Phase II Clinical Trial of Eribulin in Advanced or Recurrent Cervical Cancer
Phase: PHASE2
Conditions: Recurrent Cervical Cancer, Stage IIIA Cervical Cancer, Stage IIIB Cervical Cancer, Stage IVA Cervical Cancer, Stage IVB Cervical Cancer
Sponsor: University of Southern California

 
 
Local Protocol #: 5C-11-2 
Protocol Title: Phase II Clinical Trial of Eribulin in Advanced or 
Recurrent Cervical Cancer. 
 
Protocol version date: 6/22/2014 
 
ClinicalTrialsgov #: NCT01676818 
 
 

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UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR. 
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
CLINICAL INVESTIGATIONS SUPPORT OFFICE 
1441 Eastlake Avenue, Room 7408 MS-74 
Los Angeles, California 90089-9177 
Telephone (323) 865-0450 
 
 
PROTOCOL NUMBER: 
5C-11-2 
 
TITLE: 
Phase II Clinical Trial of Eribulin in Advanced or Recurrent 
Cervical Cancer 
 
SITE:  
Cervical Cancer 
 
MODALITY: 
Chemotherapy 
 
TYPE:  
Phase II 
 
ARMS:  
One 
 
PRINCIPAL INVESTIGATORS: 
Agustin A Garcia, MD, MMM 
 
CO-INVESTIGATORS: 
Yvonne Lin-Liu, MD, MS 
 
 
Huyen Pham, MD 
 
 
Lynda Roman, MD 
 
 
Anne Yessaian, MD 
 
 
Koji Matsuo, MD 
 
PARTICIPANTS: 
LAC+USC Medical Center 
 
 
USC/Norris Comprehensive Cancer Center & Hospital 
 
 
 
 
AMENDMENTS/REVISIONS: 
N/A 
 
THE UNIVERSITY OF SOUTHERN CALIFORNIA ASSUMES NO 
RESPONSIBILITY FOR THE USE OF THIS EXPERIMENTAL PROTOCOL 
OUTSIDE THE PARTICIPATING INSTITUTIONS 
 
 
 
 
 

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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is a phase II, non-randomized, two-stage study. Fifteen patients will be treated and evaluated in 
the first stage; if 1 or more of the 15 patients achieve a progression free survival of 6 months an 
additional 15 patients will be accrued into the second stage. 
 
 
 
 
 
 
Women with Recurrent Cervical Cancer 
Completion of Pre-Entry Examinations 
 
 
Medical history & Physical exam 
 
Weight & PS  
 
Complete blood count  
 
Electrolytes, LFT, Cr and BUN 
 
Imaging studies 
 
Blood and tissue for correlative studies 
Eribulin 1.4 mg/m2 IV 
Day 1 and 8 
 
1 cycle = 21 days 
 

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Contents 
STUDY SCHEMA ..................................................................................................................................................... 2 
1.0 
BACKGROUND AND HYPOTHESES ............................................................................................................ 5 
2.0 
OBJECTIVES AND PURPOSE ...................................................................................................................... 8 
3.0 
STUDY DESIGN ........................................................................................................................................... 8 
4.0 
DRUG INFORMATION .................................................................................................................................. 9 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS ....................................................................................... 11 
5.1 
Inclusion Criteria ................................................................................................................................... 11 
5.2 
Exclusion Criteria ................................................................................................................................... 12 
6.0 
STRATIFICATION / DESCRIPTIVE FACTORS / RANDOMIZATION SCHEME .......................................... 12 
7.0 
STUDY AGENT ADMINISTRATION ...................................................................................................................... 12 
7.1 
Ancillary Treatments ............................................................................................................................. 12 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY AND DOSE MODIFICATIONS ................................................ 12 
8.1 
General Principles for Dose Delay and Modifications .......................................................................... 12 
8.2 
Recommended Dose Delays ................................................................................................................. 13 
8.3 
Treatment Removal .............................................................................................................................. 14 
8.4 
Adverse Event Reporting ...................................................................................................................... 14 
8.5 
Serious Adverse Event Reporting .......................................................................................................... 15 
9.0 
CLINICAL AND LABORATORY EVALUATIONS AND STUDY CALENDAR .................................................. 17 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS .................................................................... 18 
10.1 
Endpoint Definitions ............................................................................................................................. 21 
10.1.1 
PRIMARY EFFICACY ENDPOINT ............................................................................................................. 21 
10.1.2 
SECONDARY EFFICACY ENDPOINTS ........................................................................................................ 21 
10.1.3 
PRIMARY TOXICITY ENDPOINTS ............................................................................................................ 21 
11.0 
SPECIAL INSTRUCTIONS .......................................................................................................................... 21 
12.0 
DATA COLLECTION AND MONITORING .................................................................................................... 23 
12.1. 
Confidentiality of Records ................................................................................................................. 23 
12.2. 
Patient Consent Form ....................................................................................................................... 23 
12.3. 
Registration Eligibility Worksheet ..................................................................................................... 23 
12.4 
Data Collection Forms and Submission Schedule ................................................................................. 23 
13.0 
STATISTICAL CONSIDERATIONS .............................................................................................................. 23 
14.0 
REGISTRATION GUIDELINE ...................................................................................................................... 25 
15.0 
STUDY MANAGEMENT .............................................................................................................................. 25 

