A Single-arm Phase Ib/II Study of the Combination of Lenvatinib and Eribulin in Advanced Adipocytic Sarcoma and Leiomyosarcoma (LEADER Study)
Phase: PHASE1
Conditions: Leiomyosarcoma, Liposarcoma, Soft Tissue Sarcoma Adult, Advanced Cancer
Sponsor: National Taiwan University Hospital

LEADER Protocol Version 5.0 2022-05-10 
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Amendments 
No. 
Date 
1 
Ver 1.0 2018-03-08 
2 
Ver 2.0 2019-01-10 
3 
Ver 3.0 2020-01-10 
4 
Ver 4.0 2021-02-08 
5 
Ver 5.0 2022-05-10 
 
STUDY PROTOCOL 
 
 
 
 
Protocol Number: SARC-IIT-001 
Identifier Number: NCT03526679 
 
A Single-arm Phase Ib/II Study of the Combination of Lenvatinib and 
Eribulin in Advanced Adipocytic Sarcoma and Leiomyosarcoma 
(LEADER study) 
 
 
 
Principal Investigator: 
Wei-Wu (Tom) Chen  M.D. 
Department of Oncology 
National Taiwan University Hospital 
 
 
 
 
The information contained in this document 
is privileged and confidential and, except to 
the extent necessary to obtain Ethics 
Committee approval and informed consent 
may not be disclosed to a third party. 
 
 
 

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CONTENT 
STUDY PROTOCOL ............................................................................................................. 1 
CONTENT ............................................................................................................................. 2 
List of Abbreviations and Definitions of Terms ................................................................ 5 
Synopsis ............................................................................................................................... 7 
Principal Investigator ........................................................................................................ 14 
Co-investigators ................................................................................................................ 14 
1 
Introduction ................................................................................................................... 16 
Background .................................................................................................................. 16 
2 
Objectives and Endpoints ............................................................................................. 17 
3 
Patient Selection Criteria .............................................................................................. 17 
3.1 
Inclusion criteria ................................................................................................... 17 
3.2 
Exclusion criteria ................................................................................................. 18 
4 
Study Design ................................................................................................................ 19 
4.1 
Overall plan of the study ...................................................................................... 19 
4.2 
Study schema ...................................................................................................... 20 
4.3 
Study period and end of study ............................................................................. 20 
5 
Study Treatment ........................................................................................................... 20 
5.1 
Treatment of lenvatinib ........................................................................................ 20 
5.2 
Treatment eribulin ................................................................................................ 21 
5.2.1 
Ancillary and concomitant medications during eribulin treatment ............. 21 
5.3 
Guidelines combination dose level adjustments in the phase Ib phase ............... 22 
5.3.1 
Schema for dose adjustments if more than 2 patients have DLT ............. 22 
5.3.2 
Definitions of DLT ..................................................................................... 23 
5.3.3 Decision on Final Phase II dose ................................................................... 24 
5.4 
Guidelines for dose delays and dose modifications ............................................. 24 
5.4.1 
Hematological toxicities ............................................................................ 24 
5.4.2 Non-hematological toxicities ......................................................................... 25 
5.4.3 Dose modification or delay durations and modification levels (after phase 
Ib) ............................................................................................................. 27 
5.5 Duration of the treatment ................................................................................. 28 
6 
Study Assessment/ Procedural Schedule ..................................................................... 28 
6.1 
Pre-treatment baseline evaluation ....................................................................... 28 
6.2 
Pre- treatment assessments ................................................................................ 29 
6.3 
Tumor Assessment during treatment ................................................................... 30 
6.3.1 
Tumor imaging criteria—RECIST 1.1 ....................................................... 30 
6.3.2 
Assessment schedules............................................................................. 31 

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6.3.3 Toxicity assessment...................................................................................... 31 
6.3.4 Follow up of patient status ............................................................................ 32 
6.4 
Biopsy during the study ....................................................................................... 32 
6.5 
Summary Table .................................................................................................... 32 
7 
Endpoints for Evaluation ............................................................................................... 35 
7.1 
Primary endpoint: Objective response rate (ORR) by RECIST 1.1 ...................... 35 
7.2 
Secondary endpoints ........................................................................................... 35 
7.2.1 
24-weeks PFS rate ................................................................................... 35 
7.2.2 
Overall survival (OS) rate at 6- and 12-months ........................................ 35 
7.2.3 
PFS and OS ............................................................................................. 35 
7.2.4 
Toxicities assessment............................................................................... 36 
7.2.5   Choi criteria for objective response rate assessment ............................... 36 
8 
Statistical Considerations ............................................................................................. 36 
8.1 
Sample size ......................................................................................................... 36 
8.2 
Statistical analysis ............................................................................................... 36 
8.2.1 
Endpoint estimates ................................................................................... 36 
8.3 
Correlative science .............................................................................................. 37 
9 
Safety Monitoring and Reporting .................................................................................. 37 
9.1 
Adverse Events Definition ................................................................................... 37 
9.1.1 
Adverse Events ........................................................................................ 37 
9.1.2 
Serious Adverse Events (Immediately Reportable to the Sponsor) .......... 37 
9.1.3 
Non-Serious Adverse Events of Special Interest (Immediately Reportable 
to the Sponsor) ......................................................................................... 38 
9.1.4 
Pregnancy ................................................................................................ 38 
9.1.5 
Progression of underlying malignancy ..................................................... 39 
9.2  
Relationship to medication ....................................................................... 39 
9.3  Reporting adverse events .................................................................................... 39 
9.3.1 Adverse events reporting .............................................................................. 39 
9.3.2 Immediate reporting requirements from investigator to sponsor and 
expedited reporting to Health Authority and Ethics Committee/Institutional 
Review Board ........................................................................................... 40 
9.4  Follow-up after adverse events ............................................................................ 40 
10 Administrative and Data Management details .............................................................. 40 
10.1 Confidentiality ...................................................................................................... 40 
10.2 Confidentiality of the study subjects .................................................................... 40 
10.3 Research budget ................................................................................................. 41 
10.4 Publication ........................................................................................................... 41 
10.5 Inventions ............................................................................................................ 42 

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10.6 Responsibilities of PIs from participating institutions ........................................... 42 
11 Ethical considerations ................................................................................................... 42 
11.1 General considerations ........................................................................................ 42 
11.2 Informed consent ................................................................................................. 43 
REFERENCES .................................................................................................................... 44 
Appendix I  Karnofsky Performance Status scale .............................................................. 45 
 

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List of Abbreviations and Definitions of Terms  
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANC 
Absolute neutrophil count 
AST 
Aspartate transaminase 
aPTT 
activated partial thromboplastin time 
Bil 
Total bilirubin 
CBC 
Complete blood count 
Ccr 
Creatinine clearance 
CR 
Complete response 
Cru 
Complete response/unconfirmed 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CT 
Computed tomography 
D/C 
Differential count 
DCR 
Disease control rate 
DOH 
Department of Health 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
 
Good clinical practice 
G-CSF 
Granulocyte colony-stimulating factor 
Gr 
Grade 
IHC 
Immunohistochemical stain 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IVF 
Intravenous infusion 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCTRC 
National Clinical Trial and Research Center,  
NS 
0.9% Normal saline 

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NTUH 
National Taiwan University Hospital 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal investigator 
PO 
Per os 
PR 
Partial response 
RECIST 
Response evaluation criteria in solid tumor 
SAE 
Serious adverse event 
SD 
Stable disease 
SPD 
Sum of the products of the greatest diameter 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
UNL 
upper normal limit 
 
 
 
 
 
 
 
 

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Synopsis  
Title of Study 
A single-arm phase Ib/II study of the combination of lenvatinib and 
eribulin in advanced adipocytic sarcoma and leiomyosarcoma 
(LEADER study) 
Rationale of 
Study 
Recently, the US Food and Drug Administration (FDA) granted 
approval to eribulin for the treatment of adipocytic sarcoma who have 
received a prior anthracycline-containing regimen based on a Phase 
III study results of improved overall survival (OS) as compared with the 
standard treatment dacarbazine. In the leiomyosarcoma cohort of the 
study, although eribulin did not demonstrate a significant benefit over 
dacarbazine, still about 5.1% of leiomyosarcoma patients treated with 
eribulin had a partial response, suggesting that eribulin may have 
activity against leiomyosarcoma1. However, the overall response rate 
(ORR) and progression-free survival (PFS) remained unsatisfactory in 
the two most common soft tissue sarcoma (STS) subtypes—adipocytic 
sarcoma and leiomyosarcoma, prompting new therapeutic options of 
STS patients. 
 
