of medullary thyroid cancers, 59 pts were 
enrolled (med age: 52; Male: 63%;) and are evaluable for response. 54% of pts required dose reduction 
for management of toxicity, and 22% were withdrawn from therapy due to toxicity. The most common 
treatment-related adverse events again were proteinuria 58% (Gr3: 2%), diarrhea 56% (Gr3: 5%), 
hypertension 48% (Gr3: 7%), fatigue 44% (Gr3: 5%), decreased appetite 41% (Gr3: 5%), nausea 34% 
(Gr3: 0), and weight decreased 32% (Gr3: 3%). No Gr4 events were reported for these event categories. 
Confirmed PRs were observed in 21pts (RR: 36%, 95% CI: 24-49) based on independent imaging review 


 
 
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(IIR) and 29 pts (RR: 49%, 95% CI: 36-62) based on investigator assessment. For patients who received 
prior VEGFR-directed treatment (n=26) RR=35% (IIR); with no prior VEGFR-directed treatment (n=33) 
RR=36 % (IIR). Median PFS by IRR is 9.0 months (95% CI: 7.0-) (based on minimum 8 month. f/u, 46% 
events observed). There was no clear difference in treatment response between RET-mutant (RET-mu) 
and RET-wild type (RET-wt) patients. Low baseline levels of ANG2, sTie-2, HGF and IL-8 were 
associated with greater tumor shrinkage and prolonged PFS whereas high baseline levels of VEGF and 
sVEGFR3 were associated with greater tumor shrinkage. 
In the Phase II trial conducted by O’day et al24, eligible patients (pts) had stage IV or unresectable stage 
III BRAF wild type (wt) melanoma with ≥1 prior treatment (26/96 [27%] pts received ≥3 treatments) and 
no prior VEGF-targeted therapy. Lenvatinib 24 mg once daily with dose reduction for toxicity was 
administered until disease progression or unmanageable toxicities. Primary endpoint was response rate 
(RR) by independent review (IRR) using RECIST 1.1. Archival tumor tissue and baseline and post 
treatment serum samples were collected for molecular analysis.  
Results: 93 patients were treated (median [m] age: 64 years; male: 69%; 95% AJCC stage IV). 
Confirmed partial responses (PRs) were observed in 8 patients (9%) with a clinical benefit rate 
(CR+PR+durable SD ≥23 wks) of 32% by IRR. Median PFS (mPFS) was 3.7 months (95% CI, 2.5-4.0) 
by IRR and median OS (mOS) was 9.5 months (95% CI, 8.3-12.9); 46% pts required dose reduction for 
management of toxicity; 12% were withdrawn from therapy due to toxicity. Treatment-related adverse 
events reported in ≥20% pts included hypertension 59% (34% Gr 3/4), fatigue 58% (16% Gr 3/4), nausea 
44% (3% Gr 3/4), diarrhea 43% (2% Gr 3/4), decreased appetite 38%, vomiting 29% (2% Gr 3), 
dysphonia 27%, and proteinuria and headache 26% each (4% and 1% Gr 3/4). Serum biomarker analysis 
showed baseline levels of serum angiogenic factors, such as angiopoietin-2, correlated with OS.  
In a phase II trial of lenvatinib conducted in endometrial cancer by Vergote et al25, Patients had 
metastatic/unresectable EC after 1 or 2 prior platinum-based treatments ≤2 prior chemotherapies, and 
ECOG PS ≤2. Patients received lenvatinib 24 mg once daily until disease progression or development of 
unmanageable toxicities. Primary endpoint was objective response rate (ORR: complete + partial 
response [CR+PR]) by RECIST 1.1. 133 pts were treated (median age: 62 years) and evaluated for safety, 
efficacy, and molecular correlative analysis. Dose reduction (31%) or treatment discontinuation (31%) 
occurred for toxicity. Median treatment duration was 112 days. The most common adverse events were 
hypertension 55% (Gr 3/4: 33%), fatigue 42% (Gr 3: 12.8%), diarrhea 35% (Gr 3: 5.3%), decreased 
appetite 35% (Gr 3: 2.3%), and nausea 32% (Gr 3: 3%); 1 patient had Gr 5 asthenia. Bowel obstruction, 
fistula formation, and perforation occurred in 3.8%, 2.3%, and 1.5%, respectively. Confirmed CR+PRs 
were observed in 19 patient (14.3%) by independent review (IRR) and 29 patients (21.8%) by investigator 
assessment (Inv). mPFS was 5.4 months and mOS was 10.6 moths. Among 50 serum factors tested, only 
BL plasma Ang-2 correlated with maximal tumor shrinkage, R = 0.36 (Spearman), p < 0.001; ORR; PFS; 
and OS. The 24 patients with low BL Ang-2 plasma levels (cut-off value <2082 pg/mL) were compared 
with the 98 pts with high BL Ang-2 (>2082 pg/mL) and improved ORR (61% vs 18%), mPFS (9.5 vs 3.7 
months), and mOS (23 vs 8.9 months) were observed.  
Phase III trials 


 
 
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In a Phase III  randomized, double-blind, multicenter study involving patients with progressive thyroid 
cancer with disease refractory to iodine-131 (I-131) by Schlumberger et al 26, 261 patients were randomly 
assigned to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and I-131 patients to 
receive placebo. At the time of disease progression, patients in the placebo group could receive open-label 
lenvatinib. The primary end point was progression-free survival (PFS). Secondary end points included the 
response rate (RR), overall survival (OS), and safety. 
The median progression-free survival (mPFS) 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). A progression-free survival benefit associated with lenvatinib was observed in all prespecified 
subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial 
responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in 
either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients 
in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (59.4%), fatigue or asthenia 
(59.0%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41.0%). Discontinuations of 
the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 
patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the 
treatment period were considered to be drug-related. 
A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) 
Versus Sorafenib in First-Line Treatment of Subjects With Unresectable Hepatocellular Carcinoma is 
currently in recruitment phase. 
2.2.1 Potential risks of Lenvatinib 
Oral lenvatinib had a manageable safety and tolerability profile in clinical trials. In patients with RAI-
refractory differentiated thyroid cancer participating in SELECT, treatment-related adverse events 
(TRAE) of any grade occurred in 97.3 % of lenvatinib recipients and 59.5 % of placebo recipients, with 
TRAEs of grade 3 or higher occurring in 75.9 and 9.9 % of patients as mentioned by Schlumberger et al. 
In this study, Serious TRAEs occurred in 30.3 and 6.1 % of lenvatinib and placebo recipients. Treatment-
emergent adverse events that lead to death occurred in 7.7 % of lenvatinib recipients and 4.6 % of placebo 
recipients, with 2.3 % of those occurring in the lenvatinib group considered to be treatment-related. 
The most common (incidence ≥30 %) TRAEs of any grade occurring in lenvatinib recipients were 
hypertension (67.8 vs. 9.2 % in the placebo group), diarrhea (59.4 vs. 8.4 %), fatigue or asthenia (59.0 vs. 
27.5 %), decreased appetite (50.2 vs. 11.5 %), decreased bodyweight (46.4 vs. 9.2 %), nausea (41.0 vs. 
13.7 %), stomatitis (35.6 vs. 3.8 %), palmar-plantar erythrodysaesthesia syndrome (31.8 vs. 8.0 %) and 
proteinuria (31.0 vs. 1.5 %) 
TRAEs led to discontinuation of the study drug in 14.2 % of lenvatinib recipients and 2.3 % of placebo 
recipients, with the most frequent of these being asthenia and hypertension (each of which occurred in 
1.1 % of lenvatinib recipients). Dosage reductions (67.8 vs. 4.6 %) or interruptions (82.4 vs. 18.3 %) 
occurred more frequently in the lenvatinib than in the placebo group. The most common adverse effects 


 
 
Page 15 of 76 
Date: February 27, 2018 
 
associated with dosage discontinuations or interruptions of lenvatinib were diarrhea (22.6 %), 
hypertension (19.9 %), proteinuria (18.8 %) and decreased appetite (18.0 %). 
TRAEs that occurred in clinical trials and for which there is a warning/precaution in US manufacturer’s 
prescribing information were hypertension, cardiac dysfunction (decreased left or right ventricular 
function, cardiac failure or pulmonary oedema), arterial thromboembolic events, hepatotoxicity, 
proteinuria, renal failure and impairment, gastrointestinal perforation and fistula formation (incidence in 
SELECT: 2 % in the lenvatinib group vs. 0.8 % in the placebo group), QT interval prolongation, 
hypocalcemia, reversible posterior leucoencephalopathy syndrome (three cases across clinical studies; n = 
1108 lenvatinib recipients), haemorrhagic events and impairment of thyroid stimulating hormone (TSH) 
suppression. 
In SELECT, the incidences of these adverse events that were of grade 3 or higher in the lenvatinib and 
placebo groups were: hypertension (~44 vs. 4 %), cardiac dysfunction (2 vs. 0 %), arterial 
thromboembolic events (3 vs. 1 %), hepatotoxicity (4 vs. 0 % for an increase in alanine aminotransferase 
level; 5 vs. 0 % for an increase in aspartate aminotransferase level), proteinuria (11 vs. 0 %), renal failure 
or impairment (3 vs. 1 %), QT interval prolongation (2 vs. 0 %), hypocalcaemia (9 vs. 2 %) and 
haemorrhagic events (2 vs. 3 %). In patients who had normal TSH levels (≤0.5 mU/mL) at baseline in 
SELECT, 57 % of lenvatinib recipients and 14 % of placebo recipients had elevations in TSH level of 
>0.5 mU/Ml.27 
2.3 Rationale for combining Lenvatinib and Eribulin 
Lenvatinib (LEN) is an oral tyrosine kinase inhibitor of the VEGFR1-3,FGFR1-4, PDGFRβ, RET, and 
KIT signaling networks[1]. It has shown activity in many solid tumors, such as NSCLC and thyroid 
cancer. Data on xenograft models have shown activity of lenvatinib in breast cancer as mentioned in 
Matsui et al. When compared with bevacizumab in breast cancer xenograft models lenvatinib provided 
better antitumor activity as described by Yano et al. Lenvatinib is approved for use in thyroid cancer. 
Clinical trials are currently under way evaluating lenvatinib in patients with hepatocellular, lung, and 
other cancers. Eribulin is a microtubule inhibitor shown to improve OS in breast cancer and with activity 
in other solid tumors such as NSCLC. Recently data from Study 309 showed an improvement in OS in 
patients with advanced sarcoma with Eribulin compared with dacarbazine, a standard treatment in 
sarcoma (data not published yet). We propose a phase II clinical trial of the combination of Eribulin and 
lenvatinib in breast cancer, non-small cell lung cancer (NSCLC) and sarcoma. 
Primary objective will be response rate with secondary objectives toxicity, progression free survival, and 
overall survival. If the combination is deemed safe future randomized phase II trials will be designed. 
2.4 Rationale for patient population 
Patients with stage IV cancer will be included in this trial.  Data on xenograft models has shown activity 
of Lenvatinib and recently it has been approved for use in radioiodine resistant thyroid cancer with 
significantly improved PFS. Furthermore, Eribulin is a microtubule inhibitor which has already shown to 
improve overall survival in breast cancer, and recently has shown activity in Sarcoma. Given the above 