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15.1 
Retention of Records ............................................................................................................................ 25 
15.2 
DATA SAFETY AND MONITORING COMMITTEE .................................................................................... 25 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ..................................................................................... 26 
17.0 
REFERENCES ............................................................................................................................................ 26 
 

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 1.0 
BACKGROUND AND HYPOTHESES 
 
 
Cervical cancer is the second most common cancer in women worldwide; and, 
in developing countries, it is the leading cause of death by cancer (1). Many patients present 
with early stage disease and subsequent treatment results in a high cure rate.  However, a 
significant number of patients either relapse or are diagnosed with locally-advanced or 
metastatic disease.  The prognosis of advanced cervical cancer remains poor as the 5-year 
relative survival rate for stage IV is 17% (2).  
The treatment of advanced or recurrent cervical cancer has been improved by the 
introduction of new active chemotherapy agents of which cisplatin is considered the most 
active and is now routinely employed as part of the initial therapy (3,4).  Tubulin targeting 
agents, such as paclitaxel and vinorelbine have also documented activity and are frequently 
used in the treatment of advanced or recurrent disease (5,6).  However, after platinum based 
therapy the overall activity of these (and other chemotherapy agents) is low with response 
rates and 6-month progression free survival of  approximately 10% at best (7). Therefore 
there is a huge need for the identification of active agents. 
Eribulin is a synthetic analog of Halichondrin B, a natural product isolated from the 
marine sponge Halichondria okadai (8). Eribulin  exerts its anticancer effects via a tubulin-
based antimitotic mechanism, leading to G2/M (GAP 2/mitosis stages of cell cycle) cell cycle 
blocks, disruption of mitotic spindles, and ultimately apoptotic cell death. Among the various 
tubulin-targeted agents, eribulin is a mechanistically unique inhibitor of microtubule dynamics, 
leading to inhibition of microtubule growth in the absence of effects on microtubule 
shortening, and formation of non-productive tubulin aggregates. This unique pattern of 
inhibitory effects on microtubule dynamics is not shared by other known tubulin-targeted 
agents. 
Eribulin inhibits cell growth in multiple human cancer cell lines, including breast, colon, 
prostate, ovarian, small and non-small cell lung, and pharyngeal squamous cell (head and 
neck cancer) carcinoma (9,10). Eribulin also exhibits potent effects in various human 
xenograft models including breast, head and neck, colon, pancreatic, ovarian, small cell lung 
and non-small cell lung cancers (9,10). 
In clinical trials eribulin has documented activity in heavily pretreated breast cancer 
patients (11,12). In a phase III randomized trial eribulin improved the response rate and 

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overall survival of patients with heavily pretreated metastatic breast cancer (13). In addition, 
activity has been reported in previously treated nonsmall cell lung, bladder and prostate 
cancer, particularly in taxane naïve patients. Of note, in a phase I clinical trial a substantial 
response was observed in a patients with cervical cancer (14). 
As important as identifying new treatments for cervical cancer is to explore why 
chemotherapy agents are active (or not) in particular cancers. Therefore we propose to 
explore the potential use of GRP 78 as a predictive marker of response to eribulin. 
Cellular- and endoplasmic reticulum (ER) stress such as chemotherapy, hypoxia, and 
nutritional excess activates the unfolded protein response (UPR) (15-18).  Maturing data 
point to variable glucose-regulated protein-78 (GRP78) expression levels, the critical 
component of the UPR, as a predictor of differential response to certain chemotherapy 
regimens in some tumors, particularly breast and prostate cancers.  GRP78, also known as 
BiP, is a multifunctional Ca-binding protein that primarily resides within the ER dynamically 
controlling ER homeostasis, stress signaling and protein quality control. Several in vitro 
studies already demonstrate the anti-apoptotic properties of GRP78 within the tumor cell and 
other cells within the tumor cell microenvironment, including tumor-associated endothelial 
cells.  GRP78 appears to also suppress doxorubicin-mediated apoptosis in part through 
inhibition of classic apoptosis-related mechanisms, including BAX and caspase-7 activation. 
In clinical studies, a retrospective analysis of 127 breast cancer patients who received 
adjuvant doxorubicin-based chemotherapy, high GRP78 levels within the tumor predicted a 
worse clinical outcome (i.e., shorter recurrence-free survival).  When the subset of patients 
who had received taxanes was evaluated separately, however, high GRP78 levels within the 
tumor actually predicted improved clinical outcome (19).  This finding was subsequently 
upheld in a separate validation cohort, thereby providing further evidence that in breast 
cancer GRP78 may be an independent predictor for response to taxane-based adjuvant 
chemotherapy (20). 
Certain tubulin classes and sub-types have recently been identified and are believed 
to play a role in the tumor cell’s responsiveness microtubule-targeting agents, including 
taxanes (21).  While the specific mechanism of action for eribulin is distinct from taxanes, 
eribulin appears to elicit its antitumor effects by exacting an irreversible mitotic block and 
G2M cell cycle arrest.  Presently, taxane-based regimens in advanced and recurrent cervical 
cancer demonstrate some antitumor activity; however, the Gynecologic Oncology Group 

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(GOG) has demonstrated in a phase III setting that it is not definitively superior to several 
other cytotoxic agents, thereby highlighting the need to identify more effective regimens that 
interrogate novel mechanisms of cytotoxicity for recurrent/advanced cervical cancer (3). 
Understanding the relationship of tumoral GRP78 levels to microtubulin-associated variables 
such as - or -tubulin, certain classes of -tubulin isotopes, and the microtubule-associated 
protein, Tau protein, and clinical outcomes with eribulin treatment may help identify certain 
subsets and profiles of patients who would benefit greatest from this class of treatment. 
 