Anti-angiogenic therapies had shown promising results in soft tissue 
sarcoma (ST). Pazopanib, an anti-angiogenic multi-kinase inhibitor, 
has shown clinical benefit with a longer median PFS of 4.6 months 
versus placebo in STS patients refractory to at least one line of 
systemic chemotherapy2. Another anti-angiogenic targeted therapy, 
regorafenib, showed significant improvement in PFS as compared with 
placebo in various STS3. In a phase I study of lenvatinib for solid 
tumors in Japan, 4 out of 6 leiomyosarcoma patients has tumor 
decreased more than 10%4. Moreover, other tyrosine receptor targets 
of lenvatinib, such as fibroblast growth factor receptor (FGFR) and 
platelet-derived growth factor receptor (PDGFR), may also plays a role 
in treating STS. In high-grade STS patients, about 30% of patients had 
FGFR1 amplification or overexpression. FGFR1-overexpression STS 
cell lines are sensitive to FGFR inhibitors such as BGJ398 and 
AZD45475. Furthermore, a monoclonal antibody of PDGFR alpha, 
olaratumab, was recently approved by the FDA in combination with 
doxorubicin for advanced STS based on a median 10-month OS 
benefit compared to doxorubicin only in a randomized phase II trial6. 
 
It has been demonstrated in various cancer types that an increased 

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quantity of tumor infiltrating lymphocyte (TILs) is associated with 
increased response to chemotherapy or improved prognosis7. One of 
the factors that had been shown to impede the migration and trafficking 
of TILs into tumor is vascular endothelial growth factor (VEGF)8. In 
renal cell carcinoma, treatment with bevacizumab, an anti-VEGF 
antibody, or in combination with atezolizumab, increased the 
recognition of tumor antigen, increased expression of MHC class I 
receptor on tumor cells, and the amount of TIL migration into the tumor 
stroma9. Many of the STS were detected with scarce TILs in the tumor 
microenvironment (Chen et al. unpublished data), thus it would be 
interesting to see if anti-angiogenic tyrosine kinase inhibitors could 
adjust the tumor microenvironment toward a more chemotherapy-
friendly milieu.  
 
Thus, we would like to propose a clinical trial to understand the anti-
tumor activity of the combination of lenvatinib and eribulin in advanced 
STS patients. 
Objectives and 
Endpoints 
Primary objective 
To evaluate the anti-tumor activity of lenvatinib and eribulin 
combination in STS. 
Primary endpoint for phase Ib 
The safety profile of the combination of lenvatinib and eribulin 
Primary endpoint for phase II 
The objective response rate (ORR) based on RECIST 1.1. 
Secondary objectives and endpoints 
 
24-week progression-free survival (PFS) rate 
 
6- and 12-months overall survival (OS) rate 
 
PFS 
 
OS 
 
Safety profile of the combination of lenvatinib and eribulin 
Study Design 
Open-label single arm phase Ib/II study 

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Schema 
 
 
Study Treatment: 
A 21 day cycle 
Table 1: Dose levels of lenvatinib and eribulin combination 
Dose level 
Lenvatinib 
Eribulin 
Dose level 11 
18mg/day D1-D21 
1.1 mg/m2 D1, D8 
Dose level 21 
14mg/day D1-D21 
1.1 mg/m2 D1, D8 
Dose level 31 
10mg/day D1-D21 
1.1 mg/m2 D1, D8 
Dose level 12 
18mg/day D1-D21 
0.7 mg/m2 D1, D8 
Dose level 22 
14 mg/da D1-D21 
0.7 mg/m2 D1, D8 
 
The first 6 patients will be treated with lenvatinib 18 mg/day D1-D21 
and eribulin 1.1mg/m2 D1 and D8 (Dose level 11). If no more than 2 (≤ 
2) patients had dose-limiting toxicity (DLT) in the first cycle (3 weeks), 
then the lenvatinib (18) and eribulin (1.1) combination will be declared 
safe. If more than 2 (> 2) patients have DLT, the investigators will 
determine which drug is more pertain to the DLT(s) and then will follow 
the customized block chart to shift the dose. If lenvatinib is determined 
to be related to DLT, the next lower dose would be dose level 21. 
Otherwise, if eribulin is determined to be the likely cause for DLT, the 
next dose level will be level 12. The lowest dose acceptable would be 
ether dose level 22 or dose level 31. If still more than 2 patients have 
DLT in the first 6 patients of dose level 22 or level 31, the combination 
of lenvatinib and eribulin will be considered too toxic in STS patients.  
 
Both agents will be continued until disease progression or intolerable 
toxicity. 
Sample Size 
(according to 
primary 
endpoint) 
The study will be based on a minimax Simon 2 stage design. The ORR 
of interest with lenvatinib and eribulin combination is 20% (P1), and 
the ORR of low interest is set at 5% (P0). With an 80% power and type 
I error of 0.05, if no patients had an objective response to lenvatinib 

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and eribulin combination after the first 13 enrollments, the trial will be 
stopped early for futility. If at least one patient had an objective 
response, the study will continue to include 27 evaluable patients. With 
an expected 10% drop-out rate, we estimate a total of 30 patients to 
be enrolled in this study 
Study Sites 
Single nation, multi-center 
Criteria for 
Inclusion and 
Exclusion 
Inclusion criteria 
To be eligible for inclusion, patients must fulfill the following criteria: 
1. A histological confirmed adipocytic sarcoma (dedifferentiated, 
myxoid, or pleomorphic) or leiomyosarcoma that is either 
inoperable locally advanced or metastatic  
2. Advanced adipocytic sarcoma and leiomyosarcoma who have 
received no more than 2 lines of systemic chemotherapy in the 
advanced setting (not including adjuvant chemotherapy). 
3. At least one measurable tumor according to RECIST 1.1. If the 
measurable lesion has previously received radiotherapy, the 
tumor must be a progressive lesion after radiotherapy. 
4. ECOG PS 0 or 1 or Karnofsky performance status (KPS) ≥ 70 
5. Patients must have adequate organ function and marrow 
reserve measured within 14 days prior to randomization as 
defined below: 
■  Hemoglobin ≥ 9.0 g/dL; 
■  Absolute neutrophil count ≥ 1,500 /
L; 
■  Platelets ≥ 75,000/
L; 
■  Total bilirubin ≤ 1.5 x upper normal limit; 
■  AST(SGOT)/ALT(SGPT) ≤ 2.5 x upper normal limit; for 
patients with liver metastases AST(SGOT)/ALT(SGPT) ≤ 5 x 
upper normal limit is allowed; 
■  Serum creatinine ≤ 1.5mg/dL or creatinine clearance ≥ 
50ml/min; 
■  aPTT < 1.5 x upper normal limit (unless on therapeutic 
anti-coagulation); 
■  Proteinuria ≤ 1+ with urine dipstick, if > 1+, 24-hour urine 
protein must be ≤ 1 g 
6. Age 20 or older. 
7. Patient’s life expectancy is more than 3 months 
8. All women of childbearing potential must have a negative 
pregnancy test obtained within 72 hours before starting 

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therapy. 
9. Patients with reproductive potential must use effective 
contraception (hormone or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study 
participation, and for 6 months after the completion of therapy. 
10. Patient needs to have adequate wash-out period from 
previous systemic treatment(s):  
(1) 2 weeks for any other oral anti-cancer targeted agents 
(2) 3 weeks for any other cytotoxic chemotherapy (except for 
mitomycin-C, which will require 6 weeks) 
(3) 3 weeks for monoclonal antibodies, including immune 
checkpoint inhibitors 
Exclusion criteria 
Patients who fulfill any of the following criteria will be excluded from 
this trial: 
1. Patients who had received lenvatinib or eribulin treatment 
2. Patients 
who 
had 
leptomeningeal 
metastasis, 
either 
diagnosed by brain imaging study or confirmed by 
cerebrospinal fluid cytology examination (patients with brain 
metastasis that are under control is eligible). 
3. Patients with clinical signs or symptoms of gastrointestinal 
obstruction and who require parenteral hydration and/or 
nutrition because of obstruction. 
4. Patients with uncontrollable hypertension (defined as systolic 
blood pressure over 140mmHg and/or diastolic pressure over 
90mmHg despite anti-hypertensive medications) 
5. Patients with the following cardiac disease  
-Prolongation of corrected QT (QTc) interval to >480 
milliseconds (ms).  
-Significant cardiovascular impairment: history of  
(a) congestive heart failure greater than New York Heart 
Association Class II;  
(b) unstable angina;  
(c) myocardial infarction;  
(d) stroke or transient ischemic attack; or  
(e) cardiac arrhythmia associated with hemodynamic 
instability within 6 months of the first dose of study drugs. 
6. Bleeding subjects at risk for severe hemorrhage.  