 
 
Page 16 of 76 
Date: February 27, 2018 
 
data, we have elected to include stage 4 breast cancer, sarcoma and Non small cell lung cancer patients in 
our trial. 
2.4.1 Micro RNA assay 
Our goal is also to quantify serum levels of microRNAs pre- and post-treatment, with the goal of 
correlating levels with patient response to treatment.  
RNA isolation. RNA will be isolated using the mirVanaTM miRNA Isolation Kit (Ambion) and 
quantified using a Nanodrop spectrophotometer. RNA quality will be determined on an Agilent 2100 
Bioanalyzer. miRNA expression profiling will be determined by NGS. We will use the HiSeq 2000 
Sequencing System (Illumina) at the GCCRI Genomics Facility to measure miRNA expression profiles. 
Samples will be barcoded to allow multiplex sequencing and subjected to a second round of Q/C.  
Data analysis. Adaptor sequences will be removed and reads of the length ≤ 15 or ≥ 30 are removed as 
they are not likely to originate from mature miRNAs. Duplicate reads will be removed with the remaining 
unique reads stored in FASTA format along with the read count. Unique reads will be aligned to the 
reference human genome (hg19) using the Bowtie short read aligner (0.12.9). Reads mapped to known 
miRNA loci as defined by miRbase (v21) will be kept for expression profiling. miRNA expression will be 
derived from counting reads perfectly matching known miRNA loci, normalized to the total number of 
uniquely mapped reads per sample. 
 Expected results. Expression profiles of serum miRNAs in 10 responders and 10 non-responders, which 
can then be compared by t-test to identify differentially expressed miRNAs that correlate with patient 
response to treatment. 
3.0 
Objective 
The overall purpose of this study is to determine the efficacy and safety of the combination of Eribulin, 
and Lenvatinib in stage 4 breast, NSCLC and sarcoma. 
Primary objective  
To determine the overall response rate of the combination of lenvatinib and Eribulin 
Secondary objectives 
 1) Determine the safety of Eribulin and lenvatinib 
 2) Define the progression free survival 
  3) Expression profile of MicroRNA 
3.1 Selection of Patients 
The target population for this study is patients with stage IV breast, NSCLC lung cancers and Sarcoma.  
This will be a multi-center trial conducted by Mays Cancer Center. At Mays Cancer Center, patients will 
be recruited by the clinical team in the Breast Center; lung center and sarcoma center. Potential patients 
may be referred to the Principal Investigator, Virginia Kaklamani, MD, at (210) 450-3830.  


 
 
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Date: February 27, 2018 
 
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers are 
not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be registered to 
the study. Study treatment may not begin until a subject is registered. Please refer to Section 11 for 
complete instructions regarding registration procedures. 
Inclusion Criteria 
• 
Stage IV breast cancer, stage IV NSCLC, stage IV sarcoma 
• 
ECOG PS 0-2 
• 
Measurable disease 
• 
No more than 4 prior chemotherapeutic regimens for metastatic disease 
• 
Patients must be ≥ 18 years. 
• 
Patients may not have received Eribulin or lenvatinib previously 
• 
Patients must have a life expectancy of greater than 12 weeks. 
• 
Patients may have had a prior diagnosis of cancer if it has been > 5 years since their last 
treatment and are considered free of disease.   
• 
Patients must have normal organ and marrow function as defined below: 
o Leukocytes ≥ 3,000/µL 
o Absolute neutrophil count ≥ 1,500/µL 
o Platelets ≥ 100,000/µL 
o Child Pugh score ≤ 10 
• 
Patients must be able to swallow and retain oral medication. 
• All patients must have given signed, informed consent prior to registration on study. 
Exclusion Criteria 
• 
Women who are pregnant or lactating are not eligible for study treatment. 
• 
Patients who are undergoing concomitant radiotherapy are NOT eligible for participation. 
• 
Patients who are receiving any other investigational agents or concurrent anticancer therapy 
are NOT eligible for participation.  Previous systemic treatment and/or radiation therapy is 
allowed with a 14 day washout period prior to registration. 
• 
Lesions that have been radiated previously cannot be considered target lesions 
• 
Prior treatment related side effects must have resolved to < Grade 2 severity per Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03), except alopecia and 
infertility. 
• 
Patients who are taking any herbal (alternative) medicines are NOT eligible for participation.  
Patients must be off any such medications by the time of registration. 
• 
Patients with known brain metastases are NOT eligible for participation unless the brain 
metastases are treated (either with surgical excision, stereotactic radiosurgery or 
radiotherapy) and have been stable based on the physician’s assessment, the patient is 
asymptomatic and has discontinued corticosteroids if taken for that purpose. 
• 
Patients with any of the following conditions or complications are NOT eligible for 
participation: 
1. GI tract disease resulting in an inability to take oral medication 
2. Malabsorption syndrome 
3. Require IV alimentation 
4. History of prior surgical procedures affecting absorption 
5. Uncontrolled inflammatory GI disease (e.g., Crohn’s, ulcerative colitis). 
6. Hypersensitivity of any  of the components of Eribulin or lenvatinib 
7. History of significant neurological ( no neuropathy more than grade 2) or psychiatric 
disorders  


 
 
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8. Significant non neoplastic liver disease (Cirrhosis, active chronic hepatitis)  
9. Immunocompromised subjects, including patients with human immunodeficiency virus  
10. Significant non neoplastic renal disease 
11. Active infection requiring systemic therapy. 
12. Significant cardiovascular impairment: history of congestive heart failure greater than 
New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, 
unstable angina, myocardial infarction or stroke within 6 months of the first dose of study 
drug; or cardiac arrhythmia requiring medical treatment 
13. Prolongation of QTc interval to more than 480 milliseconds when electrolyte balance is 
normal 
14. Major surgery within 4 weeks prior to first dose of the study drug. 
4.0 
Treatment plan 
4.1 Overview 
This will be a phase II, non-randomized trial to determine the efficacy and safety of the combination of 
Eribulin, and lenvatinib in patients with metastatic breast cancer, non-small cell lung cancer and sarcoma. 
Treatments will be given in cycles of 3 weeks (21 days) and staging scans( CT Scans) will be performed 
every 2 cycles. Bone scans and MRI brain will be optional. Toxicity assessment will take place after each 
cycle. 
Eribulin will be administered on cycle days 1 and 8; lenvatinib is an orally administered medication 
which will be given daily throughout each cycle (on cycle 1 lenvatinib will be started on day 2). On days 
when both drugs are administered, Eribulin will be administered immediately prior to lenvatinib.   
Patients will be followed after treatment discontinuation until disease recurrence or death. An evaluable 
patient for toxicity is any patient who has received at least 1 dose of any of the study drugs. An evaluable 
patient for efficacy is any patient who has received at least 2 cycles of therapy. 
There will be a safety run-in phase. Ten patients will receive lenvatinib at 20 mg daily and Eribulin at 1.4 
mg/m2 day 1 and day 8 of a 21 day cycle. Eribulin will be given on day 1 and lenvatinib at 20 mg daily 
will be started on day 2. After completion of 1 cycle of therapy for the first 10 patients the PI will have a 
teleconference with the medical team at EISAI and decide whether to continue at the same dose or 
increase the dose to 24 mg daily of lenvatinib and Eribulin at 1.4 mg/m2 day 1 and day 8 of a 21 day 
cycle.  
4.2 Study Drug Administration 
Eribulin 
Eribulin will be administered intravenously (IV) on days 1 and 8 of each cycle at a dose of 1.4 mg/m2 
over a 2-5 minute time period; on cycle day 1 in the Phase II portion of the trial; this will be immediately 
prior to Lenvatinib administration. Eribulin will be administered to the patient in the clinic (for drug 
preparation instructions, see section 7.0).  Each cycle will last 21 (+/- 3) days.  Laboratory tests will be 
performed within 2 days prior to days 1 and 8 of all cycles to assess toxicity and confirm that it is safe to 
proceed with treatment (see Section 7.0 for a complete listing of assessments). The dose of Eribulin will 
be calculated based on the BSA at study entry and should only be recalculated if there is >10% change in 
body weight from baseline. The actual body weight will be used for these calculations. 


 
 
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Date: February 27, 2018 
 
Lenvatinib 
Lenvatinib will be self-administered by patients orally once a day during the study period. Patients will 
self-administer lenvatinib at home, except on study visit days. On these visit days, patients should take 
lenvatinib after chemotherapy is administered. Patients will be instructed to take each dose orally once 
daily, with or without food, starting on day 2 of cycle 1. The capsules should be swallowed whole without 
chewing, dissolving, or opening them. Patients should be instructed to take their dose of study drug at the 
same time each day. If the usual dosing time is missed, the patient should take the dose that day as soon 
as they remember as long as this is within 12 hours of the usual time the patient takes the dose. If it has 
been over 12 hours then this will be considered a missed dose. Patients should not make up missed or 
vomited doses; dosing should resume on the next calendar day unless otherwise instructed. Patients will 
be given a medication diary to record all doses taken, missed/skipped, or vomited. This diary will be 
reviewed with study personnel prior to dispensing medication for the next cycle. 
  