GRP78 in cervical cancer: The role of endoplasmic reticulum stress and cancer progression 
and chemoresistance has been previously described, and is an area of institutional expertise 
at USC Norris Cancer Center (15-18).  While the body of literature about cervical cancer and 
endoplasmic reticulum stress is nascent, Carter and colleagues in 2004 introduced the 
association between endoplasmic reticulum stress, and its major mediator GRP78, and 
sensitivity of cervical cancer cells to cytotoxic therapies in a series of in vitro studies (22).  
The body of literature about GRP78 in cancer therapeutics, however, is robust and under 
active investigation. 
 
Hypothesis 
Hypothesis #1:  We hypothesize that GRP78 levels within primary cervical tumors are 
associated with responsiveness to microtubule-targeting agents, such as eribulin.  
Specifically, primary tumors that express higher levels of GRP78 may be associated with a 
more favorable clinical response to eribulin, as exhibited clinically by a longer time to 
progression (TTP), as well as a more favorable biological and biochemical profile (i.e., 
increased apoptosis, decreased proliferation, higher levels of specific microtubule-associated 
proteins, including  protein).   
 
Hypothesis #2:  We hypothesize that a dynamic trend of quantitative GRP78 levels in 
serum from recurrent cervical cancer patients undergoing treatment with eribulin treatment 
will be associated with responsiveness to treatment.  Specifically, we hypothesize that patient 
who exhibit increasing levels of serum GRP78 will have an improved clinical response to 
eribulin treatment. 

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Based on the findings that cervical cancer remains one of the most common cancers 
in women worldwide and the lack of effective treatments for recurrent disease it is imperative 
to identify new therapies. Furthermore, it is essential to identify prognostic or predictive 
markers of response to treatment. We therefore propose to conduct a phase II clinical trial to 
evaluate the activity of eribulin in patients with previously treated cervical cancer and to study 
the potential role of GRP78 as a marker of response to treatment. 
 
 
2.0 
OBJECTIVES AND PURPOSE 
 
Primary Objectives:  
 
To evaluate the activity of eribulin in the management of advanced or recurrent 
cervical cancer (PFS) 
 
Secondary Objectives: 
 
To describe the toxicity profile of Eribulin in patients with advanced or recurrent 
cervical cancer 
 
To estimate the survival of patients with advanced or recurrent cervical cancer 
treated with Eribulin 
 
To evaluate potential correlative studies as predictive or prognostic makers in 
this patient population (GRP78 levels in tissue and blood, p53 expression, 
apoptosis with TUNEL assay, apoptosis-related proteins Bcl-2 and Bax using 
IHC, proliferation with Ki67 IHC, and expression levels of microtubule-
associated variables, including  protein, total - and -tubulin, and classes II-
IV -tubulin isotopes with IHC) 
 
 
3.0 
STUDY DESIGN 
 
This is an open label single arm phase II clinical trial of eribulin in patients with 
advanced cervical cancer. Eligible patients will be treated with Eribulin 1.4 mg/m2 IV 
administered as a 2-5 min bolus on days 1 and 8 of a 21 day cycle.  

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4.0 
DRUG INFORMATION 
 
For more detailed information consult the HALAVEN™ Package Insert (Appendix A) 
 
Names: Eribulin mesylate (E7389, HALAVEN™).  
 
Description: HALAVEN (eribulin mesylate) Injection is a non-taxane microtubule dynamics 
inhibitor. Eribulin mesylate is a synthetic analogue of halichondrin B, a product isolated from 
the marine sponge Halichondria okadai. The chemical name for eribulin mesylate is 
11,15:18,21:24,28-Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2-
i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 2-[(2S)-3-amino-2-
hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, 
(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, 
methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free base). The 
empirical formula is C40H59NO11•CH4O3S. 
 
HALAVEN is 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). 
 
Mechanism of Action: 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. 
 
How Supplied: Commercially available in injection, 1 mg/2 mL (0.5 mg/mL) single use vials. 
The drugs will be supplied by Eisai Inc. 
 
Preparation: Aseptically withdraw the required amount of HALAVEN from the single-use vial 
and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. 
Do not dilute in or administer through an intravenous line containing solutions with 
dextrose. Do not administer in the same intravenous line concurrent with the other medicinal 
products. 

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Storage: Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° -86° F). Do not 
freeze. Store the vials in their original cartons. Store undiluted HALAVEN in the syringe for up 
to 4 hours at room temperature or for up to 24 hours under refrigeration (40°F or/ 4°C). Store 
diluted solutions of HALAVEN for up to 4 hours at room temperature or up to 24 hours under 
refrigeration. Discard unused portions of the vial. 
 