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7. Major surgical procedure, open biopsy, or significant traumatic 
injury within 28 days prior to enrollment. 
8. History of allergic reaction to compounds of similar chemical 
composition to the study drugs 
9. Pregnancy or lactation. 
10. Patients with latent HBV (positive HBsAg or HBeAg) or HCV 
infection (positive anti-HCV antibody)  
Study Medication Lenvatinib 18mg/day, D1-D21 PO 
Eribulin 1.1 mg/m2 D1, D8 IVF 
Every cycle is 21 days 
(The above listed dose is the expected dose, but the final starting dose 
will be determined in the phase Ib part) 
 
Figure 1. Dose adjustment directions by DLT 
 
 
 
When a safe combination dose is determined, this dose would 
become the initial dose for the following patients. Dose adjustment 
for study drugs for adverse events that occur after cycle 1 should 
follow the protocol guidelines. 
Lenvatinib
10 mg/day
Lenvatinib
14 mg/day
Lenvatinib
18 mg/day

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DLT is defined as 
(1) Grade 4 diarrhea 
(2) Grade 3 or higher proteinuria 
(3) Grade 3 or higher hand foot syndrome   
(4) Grade 3 or 4 peripheral neuropathy 
(5) Neutropenia Grade 4 that lasted >5 days 
(6) Neutropenia Grade 3 or 4 complicated by fever and/or infection 
(Absolute Neutrophil Count [ANC] < 1.0 x 109/L, fever ≥38.5°C) 
(7) Thrombocytopenia Grade 4 of any duration 
(8) Thrombocytopenia Grade 3 complicated by bleeding and/or which 
required platelet or blood transfusion 
(9) Other Grade 3 or 4 clinically significant non-hematologic toxicities 
(except for inadequately treated nausea and/or vomiting) considered 
related to study drug 
(10) Failure to administer ≥ 75% of the planned dosage of 
combination therapy as a result of treatment related (at least possibly 
related) toxicity during Cycle 1. 
(11) Grade 3 or above hypertension not able to be controlled by 
medication 
(12) Grade 3 or above gastrointestinal perforation 
(13) Grade 4 hemorrhage 
(14) Grade 3 thromboembolic event 
(15)Grade 3 or above wound dehiscence requiring medical or 
surgical intervention 
Therapeutic 
Assessments 
1. Therapeutic assessment by CT or MRI will be performed from week 
8, 16, and 24 and then every 12 weeks afterwards. A +/- 3 days 
window is allowed.   
2. Biopsy will be performed at baseline and after the first tumor 
assessment (optional) 

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Trial Personnel 
Principal Investigator 
 
 
Date 
(yyyy/mm/dd) 
 
 
 
/  
/  
Wei-Wu (Tom) Chen, M.D. 
Department of Oncology  
National Taiwan University Hospital, Taipei, Taiwan 
 
 
Co-investigators 
 
Ruey-Long Hong, MD, PhD 
Department of Oncology 
National Taiwan University Hospital, Taipei, Taiwan 
 
Jhe-Cyuan Guo, MD 
Department of Oncology  
National Taiwan University Hospital, Taipei, Taiwan 
 
Chih-Wei Yu, MD 
Department of Medical Imaging   
National Taiwan University Hospital, Taipei, Taiwan 
  
Jen-Chieh Lee, MD, PhD 
Department of Pathology 
National Taiwan University Hospital, Taipei, Taiwan 
 
Hsiang-Fong Kao, MD 
Department of Oncology 
National Taiwan University Hospital, Taipei, Taiwan 
 
Dwang-Ying Chang, MD 
Department of Oncology 
National Taiwan University Hospital, Taipei, Taiwan 
 

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I-Chun Chen, MD 
Department of Oncology 
National Taiwan University Hospital, Taipei, Taiwan 
 
Tsung-Hao Liu, MD 
Department of Oncology 
National Taiwan University Hospital, Taipei, Taiwan 
 
Wei-Li Ma, MD 
Department of Oncology 
National Taiwan University Hospital, Taipei, Taiwan 
 

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1 Introduction 
Background 
Recently, the US Food and Drug Administration (FDA) granted approval to eribulin 
for the treatment of adipocytic sarcoma who have received a prior anthracycline-
containing regimen based on a Phase III study results of improved overall survival (OS) 
as compared with the standard treatment dacarbazine. In the leiomyosarcoma cohort of 
the study, although eribulin did not demonstrate a significant benefit over dacarbazine, 
still about 5.1% of leiomyosarcoma patients treated with eribulin had a partial response, 
suggesting that eribulin may have activity against leiomyosarcoma [1]. However, the 
overall response rate (ORR) and progression-free survival (PFS) remained 
unsatisfactory in the two most common soft tissue sarcoma (STS) subtypes—adipocytic 
sarcoma and leiomyosarcoma, prompting new therapeutic options of STS patients. 
 
Anti-angiogenic therapies had shown promising results in soft tissue sarcoma (ST). 
Pazopanib, an anti-angiogenic multi-kinase inhibitor, has shown clinical benefit with a 
longer median PFS of 4.6 months versus placebo in STS patients refractory to at least 
one line of systemic chemotherapy [2]. Another anti-angiogenic targeted therapy, 
regorafenib, showed significant improvement in PFS as compared with placebo in 
various STS [3]. In a phase I study of lenvatinib for solid tumors in Japan, 4 out of 6 
leiomyosarcoma patients has tumor decreased more than 10% [4]. Moreover, other 
tyrosine receptor targets of lenvatinib, such as fibroblast growth factor receptor (FGFR) 
and platelet-derived growth factor receptor (PDGFR), may also plays a role in treating 
STS. In high-grade STS patients, about 30% of patients had FGFR1 amplification or 
overexpression. FGFR1-overexpression STS cell lines are sensitive to FGFR inhibitors 
such as BGJ398 and AZD4547 [5]. Furthermore, a monoclonal antibody of PDGFR alpha, 
olaratumab, was recently approved by the FDA in combination with doxorubicin for 
advanced STS based on a median 10-month OS benefit compared to doxorubicin only 
in a randomized phase II trial [6]. 
 
It has been demonstrated in various cancer types that an increased quantity of 
tumor infiltrating lymphocyte (TILs) is associated with increased response to 
chemotherapy or improved prognosis [7]. One of the factors that had been shown to 
impede the migration and trafficking of TILs into tumor is vascular endothelial growth 
factor (VEGF) [8]. In renal cell carcinoma, treatment with bevacizumab, an anti-VEGF 
antibody, or in combination with atezolizumab, increased the recognition of tumor antigen, 
increased expression of MHC class I receptor on tumor cells, and the amount of TIL 
migration into the tumor stroma [9]. Many of the STS were detected with scarce TILs in 
the tumor microenvironment (Chen et al. unpublished data), thus it would be interesting 

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to see if anti-angiogenic tyrosine kinase inhibitors could adjust the tumor 
microenvironment toward a more chemotherapy-friendly milieu.  
 
Thus, we would like to propose a clinical trial to understand the anti-tumor activity 
of the combination of lenvatinib and eribulin in advanced STS patients.   
2 Objectives and Endpoints 
Objectives and related endpoints are described in Table 1 below. 
 
Table 1 Objectives and related endpoints 
Objectives 
Endpoints 
Definition and 
analysis 
Primary (phase Ib) 
 
 
To evaluate the safety of lenvatinib and 
eribulin combination in STS 
Dose limiting toxicities 
(DLT) 
Refer to section 5.3 
 
Primary (phase II) 
 
 
To evaluate anti-tumor activity of lenvatinib 
and eribulin combination in STS 
Objective Response Rate 
(ORR) 
Refer to Section 7.1 
Secondary (phase II) 
 
Refer to Section 7.2 
To evaluate the disease control ability of 
lenvatinib and eribulin in STS 
(Progression-free survival) 
PFS rate at 24- weeks 
Refer to Section 7.2.1 
 
Overall survival rate at 6- 
and 12-months 
Refer to Section 7.2.2 
 
PFS and OS 
Refer to Section 7.2.3 
To evaluate the safety dose combination of 
lenvatinib and eribulin in STS 
Incidence, type, intensity, 
severity and seriousness 
of Adverse Events (AEs) 
and frequency of dose 
interruptions 
Refer to section 7.2.4 
To evaluate anti-tumor activity of lenvatinib 
and eribulin combination in STS using 
other assessment method  
Objective Response Rate 
(ORR) by Choi criteria 
Refer to section 7.2.5 
3 Patient Selection Criteria 
3.1 Inclusion criteria 
To be eligible for inclusion, patients must fulfill the following criteria: 