4.3 Supportive Care Guidelines 
 
Supportive therapy for neutropenia: 
If grade 3 or 4 neutropenia develops (ANC<1000/ul), G-CSF (Neupogen) can be administered, at the 
discretion of the treating investigator, until resolution of neutropenia. Neulasta (PEG-filgrastim) 6mg SC 
for 1 dose is recommended. If Neulasta is given, chemotherapy cannot be administered within 14 days. 
Neupogen can also be given at the discretion of the treating investigator. NOTE: Neupogen can be given 
any time before or after chemo. HOWEVER, Neulasta cannot be given within 14 days of chemotherapy.  
 
Supportive therapy for neuropathy 
Gabapentin or similar medications can be given at the discretion of the treating physician per institutional 
practice. 
 
Dose Delays & Dose Modifications 
Toxicities will be graded using NCI CTCAE version 4.03 (see Appendices). Dose delays and 
modification of lenvatinib and Eribulin are summarized below (for post-DLT period in phase II patients 
only). Individual patient dose reductions are also provided in separate tables. 
 
 


 
 
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Date: February 27, 2018 
 
Dose Delay& Modification for Eribulin and Lenvatinib 
Toxicity 
Adverse event 
Dose Reduction/Delay 
Eribulin 
Lenvatinib 
Hematologic 
toxicity 
attributed to any 
or all treatment 
 
Platelets 75000-
99999/mm3 within 24 
hrs prior to scheduled 
therapy 
 
 
 
 
If Day 1: Hold 
until recovery of 
platelets 
>100,000/mm3. 
Resume at the 
same level after 
recovery 
If Day 8: No 
intervention 
 
 
No dose modification necessary 
 
 
 
 
ANC <1000/mm3 or 
Platelets 25000-
74999/mm3 within 24 
hrs prior to scheduled 
therapy 
 
If Day 1: Hold 
until recovery to 
ANC >1000/mm3 
and Platelets 
100000/mm3. 
Resume at same 
level after 
recovery 
 
If Day 8: Hold 
until recovery to 
ANC >1000/mm3 
and Platelets 
75000/mm3. 
Resume at same 
level after 
recovery 
 
Hold until recovery to ANC >500/mm3 and 
platelets more than 25000, Resume at same 
level after recovery. 
 
Platelets <25000/mm3 
or Platelets 25000-
50000/mm3complicated 
by bleeding, easy 
bruising, petechiae, or 
requiring platelet 
transfusion 
If Day 1: Hold 
until recovery to 
Platelets 
100000/mm3. 
Resume at same 
level after 
recovery 
 
If Day 8: Hold 
until recovery to 
Platelets 
75000/mm3. 
Resume at same 
level after 
recovery 
 
Hold until recovery of Platelets 25000/mm3. 
Resume at current dose level. 
 


 
 
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Date: February 27, 2018 
 
Prolonged neutropenia 
(ANC<500/mm3 for >7 
days) 
Hold until 
recovery to 
ANC>1000/mm3. 
Resume at one 
dose level below 
current dose 
level 
Hold until recovery to ANC>500/mm3. 
Resume at same level dose. 
Febrile neutropenia 
(ANC <1000/mm3 with 
temperature of 
>38.5oC) 
Hold until 
recovery to 
ANC>1000/mm3. 
Resume at one 
dose level below 
current dose 
level 
Hold until recovery to ANC>1000/mm3. 
Resume at same dose level 
Anemia 
No reduction or 
delay 
No reduction of delay 
Hepatic toxicity 
Grade  4 AST, ALT or 
Total Bilirubin   
Child Pugh Score 
For patients with 
known liver 
dysfunction and 
Child Pugh score 
A, Eribulin 
should be started 
at a dose of 
1.1mg/m2. For 
patients with 
known liver 
dysfunction and 
Child Pugh score 
B, Eribulin 
should be started 
at a dose of 
0.7mb/m2. 
Eribulin should 
not be 
administered in 
patients with 
Child Pugh score 
C. If during 
treatment there is 
grade 3,4 liver 
toxicity then 
dose reduce by 1 
dose level.  
Hold until recovery to Grade 1 or baseline. 
Resume at reduced dose of 20 mg po daily if 
first occurrence, reduce to 14 mg po daily on 
second occurrence and 10 mg po daily on third 
occurrence. 


 
 
Page 22 of 76 
Date: February 27, 2018 
 
Peripheral 
neuropathy 
Grade 3 or 4 
 
Hold until 
recover to <grade 
2. Reduce dose 
by one dose 
level. If 
neuropathy fails 
to recover to 
grade 2 within 3 
weeks, Eribulin 
should be 
discontinued. 
No modifications necessary 
Non-
hematologic 
toxicity grade 3 
or 4 attributed 
to any or all 
treatment 
(except for 
neuropathy) 
Grade 3 or 4 
nausea/vomiting despite 
optimal antiemetic 
treatment 
Hold until 
nausea/vomiting 
have resolved to 
<grade 1. 
Resume at same 
dose level 
Hold until nausea/vomiting have resolved to 
<grade 1. Resume at same dose. 
>Grade 2 stomatitis 
Hold until 
stomatitis has 
resolved to 
<grade 1. 
Resume at one 
dose level below 
current dose 
level 
Hold until recovery to <grade 1. Resume at the 
same dose level 
Hypertension 
Grade 3 Hypertension 
Or life threatening 
Hypertension 
No dose 
modification 
necessary. 
Withhold lenvatinib for Grade 3 hypertension 
that persists despite optimal 
antihypertensive therapy; resume at one dose 
level below current dose level. Discontinue for 
life threatening hypertension. 
Cardiac 
dysfunction or 
Hemorrhage. 
 
Grade 3 or Grade 4 
events 
No dose 
modification 
necessary 
Withhold lenvatinib for development of Grade 
3 event until improved to Grade 0 or 1 or 
baseline. Either resume at a reduced dose or 
discontinue lenvatinib depending on the 
severity and persistence of the adverse event. 
 
Proteinuria  
 
>2 gms or less than 2 
gms 
No dose 
modification 
necessary. 
Withhold lenvatinib for <2 grams of 
proteinuria/24 hours. Resume at next dose 
level below current dose level; 2) when 
proteinuria is >2 gm/24 hours. Discontinue 
lenvatinib for nephrotic syndrome. 
QTc 
Prolongation 
 
Grade 3 or greater 
No dose 
modification 
necessary 
Monitor and correct electrolyte abnormalities 
in all patients. Withhold lenvatinib for the 
development of Grade 3 or greater QT interval 
prolongation. Resume lenvatinib at a one dose 
level below previous dose level when QT 
prolongation resolves to Grade 0 or 1 or 
baseline.  
 


 
 
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Date: February 27, 2018 
 
Day 8 dose of Eribulin may be delayed for a maximum of 1 week. If toxicities do not improve enough 
after 1 week delay then omit day 8 dose of Eribulin. If day 8 of Eribulin is omitted two consecutive cycles 
Eribulin should be resumed at one dose below current dose level. 
Eribulin Dose Modifications 
Starting dose and dose modifications for unacceptable toxicity that is thought to be related to Eribulin are 
listed below. Dose adjustments are to be made according to the greatest degree of toxicity. The most 
common toxic effects of Eribulin are fatigue, neutropenia (including neutropenic fever), peripheral 
neuropathy, and alopecia. 
 
Eribulin Dose Modifications, TABLE 1 
0 
1.4 
-1 
1.1 
-2 
0.7 
 
 
 
NOTE: Patients requiring a third dose reduction should be taken off study unless in the opinion of 
the investigator and/or the DSMB there is reason to believe that the patient is still experiencing 
clinical benefit(in such cases the DSMB will issue written approval). 
Lenvatinib Dose Modifications 
Recommended Dose Modifications for Persistent and Intolerable Grade 2 
or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalities, TABLE 2 
0 
20 
-1 
14 
Note:  Based on toxicity data of 1st 10 patients in Phase 2, starting 
Lenvatinib dose was not increased to 24 mg daily 
 
Other Toxicities with Lenvatinib 
In the SELECT trial, QT/QTc interval prolongation was reported in 9% of lenvatinib-treated patients and 
2% of patients in the placebo group. The incidence of QT interval prolongation of Grade 3 or greater was 
2% in lenvatinib-treated patients compared to no reports in the placebo group. In the same trial, events of 
gastrointestinal perforation or fistula were reported in 2% of lenvatinib-treated patients and 0.8% of 
patients in the placebo group. 9% of lenvatinib-treated patients experienced Grade 3 or greater 
hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to 
replacement and dose interruption/dose reduction. 
 
Across clinical studies in which 1108 patients received lenvatinib, there were 3 reported events of 
reversible posterior leukoencephalopathy syndrome (RPLS).  It is recommended to confirm the diagnosis 
with MRI and hold Lenvatinib until the resolution of the RPLS. 
 


 
 
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Lenvatinib impairs exogenous thyroid suppression. In the SELECT trial, 88% of all patients had a 
baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a 
normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post-baseline in 57% of 
Lenvatinib-treated patients as compared with 14% of patients receiving placebo. It is recommended to 
monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. 
 
GI perforation and fistula formation has been reported in 2 % of the patients compared to 0.8 % patients 
in the placebo group. It is recommended to discontinue Lenvatinib in patient who had life threatening 
perforation or fistula formation. 
 
4.4 Concomitant medications 
 
All concomitant treatments, including blood and blood products, must be reported in the patient’s 
electronic medical record. 
 
4.5 Not Permitted 
 
Patients who are taking any herbal (alternative) medicines are NOT eligible for participation.  Patients 
must be off any such medications by the time of registration. Patients who are undergoing concomitant 
radiotherapy or chemotherapy are NOT eligible for participation. Patients may not have received Eribulin 
or lenvatinib previously. Length of the washout period from prior chemotherapy or radiation therapy will 
be 14 days.  
 