Route of Administration: Intravenous 
Adverse Events and Potential Risks with a Per-Patient Incidence of at least 10% 
 
All Grades (%) 
> Grade 3 (%)
Blood and Lymphatic System Disorders
Neutropenia 
Anemia 
 
82 
58 
 
57 
2 
Nervous System Disorders 
Peripheral Neuropathy 
Headache 
 
35 
19 
 
8 
< 1 
General Disorders 
Asthenia/Fatigue 
Mucosal Inflammation 
Pyrexia 
 
54 
9 
21 
 
10 
1 
< 1 
Gastrointestinal Disorders 
Constipation 
Diarrhea 
Nausea 
Vomiting 
 
25 
18 
35 
18 
 
1 
0 
1 
1 
Musculoskeletal and Connective Tissue Disorders
Arthralgia/Myalgia 
Back Pain 
Bone Pain 
Pain in Extremity 
 
22 
16 
12 
11 
 
< 1 
1 
2 
1 
Investigations 
Decreased weight 
 
21 
 
1 
Metabolism and Nutrition Disorders
Anorexia 
 
 

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20
1 
Respiratory, thoracic and mediastinal disorders
Cough 
Dyspnea 
 
14 
16 
 
0 
4 
Skin and subcutaneous Disorders
Alopecia 
 
45 
 
NA 
Infections 
Urinary Tract Infection 
 
10 
 
1 
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
 
5.1 
INCLUSION CRITERIA   
 
 Histologically confirmed diagnosis of invasive cervical cancer 
 Measurable Disease (RECIST 1.1) 
 0-1 prior chemotherapy regimens for recurrent or advanced disease. 
Platinum based chemotherapy administered as a radiation sensitizer 
agent is allowed and does not count as prior therapy 
 Adequate organ function defined as: 
o bone marrow (AGC > 1,500, platelet > 100,000),  
o renal (serum creatinine < 2.0 mg/dl)  
o hepatic function (bilirubin < 1.5 times the upper limit of the normal 
range (ULN), and alkaline phosphatase, alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST) < 3 x ULN (in the case 
of liver metastases, < 5 x ULN). 
 Peripheral neuropathy grade 0-2 
 Recovery of all chemotherapy or radiation-related toxicities to Grade < 1, 
except for alopecia and peripheral neuropathy. 
 Performance status 0-2 
 Signed Informed Consent 
 Patients > 18 years old 
 
 

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5.2 
EXCLUSION CRITERIA 
 
 Prior treatment with Eribulin 
 Chemotherapy, radiation, or biological or targeted therapy within 3 weeks 
 Hormonal therapy within 1 week 
 Any investigational drug within 4 weeks 
 Known brain metastases, unless previously treated and asymptomatic 
for 3 months and not progressive in size or number for 3 months  
 
6.0 
STRATIFICATION / DESCRIPTIVE FACTORS / RANDOMIZATION SCHEME 
 
  
There will be no formal stratification. Descriptive factors include age, histology, number 
of prior lines of therapy, prior platinum as a radiation sensitizer.  
 
7.0 
STUDY AGENT ADMINISTRATION  
 
 
 
Patients will be treated with Eribulin 1.4 mg/m2 administered on days 1and 8, 
repeated every 21 days.    
 
AGENT 
DOSE 
ROUTE 
DAYS 
ReRx INTERVAL 
Eribulin 
1.4 mg/m2 
i.v. bolus  
over 2-5 mins 
1,8 
3 weeks 
 
 
 
 
7.1 
ANCILLARY TREATMENTS   
 
 Routine prophylactic use of granulocyte colony stimulating growth factors is not 
allowed. Growth factors can be used as per ASCO guidelines (23) 
 
 Routine use of steroids, H1 or H2 blockers is not required. 
 
 Antiemetic prophylaxis as per standard of care. 
 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY AND DOSE MODIFICATIONS 
 
 
8.1 
GENERAL PRINCIPLES FOR DOSE DELAY AND MODIFICATIONS 
 
 
The dose of eribulin may be reduced or discontinued during any cycle in 
accordance with the toxicity modifications described below. 
 
Toxicities will be managed by treatment delay and dose reduction. Once the 
dose has been reduced, it cannot be increased at a later date. 
 

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8.2 
RECOMMENDED DOSE DELAYS 
 
As a general rule, participants should be assessed for peripheral neuropathy and complete 
blood count lab values should be obtained and reviewed prior to each dose. 
 
 
Do not administer eribulin on Day 1 or Day 8 if any of the following parameters are 
evident: 
o ANC < 1,000/mm3 
o Platelets < 75,000/mm3 
o Grade 3 or 4 non-hematological toxicities (Section 8.2 and 8.3 have 
additional details) 
 
 
The Day 8 dose may be delayed for a maximum of 1 week: 
o If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit 
the dose 
o If toxicities resolve or improve to a ≤ Grade 2 severity by Day 15, administer 
eribulin at a reduced dose and initiate the next cycle no sooner than 2 weeks 
later 
The following chart is a representation of dose modifications per event.  Consult 
the principal investigator for additional information. 
 