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1. A histological confirmed adipocytic sarcoma (dedifferentiated, myxoid, or 
pleomorphic) or leiomyosarcoma that is either inoperable locally advanced or 
metastatic  
2. Advanced adipocytic sarcoma and leiomyosarcoma who have received no more than 
2 lines of systemic chemotherapy in the advanced setting (not including adjuvant 
chemotherapy) 
3. At least one measurable tumor according to RECIST 1.1. If the measurable lesion 
has previously received radiotherapy, the tumor must be a progressive lesion after 
radiotherapy. 
4. ECOG PS 0 or 1 or Karnofsky performance status (KPS) ≥ 70 
5. Patients must have adequate organ function and marrow reserve measured within 
14 days prior to randomization as defined below: 
■  Hemoglobin ≥ 9.0 g/dL; 
■  Absolute neutrophil count ≥ 1,500 /µL; 
■  Platelets ≥ 75,000/µL; 
■  Total bilirubin ≤ 1.5 x upper normal limit; 
■  AST(SGOT)/ALT(SGPT) ≤ 2.5 x upper normal limit; for patients with liver 
metastases AST(SGOT)/ALT(SGPT) ≤ 5 x upper normal limit is allowed; 
■  Serum creatinine ≤ 1.5mg/dL or creatinine clearance ≥ 50ml/min; 
■  aPTT < 1.5 x upper normal limit (unless on therapeutic anti-coagulation); 
■  Proteinuria ≤ 1+ with urine dipstick, if > 1+, 24-hour urine protein must be ≤ 1 g 
6. Age 20 or older. 
7. Patient’s life expectancy is more than 3 months 
8. All women of childbearing potential must have a negative pregnancy test obtained 
within 72 hours before starting therapy. 
9. Patients with reproductive potential must use effective contraception (hormone or 
barrier method of birth control; abstinence) prior to study entry, for the duration of 
study participation, and for 6 months after the completion of therapy. 
10. Patient needs to have adequate wash-out period from previous systemic treatment(s):  
(1) 2 weeks for any other oral anti-cancer targeted agents 
(2) 3 weeks for any other cytotoxic chemotherapy (except for mitomycin-C, which will 
require 6 weeks) 
(3) 3 weeks for monoclonal antibodies, including immune checkpoint inhibitors 
 
3.2 Exclusion criteria 
Patients who fulfill any of the following criteria will be excluded from this trial: 
1. Patients who had received lenvatinib or eribulin treatment 
2. Patients who had leptomeningeal metastasis, either diagnosed by brain imaging 

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19 
study or confirmed by cerebrospinal fluid cytology examination (patients with brain 
metastasis that are under control is eligible). 
3. Patients with clinical signs or symptoms of gastrointestinal obstruction and who 
require parenteral hydration and/or nutrition because of obstruction. 
4. Patients with uncontrollable hypertension (defined as systolic blood pressure over 
140mmHg and/or diastolic pressure over 90mmHg despite anti-hypertensive 
medications) 
5. Patients with the following cardiac disease  
-Prolongation of corrected QT (QTc) interval to >480 milliseconds (ms).  
-Significant cardiovascular impairment: history of  
(a) congestive heart failure greater than New York Heart Association Class II;  
(b) unstable angina;  
(c) myocardial infarction;  
(d) stroke or transient ischemic attack; or  
(e) cardiac arrhythmia associated with hemodynamic instability within 6 months of 
the first dose of study drugs. 
6. Bleeding subjects at risk for severe hemorrhage.  
7. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to enrollment. 
8. History of allergic reaction to compounds of similar chemical composition to the study 
drugs 
9. Pregnancy or lactation. 
10. Patients with latent HBV (positive HBsAg or HBeAg) or HCV infection (positive anti-
HCV antibody) 
4 Study Design 
4.1 Overall plan of the study 
This is a single country multi-center, open-label phase Ib/II single-arm study in advanced 
adipocytic and leiomyosarcoma patients. Patients will be treated with the combination of 
lenvatinib and eribulin until disease progression, intolerable toxicity, or patient withdrawal.  
 
The first 6 patients will be enrolled in a phase Ib run-in period to evaluated the safety of the 
combination of lenvatinib and eribulin. If more than 2 patients experience dose-limiting 
toxicity(s), dose adjustments will be carried out according a pre-determined plan. If there are 
still more than 2 patients in the lowest pre-specified dose of combination, the combination 
would be declared too toxic for further treatment in STS patients.   
 

LEADER Protocol Version 5.0 2022-05-10 
20 
4.2 Study schema 
(Please refer to Figure 1) 
4.3 Study period and end of study 
 Expected recruitment rate: 1 patient/ month 
 Expected enrollment duration of the study: 24 months 
 Expected follow-up period: 12 months after the last patient accrual. 
 Proposed extension of study timeline to 2022/12/13 for complete recruitment, follow-up, 
and analysis 
 Expected total patient accrual: 30 patients 
 End of study: 
- 
This will be a 2-stage study design based on the method proposed by Simon et al. 
The first stage will recruit 13 patients including 6 patients in the phase Ib part. If 0 
patients had any objective response, the study will be unlikely to meet the pre-
determined endpoint, and thus will be terminated early. If one or more patients had 
objective response, a total of 30 patients could be recruited.  
- 
The study may also terminate early if the combination is too toxic, i.e. that there are 
more than 2 patients met the DLT criteria in the lowest pre-determined combination 
dose (detail see Figure 2) in phase Ib part.  
- 
 
Figure 1. The schema of the study 
5 Study Treatment 
5.1 Treatment of lenvatinib 
Lenvatinib will be given on a once a day daily basis in a 21-day cycle. 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 1 of 

LEADER Protocol Version 5.0 2022-05-10 
21 
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. 
5.2 Treatment eribulin 
Eribulin will be given as IV infusion or slowly infusion within 15 or 30 minutes in a 100 
or 250ml of 0.9% NaCl solution. Eribulin will be given on days 1 and 8 of every 21-days 
cycle. Eribulin will be given prior to Lenvatinib administration on days 1 and 8. Each 
cycle will last 21 (+/- 3) days. Laboratory tests will be performed within 3 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 6.5) 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. 
 
5.2.1 Ancillary and concomitant medications during eribulin treatment 
1. 
Intravenous antihistamine medication and/or steroids could be considered, but not 
necessary, before eribulin. 
2. 
G-CSF could be administrated subcutaneously or intravenously according to the 
Taiwan National Health Insurance Policy Guideline. The use of prophylactic G-CSF 
is at the investigator’s discretion but would not be financially covered by the study. 
3. 
Patients who are taking any herbal (alternative) medicines are NOT eligible for 
participation. 
4. 
Patients who are undergoing concomitant radiotherapy or chemotherapy are NOT 
eligible for participation. Radiotherapy is not permitted during study 
5. 
Bisphosphonate or other anti-resorptive agents are acceptable during the study 
treatment 
6. 
Drug that would lead to QTc prolongation are prohibited during treatment (eg, 
arrhythmatic drugs such as amiodarone, procainamide; antibiotics such as 
quinolones and macrolides; antipsychotics drug such as quetiapine, olanzapine, 
amitriptyline). 
  

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22 
5.3 Guidelines combination dose level adjustments in the phase Ib phase 
The phase Ib (run-in) phase will be the first 6 patients. This is to monitor the safety of the 
combination of lenvatinib and eribulin in STS patients. However, this study is not the first 
study to use the combination of lenvatinib and eribulin in cancer patients. Thus the risk of 
unexpected DLT may be lower than traditional phase Ib studies. When a safe combination 
dose is determined, this dose would become the initial dose for the following patients. Dose 
adjustment for study drugs for adverse events that occur after cycle 1 should follow the 
protocol guidelines (section 5.4). 
 
5.3.1 Schema for dose adjustments if more than 2 patients have DLT  
 
The first 6 patients will be treated with lenvatinib 18 mg/day D1-D21 and eribulin 1.1 mg/m2 
D1 and D8 (Dose level 11). If no more than 2 (≤ 2) patients had dose-limiting toxicity (DLT) in 
the first cycle (3 weeks), then the lenvatinib (18) and eribulin (1.1) combination will be 
declared safe. If more than 2 (> 2) patients have DLT, the investigators will determine which 
drug is more pertain to the DLT(s) and then will follow the customized block chart to shift the 
dose. If lenvatinib is determined to be related to DLT, the next lower dose would be dose level 
21. Otherwise, if eribulin is determined to be the likely cause for DLT, the next dose level will 
be level 12. The lowest dose acceptable would be ether dose level 22 or dose level 31. If still 
more than 2 patients have DLT in the first 6 patients of dose level 22 or level 31, the 
combination of lenvatinib and eribulin will be considered too toxic in STS patients. 
 
Table 1: dose levels of lenvatinib and eribulin combination 
 
Dose levels* 
Lenvatinib 
Eribulin 
Dose level 11 
18mg/day D1-D21 
1.1 mg/m2 D1, D8 
Dose level 21 
14mg/day D1-D21 
1.1 mg/m2 D1, D8 
Dose level 31 
10mg/day D1-D21 
1.1 mg/m2 D1, D8 
Dose level 12 
18mg/day D1-D21 
0.7 mg/m2 D1, D8 
Dose level 22 
14 mg/da D1-D21 
0.7 mg/m2 D1, D8 

LEADER Protocol Version 5.0 2022-05-10 
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Figure 2. Schematic dose adjustment directions if more than 2 patients have DLT 
 
The Principal Investigator will be responsible to determine the association as to which drug 
is more likely to be associated with the DLT and the next dose level to be started in the next 
step of the phase Ib (run-in) phase.  
 