4.6 Permitted 
 
Supportive care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the treating physician.  Concurrent treatment with bisphosphonates or denosumab is allowed. 
Erythropoietin may be administered at the discretion of the investigator, consistent with institutional 
guidelines.  G-CSF should be administered according to the guidelines in this protocol. 
 
4.7 Duration of Therapy 
Patients may continue on study therapy until disease progression or until unacceptable toxicity occurs. 
Patients will go off study therapy if any of the following occurs: 
• 
The patient experiences any grade 4 toxicity after 2 dose modifications, as recommended by the 
protocol. If treatment is held for 2 consecutive treatment cycles due to toxicity, the patient must 
go off treatment. 
• 
The patient withdraws consent from treatment or from the study as a whole. 
• 
There is disease progression. 
• 
The treating physician feels it is necessary (e.g. due to patient non-compliance or other safety 
concerns). 
 
4.8 Follow-up Post Therapy 
 
Patients will be followed every 6 months at the time of routine clinic visit or via phone call with study 
personnel after completion of treatment until death.   


 
 
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Date: February 27, 2018 
 
Treatment after study completion will be left to the discretion of the treating physician(s) and will not be 
considered part of this study. However, patients should still be followed for study endpoints including 
date of progression and survival status. 
5.0 
Response Assessment 
Patients with measurable disease are eligible for the study. Response to treatment will be assessed using 
RECIST 1.1 guidelines. Response and progression will be assessed in this study via physical exam and 
imaging.  
5.1 Definitions 
 
5.1.1 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. 
5.1.2 Non measurable disease 
All other lesions or sites of disease, including small lesions (those with a longest diameter of < 20 mm 
with conventional techniques or < 10 mm with spiral CT scan) as well as those that can be assessed as to 
changes in size but cannot be clearly measured, are considered non-measurable disease. Other examples 
include bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI).  
 
5.1.3 Target Lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total representative of 
all involved organs should be identified as target lesions and recorded and measured at baseline.  Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability 
for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest 
diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline 
sum LD will be used as reference by which to characterize the objective tumor response. 
5.1.4 Non-Target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Non-target lesions include measurable lesions that exceed the maximum numbers 
per organ or total of all involved organs as well as non-measurable lesions. Measurements of these lesions 
are not required, but the presence or absence of each should be noted throughout follow-up. 
 
5.2 Guidelines for Evaluation of Measureable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 
4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation 
by clinical examination when both methods have been used to assess the antitumor effect of a treatment. 


 
 
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5.2.1 Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes). In the case of skin lesions, documentation by color photography, including a ruler 
to estimate the size of the lesion, is recommended.  
5.2.2 Cytology, Histology 
These techniques can be used to differentiate between partial responses (PR) and complete responses 
(CR). 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 (PD). 
5. 3 Response Criteria 
Response will be based on evaluation of target and non-target lesions. To be assigned a best response of 
partial response (PR) or complete response (CR), changes in tumor measurements must be confirmed by 
repeat studies that should be performed at a minimum of 4 weeks after the criteria for response are first 
met. A best response of SD will not require a confirmatory measurement; however, best overall response 
of SD will not be assessed unless a patient has received at least 2 complete cycles of treatment. 
5.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, 
taking as reference the baseline sum LD. 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started or the appearance of one or more new 
lesions. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum LD since the treatment started 
5.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level. 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions 


 
 
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Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail, and the progression status should be confirmed at a later 
time by Dr. Kaklamani and the UTHSA Data Safety Monitoring Committee assigned to this protocol.  
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
5.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria (see section 6.4). 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.” Every effort should be made to document the objective progression, even after 
discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends on this determination, it is recommended that the residual lesion 
be investigated (fine needle aspirate/biopsy) before confirming the complete response status. 
5.3.4 Endpoint Assessment 
The overall response rate (ORR) will be defined as response after scans assessed after two cycles of 
therapy (1 cycle = 3 weeks). Clinical response will be assessed by the treating physician as outlined 
above. All patients who are on study after 2 cycles will be considered evaluable for the response 
endpoints. 
Progression-free survival (PFS) will be defined as the time from the first study treatment to the first 
occurrence of progression or death. All patients who receive at least one dose of each drug will be 
evaluable for this endpoint. 
Toxicity will be assessed NCI CTCAE v 4.03. The incidence, nature, and severity of adverse events will 
be determined. All patients who receive at least one dose of study drug will be considered evaluable for 
toxicity and safety endpoints. 


 
 
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6.0 
Study Parameters 
Procedures 
Screening & 
Baseline 
Cycle 1  
Every cycle2 
Every 2 cycles or at 
study termination 
End of study 
visit7 
Follow-Up6 
Tissue procurement1 
X 
 
 
X5 
 
 
Informed consent 
X 
 
 
 
 
 
Eribulin administration 
 
 
X 
(Days 1 & 8)  
 
 
 
Lenvatinib 
 
 
X 
once daily 
(starting on day 
2 of cycle 1) 
 
 
 
Medical history3  
X 
 
X 
 
X 
 
Physical exam3 
X 
 
X 
 
X 
 
CBC w/ diff 
X3 
 
X 
 
X 
 
Comprehensive chemistry 
panel 
X3 
 
X 
 
 
 
TSH 
X 
 
X 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
EKG 
X 
 
     X10 
 
 
 
Blood draw for micro RNA 
assay9 
 
X 
 
 
X 
 


 
 
Page 29 of 76 
Date: February 27, 2018 
 
Procedures 
Screening & 
Baseline 
Cycle 1  
Every cycle2 
Every 2 cycles or at 
study termination 
End of study 
visit7 
Follow-Up6 
Urine analysis11 
X 
 
 
X 
 
 
Imaging8  
X4 
 
 
X 
 
 
Toxicity assessment 
 
 
X 
 
 
 
Biopsy 
 
 
 
X5 
 
 
Survival status 
 
 
 
 
 
X 
1Archival tissue or a fresh biopsy will be required to procure tissue for study purposes. Biopsy does not need to be repeated for study purposes if archived tissue is available. 
Tissue procurement is voluntary 
2A cycle is defined as 3 weeks or 21 days (+/- 3 days).  Eribulin will be given on cycle days 1 and 8 and lenvatinib starting on day 2 of cycle one and then continuously. 
3Pre-study laboratory tests, medical history, and physical exam (including performance status and review of systems) must be completed within 28 days prior to registration. 
Pre-study CBC and CCP will be repeated on day 1 prior to treatment administration. 
4Pre-study imaging must be performed within 28 days prior to registration. 
5At the initiation and completion of study treatment (or at the time of early withdrawal), tissue samples should be obtained for correlative studies. This is voluntary and will 
only be done on patients who consent to it.  
6Patients will be followed every 6 months, at the time of routine clinic visit or via phone, until death, to document disease progression and survival. 
7Within 30 days of last dose of study medications.   
8Imaging modality is left to the discretion of the investigator. However the same imaging modality should be used every two cycles to assess disease status.  
9Blood samples for microRNA assay will be collected on Cycle 1, Day 1 and at the end of treatment. 
10Repeat EKG with every cycle in patients with congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia 
and III antiarrhythmics. 
11Lenvatinib may cause proteinuria. Patients with 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. If 24hr urine protein 
>2 g then suspend lenvatinib until it decreases to <2g and dose reduce by one dose level. IIf nephrotic syndrome then permanently discontinue lenvatinib.  


 
 
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7.0 
Drug formulation and Procurement 
 
7.1 Eribulin 
 
Other Names 
Halaven; eribulin mesylate 
 
Classification 
Eribulin is a non-taxane, synthetic analogue of halichondrin B (a product isolated from the marine sponge 
Halichondria okadai). 
Mode of Action 
Eribulin is a non-taxane microtubule dynamics inhibitor. Eribulin inhibits the growth phase of 
microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates.  
Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, 
disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. 
Storage & Stability 
Vials should be stored in their original cartons at 25°C (77°F); excursions are permitted to 15°-30°C (59°-
86°F). Do not freeze. Undiluted Eribulin may be stored for up to 4 hours at room temperature, or for up to 
24 hours under refrigeration (4°C or 40°F). Diluted solutions of Eribulin may be stored for up to 4 hours 
and room temperature or up to 24 hours under refrigeration. Discard unused portions of the vial. 
Protocol Dose 
Eribulin will be given at a dose of 1.4 mg/m2 administered intravenously over 2-5 minutes.  
Preparation 
Eribulin will be supplied in commercially-labeled vials as a clear, colorless, sterile solution for 
intravenous administration.  Each vial contains 1 mg of Eribulin mesylate as a 0.5 mg/ml solution in 
ethanol: water (5:95).  Eribulin should be administered undiluted or diluted in 100 mL of 0.9% sodium 
chloride injection, USP. 
Protocol Administration 
Eribulin will be administered via intravenous infusion over 2-5 minutes.  Treatments will be administered 
on cycle days 1 and 8. 
Incompatibilities 
Eribulin should not be diluted in, or administered through, an intravenous line containing solutions with 
dextrose.   
Availability 
Eribulin will be supplied by Eisai, Inc in vials labeled for clinical use containing 1 mg/2mL Eribulin 
mesylate as a 0.5 mg/ml solution in ethanol: water (5:95).  To order drug, please contact EISAI IIS 
Department at Phone: 866-434-8176 or Eisai_iisgrants@eisai.com 


 
 
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Date: February 27, 2018 
 
Side Effects 
Detailed information regarding side effects and rates of adverse events of Eribulin can be found in the 
package insert.  Some of the most common side effects include: 
Hematologic:  The most common hematologic toxicities (occurring in ≥ 25% of patients) are neutropenia 
and anemia.  The most common serious adverse events were febrile neutropenia (4%) and neutropenia 
(2%). 
Gastrointestinal:  Most common are nausea and constipation (occurring in ≥ 25% of patients).  Other GI 
adverse events include diarrhea and vomiting. 
Neurologic:  Peripheral neuropathy (incidence of ≥ 25%) is the most common. 
Other:  Asthenia/fatigue and alopecia are the most common (occurring in ≥ 25% of patients) 
miscellaneous adverse events. 
Nursing Implications 
Monitor CBC and platelet counts.   
Monitor for signs of neuropathy. 
Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs 
known to prolong the QT interval, and electrolyte abnormalities. 
 