EVENT DESCRIPTION  
RECOMMENDED ERIBULIN DOSE  
Permanently reduce the 1.4 mg/m2 eribulin dose for any of the following:
o 
ANC <500 cells/mm3 for >7 days 
o 
ANC <1,000 cells/mm3 with fever or infection 
o 
Platelets <25,000/mm3  
o 
Platelets <50,000/mm3 requiring transfusion 
o 
Non-hematologic Grade 3 or 4 toxicities 
o 
Omission or delay of Day 8 dose in previous cycle for toxicity  
1.1 mg/m2  

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EVENT DESCRIPTION  
RECOMMENDED ERIBULIN DOSE  
Occurrence of any event requiring permanent dose reduction while 
receiving 1.1 mg/m2  
0.7 mg/m2  
Occurrence of any event requiring permanent dose reduction while 
receiving 0.7 mg/m2  
Discontinue eribulin  
 
Note: if subject meets criteria to be removed from study due to toxicity but is deemed 
to have clinical benefit from treatment, continuation of treatment and reduction or 
modification of the dose can be discussed with the principal investigator. 
 
 
 
 
8.3 
TREATMENT REMOVAL 
 
Patients will be removed from treatment in the event of:  
 Peripheral neuropathy Grade >2 that does not improve as in Section 8.1 
 Grade 3 or 4 hypersensitivity/infusion reaction. 
 Inability of subject to comply with study requirements. 
 Determination by the investigator that it is no longer safe for the subject 
to continue therapy. 
 Progression of disease (as defined in Section 10.1).  
 Delay of treatment ≥ 2 weeks. 
 Patient may choose to withdraw her participation at any time for any 
reason 
 
8.4 
ADVERSE EVENT REPORTING  
Any adverse events will be initially reported to Dr. Garcia at (323)865-3000 or any of 
the listed research personnel, who will inform the IRB within 7 days.  The principal 
Investigator will comply with all safety reporting regulations as set forth the Code of 
Federal Regulations. Any correspondence to the FDA regarding adverse events or 
other safety issues will be simultaneously copied via facsimile or email to Eisai. 

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The Principal Investigator will cooperate with Eisai in all of their efforts to capture
 
information on the safety profile of the Study Drug, including, but not limited to the
 
following: 
 
Notify Eisai of all serious suspected adverse drug reactions occurring in an individual
 
who has been exposed to the Study Drug, and where the Study Drug is suspected
 
product. 
 
8.5 
SERIOUS ADVERSE EVENT REPORTING 
 
Where adverse drug reaction is defined as: 
A noxious and unintended response to a medicinal product related to any dose. 
A causal relationship between the medicinal product and the adverse response 
is at least a reasonable possibility. 
 
And serious is defined as: 
A serious adverse event (experience) or reaction is any untoward medical 
occurrence that at any dose: 
 Results in death 
 Is life threatening 
(Note: the term life-threatening in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity, or 
 
Is a congenital anomaly/birth defect 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require interventions to prevent one of the other 
outcomes listed in the definition above. These should also usually be considered 
serious. 
All Serious Adverse Events (SAEs) will be reported to the IRB.  Also, the Principal 
Investigator will report SAEs via the MedWatch Form 3500A to the FDA, which can be 
accessed at: 
http://www.accessdata.fda.gov/scripts/MedWatch/ 
MedWatch forms will be sent to the FDA online at the above internet address or to the 
following: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD  20852-9787 
FAX:  1-800-FDA-0178 (1-800-332-0178) 

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The notification of a serious suspected adverse drug reaction should occur as soon as 
possible, but no later than one business day, and should be done by fax or email via 
the Eisai standard serious adverse event report form (attached hereto as Appendix B). 
The contact details for the notification are: 
 
 
 
 
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 
In addition, the Principal Investigator agrees to notify Eisai immediately of any other 
information that suggests a change to the safety profile of the Study Drug. 
 
 
 
 

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9.0 
CLINICAL AND LABORATORY EVALUATIONS AND STUDY CALENDAR 
 
 
 
 
 
 
 
 
 
 
 
 
1 Within 24 hrs 
2 As clinically indicated 
3 From paraffin embedded prior biopsy 
4 Cycles 1-6 
5 Within 28 days of each cycle 
6 CXR is only required in the event that a CT of the chest is not done.  Should a CXR be given in place 
of a CT scan, an additional CXR should be repeated every 2 cycles. 
 
 
 
 
 
 
 
Parameter 
Pre- 
Treatment5 
Each 
Cycle 1 
 
Every 2 
Cycles 
Every 4 
Cycles 
Follow-Up 
(every 3 
mos.) x 2 yrs 
End of 
Study 
History & 
Physical  
Exam 
X 
X 
 
 
x 
 
Weight,  
Performance 
Status 
X 
X 
 
 
 
 
Toxicity Assessment 
 
X 
Day 1 
and 8 
 
 
 
 
WBC (differential),  
Hgb, platelets 
X 
X 
Day 1 
and 8
 
 
 
 
Electrolytes, 
MG, BUN, Cr 
X 
X 
 
 
 
 
LFT (Bilirubin, AST, ALT, 
Alkaline phosphatase  
 
X 
 
 
 
 
EKG 
X 
 
 
X 
 
 
CXR 
X 
X 6
 
 
 
Radiology, x-ray or Scans for 
disease measurement 
X 
 
X 
 
 
 
Tissue collection 3 
 
X 
 
 
 
 
 
Peripheral Blood Collection for 
Correlative Studies 
 
X4 
 
 
 
X
Eribulin  
 
Day 1 
and 8 
 
 
 
 

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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
 
 
The outcome status (in terms of toxicity, response, reason off study, progression, and 
survival) of all eligible patients will be reported. All eligible patients who begin 
treatment will be included in the analysis of response, survival and time-to-failure.  
Toxicities and adverse events including laboratory adverse events will be graded and 
summarized according to the National Cancer Institute CTCAE, v4.3 (available on the 
NCI website at: http://ctep.cancer.gov/forms/CTCAEv4.pdf).   
 