 
5.3.2 Definitions of DLT 
Dose limiting toxicities (DLT) include the following: 
(1) Grade 4 diarrhea 
(2) Grade 3 or higher proteinuria 
(3) Grade 3 or higher hand foot syndrome   
(4) Grade 3 or 4 peripheral neuropathy 
(5) Neutropenia Grade 4 that lasted >5 days 
(6) Neutropenia Grade 3 or 4 complicated by fever and/or infection (Absolute Neutrophil 
Count [ANC] < 1.0 x 109/L, fever ≥38.5°C) 
(7) Thrombocytopenia Grade 4 of any duration 
(8) Thrombocytopenia Grade 3 complicated by bleeding and/or which required platelet 
or blood transfusion 
(9) Other Grade 3 or 4 clinically significant non-hematologic toxicities (except for 
inadequately treated nausea and/or vomiting) considered related to study drug 
(10) Failure to administer ≥ 75% of the planned dosage of combination therapy as a 
result of treatment related (at least possibly related) toxicity during Cycle 1. 
(11) Grade 3 or above hypertension not able to be controlled by medication 
Lenvatinib
10 mg/day
Lenvatinib
14 mg/day
Lenvatinib
18 mg/day

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(12) Grade 3 or above gastrointestinal perforation 
(13) Grade 4 hemorrhage 
(14) Grade 3 thromboembolic event 
(15) Grade 3 or above wound dehiscence requiring medical or surgical intervention 
 
5.3.3 Decision on Final Phase II dose 
The final phase II dose will depend on the final result from the phase Ib part, as to which 
dose level did the phase Ib part confirmed to be safe (Dose 11 or 12 or 21, etc). Patients 
who received the same dose as to the phase II part will be included into part of the phase II 
efficacy analysis. (Please also refer to section 10.6 on how two institutions collaborate and 
determine on this issue) 
  
5.4 Guidelines for dose delays and dose modifications   
This part for the guideline is for all phase Ib and phase II patients.. 
Dose modification is made according to the greatest degree of toxicity that is graded base on 
Common Terminology Criteria for Adverse Events v4.03 (CTCAE). The CTCAE v4.03 can be 
downloaded from the CTEP home page. All appropriate treatment areas should have access 
to a copy of the CTCAE v4.03. 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
 
5.4.1 Hematological toxicities 
Toxicity  
Adverse event  
Dose Reduction/Delay 
 
 
Eribulin  
Lenvatinib 
Hematologic 
toxicity 
attributed to 
any 
or all 
treatment 
 
ANC <1000/mm3 or 
Platelets 25000- 
74999/mm3 within 3 
days prior to 
scheduled 
therapy 
 
If Day 1: Hold until 
recovery to ANC 
>1000/mm3 and Platelets 
>75000/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/ mm3, 
Resume at same 
level after recovery. 
Platelets <25000/ mm3 
or Platelets 25000- 
50000/ mm3 
complicated 
If Day 1: Hold until 
recovery to Platelets > 
75000/ mm3. Resume at 
same level after recovery 
Hold until recovery 
of Platelets 
25000/mm3. 
Resume at current 

LEADER Protocol Version 5.0 2022-05-10 
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by bleeding, easy 
bruising, petechiae, or 
requiring platelet 
transfusion 
If Day 8: Hold until 
recovery to Platelets > 
75000/ mm3, Resume at 
same level after recovery 
dose level. 
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 
>38.50C) 
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 
5.4.2 Non-hematological toxicities 
Toxicity  
Adverse event  
Dose Reduction/Delay 
 
 
Eribulin  
Lenvatinib 
Hepatic 
toxicities 
Grade 3/4 toxicity 
of AST/ALT/ Total 
bilirubin 
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 14 mg po 
daily if first occurrence, reduce 
to 10 mg po daily on second 
occurrence and 8 mg po daily 
on third occurrence. 
 
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 
Nonhematologic 
toxicity grade 3 
or 4 attributed 
Grade 3 or 4 
nausea/ vomiting 
despite optimal 
Hold until 
nausea/ vomiting 
have resolved to 
Hold until nausea/ vomiting 
have resolved to 
≤ grade 1. Resume at same 

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to any or all 
treatment 
(except for 
neuropathy) 
antiemetic 
treatment 
≤ grade 1. 
Resume at same 
dose level. 
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 4 
events 
No dose 
modification 
necessary 
Withhold lenvatinib for the 
development of Grade 3 event 
until improved to Grade 0 or 
1or baseline. Either resume at 
a reduced dose or discontinue 
lenvatinib depending on the 
severity and persistence of the 
adverse event 
Proteinuria 
Grade 3 or 
nephrotic 
syndrome (see 
footnote) 
No dose 
modification 
necessary 
Withhold lenvatinib until ≤ 
Grade 2 (proteinuria 2+ or 3+ 
or 24-hour urinary protein < 
3.5g). Resume at next dose 
below current dose. 
Discontinue lenvatinib if 
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 

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greater QT interval 
prolongation. Resume 
lenvatinib at one dose level 
below the current dose when 
QTc prolongation resolves to 
Grade 0 or 1.  
Hand foot 
syndrome 
Grade 2  
No modification 
necessary 
Withhold until ≤ Grade 1. 
Resume at the same dose or 
below current dose at 
physicians discretion 
Grade 3/4  
No modification 
necessary 
Withhold until ≤ Grade 1. May 
resume at the same dose or 
below current dose at 
physicians discretion 
 
For other grade 3/4 non-hematological toxicities not specifically mentioned in the table: 
the investigator could decrease the dose of the responsible drug after returning to 
grade 1 at the physician’s discretion.  
 
If a patient has simultaneous multiple grade 2 adverse events or an intolerable grade 2 
adverse events as per CTCAE, the investigator could decrease the dose of the 
responsible drug after discussion with the Principal Investigator and adjust according to 
5.4.3. 
 
Proteinuria: Grade 2: urine dipstick proteinuria 2+ and 3+; if urine dipstick proteinuria 
4+, check 24-hour urine protein, if >= 3.5g/day, confirms grade 3 proteinuria. If <3.5 
g/day, follow grade 2 proteinuria schedule 
 
5.4.3 Dose modification or delay durations and modification levels (after phase Ib) 
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 modification levels 
Dose level 0 
1.1mg/m2 
Dose level -1  
0.7 mg/m2 
Lenvatinib dose modification levels 
Dose level 0  
18 mg /day 
Dose level -1 
14 mg/ day 

LEADER Protocol Version 5.0 2022-05-10 
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Dose level -2 
10 mg/ day 
Dose level -3 
8 mg/ day 
 
5.5 Duration of the treatment 
 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: 
o 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. 
o The patient withdraws consent from treatment or from the study as a whole. 
o There is disease progression. 
o The treating physician feels it is necessary (e.g. due to patient non-compliance 
or other safety concerns) 
 
6 Study Assessment/ Procedural Schedule 
6.1 Pre-treatment baseline evaluation  
Table 6 Assessments necessary before randomization 
Investigations 
Timing prior to treatment 
Informed consent  
within 28 days 
Criteria 
All inclusion criteria met 
All exclusion criteria not met 
within 28 days 
Medical History 
Initial sarcoma AJCC stage 
Previous chemotherapy and hormonal 
therapy treatment history  
Radiotherapy history 
within 28 days 
Physical Exam  
Height, Weight, Blood pressure 
Karnofsky Performance status 
Existing symptoms and signs 
Concurrent medications 
within 14 days  
Hematology 
CBC 
Differential 
within 14 days 

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Coagulation 
Biochemistry 
Serum creatinine and creatinine clearancea 
BUN 
Electrolytes (Na, Ca, K, Mg) 
Albumin 
Total bilirubin 
Alkaline phosphatase 
AST and ALT 
LDH 
Urinalysis 
Serum or urine pregnancy testb  
within 14 days  
Imaging 
Chest / Abdominal/pelvis CT scan (or MRI if 
patient is contraindicated for CT) 
within 28 days 
Other 
Investigations 
12-Lead ECG 
within 14 days 
a May be calculated using Cockroft-Gault formula. 
b Required for women of childbearing potential only within 72 hours of registration. 
   