7.2 Lenvatinib 
 
Other names 
Lenvima  
 
Classification 
LENVIMA, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4-[3- 
chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamidemethanesulfonate. 
  
Mode of action 
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular 
endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). 
Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, 
and cancer progression in addition to their normal cellular functions, including fibroblast growth factor 
(FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, 
and RET. 
 
Storage and Stability 
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) 
Protocol dose 
Lenvatinib is administered at a dose of 20 mg orally. 
 


 
 
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Date: February 27, 2018 
 
Preparation 
LENVIMA 4 mg capsules are supplied as hard hyperomellose capsules with yellowish-red 
body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 4 mg” on 
the body. 
 
LENVIMA 10 mg capsules are supplied as hard hyperomellose capsules with yellow body 
and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 10 mg” on the 
body. 
 
Protocol administration 
Lenvatinib is administered orally 20 mg po daily. It will be administered immediately after the Eribulin 
administration. 
Incompatibilities 
None 
Availability 
Lenvima will be supplied by Eisai, Inc in cards containing 10 mg and 4 mg capsules.  To order drug, 
please contact EISAI IIS Department at Phone: 866-434-8176 or Eisai_iisgrants@eisai.com 
Side effects 
Detailed information regarding side effects and rates of adverse events of lenvatinib can be found in the 
package insert.  Some of the most common side effects include: 
Hypertension  
The median time to onset of new or worsening hypertension was 16 days for LENVIMA-treated patients. 
The incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of 
Grade 4 hypertension was less than 1% in LENVIMA-treated patients and none in the placebo group. 
Cardiac dysfunction 
Cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary 
edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or 
greater) of patients in the placebo group. The majority of these cases in LENVIMA-treated patients were 
based on findings of decreased ejection fraction as assessed by echocardiography 
Hepatic toxicity 
4% of LENVIMA-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% 
experienced an increase in aspartate aminotransferase (AST) that was Grade 3 or greater. No patients in 
the placebo group experienced Grade 3 or greater increases in ALT or AST. Across clinical studies in 
which 1108 patients received LENVIMA, hepatic failure (including fatal events) was reported in 3 
patients and acute hepatitis was reported in 1 patient. 
Other adverse effects include renal failure or improvement, proteinuria, gastro intestinal fistula and 
perforation, arterial thrombotic events,  QT interval prolongation, PRES, hypocalcemia and hemorrhagic 
events. 
Nursing complications 
Advise nursing women to discontinue breastfeeding during treatment with LENVIMA 


 
 
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8.0 
Statistical Considerations 
 
8.1 Proposed sample size 
 
8.1.1 Safety run in phase 
The number of subjects in the safety run-in phase will be 10. In the phase II trial the number of patients 
will be 30. Three patients will receive lenvatinib at 20 mg qd and Eribulin at 1.4 mg/m2 day 1 and day 8 
of a 21 day cycle. Eribulin will be given on day 1 and lenvatinib will be started on day 2. If no DLTs are 
experienced, then the Phase II trial will be initiated at a dose of 24 mg daily of lenvatinib and Eribulin at 
1.4 mg/m2 day 1 and day 8 of a 21 day cycle. If there is a DLT, then three more patients will be treated at 
that dose level. If no more DLTs are observed, then the phase II trial can commence at lenvatinib dose of 
20 mg qd and Eribulin at 1.4 mg/m2 day one and day 8 of a 21 day cycle. If there is another DLT, then 
there will be a dose reduction of lenvatinib to 14 mg daily.  
8.1.2 Phase II 
We will use group of n= 30 patients at the MTD.  The expected poor response rate is p=0.20 or less, while 
p>=0.4 or more would be considered successful/good. We intend to proceed by calculating a response 
rate and providing a 95% confidence interval in the experimental group. This interval will have an 
approximate half width 2x [0.5/sqrt(30)]=  0.18 or less. We will test the hypothesis that the response rate 
is larger than 0.2 in the following way: if the lower bound of the one sided  90%  exact confidence 
interval for underlying p is greater than 0.2, we will consider this evidence that p>0.2 i.e. of good 
response, and worthy of further investigation. Equivalently, using a one sided exact test of H0: p=0.2 
versus H1: p>0.2, with power at p=0.4 being over 80%, we have the power analysis below.  
Numeric Results for testing H0: P = P0 versus H1: P > P0 
Test Statistic: Exact Test 
 
 Given H0 Given H1 Difference 
Target 
Actual 
 Reject H0 
Power 
N 
(P0) 
(P1) 
(P1 - P0) 
Alpha 
Alpha 
Beta If R>=This 
0.8237 
30 
0.2000 
0.4000 
0.2000 
0.1000 
0.0611 
0.1763 
10 
 
8.2 Data analysis 
Data will be analyzed by the PI and Dr Michalek using Stata statistical software. We will provide 
descriptive statistics and confidence intervals for all variables of interest for which data are collected. 
8.3 Correlative science 
Objective. To quantify serum levels of microRNAs pre- and post-treatment, with the goal of correlating 
levels with patient response to treatment.  
RNA isolation. RNA will be isolated using the mirVanaTM miRNA Isolation Kit (Ambion) and 
quantified using a Nanodrop spectrophotometer. RNA quality will be determined on an Agilent 2100 
Bioanalyzer.  


 
 
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Date: February 27, 2018 
 
miRNA expression profiling by NGS. We will use the HiSeq 2000 Sequencing System (Illumina) at the 
GCCRI Genomics Facility to measure miRNA expression profiles. Samples will be barcoded to allow 
multiplex sequencing and subjected to a second round of Q/C.  
Data analysis. Adaptor sequences will be removed and reads of the length ≤ 15 or ≥ 30 are removed as 
they are not likely to originate from mature miRNAs. Duplicate reads will be removed with the remaining 
unique reads stored in FASTA format along with the read count. Unique reads will be aligned to the 
reference human genome (hg19) using the Bowtie short read aligner (0.12.9). Reads mapped to known 
miRNA loci as defined by miRbase (v21) will be kept for expression profiling. miRNA expression will be 
derived from counting reads perfectly matching known miRNA loci, normalized to the total number of 
uniquely mapped reads per sample. 
 Expected results. Expression profiles of serum miRNAs in 10 responders and 10 non-responders, which 
can then be compared by t-test to identify differentially expressed miRNAs that correlate with patient 
response to treatment. 
Blood samples for microRNA assay will be collected on Cycle 1, Day 1 of treatment, and at the end of 
treatment. QIAGEN PAXgene Blood RNA tubes will be used to collect the samples.  
Blood samples will be sent to Dr Pertsemlidis’s lab: 
Xiuye Ma (ma@uthscsa.edu) 
Greehey Children's Cancer Research Institute 
UT Health Science Center at San Antonio 
8403 Floyd Curl Drive, MC 7784 
San Antonio, TX 78229-3900 
T (210) 562-9062 
 
Tissue specimens from before and after treatment will be stained for markers of both angiogenesis and of 
hypoxia, CD-36 and carbonic anhydrase 9 (CA9) respectively, to see if the combination is effective at 
reducing hypoxia and the effects on angiogenesis.  We will also look at the effects on reversal of EMT by 
performing IHC for E-cadherin, N-cadherin and vimentin to see if there is a reversion with treatment as 
has been seen in vitro and in animal models. 
All IHC will be performed in Dr Susan Moobery’s lab: 
UT Health San Antonio 
7703 Floyd Curl Drive, Mail Code 7764 
San Antonio, TX 78229-3900  
Phone: 210-567-4788 
9.0 
Adverse Events Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of subjects enrolled in the studies as well as those who will enroll in future studies using 


 
 
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Date: February 27, 2018 
 
similar agents.  Subjects must be carefully monitored for AEs. This monitoring also includes clinical 
laboratory tests.  Adverse events should be assessed in terms of their seriousness, intensity, and 
relationship to the study drug, or other chemotherapy/treatment. Adverse events are reported in a routine 
manner at scheduled times during a trial.  Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care. 
 
All patients experiencing an adverse event, regardless of its relationship to study drug, will be monitored 
until:  
• 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
• 
any abnormal laboratory values have returned to baseline;  
• 
there is a satisfactory explanation other than the study drug for the changes 
observed; or 
• 
death occurs. 
 
Therapeutic monitoring should be performed following dose modification in a manner consistent with the 
local clinical standard of care.  In general, subjects should be closely monitored for side effects of all 
concomitant medications regardless of the path of drug elimination. 
9.2 Definitions & Descriptions 
9.2.1Adverse event (AE) 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study treatment and 
which does not necessarily have a causal relationship with this treatment. An AE can, therefore, be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an experimental intervention, whether or not related to the 
intervention. A “drug-related toxicity" includes as events, any toxicity considered related, probably 
related, or possibly related to study drugs. Toxicities clearly not related to the drug, such as disease 
progression, environmental, unrelated trauma may not be considered “drug related toxicity”. 
9.2.2 Severity of AEs 
All adverse events will be graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. The CTCAE v. 4.03 is available at  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly 
affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
 


 
 
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9.2.3 Serious Adverse events 
All SAEs, regardless of attribution, occurring during the study or within 30 days of the last administration 
of study drug must be reported upon discovery or occurrence.  Additional expedited or routine reporting 
may be required, depending on the nature of the SAE. A “serious” adverse event is defined in regulatory 
terminology as any untoward medical occurrence that: 
• 
Results in death.  If death results from (progression of) the disease, the disease should be reported 
as the event (SAE) itself. 
• 
Is life-threatening. The patient was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization for ≥ 24hours. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event. 
• 
Any event that does not meet the above criteria, but that in the judgment of the investigator 
jeopardizes the patient, may be considered for reporting as a serious adverse event. The event 
may require medical or surgical intervention to prevent one of the outcomes listed in the 
definition of “Serious Adverse Event“. Examples: allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency. 
9.2.4 Exceptions to the Definition of SAE 
Certain hospitalizations or prolongation of hospitalizations should not be considered SAEs, including 
those that meeting the following criteria: 
• 
An admission resulting in a hospital stay of less than 12 hours. 
• 
An admission that is pre-planned (i.e. elective or scheduled surgery arranged prior to the start of 
the study). 
• 
An admission that is not associated with an AE (i.e. social hospitalization for purposes of respite 
care) 
9.2.5 Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO) 
A UPIRSO includes events that meet ALL of the following criteria: 
• 
Are unanticipated in terms of nature, severity, or frequency  
• 
Place the research subject or others at a different or greater risk of harm, AND  
• 
Are deemed to be related or possibly related to participation in the study   
10.0 
Adverse event reporting 
 
Steps to determine if expedited reporting is required 
This includes all events that occur within 30 days of the last dose of protocol treatment. Any event that 
occurs more than 30 days after the last dose of treatment and is attributed (possibly, probably, or 
definitely) to the agent(s) must also be reported accordingly. 
Identify the type of adverse event using the NCI CTCAE v 4.03. 
Grade the adverse event using the NCI CTCAE v 4.03. 