Response will be evaluated according to the RECIST criteria v1.1:  
 
Eligibility 
Only patients with measurable disease (at least one measurable lesion) at baseline 
should be included in protocols where objective tumor response is the primary 
endpoint.  
Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter 10 mm and 2x slice thickness on CT scan.  Lymph 
nodes must be >15 mm in short axis.  Bone lesions may be measurable if there is a 
lytic/soft tissue component that meets minimum size criteria.  CXR lesions must be >20 
mm. 
Non-measurable lesions - all other lesions, including small lesions or lesions not 
conventionally measurable (i.e. leptomeningeal disease, ascites, pleural/pericardial 
effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, and 
also abdominal masses that are not confirmed) should be noted and followed by 
imaging techniques but not measured. 
 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 will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Methods of Measurement  
 
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm.  This applies to tumors of the chest, 
abdomen and pelvis. Head and neck tumors and those of extremities usually require specific 
protocols. 

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19
 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable.  
 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid 
nodules. US might also be useful to confirm the complete disappearance of superficial 
lesions usually assessed by clinical examination. 
 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., 
after treatment to differentiate between residual benign lesions and residual malignant lesions 
in tumor types such as germ cell tumors). 
 
Baseline documentation of “Target” and “Non-Target” lesions 
All measurable lesions up to a maximum of five lesions total (2 per organ), representative of 
all involved organs should be identified as target lesions and recorded and measured at 
baseline.  
Lymph node measurements should reflect the short diameter 
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.  
 
Response Criteria 
 
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 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 
 
Evaluation of non-target lesions 
 
* Complete 
Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level 
* Incomplete 
Persistence of one or more non-target lesion(s) or/and 

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Response/          
Stable Disease 
(SD):  
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 (1)  
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 later on by the review panel (or study chair). 
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 PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria  
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
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) to confirm the complete response status. 
 
Confirmation 
 
The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed.  In cases where confirmation of response is not feasible, it 
should be made clear when reporting the outcome of such studies that the responses are 
not confirmed. 
 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks after 
the criteria for response are first met. Longer intervals as determined by the study protocol 
may also be appropriate.  
 
In the case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined 
in the study protocol  

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Duration of overall response 
 The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever status is recorded first) until the first date that recurrence or PD 
is objectively documented, taking as reference for PD the smallest measurements 
recorded since the treatment started. 
 
Duration of stable disease 
 SD is measured from the start of the treatment until the criteria for disease progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started.  
 
The clinical relevance of the duration of SD varies for different tumor types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval 
required between two measurements for determination of SD. This time interval should 
take into account the expected clinical benefit that such a status may bring to the 
population under study.  
 
10.1 
ENDPOINT DEFINITIONS  
 
10.1.1 PRIMARY EFFICACY ENDPOINT 
Progression-free survival is defined as the time from first day of treatment to the 
first observation of disease progression or death due to any cause.  If a patient 
has not progressed or died, progression-free survival is censored at the time of 
last follow-up.   
10.1.2 SECONDARY EFFICACY ENDPOINTS 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment started).   
Overall survival is defined as the time from first day of treatment to time of 
death due to any cause.  If a patient is still alive, survival time is censored at the 
time of last follow-up.  
10.1.3 PRIMARY TOXICITY ENDPOINTS 
The primary toxicity endpoint is any occurrence of grade 3+ hematologic and 
non-hematologic toxicity according to CTCAE4.3.  
11.0 
SPECIAL INSTRUCTIONS 
 