6.2 Pre- treatment assessments 
Table 7 Assessments necessary before every cycle of treatment 
Investigations 
Timing prior to administration 
of treatment 
Medical History 
Previous treatment toxicity 
within 3 days 
Physical Exam  
Height, Weight, Vital signs 
Karnofsky performance status 
Existing symptoms and signs 
Concurrent medications 
within 3 days 
Hematology 
CBC 
Differential 
within 3 days 

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Biochemistry 
Serum creatinine and creatinine 
clearancea 
BUN 
Electrolytes (Na, Ca, K, Mg) 
Total protein/ Albumin 
Total bilirubin 
Alkaline phosphatase 
AST and ALT 
LDH 
Urinalysis 
within 3 days 
a May be calculated using Cockroft-Gault formula. 
   
6.3 Tumor Assessment during treatment 
6.3.1 Tumor imaging criteria—RECIST 1.1  
1. The tumor response will be determined by applying RECIST 1.1. Assessment schedule 
of week 8, 16, 24 and every 12 weeks afterwards, according to the regulation of the 
payment of image study by National Health Insurance. The measurability of a tumor is 
defined as follows: 
 
Measurable disease - the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, it can be still be considered as 
a measurable target according to its clinical course.   
 
Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm 
with spiral CT scan. 
 
Non-measurable lesions - all other lesions, including small lesions (longest 
diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan) and 
inflammatory breast 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. Clinical 
lesions including skin nodules and palpable lymph nodes will be considered measurable 
when they are superficial. For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
2. Methods of measurement 
CT and MRI are the best and reproducible methods currently available to measure 

LEADER Protocol Version 5.0 2022-05-10 
31 
target lesions selected for response assessment. Spiral CT should be performed using a 5 
mm contiguous reconstruction algorithm.  
3. Baseline documentation of "Target" and "Non-Target" lesions 
All measurable lesions up to a maximum of five lesions in total (maximum two lesions 
in one organ) 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. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up. 
4. Evaluations included following the RECIST 1.1 
 Complete response (CR): the disappearance of all known disease, determined by two 
observations not less than 4 weeks apart. 
 
Partial response (PR): A 30% or greater decrease in the sum of LD of all lesions in 
reference to the baseline sum LD. In addition, there may be no appearance of new 
lesions or progression of any lesion. 
 
Stable disease (SD): Neither sufficient increase to qualify for PD nor sufficient 
shrinkage to qualify for PR. 
 
Progressive disease (PD): A 20% or greater increase in the sum of LD of all target 
lesions, taking as reference the smallest sum LD recorded at or following baseline. 
 
Once a patient reached PR or CR of his/her tumor assessment, another image will be 
done 4weeks later. A confirmed PR or CR is defined as both these image tumor 
assessment is in the same category (PR or CR). 
 
6.3.2 Assessment schedules 
 
Tumor assessment by CT scan or MRI will be obtained at baseline (as specified in 
section 6.1), 8 weeks, and 16 weeks and 24 weeks and every 12 weeks afterwards. A 
+/- 7 days window is acceptable. 
 
Investigator assessment of the tumor response will be recorded and the investigator will 
decide treatment plan according to local assessment.  
6.3.3 Toxicity assessment 
 
Each patient will be evaluated for toxicity at baseline, every visit, and as needed at any 
time during the treatment, based on CTCAE 4.03 criteria.   

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6.3.4 Follow up of patient status 
 
Patients with grade 3 or 4 toxicity after treatment will be followed-up until the toxicity 
resolved to grade 1 or 2.  
 
All patients will be followed for survival at least 6 months after end-of-treatment. Follow-
up interval should be every 8 weeks +/- 1 week. 
 
6.4 Biopsy during the study 
 
A biopsy of either the primary or metastatic tumor will be taken at baseline (within 4 
weeks of initiation of treatment) and after the first tumor assessment. If a disease 
progression is noted before cycle 3, a biopsy is still suggested.  
 Biopsy samples will be used for biomarker testing that included: FGFR pathway analysis 
and NanoString platform for mRNA analysis of tumor immune microenvironment and 
biomarker assessment. 
 A pre-treatment biopsy will be mandatory for at least 10 patients. If there is a safety 
concern regarding biopsy, the biopsy could be waived after discussion with the Principal 
Investigator. The second biopsy will be optional but is strongly suggested.  
 A 10ml blood will be drawn +/- 3 days of each biopsy for peripheral blood (PB) analysis 
and the comparison between PB changes and association with the tumor 
microenvironment 
6.5 Summary Table 
Table 8 Flow sheet of LEADER Trial 

LEADER Protocol Version 5.0 2022-05-10 
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    L: Lenvatinib, E: eribulin, CBC: complete blood chemistry, ECG: electrocardiogram, KPS: Karnofsky performance status, 
ECOG: Eastern Cooperative Oncology Group 
Study 
Screening 
L + E Cycle 1 
(21 days/cycle) 
L + E Cycle 2 
(21 days/cycle) 
L+E Cycle 3 and 
afterwards 
(21 days/cycle) 
End of Treatmenti 
Week 
0 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
 
Time window 
-28~0 
-14~0 
-3~0 
-3~0 
 
-3 ~ 
+3 k 
-3 ~ 
+3 k 
 
-3 ~ 
+3 k 
3 ~ 
+3 k 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical historyb 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
X 
X 
 
X 
X 
 
Xj 
 
 
X 
Performance status (KPS 
or ECOG) 
 
X 
X 
 
 
X 
 
 
 
 
 
X 
Laboratory assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology    
(CBC+diff, plts) 
 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
Serum chemistryc 
 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
Coagulation 
 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Pregnancy testd 
 
X 
X 
 
 
 
 
 
 
 
 
 
Adverse event assessmente 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor assessmentf 
 
X 
 
 
 
 
 
 
 
X 
 
 
12-Lead ECGg 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Biopsyh 
X (within 
4 weeks 
 
 
 
 
 
 
 
 
Xh 
 
 

LEADER Protocol Version 5.0 2022-05-10 
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a Medical history, physical examination, vital signs, Karnofsky or ECOG performance status, ECG, adverse events assessment, and 
concomitant medications may be omitted on Day 1 if these evaluations have been completed within 14 days prior to starting study treatment. 
Hemogram and biochemistry needs to be repeated within 3 days of Day 1. 
b History only – survival status, details of recurrent/metastatic disease, new treatments. 
c Serum creatinine and creatinine clearance, BUN, Electrolytes (Na, Ca, K, Mg), Total protein, Albumin, Alkaline phosphatase, AST and ALT, 
Total bilirubin, and LDH. 
d Women of childbearing potential  
e AEs recorded at every visit, and as needed at any time during the treatment. After end of treatment, AEs will be recorded until 28 days after 
end of treatment (EOT). The investigator is not required to actively monitor patients for adverse events afterwards. However, the sponsor 
should be notified if the investigator becomes aware of any post-study serious adverse events or non-serious adverse events of special 
interest. Other AE reporting details please refer to section 9.3. 
  f Tumor assessment by CT or MRI will be carried out on week 8, week 16, week 24, and every 12 weeks afterwards with a +/- 7 days window. 
The week 8 and week 24 images will be sponsored by the study and week 16 and images after week 24 will be performed according the 
National Health Insurance Payment system. If a patient reached CR or PR according to RECIST on the 8-, 16-, or 24-week cycle, a confirmed 
imaging more than 4 weeks later will be sponsored by the study.  
  g12-Lead ECG will be performed before every cycle to monitor the QTc for the first 4 cycles, then every 9 weeks afterwards. 
 h The first biopsy will be performed within 4 weeks of treatment starts, the second biopsy will be taken after 1st tumor assessment. At least 10 
patients are required to take the pre-treatment biopsy and the second biopsy after treatment is optional but strongly suggested.  
I Survival follow-up interval is 8 weeks +/- 1 weeks for at least 6 months or death 
J If in later cycles patient is using only lenvatinib as single agent treatment, D8 visit and blood test could be omitted 
k two eribulin injections should be at least ≥ 5 days apart  
 

LEADER Protocol Version 5.0 2022-05-10 
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7 Endpoints for Evaluation 
7.1 Primary endpoint: Objective response rate (ORR) by RECIST 1.1 
 Complete response (CR): the disappearance of all known disease, determined by two 
observations not less than 4 weeks apart. 
 
Partial response (PR): A 30% or greater decrease in the sum of LD of all lesions in 
reference to the baseline sum LD. In addition, there may be no appearance of new 
lesions or progression of any lesion. 
 
Stable disease (SD): Neither sufficient increase to qualify for PD nor sufficient 
shrinkage to qualify for PR. 
 
Progressive disease (PD): A 20% or greater increase in the sum of LD of all target 
lesions, taking as reference the smallest sum LD recorded at or following baseline. 
 
Once a patient reached PR or CR of his/her tumor assessment, another image will be 
done 4weeks later. A confirmed PR or CR is defined as both these image tumor 
assessment is in the same category (PR or CR). 
 
An ORR is defined as the either a CR or PR as defined by RECIST 1.1  
 
The best response as defined by RECIST 1.1 will be used for ORR assessment. The 
best response is defined as the most proximal response assessment before disease 
progression. If the first response evaluation showed disease progression, then the best 
response is PD.  
 