 
 
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Date: February 27, 2018 
 
Determine whether the adverse event is related to the protocol therapy.   
 
Attribution categories are as follows: 
Definite: AE is clearly related to the study treatment (attribution should be separated by each study drug) 
Probable: AE is likely related to the study treatment (attribution should be separated by each study drug) 
Possible: AE may be related to the study treatment (attribution should be separated by each study drug) 
Unrelated: AE is clearly NOT related to the study treatment (attribution should be separated by each 
study drug 
 
Determine the prior experience of the adverse event.  Expected events are those that have been previously 
identified as resulting from administration of the specific agent. An adverse event is considered 
unexpected, for expedited reporting purposes only, when either the type of event or the severity of the 
event is not listed in: 
• 
the current protocol, the drug package insert; 
• 
or the current Investigator’s Brochure. 
 
10.1 Expedited Reporting of SAEs 
Reporting 
All SAEs must be reported following the DSMB outlined in the appendix of this protocol within 24 hours 
of becoming aware of the event. Completion of the Mays Cancer Center SAE Form is required.   The 
completed form should assess whether or not the event qualifies as a UPIRSO.  The report should also 
include: 
• 
Protocol description and number 
• 
Patient’s Identification Number 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Hospital Discharge Summary (if available) 
 
All SAEs will be reported to, and reviewed by, the DSMB at their next meeting.   
Reporting to Eisai 
 
All SADRs must also be reported to Eisai within 24 hours of becoming aware of the event.  The report 
should use the FDA Medwatch.  Reports can be sent to: 
 
Eisai Medical Services  
100 Tice Blvd.  
Woodcliff Lake, NJ 07677  
Tel: 1-888-274-2378  
Fax: -1-732-791-1111  
Email: ESI_Safety@eisai.com 
Reporting to the UT Health San Antonio IRB 
Any death of a subject that is unanticipated in nature and at least possibly related to study participation 
will be promptly reported to the UT Health San Antonio Mays Cancer Center Regulatory Affairs Division 


 
 
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Date: February 27, 2018 
 
for reporting within 24 hours of notification. Other SAE’s that are life threatening, but not fatal, should be 
reported to Mays Cancer Center Regulatory Affairs within 7 days of notification. 
The following SAEs will be reported to the Mays Cancer Center Regulatory Affairs for reporting to the 
UT Health San Antonio IRB at the time of continuing review: 
The following SAEs will be reported to the Mays Cancer Center Regulatory Affairs for reporting to the 
UT Health San Antonio IRB at the time of continuing review: 
• 
All deaths of UT Health San Antonio subjects that were not previously reported 
• 
All deaths of non-UT Health San Antonio subjects that are deemed to be unanticipated in 
nature and unrelated to participation 
• 
Other UPIRSO’s 
• 
All other SAEs not previously reported to the UT Health San Antonio IRB as UPIRSOs 
 
In addition, participating sites should follow local guidelines for reporting of SAEs to their IRB as 
required. 
In addition, participating sites should follow local guidelines for reporting of SAEs to their IRB as 
required. 
Reporting to the FDA: 
The Mays Cancer Center Regulatory Affairs division will notify FDA within 7 calendar days of any SAE 
that is associated with study treatment, is unexpected, and is fatal or life-threatening. The Mays Cancer 
Center Regulatory Affairs Division will notify the FDA within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not fatal or life-threatening. This 
includes any previous SAEs that were not initially deemed reportable, but are later determined to meet the 
criteria for reporting (i.e. by the DSMB).  In these instances, an FDA Med Watch Form will be 
completed. 
10.2 Routine Reporting 
 
All other adverse events, such as those that are expected, or are unlikely or definitely not related to the 
study participation, are to be reported on the appropriate eCRF according to the time intervals noted in the 
Schedule of Events.  Routine AEs will be reviewed by the assigned DSMB for the study in accordance 
with the Cancer Therapy and Research Center’s Multi-site DSMP Procedures. These will be reviewed by 
the DSMB on an on-going basis.  A summary of all these events will be reported annually to the UT 
Health San Antonio IRB as part of the continuing review process. 
11.0 
Study Management 
11.1 Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations. The IRB should approve the consent form and protocol. 


 
 
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In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study 
and will be given the opportunity to review the consent form. Each consent form must include all the 
relevant elements currently required by the FDA Regulations and local or state regulations. Once this 
essential information has been provided to the patient and the investigator is assured that the patient 
understands the implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form. 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. 
Registration Procedures 
Patients may not begin protocol treatment prior to registration. All patient registrations will be centralized 
through the Research/Nurse Coordinator of this study at the Institute for Drug Development at the Mays 
Cancer Center of the UT Health San Antonio. Please contact the assigned Mays Cancer Center 
Research/Nurse Coordinator for questions regarding patient registration procedures.   
11.1.1 Access to IDEAS  
 
Eligible patients will be registered to the study via the web-based application IDEAS. Please note that a 
username and password is required to use this program, and will be provided during site activation prior 
to training on the IDEAS system.   
11.1.2 Registering a Patient for the Safety run in Portion of the Study 
 
For potential patients for the phase I portion of this study, please email the UT Health San Antonio 
Nurse/Research Coordinator prior to consenting a patient to determine whether a slot is available on the 
current cohort. An email confirming the reservation and expiration date will be sent by the UT Health San 
Antonio Nurse/Research Coordinator. In order for registrations to be processed efficiently, study teams 
are asked to inform the UT Health San Antonio Nurse/Research Coordinator of the date and time that the 
patient will need to be registered. Detailed instructions and project coordinator contact information 
regarding registration procedures will be provided separately from this protocol. 
To register a patient, please complete and submit the following items to confirm eligibility and receive a 
subject identification number:  
• 
Eligibility checklist (signed and dated by the treating physician  
• 
Signed and dated informed consent document   
• 
Pathology Report 
 


 
 
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Affiliates sites are required to de-identify, scan, and e-mail the following source documents in order to 
confirm eligibility prior to registration for phase I patients: 
• 
Complete medical and surgical history, current medications, history of clinically significant 
infections, and physical exam [including weight, height, ECOG PS, vital signs (pulse, 
temperature, respiratory rate, blood pressure, oxygen saturation)]  
• 
Lab results (baseline CBC w/diff, baseline CMP) 
• 
Documentation that archival tissue is available or documentation that a biopsy will be done 
• 
Negative serum pregnancy test (if applicable)  
• 
Copy of baseline imaging report 
 
UT Health San Antonio study teams are NOT required to submit a separate email for UT Health San 
Antonio participants, provided that the required documentation listed above is readily available in the 
patient’s electronic medical record (EMR). However, any information that is not available in the EMR 
must be de-identified and retained in the subject’s research record.  
The Nurse/Research Coordinator will review all source documentation required to confirm eligibility with 
the PI. Once confirmed, the Nurse/Research Coordinator will register the patient, assign a subject 
identification number, provide a cohort assignment, and send a confirmation of registration to the study 
team. Registration will then be complete and the patient may begin study treatment.   
11.1.3 Registering a Patient to the Phase II Portion of the Study 
BEFORE a patient can be treated on study, please complete and submit the following items to confirm 
eligibility and receive a subject identification number:  
• 
Eligibility checklist (signed and dated by the treating physician) 
• 
Signed and dated informed consent document 
• 
Pathology Report  
 
The Nurse/Research Coordinator will review the submission with the PI, register the patient, assign an 
identification number, and send a confirmation of registration to involved personnel. Registration will 
then be complete and the patient may begin study treatment.  
12.0 
Data Management and Monitoring 
This study will be monitored as an Investigational Initiated study, which requires auditing after the first 
patient has completed 1 cycle of treatment at each site and at least an annual audit, as outlined in the 
Cancer Therapy and Research Center’s DSMP.  Please refer to Appendix III for more specific details on 
the monitoring plan.  Data submission requirements can be found in Appendix IV for both phase I 
patients and phase II patients. 
Adherence to the Protocol 
 
Except for an emergency situation in which proper care for the protection, safety, and well-being of the 
study patient requires alternative treatment, the study shall be conducted exactly as described in the 
approved protocol.  


 
 
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Emergency Modifications 
 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB approval. 
  
For any such emergency modification implemented, the coordinating site must be notified of the event 
within five business days of making the change.  
Other Protocol Deviations 
According to the IRB, a protocol deviation is any unplanned variance from an IRB approved protocol 
that:  
o Is generally noted or recognized after it occurs 
o Has no substantive effect on the risks to research participants 
o Has no substantive effect on the scientific integrity of the research plan or the value of the 
data collected  
o Did not result from willful or knowing misconduct on the part of the investigator(s).  
 
A protocol deviation is considered an instance of promptly reportable event if the occurrence: 
• 
Has harmed or increased the risk of harm to one or more research participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, State laws, 
or University policies. 
 
