Clinical trial NCT01908101
Conditions: Recurrent Breast Carcinoma Stage IV Breast Cancer
Sponsor: University of Washington
Start date: 2014-01-08; Completion date: 2019-05-04
Enrollment: 86 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well eribulin mesylate works in treating patients with previously treated breast cancer that has spread to other places in the body. Drugs used in chemotherapy, such as eribulin mesylate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVES:

I. Progression free survival (PFS).

SECONDARY OBJECTIVES:

I. Frequency of alopecia with absence or decrease to \< 50%.

II. Incidence of grade 3 and 4 neutropenia of \< 30%.

III. Incidence of sensory neuropathy (all grades) to \< 25%.

TERTIARY OBJECTIVES:

I. Assess the role of circulating endothelial cell precursors (CEPs) and apoptotic circulating endothelial cells (CECs), in predicting early response to treatment.

OUTLINE:

Patients receive eribulin mesylate intravenously (IV) over 2-5 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Arms: arm 1: Patients receive eribulin mesylate IV over 2-5 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Eribulin Mesylate intervention 2: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
IRO REC'ili JUN 06 2019 
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UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Department of Medicine, Division of Oncology 
Seattle Cancer Care Alliance 
Seattle, Washington 
Protocol Title: 	
Phase II Trial of Metronomic Eribulin (Halaven) In 
Pretreated Metastatic Breast Cancer (MBC) 
Current Version Date: 	
03/02/17 
Previous Version: 	
09/07/16 
Co-principal 
Investigators: 
Sub-Investigators: 
Coordinating Center: 
FHCRC IRB Approval 
Hannah Linden, MD 
Professor of Medicine 
University of Washington 
Seattle Cancer Care Alliance 
825 Eastlake Avenue East 
Mail Stop G3-630 
Seattle, WA 98109-1023 
Phone: 	
(206) 288-1234 
Fax: 	(206) 288-2054 
Email: 	
hmlinden@u.washington.edu  
Pavani Chalasani, MD 
Assistant Professor of Medicine 
Arizona Cancer Center 
P.O. Box 245024 
1515 North Campbell Avenue 
Tucson, AZ 85724-5024 
Phone: 	
(520) 626-0191 
Fax: 	(520) 626-2225 
Email: 	
PChalasani@uacc.arizona.edu  
University of Washington  
Vijayakrishna K. Gadi, MD 
Julie Gralow, MD 
Larissa Korde, MD 
Lupe Salazar, MD 
Jennifer Specht, MD 
Fred Hutchinson Cancer Research Center 
Barry Storer, PhD 
Seattle Cancer Care Alliance Network 
825 Eastlake Avenue East 
Mail Stop LG-200 
Seattle, WA 98109-1023 
sccanetresearch@seattlecca.org  
(206) 288-7232 or (888) 201-0060 (toll free) 
, 
JUN 26 2019 
Document Released Date 	
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TABLE OF CONTENTS 
1. Background 	
4 
1.1 Breast Cancer 
1.2 Eribulin 
2. Rationale 	
4 
3. Trial Objectives 	
6 
4. Trial Design 	
6 
5. Subject Selection 	
6 
5.1 Inclusion Criteria 
5.2 Exclusion Criteria 
6. Trial Treatments 	
8 
6.1 Drug Supplies 
6.1.1 Formulation and Packaging 
6.1.2 Preparation and Dispensing 
6.2 Treating the Patient 
6.2.1 Conditions Prior to Administering Treatment 
6.2.2 Eribulin Administration 
6.2.3 Dose Modifications 
6.3 Concomitant Medication 
7. Trial Procedures 	
11 
7.1 Screening Visit 
7.2 Day 1 of Each Cycle 
7.3 Day 8 and 15 of Each Cycle 
7.4 End of Treatment Visit 
7.5 Subject Withdrawal 
8. Assessments 	
13 
8.1 Efficacy Assessments 
8.1.1 Definition of Measurable and Non-Measurable Disease 
8.1.2 Baseline Documentation of Tumor Burden 
8.1.3 Response Criteria 
8.2 Time to Event Measures 
8.3 Correlative Science 
9. Adverse Event Reporting 	
15 
9.1 Adverse Events 
9.2 Definition of an Adverse Event 
9.3 Serious Adverse Events 
9.4 Adverse Event Reporting Requirements 
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10. Data analysis/Statistical Methods 	
17 
10.1 Sample Size Determination 
10.2 Efficacy Analysis 
10.3 Analysis of Other Endpoints 
11. Registration Guidelines 	
18 
12. Data Submission Schedule 	
18 
13. Study Monitoring 	
19 
14. References 	
21 
APPENDIX 1 Schedule of Assessments 	
23 
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1. Background 
1.1 	
Breast Cancer 
Breast cancer is the most frequently diagnosed cancer in women in the United States. 
In 2012, the National Cancer Institute estimates that 226,870 new cases of breast 
cancer will be diagnosed making it the most common non-skin cancer. Despite 
optimal treatment, approximately 30% of breast cancer patients develop disease 
recurrence requiring additional treatment. Despite an increase in the active agents 
available to treat metastatic disease, overall survival has changed little over the past 
few decades. 
1.2 Eribulin 
Eribulin mesylate 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. 
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. 
In 2010, the Food and Drug Administration approved eribulin mesylate under the trade 
name HALAVEN for the treatment of patients with metastatic breast cancer who have 