7.2 Secondary endpoints 
7.2.1 24-weeks PFS rate 
The definition of 24-week PFS rate is the percentage of patients who had NOT has an event 
before or at 24-week after treatment starts. An event is defined as follows:  
 
Disease progression (PD according to RECIST 1.1) 
 
Death due to any cause 
.  
 
7.2.2 Overall survival (OS) rate at 6- and 12-months 
The definition of 6- and 12-months OS rate is the percentage of patients who had NOT has 
an event before or at 6 or 12 months. An event is defined as follows: Death due to any cause. 
 
7.2.3 PFS and OS  
PFS is measured from the time of randomization to the time of disease progression (either 
CNS or extra-CNS, according to RECIST 1.1), or death due to any cause. Patients who have 
not had an event at the time of data analysis will be censored at the date on which they are 

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last known to be alive and event-free, on or before the clinical data cutoff date of the 
respective analysis. 
OS is measured from the time of randomization to the time of death. Patients who had not 
recorded a death event at the time of statistical analysis will be censored at the last time point 
the patient was known to be alive.  
 
7.2.4 Toxicities assessment 
Toxicities will be assessed according to CTCAE 4.03. All grade 3 or 4 toxicities need to be 
recorded until they resolved to grade 1 or 2. 
 
7.2.5 Choi criteria for objective response rate assessment 
Choi criteria are based on changes in tumor size and density following contrast administration 
on the CT scan. By Choi, radiological PR is defined by the presence of a decrease in tumor 
size≥10% or a decrease in tumor density/contrast enhancement (CE) on CT scan/MRI≥15%; 
progression(PD) is defined by the appearance of new lesions or by the increase in tumor, 
greatest maximal diameter≥10%, without any criteria for PR by tumor density/CE or by 
increase in tumor density/CE≥15% [11]. 
8 Statistical Considerations 
8.1 Sample size  
The study will be based on a minimax Simon 2 stage design. The ORR of interest with 
lenvatinib and eribulin combination is 20% (P1), and the ORR of low interest is set at 5% (P0). 
With an 80% power and type I error of 0.05, if no patients had an objective response to 
lenvatinib and eribulin combination after the first 13 enrollments, the trial will be stopped early 
for futility. If at least one patient had an objective response, the study will continue to include 
27 evaluable patients. With an expected 10% drop-out rate, we estimate a total of 30 patients 
to be enrolled in this study. 
If no dose de-escalation is needed in the phase Ib part, the 6 patients will be considered 
eligible to be included in the phase II part statistical analysis. If a lower dose is selected as 
the dose to go forward, only patients with the same dose as the phase II part will be included 
in the phase II statistical part.  
 
8.2 Statistical analysis 
8.2.1 Endpoint estimates 
We will provide descriptive statistics and confidence intervals for all variables of interest for 
which data are collected.  
 

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8.3 Correlative science 
Objective: to find a predictive biomarker for the combination of eribulin and lenvatinib 
Biopsy samples will be acquired for analysis  
(1) FGFR pathways will be analyzed by FISH protocol and Sanger sequencing for mutation 
analysis 
(2) mRNA will be purified, test for quality control, and sent for Nanostring nCounter plaform 
for analyzing the tumor microenvironment 
(3) serum biomarkers of immune cytokines and chemokines will be analyzed by Cyokine 
profiling kits  
9 Safety Monitoring and Reporting 
9.1 Adverse Events Definition 
9.1.1 Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution. An adverse event can therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study treatment (e.g., screening invasive procedures such 
as biopsies) 
 
9.1.2 Serious Adverse Events (Immediately Reportable to the Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Fatal (i.e., the adverse event actually causes or leads to death) 
 
Life threatening (i.e., the adverse event, in the view of the investigator, places the patient 
at immediate risk of death) 

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This does not include any adverse event that had it occurred in a more severe form 
or was allowed to continue might have caused death. 
 
Requires or prolongs inpatient hospitalization. Hospitalization because of disease 
progression or planned intervention (eg, follow-up imaging, biopsy) are not considered 
SAE.  
 
Results in persistent or significant disability/incapacity (i.e., the adverse event results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study 
drug 
 
Significant medical event in the investigator's judgment (e.g., may jeopardize the patient 
or may require medical/surgical intervention to prevent one of the outcomes listed above) 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity 
of an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE 
criteria); the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the CRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event).  
 
9.1.3 Non-Serious Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) 
Non-serious adverse events of special interest are required to be reported by the investigator 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event). Adverse 
events of special interest for this study include the following: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law.  
 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent. A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings indicating an infection in a patient exposed to a medicinal product. 
This term only applies when a contamination of the study drug is suspected. 
 
9.1.4 Pregnancy 
Every patient must be instructed to immediately inform the investigator if she becomes 

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pregnant during the study. The investigator should report all pregnancies within 24 hours to 
the sponsor. The investigator should counsel the patient, discuss the risks of continuing with 
the pregnancy and the possible effects on the fetus. Monitoring of the patient should continue 
until conclusion of the pregnancy. Pregnancies occurring up to 6 months after the completion 
of the test “drug” must also be reported to the investigator. 
 
9.1.5 Progression of underlying malignancy 
Progression of underlying malignancy is not reported as an adverse event if it is clearly 
consistent with the suspected progression of the underlying cancer as defined by RECIST 
criteria, or other criteria as determined by protocol. Hospitalization due solely to the 
progression of underlying malignancy should NOT be reported as a serious adverse event. 
Clinical symptoms of progression may be reported as adverse events if the symptom cannot 
be determined as exclusively due to the progression of the underlying malignancy, or does 
not fit the expected pattern of progression for the disease under study. If there is any 
uncertainty about an adverse event being due only to the disease under study, it should be 
reported as an AE or SAE. 
   
9.2  
Relationship to medication 
Table 9 AE Relationship to study medication 
Unrelated 
This category is applicable to those AEs which are judged to be clearly and incontrovertibly due 
only to extraneous causes (disease, the environment, etc.) 
Unlikely 
This category is applicable to an AE that does not follow an anticipated response to the trial 
medication, which may be attributable to something other than the trial medication, and which is 
more likely to have been produced by the subject’s clinical state or concomitant therapy. 
Possible 
This category is applicable to an AE that follows a reasonable temporal sequence from 
administration of the trial medication, that may be an anticipated response to the trial medication, 
but that could have been produced by the subject’s clinical state or concomitant therapy. 
Definite 
The category is applicable to an AE that follows an anticipated response to the trial medication, 
and that is confirmed by both improvement upon stopping the trial medication (de-challenge), 
and reappearance of the reaction on repeated exposure (re-challenge). 
 
9.3  Reporting adverse events 
9.3.1 Adverse events reporting 
All adverse events spontaneously reported by the patient or observed by the investigator 
must be recorded in the CRF. After initiation of protocol treatment, all adverse events, 
regardless of relationship to study drug, will be reported. AEs will be recorded until 28 days 
after end of treatment (EOT). After this period, the investigator is not required to actively 
monitor patients for adverse events; however, the sponsor should be notified if the 
investigator becomes aware of any post-study serious adverse events. 

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9.3.2 Immediate reporting requirements from investigator to sponsor and expedited 
reporting to Health Authority and Ethics Committee/Institutional Review Board 
Serious adverse events, non-serious adverse events of special interest, and pregnancies 
must be reported to Dr. Wei-Wu Chen, Department of Oncology, National Taiwan University 
Hospital by telephone or email (Tel: 0972652264, Email: tomwchen@ntuh.gov.tw) within 24 
hours. The Sponsor will advise the investigator of any further information or documentation 
that is required. The investigator should also evaluate all serious adverse events and 
expeditiously report to the Ethics Committee/IRB (Institutional Review Board) according to 
their requirement and timeline.  
9.4  Follow-up after adverse events 
Any adverse events greater or higher than grade 3 that are still continuing at the time of one 
month after last course of protocol treatment final visit must be followed-up until resolution or 
stabilization, unless in the investigator’s opinion, the condition is unlikely to resolve due to the 
patient’s underlying disease. 
All pregnancies reported during the study should be followed until pregnancy outcome 
is obtained. 
 
10  Administrative and Data Management details 
To ensure accurate, complete, and reliable data, the investigator will do the following: Keep 
records of laboratory tests, clinical notes, and patient’s medical records in the patient’s files 
as original source documents for the study. 
10.1 Confidentiality 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will be 
divulged to the institutional review board, ethics review committee (IRB/ERC) or similar or 
expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees. Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication. We will code the patients number to, 
secure the patients CRF in a storage with lockers or computer files with no security breaches.  
10.2 Confidentiality of the study subjects 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data. By signing the consent form, the subject 

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41 
agrees to this process. If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor. By signing this protocol, 
the investigator agrees to treat all subject data used and disclosed in connection with this trial 
in accordance with all applicable privacy laws, rules and regulations. 
 