Protocol Deviations: Study personnel will promptly report all deviations to the Mays Cancer Center 
Regulatory Affairs Division at: regulatoryaffairs@uthscsa.edu after becoming aware of the event using 
the Mays Cancer Center Protocol Deviation Tracking Form. 
Amendments to the Protocol  
 
Should amendments to the protocol be required, the amendments will be originated and documented by 
the Principal Investigator. It should also be noted that when an amendment to the protocol substantially 
alters the study design or the potential risk to the patient, a revised consent form might be required.  
The written amendment, and if required the amended consent form, must be sent to the IRB for approval 
prior to implementation.  
13.0 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol 
and amendments, IRB correspondence and approval, signed patient consent forms). 


 
 
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Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that the study investigator must retain all study 
documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking 
regulatory approval and marketing, these documents shall be retained for at least two years after the last 
approval of marketing application in an International Conference on Harmonization (ICH) region. In all 
other cases, study documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
14.0 
Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator 
is responsible for personally overseeing the treatment of all study patients. The Principal Investigator 
must assure that all study site personnel, including sub-investigators and other study staff members, 
adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records or de identified 
documents to permit verification of proper entry of data. At the completion of the study, all case report 
forms will be reviewed by the Principal Investigator at each site and will require his/her final signature to 
verify the accuracy of the data. 
14.1 Publication Policy 
All potential publications and/or data for potential publications (e.g. manuscripts, abstracts, posters, 
clinicaltrials.gov releases) must be approved in by the PI of this study prior to release. If the investigator’s 
wish to obtain monitored data prior to this point (or prior to the point dictated by study design), the 
investigator must send a written request for data to the PI of this study that includes justification. If the 
request is approved, data will be provided no later than 4 weeks after this request approval. The 
investigators are expected to use only monitored, accurate and approved data in all publications. The 
investigators should submit a copy of the manuscript to the biostatistician to confirm that approved data 
are used appropriately.  Once the biostatistician gives final approval, the manuscript may be submitted to 
external publishers. 
15.0 
Pathology Requirements 
Biopsy proven disease by confirmation of biopsy specimen at the treating institution pathology 
department is required for enrollment to the study. Biopsy material will be reviewed by the pathology 
department at the treating institution.   


 
 
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16.0 
Samples for Correlative Studies 
Correlative studies will be conducted as secondary outcome measures to provide information on response 
prediction. We will perform assays to detect micro RNA and correlate response pre and post treatment.  
We will use the HiSeq 2000 Sequencing System (Illumina) at the GCCRI Genomics Facility to measure 
miRNA expression profiles. Samples will be barcoded to allow multiplex sequencing and subjected to a 
second round of Q/C.  
Blood Sample Collections 
1. Red-top vacutainer tubes (not SST), upright at RT for 30 minutes, then centrifuged in a horizontal 
rotor for 20 min at 1100-1300g. Within 1 hour of centrifugation, pipette aliquots of 150 to 250 ul 
serum into labeled cryovials. These need to be stored at -80oC and transported on dry ice.   
2. Blood samples for microRNA assay will be collected on Cycle 1, Day 1 of treatment, and at the 
end of treatment. QIAGEN PAXgene Blood RNA tubes will be used to collect the samples and 
will and stored at -20oC. 
 Blood samples will be sent to Dr Pertsemlidis’s lab: 
Xiuye Ma  
Greehey Children's Cancer Research Institute 
UT Health San Antonio 
8403 Floyd Curl Drive, MC 7784 
San Antonio, TX 78229-3900 
T:  (210) 562-9062 
Email:  ma@uthscsa.edu 
 
Tissue specimens from before and after treatment will be stained for markers of both angiogenesis and of 
hypoxia, CD-36 and carbonic anhydrase 9 (CA9) respectively, to see if the combination is effective at 
reducing hypoxia and the effects on angiogenesis.  We will also look at the effects on reversal of EMT by 
performing IHC for E-cadherin, N-cadherin and vimentin to see if there is a reversion with treatment as 
has been seen in vitro and in animal models.  Ten unstained slides thickness of 5 micron will be requested 
from pathology 
All IHC will be performed in Dr Susan Moobery’s lab: 
UT Health San Antonio  
7703 Floyd Curl Drive, Mail Code 7764 
San Antonio, TX 78229-3900  
Phone: 210-567-4788 
 
 


 
 
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I Appendix Lenvatinib Package Insert 
 
LENVIMA (lenvatinib) capsules, for oral use 
Initial U.S. Approval: 2015 
Recommended Dose 
 
 
 
 
 
 
 
 
The recommended daily dose of LENVIMA is 24 mg (two 10 mg capsules and one 4 mg 
capsule) orally taken once daily with or without food [see Clinical Pharmacology (12.3)]. 
Continue LENVIMA until disease progression or until unacceptable toxicity occurs. 
Take LENVIMA at the same time each day. If a dose is missed and cannot be taken within 
12 hours, skip that dose and take the next dose at the usual time of administration. 
Severe Renal or Hepatic Impairment 
The recommended dose of LENVIMA is 14 mg taken orally once daily in patients with 
severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min calculated by the 
Cockroft-Gault equation) or severe hepatic impairment (Child-Pugh C). 


 
 
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         INDICATIONS 
 
    
   CONTRAINDICATIONS 
 
                 None 
 


 
 
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II. 
Appendix – Common Toxicity Criteria for Adverse Events 
 
Toxicity will be graded according to the NCI’s Common Toxicity Criteria for Adverse Events (CTCAE) 
version 4.03.  The CTCAE version 4.03 can be accessed at the following link: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf  
III. 
Appendix – Data Safety & Monitoring Plan 
 
Data and Safety Monitoring Oversight 


 
 
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A Data and Safety Monitoring Plan is required for all an individual protocols conducted at Mays Cancer 
Center. All protocols conducted at Mays Cancer Centerare covered under the auspices of the Mays Cancer 
CenterInstitutional Data Safety Monitoring Plan (DSMP).   
 
The Mays Cancer Center Institutional DSMP global policies provide individual trials with:  
• 
institutional policies and procedures for institutional data safety and monitoring,  
• 
an institutional guide to follow, 
• 
monitoring of protocol accrual by the Mays Cancer Center Protocol Review Committee, 
• 
review of study forms and orders by the Forms Committee, 
• 
tools for monitoring safety events, 
• 
independent monitoring and source data verification by the Mays Cancer Center QA 
Monitor/Auditor 
• 
monitoring of UPIRSO’s by the Director of Quality Assurance and DSMC, 
• 
determining level of risk (Priority of Audit Level Score – PALS) ,  
• 
oversight by the Data Safety Monitoring Committee (DSMC),  and 
• 
Verification of protocol adherence via annual audit for all Investigator Initiated Studies by the 
Mays Cancer Center Quality Assurance Division. 
 
Monitoring Progress and Safety 
Due to the risks associated with participation in this protocol, the Mays Cancer Center DSMB #2 in 
conjunction with the Principal Investigator will perform assessment of adverse events, adverse event trends 
and treatment effects on this study.  The Mays Cancer Center DSMB #2 acts as an independent Data Safety 
Monitoring Board (DSMB) for IIS conducted at Mays Cancer Center.  The Mays Cancer Center DSMB #2 
will monitor data throughout the duration of a study to determine if continuation of the study is appropriate 
scientifically and ethically.  An additional layer of review is provided by the Mays Cancer Center Data 
Safety Monitoring Committee (DSMC) who will review DSMB quarterly reports.   
 
Baseline events and adverse events will be captured using the Mays Cancer Center Master Adverse Events 
Document for each patient using CTCAE V. 4.03 for the grading and attribution of adverse events. Usage 
of the Mays Cancer Center Master Adverse Events Document centrally documents:  
• 
the event and grades the seriousness of the event,  
• 
if the event was a change from baseline,   
• 
the determination of the relationship between the event and study intervention,  
• 
if the event was part of the normal disease process, and  
• 
What actions were taken as a result of the event.  
 
Safety Definitions: 
 
For this study, the following safety definitions will be applicable: 


 
 
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Adverse Event Definition: An adverse event (AE) is defined as any untoward or unfavorable medical 
occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the research  For this study, all 
adverse events will be documented starting with cycle 1 day 1 and ending 30 days after the last dose of 
study drug is received.  
 
Serious Adverse Event Definition: is any adverse event that: 
1. results in death; 
2. is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
3. results in inpatient hospitalization or prolongation of existing hospitalization; 
4. results in a persistent or significant disability/incapacity; 
5. results in a congenital anomaly/birth defect; or 
6. based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition  
 
Unanticipated Problems Involving Risks to Subjects or Others Definition: Unanticipated problem 
involving risk to subjects or others includes any incident, experience or outcome that meets all of 
the following criteria: 
 
unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject population being studied 
(note: the unfounded classification of a serious adverse event as “anticipated” constitutes serious 
non-compliance); 
definitely related or probably related to participation in the research; and 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized 
 
Reporting Requirements 
For this study, the Master Adverse Events Documents collected on patients for this protocol will be 
reviewed by the Principal Investigator on a monthly basis to determine if a serious safety problem has 
emerged that result in a change or early termination of a protocol such as: 
• 
dose modification, 
• 
suspending enrollment due to safety or efficacy, or 
• 
termination of the study due to a significant change in risks or benefits.   
 


 
 
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The PI will provide the DSMB #2 with the monthly findings for discussion and review during their meetings. 
Serious adverse events will be revised as they occur to determine if a DLT and the MTD has been reached.  
Adverse events and serious adverse events from all sites will be reviewed by DSMB#2 to determine if it is 
appropriate to escalate to the next dose level prior to opening the next cohort or determine that dose 
expansion at the current dose level is warranted. 
For this protocol the number, frequency, and severity of adverse events and dose-limiting toxicities 
(DLTs) will be recorded (as defined by the NCI Common Terminology Criteria for Adverse Events or 
CTCAE v 4.03). The MTD will be defined as the dose level at which ≤ 1 (out of 3 or 6 patients) exhibit a 
DLT.    
 
Dose-Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD) 
DLT evaluation will occur weekly for the first cycle (1 cycle = 21 days).  
Any enrolled and treated patient should be evaluated for DLT purposes. 
 The DLT period as a whole will be the first cycle of treatment.  (Adverse events, however, will continue 
to be collected for the duration of treatment).   
 