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To determine the association between responsiveness to eribulin and prognostic 
factors such as apoptosis markers, proliferation, pAkt, EGFR, and ER stress, we propose 
examination of primary tumor specimens using immunohistochemistry.  At the time of 
enrollment, the original cervical tumor tissue and corresponding H&E slide from all patients 
will be retrieved from the pathology archive.  Because of the nature of the patient population 
at this institution, the primary diagnosis of cervical cancer is typically made within this same 
institution.  If sufficient tissue is remaining within the paraffin block, 20 additional unstained 
sections will be obtained from these paraffin blocks for immunohistochemistry.  Blocks will be 
retrieved by the USC-Norris Translational Pathology Core under the direction of Dr. Sue Ellen 
Martin and the lab manager, MoLi Chen.  These immunohistochemistry experiments will be 
performed in Dr. Yvonne Lin-Liu’s laboratory in the Harlyne Norris Research Tower at the 
USC Norris Comprehensive Cancer Center.  Scoring will be performed by a board-certified 
gynecologic pathologist. 
In patients who undergo a biopsy or surgical procedure to demonstrate recurrent cervical 
cancer, the archived paraffin block will be retrieved in addition to the original tumor block, and 
20 unstained sections will be obtained from the paraffin block for immunohistochemical 
comparison of the paired primary and recurrent tumor.  The priority of immunohistochemical 
studies are as follows:  1) expression levels of microtubule-associated variables, including  
protein, total - and -tubulin, and classes II-IV -tubulin isotopes, 2) pAkt/EGFR, 3) UPR 
markers (CHOP, GRP78, eIF2), 4) p53, 5) TUNEL, Bcl-2, Bax, 6)  Ki67. 
For the serum studies measuring GRP78, we plan to utilize an ELISA-based tool.  Serum 
specimens will be obtained prior to the infusion of each eribulin as described in the protocol.  
We will plan to obtain a maximum of 7 serial serum samples (cycles 1-6, end of study drug) in 
order to permit interval radiographic assessment of tumor volume as dictated in the primary 
treatment protocol.  Serum will be collected into a separate (standard 6mL) Vacutainer at the 
time of standard pre-chemotherapy labs (plain red-top tube containing no anticoagulants or 
preservatives).  Since all chemotherapy patients on protocol are seen in clinic on a 
designated day each week, the blood will be collected and transported to Dr. Lin-Liu’s lab for 
processing (i.e., centrifugation, pipette-transfer into tube for -80C storage prior to batching 
for assay and analysis).  Specimen procurement will be performed by the USC-Norris 
Translational Pathology Core.  The tumor volume will be ascertained by the study radiologist 
in accordance with the primary protocol. 

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12.0 
DATA COLLECTION AND MONITORING 
 
12.1. CONFIDENTIALITY OF RECORDS 
The original data collection forms will be kept in secure file cabinets in the CISO. 
12.2. PATIENT CONSENT FORM 
At the time of registration, three signed and dated copies of the patient Informed 
Consent form with the Human Rights and the HIPAA authorization must be available 
(for patient, patient's medical chart and one for the Clinical Investigations Support 
Office). 
12.3. REGISTRATION ELIGIBILITY WORKSHEET 
At the time of registration, the information requested on the On-Study/Eligibility 
Worksheet Form will be completed by the Study Coordinator and reviewed by the PI. 
12.4 DATA COLLECTION FORMS AND SUBMISSION SCHEDULE 
All data will be collected using USC CISO data collection forms.  The original data 
collection forms will reside at USC in secure location. 
 
Within two weeks of registration, the data manager will complete the On-Study
 
 
Form (Form OS). 
 
Within two weeks of completion of each course of treatment, the data manager  
 
must complete the following: 
 
 
Treatment and Adverse Event Form  
 
 
Supplemental Data Form (if applicable) 
 
 
Flow Sheets (These are to be submitted along with each treatment form.) 
Each time a patient is evaluated for response and/or new follow-up information is 
obtained the data manager will complete the Response/Off-Study/Follow-Up Form. 
13.0 
STATISTICAL CONSIDERATIONS 
Study Design:   This is a two-stage, single arm study to obtain preliminary evidence of 
efficacy of Eribulin in the treatment of recurrent cervical cancer.  Current chemotherapy 
treatments for recurrent cervical cancer are associated with response rates and 6-month 
progression-free survival rates no higher than 10%.  The objective of this study is to 
determine whether there is evidence that treatment with Eribulin will result in response and 6-
month PFS rates that exceed 10%, suggesting promising activity and encouraging further 
study. 

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24
The primary efficacy endpoint will be 6-month progression-free survival (PFS6). The 
secondary efficacy endpoint will be best overall response (BOR). A total of 30 patients who 
are fully evaluable for PFS6 will be enrolled on this study.   Patients who are not fully 
evaluable for PFS6 will be replaced.  Replaced patients will nonetheless be included in the 
final efficacy analysis. PFS6 will be the endpoint for interim monitoring. 
An interim analysis will occur when 15 patients have been evaluated for PFS6, with 
final analysis once 30 patients have been evaluated for PFS6.  ≥1/15 patients who achieve 
PFS6 are required to continue study accrual to 30 patients.  ≥6/30 patients who achieve PFS6 
will be considered sufficient evidence of efficacy to warrant further study.  The study will be 
terminated if fewer than 1/15 patients are progression-free at 6 months.  The study may 
remain open pending the interim results on the first 15 patients, but will be suspended to 
enrollment if the 20th patient is enrolled before the interim results are available.  
Sample size justification. This design has one-sided Type I error of <0.10 (0.072) for 
a true PFS6 rate of 10%, and power of at least 0.80 for a true PFS6 rate of 26%. Hence this 
study has sufficient power to detect moderate and clinical important improvements in PFS6 
rate due to Eribulin treatment when compared to past experience with chemotherapy 
treatment of recurrent cervical cancer.  
Additional efficacy analyses.  Product limits estimates of 6-month PFS will be 
computed using all patients enrolled on the study.  95% confidence intervals will be based on 
Greenwood standard errors. In addition, exact 95% binomial confidence intervals will be 
compute for the BOR rate. 
Toxicity analyses.  The rate of Grade 3+ hematology and non-hematologic toxicities 
will be computed for course 1 and for all courses combined. 
Interim Monitoring of Toxic Death. The occurrence of toxic death (TD) at any time 
will be a primary endpoint for safety monitoring. A population TD rate that exceeds p=0.05 will 
be considered unacceptable.  Monitoring will be based on a Bayesian rule on the binomial 
frequency of TD using a Beta(1,3) prior.  A posterior probability of ≥90% that the population 
TD rate p exceeds 0.05 will be sufficient to require that the cause and circumstances of the 
TDs be reviewed immediately with the study committee and with the Data and Safety 
Monitoring Committee to determine whether modifications to or termination of the study are 
warranted.  Operationally this will occur if 1 TD occurs within the first 8 patients, or 2 occur 