10.3 Research budget 
(1) CT/ MRI imaging of the first and second assessment (Taiwan’s National Health 
Insurance Bureau will reimburse tumor imaging assessment every 3 months)  
30 patients x 2 times = 60 assessments for first 2 assessments at week 8 and 16, 
respectively. Others including assessments at baseline and after 16 weeks will be 
covered by NHI insurance. 
with multi-parts CT or MRI imaging averaging NTD $20,000 / exam 
Total = 20,000 * 2 * 30 = NTD $1,200,000 
(2) FGFR pathway analysis 
FGFR1/chromosome 8 FISH probe 
FRS2/chromosome 12 FISH probe 
FGFR4 K353 and E550 mutation detection PCR primer 
Total = NTD $ 250,000  
(3) NanoString platform for mRNA analysis of tumor immune microenvironment and 
biomarker assessment. The NanoString nCounter PanCancer Immune Profiling Panel 
will be used for analysis 
30 patients x 2 biopsies = 60 biomarker samples  
with each NanoString analysis = NTD $18,000/ analysis 
Total = 18,000 * 60 = NTD $ 1,080,000 
 
 The drug will be fully sponsored by Eisai.  
 The research personnel (study nurses) will be supported by the Department of 
Oncology, National Taiwan University Hospital. 
 Eisai partially supported with research fund, other parts of the research fund will be 
supported by intra-mural grant or grants from Clinical Trial Center.  
 
10.4 Publication   
Eisai supports the exercise of academic freedom and, subject to the relevant provisions in 
this Agreement, encourages the Investigator to publish the results of the Study. 
 Pre-Publication Review. To ensure against inadvertent disclosure of unprotected 
Inventions (see Section 10.5, Inventions), the Investigator shall provide Eisai an 

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opportunity (a minimum of 60 days before submission or other public disclosure) to 
review any proposed publication, abstract, or other type of disclosure that reports the 
results of the Study. 
 Standards. The Investigator shall comply with all applicable guidelines, recognized 
ethical standards concerning publications and authorship. 
 Disclosure of Support. The Investigator shall disclose Eisai’s support of the Study in 
any publication of Study results. 
 
10.5 Inventions 
Any invention or discovery which results from the conduct of the Study and which relates to 
Study Drug or its use as a treatment or any other Eisai product (“Invention”) shall be the 
exclusive property of Eisai. The Investigator hereby irrevocably assign, and ensure all Study 
Sites and Research Staff assign, to Eisai (or its nominee) all right, title and interest in all such 
Inventions, including all intellectual property rights therein, and further agree to assist Eisai 
and to do all such acts and things as Eisai may advise are necessary or desirable in 
connection with any such assignment. 
 
10.6 Responsibilities of PIs from participating institutions 
Two institutions in Taiwan (National Taiwan University Hospital (NTUH) and Taipei Veterans 
General Hospital (TVGH)) will participate in the clinical trial. While NTUH and the PI Dr. 
Wei-Wu Chen is the sponsor of the study, TVGH also plays an integral role in this study.  
There will be a meeting convened between the two institutions at least every 6 months (can 
be shorter if one of the PI of each site considers necessary) to discuss and share the 
observations noted during the course of the clinical trial. However, the meeting will only be 
convened if the second site (TVGH) has started to enroll patients.  
 
The PI from each institution will be responsible to determine the causative agent for the DLT 
in the phase Ib part. After 6 patients have completed the phase Ib part, the two PIs from 
both institutions will also meet together to determine whether it is safe to start the phase II 
part.  
This is a competitive enrollment between two institutions and thus no strict enrolling limits 
will be set for each institution.  
11 Ethical considerations 
11.1 General considerations 
This study will be conducted in accordance with the ethical principles that have their origin in 

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the Declaration of Helsinki and will be consistent with Good Clinical Practice (GCP) and 
applicable regulatory requirements. The study will be conducted in compliance with the 
protocol. The protocol and any Amendments and the subject informed consent will receive 
Institutional Review Board (IRB) approval prior to initiation of the study. The rights, safety and 
well-being of the trial subjects are the most important considerations and should prevail over 
interests of science and society. 
 
11.2 Informed consent 
Freely given written informed consent must be obtained from every subject or their legally 
acceptable representative (LAR) prior to clinical trial participation, including informed consent 
for any screening procedures conducted to establish subject eligibility for the trial. 
 
 
 

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REFERENCES 
 
 
(1) Schöffski P, Chawla S, Maki RG et al. Eribulin versus dacarbazine in previously treated patients 
with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 
trial. Lancet. 2016 Apr 16;387(10028):1629-37 
(2) van der Graaf WT, Blay JY, Chawla SP et al. Pazopanib for metastatic soft-tissue sarcoma 
(PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012 May 
19;379(9829):1879-86 
(3) Mir O, Brodowicz T, Italiano A, et al. Safety and efficacy of regorafenib in patients with 
advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, 
phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1732-1742 
(4) Nakamichi S, Nakihara H, Yamamoto N, et al. A phase 1 study of lenvatinib, multiple receptor 
tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother 
Pharmacol. 2015 Dec;76(6):1153-61 
(5) Chudasama P, Renner M, Straub M, et al. Targeting Fibroblast Growth Factor Receptor 1 for 
Treatment of Soft-Tissue Sarcoma. Clin Cancer Res 2017 Feb 15;23(4):962-973. 
(6) Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone 
for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. 
Lancet. 2016 Jul 30;388 (10043):488-97.  
(7) Savas P, Salgado R, Denkert C, et al. Clinical relevance of host immunity in breast cancer: from 
TILs to the clinic. Nat Rev Clin Oncol. 2016 Apr;13(4):228-41. 
(8) Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with 
metastatic melanoma. Cancer Immunol Res. 2014 Jul;2(7):632-42 
(9) Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances 
antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016 Aug 
30;7:12624. 
(10) Taieb S, Saada-Bouzid E, Tresch ET, et al. Comparison of response evaluation criteria in solid 
tumours and Choi criteria for response evaluation in patients with advanced soft tissue sarcoma 
treated with trabectedin: a retrospective analysis. Eur J Cancer, 2015; 52:202-9 
(11) Choi H, Charnsangavej C, Faria SC et al. Correlation of computed tomography and positron 
emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single 
institution with imatinib mesylate: proposal of new computed tomography response criteria. J 
Clin Oncol 2007; 25:1753-9 

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Appendix I  Karnofsky Performance Status scale 
 
Table 1 Karnofsky Performance Status scale definitions rating (%) criteria 
Able to carry on normal activity and to work; 
no special care needed. 
100  Normal no complaints; no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease.  
Unable to work; able to live at home and care 
for most personal needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but 
is able to care for most of his 
personal needs. 
50 
Requires considerable assistance 
and frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital 
admission is indicated although 
death not imminent. 
20 
Very sick; hospital admission 
necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes 
progressing rapidly. 
0 
Dead 
 
 
 

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Table 2 Karnofsky Performance Status scale and ECOG scale 
Karnofsky 
Scales  
Zubrod-ECOG-WHO 
Normal, no complaints  
(常沒有任何抱怨，確定沒有疾病) 
100  
0  
Normal activity fully ambulatory 
(無症狀) 
Able to carry on normal activities, Minor signs or symptoms 
of disease (可以正常活動，有一些疾病症狀) 
90  
1  
Symptoms, but nearly fully ambulatory  
  
 
           (有症狀，完全步行，但對生活無影響) 
Normal activity with effort  
(可以稍微正常活動，已經有一些疾病的症狀) 
80  
Cares for self.  Unable to carry on normal activity or to do 
active work  (需要自己照顧，無法從事正常活動) 
70  
2  
Some bed time, but needs to be in bed less 
than 50% of normal daytime  
Requires occasional assistance, but able to care for most of 
his needs  (有時需要別人幫助，能照顧患者大部分的需
要) 
60  
           (躺在床上的時間<50%) 
  ≦2 分才能接受針劑化學治療 
Requires considerable assistance, and frequent medical 
care(需要考慮別人幫助，經常給予醫療照顧)  
50  
3  
Needs to be in bed more than 50% of normal 
daytime  
Disabled.  Requires special care and assistance  
(傷殘，需要特別照顧及幫助) 
40  
           (躺在床上的時間>50%) 
Severely disabled.  Hospitalization indicated though death 
not imminent   (嚴重傷殘，尚未有死亡的危險) 
30  
4  
Unable to get out of bed  
Very sick.  Hospitalization Necessary.  Active supportive 
Treatment necessary    (病情嚴重，尚未有死亡的危險) 
20  
           (長期完全臥床) 
Moribund    (病況緊急，很快有死亡的危險) 
10  
Dead  
0  
5  
Dead