In general, a non-hematologic DLT is defined as any Grade ≥ 3 toxicity, and a hematologic DLT is 
defined as any Grade ≥ 4 toxicity, both by CTCAE v4.03 criteria.   
 
In addition, the following criteria and exceptions apply: 
• 
ANC < 500/mm3 for > 7 days despite GCSF support is a DLT. 
• 
Platelet count < 20,000/mm3 for more than 3 days that is considered drug-related is a 
DLT. 
• 
For nausea, vomiting, or diarrhea, patients must have Grade 3 or 4 toxicity that persists at 
this level despite use of optimal symptomatic treatment (per local institutional 
guidelines), in order for these to be considered a DLT. 
• 
Grade 3 thromboembolic events are not considered DLT. 
• 
Any Grade 3 rash that resolves to Grade ≤ 2 within a 10 day period (including with 
symptomatic treatment) will not be considered a DLT. 
• 
Cases involving hyperbilirubinemia that is primarily indirect, and considered not 
reflective of underlying liver disease (ie, resulting from transfusion of red blood cells), 
will not be considered a DLT. 
• 
A DLT must be attributed to one of the two investigational drugs. A “drug-related 
toxicity" includes as events, any toxicity considered related, probably related, or possibly 
related to study drugs. Toxicities clearly not related to the drug, such as disease 
progression, environmental, unrelated trauma may not be considered “drug related 
toxicity” 
 


 
 
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• 
As per the Mays Cancer Center DSMP, any protocol modifications, problematic safety 
reports, unanticipated problems, and suspension or early termination of a trial must be 
reported to the DSMB #2 and all members of the research team at UT Health San 
Antonio and all affiliate sites. Furthermore, the PI of this study will promptly notify all 
study affiliates, the UT Health San Antonio IRB, the Mays Cancer Center DSMC, and 
the FDA via a FDA Form 3500Aa written IND safety report of any adverse events that 
are either serious and/or unexpected.  Suspension and early termination of a trial must 
also be reported immediately to the Director of Quality Assurance who will promptly 
notify the sponsor and the UT Health San Antonio IRB.  
 
• 
The PI will review data on adverse events from case report forms from all sites on a 
monthly basis and serious adverse events per occurrence to determine the significance of 
the reported events and will provide findings to DSMB#2.  The DSMB #2 will review the 
information provided by the PI and report to the Mays Cancer Center DSMC on a 
quarterly basis, unless an emergent issue has been identified. The Investigator Initiated 
Study Quarterly DSMB Report Form includes information on adverse events, current 
dose levels, number of patients enrolled, significant toxicities per the protocol, patient 
status (morbidity and mortality) dose adjustments with observed response, and any 
interim findings.  Any trend consisting of three or more of the same event will be 
reported to the Mays Cancer Center DSMB for independent review outside of the 
quarterly reporting cycle, which begins quarterly after the end of the first subject’s DLT 
evaluation period. The DSMB #2 will also provide its findings to the Mays Cancer 
Center’s Regulatory Affairs Division so that it may be provided to the UT Health San 
Antonio IRB and affiliate sites with the protocol’s annual progress report. Conflict of 
interest is avoided by the independent reviews of the Mays Cancer Center DSMB #2, 
Mays Cancer Center DSMC, and by ongoing independent review of UPIRSO trends by 
the Director of Quality Assurance.  
 
• 
All SAE and UPRISO’s will be reported following Mays Cancer Center, UT Health San 
Antonio institutional and FDA guidelines 
 
 
 


 
 
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AE’s and SAE events that occur during clinical trials with or without an Investigational New Drug (IND) 
application are mandatory reports submitted to FDA via Medwatch FDA F3500A within 15 days for 
events that have at least a possible relationship with the drug. 
 
Assuring Compliance with Protocol and Data Accuracy 
As with all studies conducted at Mays Cancer Center, the PI has ultimate responsibility for ensuring 
protocol compliance, data accuracy/integrity and responding to recommendations that emanate from 
monitoring activities.   Each site will be audited for accuracy after the end of the first cycle for the first 
patient enrolled.  Protocol compliance, data accuracy and reporting of events is further ensured by an annual 
audit conducted by the Data Safety Officer, whose audit report is shared with the PI, the research team, and 
will be reviewed by the Mays Cancer Center DSMC.  
Mays Cancer Center DSMB Membership 
The Mays Cancer Center has two DSMB’s with a primary set of members specific to the histology of the 
study consisting of UT Health San Antonio faculty and staff.  This Protocol is under the jurisdiction of 
DSMB#2 for Solid Tumor Studies.  
As per NCI guidelines and to eliminate conflict of interest (financial, intellectual, professional, or regulatory 
in nature), the Mays Cancer Cente rDSMB specific to this study will not treat patients on this protocol.  
Usage of the DSMB specific to the histology has been created to ensure that experts in that histology are 
represented on the DSMB assembled for this protocol, but may be expanded, at the PI’s discretion, to 
include other members which may include: 
• 
experts in the fields of medicine and science that are applicable to the study (if not currently 
represented on the DSMB),  
• 
statistical experts,  
• 
lay representatives,  
• 
multidisciplinary representation, from relevant specialties including experts such as bioethicists, 
biostatisticians and basic scientists, and 
• 
others who can offer an unbiased assessment of the study progress.  
Additional or alternate membership of in the DSMB is selected by the DSMC chair, in conjunction with 
the PI of this protocol.   
Mays Cancer Center DSMB Charter and Responsibilities 
The Mays Cancer Center DSMB will provide information on the membership composition, including 
qualifications and experience to both the UT Health San Antonio IRB and Mays Cancer Center PRC for 
review.  The Mays Cancer Center DSMB for this study will act as an independent advisory board to the PI 
and will report its findings and recommendations to the PI, the UT Health San Antonio IRB and the Mays 
Cancer Center DSMC. Mays Cancer Center DSMB reports will utilize the Investigator Initiated Study 
Quarterly DSMB Report Form and meetings will occur on a monthly basis to review any updates from the 
prior meeting.   


 
 
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Once the protocol is activated, if not already established elsewhere in the protocol the Mays Cancer Center 
DSMB will establish and provide:  
• 
procedures for maintaining confidentiality;  
• 
statistical procedures including monitoring guidelines, which will be used to monitor the identified 
primary, secondary, and safety outcome variables; 
• 
consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants or 
the ethics of the study;  
• 
plans for changing frequency of interim analysis as well as procedures for recommending protocol 
changes; 
• 
recommendation of dose escalation, MTD recommendation of early termination based on efficacy 
results;  
• 
recommendation of termination due to unfavorable benefit-to-risk or inability to answer study 
questions;  
• 
recommendation of continuation of ongoing studies;  
• 
recommend modification of sample sizes based on ongoing assessment of event rates; and 
• 
review of final results and publications. 
 
IV Appendix - Data Collection & Submission 
 
Study-specific instructions regarding the entry and submission of data using paper CRFs or eCRFs using 
an electronic data system (e.g. REDCap or Excel), will be provided at the time of training prior to study 
activation.  
Mays Cancer CenterMulti-site Compliance Policies of the Mays Cancer Center at the UT Health Science 
San Antonio DSMP regarding data collection and submission will be strictly enforced. 
Study Chart 
In addition to the regular hospital chart, a separate patient folder will be kept which includes the patient's 
signed, dated informed consent document. 
PLEASE NOTE: FOR SAFETY RUN-IN PATIENTS, ACCRUAL MAY BE SUSPENDED IF DATA 
IS NOT SUBMITTED BY THE DUE DATES SPECIFIED BELOW 
Case Report Forms to be submitted prior to registration 
Please refer to Section 12.3 for all forms/data to be submitted prior to registration.   
Case Report Forms to be submitted within 5 days of registration: 
• 
Concomitant Medications Form: This should be updated to reflect the patients’ information at the 
time of registration. From that point, it should be updated as needed. 
• 
Master Adverse Event Form: Update to reflect the adverse events that are present at baseline. 
• 
RECIST Disease Measurements Form: Should reflect disease measurements at baseline.    


 
 
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• 
On-Study Form: Will include dates and results of all tests and labs required to be performed 
prior to registration. 
 
Case Report Forms to be submitted during the 21 day DLT Evaluation Period (THIS IS ONLY A 
REQUIREMENT FOR PHASE I PATIENTS)  
• 
Lab Results No more than 48 hours after the 21 day DLT period ends 
• 
Adverse Events Form: No more than 48 hours after the 21 day DLT period ends 
• 
Patient Vitals Form: Each exam conducted during the DLT period, no more than 48 hours after 
the 21 day DLT period ends 
• 
Concomitant Medications Form: Updated as necessary 
• 
Treatment Cycle Summary Form: No later than 48 hours after the end of 21 day DLT period 
 
Case Report Forms to be submitted at the end of each cycle:   
• 
Labs Results r Form 
• 
Master Adverse Events Form  
• 
Patient Vitals Form 
• 
Concomitant Medications Form: Updated as needed 
• 
Treatment Cycle Summary Form   
 
Case Report Forms to be submitted after every 2 cycles, when disease is assessed 
• 
RECIST Disease Measurements Form: Complete measurements for each assessment.   
 
Case Report Forms to be submitted no later than 1 week after End of Treatment Visit: 
• 
Off-treatment Form:  
• 
Patient Vitals Form 
• 
Lab Results Form  
• 
Master Adverse Events Form: All AEs should be finalized within 30 days of last dose 
 
Case Report Forms to be completed during follow-up: 
• 
Survival Status Form: Survival status and date of disease progression (if/when applicable) should 
be completed every 6 months until death.   


 
 
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V. Appendix – Table of Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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VI. Appendix SAE Reporting Form 
 


 
 
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References 
 
 
1.1 R.S. Kerbel, Tumor angiogenesis N Engl J Med, 358 (2008), pp. 2039–2049 
 
2   H. Hurwitz, L. Fehrenbacher, W. Novotny, T. Cartwright, J. Hainsworth, W. Heim, et al. 
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer 
N Engl J Med, 350 (2004), pp. 2335–2342 
 
3 A. Sandler, R. Gray, M.C. Perry, J. Brahmer, J.H. Schiller, A. Dowlati, et al. 
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