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25
within the first 19 patients.  A posterior probability of ≥97.5% that p exceeds 0.05, with the 
occurrence of at least 2 TDs, will be considered very compelling evidence that the population 
toxic death rate exceeds 5%, and will require immediate termination of the study unless a 
convincing rationale for continuing the study exists.  Operationally this will occur when 2 TDs 
within the first 10 patients, 3 within the first 19, or 4 during the study are observed. 
Analysis of correlative endpoints.  The analysis of GRP78 IHC score and GRP78 
serum level, as well as other correlative markers (e.g. Tau-protein, alpha- & beta-tubulin), will 
be analyzed via Cox regression analysis for PFS, and via logistic regression for BOR rate.  
The power of these analyses is difficult to determine, since there is little preliminary data on 
the distribution of these endpoints in tumor and serum.  However, the power of these 
analyses can be appreciated from the following.  If, for example, GRP78 IHC level is divided 
at the median, and BOR rate is 25% with Eribulin in this population, there will be 73% power 
to detect a difference in BOR rate of 5% vs 45% in the two resulting group, based on a two-
sample two-sided test of proportions with 5% Type I error.  Hence it is likely that only 
profound associations between measures of efficacy and levels of GRP78 and other 
correlative endpoints will be detectable.  Actually analyses based on ordered categorical and 
continuous measures will be somewhat more powerful than this, Similar considerations apply 
to the other correlative endpoints that will be studied.  
14.0 
REGISTRATION GUIDELINE 
 
The consent process will take place in the privacy of an examination room. The patients will be given 
sufficient time to review the consent form, including taking the consent form home to review.  
 
All patients will be registered in the Cancer Center database Café.   Patients will not be randomized or 
stratified. 
 
15.0 
STUDY MANAGEMENT 
 
 
15.1 RETENTION OF RECORDS 
 
All documentation of adverse events, records of study drug receipt and dispensation, 
and all IRB correspondence for at least 2 years after the investigation is completed. 
15.2 DATA SAFETY AND MONITORING COMMITTEE 
 
The Data and Safety Monitoring Committee (DSMC) at the USC Norris 
Comprehensive Cancer Center (NCCC) is an independent body and is responsible for 
the safety of study subjects through the review of new protocols to ensure an 
adequate adverse event reporting plan and through the real-time and periodic 

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26
monitoring of severe adverse events (SAEs) or those that require expedited reporting. 
The DSMC also performs real-time, quarterly and annual study progress and safety 
review, as well as efficacy/futility review as outlined in the NCCC Data and Safety 
Monitoring Plan (available upon request).  After each review, the DSMC reports the 
results of each review and make recommendations to the study PI, IRB, and CIC.  
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
All patients will have signed an informed consent for participation in research activities in 
accord with all institutional, NCI and Federal and State regulations, and will have been given 
a copy of all signed documents. The study will be conducted in adherence to ICH Good 
Clinical Practice. 
 
 
17.0 
REFERENCES 
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2) Ahmedin Jemal A, Siegel R,  Xu J, Ward E. Cancer Statistics, 2010. CA Cancer J 
Clin 2010; 60: 277-300. 
3) Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing 
doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a 
Gynecologic Oncology Group study. J Clin Oncol. 2009; 27:4649-55.  
4) Vale C, Tierney JF, Stewart LA, et al. Reducing uncertainties about the effects of 
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5) Garcia AA, Blessing JA, Vaccarello L, et al. Phase II clinical trial of docetaxel in 
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6) Muggia FM, Blessing JA, Waggoner S, et al. Evaluation of vinorelbine in persistent 
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7) Monk BJ, Sill MW, Burger RA, et al. Phase II trial of bevacizumab in the treatment 
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8) Jimeno A. Eribulin: rediscovering tubulin as an anticancer target. Clin Cancer Res 
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9) Hamel E. Natural products which interact with tubulin in the vinca domain: 
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13) Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus 
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16) Li J, Lee AS. Stress induction of GRP78/BiP and its role in cancer.  Curr Mol Med. 
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17) Ni M, Zhang Y, Lee AS.  Beyond the endoplasmic reticulum: atypical GRP78 in cell 
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19) Lee E, Nichols P, Spicer D, et al. GRP78 as a novel predictor of responsiveness to 
chemotherapy in breast cancer. Cancer Res 2006 Aug 15;66(16):7849-53 
20) Lee E, Nichols P, Groshen S, et al. GRP78 as potential predictor for breast cancer 
response to adjuvant taxane therapy. Int J Cancer 2011 Feb 1;128(3):726-31 
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