previously received at least two chemotherapeutic regimens for the treatment of 
metastatic disease. Prior therapy should have included an anthracycline and a taxane 
in either the adjuvant or metastatic setting. 
2. Rationale 
Anti-tubulin therapy is an established cornerstone of chemotherapeutics for MBC. 
Work at our center and others has shown a favorable therapeutic index for weekly 
metronomic vinorelbine (1-4). Given the efficacy and tolerability, including lack of 
alopecia and nausea, many clinicians use vinorelbine early in therapy for metastatic 
breast cancer. Eribulin (HalavenC) is the first new therapeutic in breast cancer to 
show a survival advantage in salvage therapy. However, the tolerability of the FDA 
approved dose and schedule may limit its use in clinical practice, the number of 
patients offered the therapy, and the number of doses administered (duration of use) 
in metastatic breast cancer. The history of other effective and tolerable agents, 
including paclitaxel, capecitabine, as well as, vinorelbine, suggest that a low dose 
metronomic schedule of eribulin would be effective, well tolerated and result in a 
longer time to progression (UP), and higher quality of life during therapy as has been 
seen clinically with low dose metronomic programs of capecitabine (5). In phase I 
studies, Eribulin showed activity at doses well below the maximally tolerated 
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1.4mg/m2  given 2/3 weeks, suggesting a lower metronomic schedule would not 
compromise efficacy. 
Eribulin has a novel mechanism of microtubule inhibition providing dynamic inhibition 
which is irreversible (6-7). Eribulin was studied in two phase 2 trials for patients with 
MBC in the salvage setting. In the first (8), patients with prior anthracyclines and 
taxanes exposure were given eribulin at 1.4 mg/m2 on days 1, 8 and 15 of a 28-day 
cycle, subsequently modified to days 1 and 8 of a q 21-day cycle due neutropenia 
seen on day 15; the median number of prior chemotherapy regimens was 4. A partial 
response (PR) rate of 11.5% was seen, with median progression free survival of 2.6 
months and median survival of 9 months. Grade 3 of 4 neutropenia was appreciated 
in 64%, febrile neutropenia in 4%, and peripheral neuropathy in 5%. In the second 
trial (9) prior capecitabine, anthracycline and taxane exposure were required. The 
same dose was given on the q 21-day cycle. The median number of prior 
chemotherapy regimens was 4. The response rate was 9.3% (investigator-reported, 
14%), median progression-free survival was 2.6 months, and median survival was 10.4 
months. Grade 3 of 4 neutropenia was seen in 54%, febrile neutropenia in 5.5%, and 
grade 3 neuropathy in 6.9%. 
These phase II studies set the stage for the pivotal phase III EMBRACE trial, comparing 
eribulin in the same dose and schedule (days 1 and 8 every 3 weeks) to physician's 
choice of salvage therapy among anthracycline- and taxane-pretreated MBC patients, 
with at least two prior regimens for advanced disease. In a major advance in 
metastatic breast cancer, overall survival, the primary endpoint, was improved from 
9.3 months to 13.1 months in patients receiving eribulin (4). There was a longer but 
not significant difference in progression free survival (3.7 vs 2.2 months), and the 
response rate was higher for eribulin (12.2 vs. 4.7%, p=.002). Similar to the findings in 
phase II, the dominant grade 3 of 4 toxicity was neutropenia (45%) for eribulin, which 
was higher than in the control arm. Peripheral neuropathy occurred in 8.2%. The 
overall incidence of reported treatment-related serious adverse events was 12% for 
eribulin and 7% for the control treatments. Based on the outcome of EMBRACE, 
eribulin is now an FDA- approved therapy in the salvage setting for MBC. 
We believe that the optimal schedule of eribulin has yet to be defined and that an 
approach similar to that used with vinorelbine could improve the tolerability of the 
agent without sacrificing efficacy. A lower dose metronomic schedule would allow 
responding patients to remain on treatment, resulting in a longer time to progression, 
and greater use of the drug in practice. Based on the phase I studies of eribulin we 
propose a dose of 0.9 mg/m2  on days 1, 8 and 15 every 4 weeks as a metronomic 
schedule in a phase II trial, with the hope of averting alopecia and significant 
cytopenias. Given the lack of pharmacologic interaction between the drugs and the 
efficacy of vinorelbine with anti-HER2 agents(2, 10), we would propose to allow 
inclusion of HER2 positive patients with concomitant use of trastuzumab. 
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3. Trial Objectives 
Primary: 
• 
Progression free survival (PFS). We hypothesize that metronomic dosing of 
eribulin will result in a PFS of 4-6 months. 
Secondary: 
• 
Frequency of alopecia with absence or decrease to <50% 
• 
Incidence of grade 3 and 4 neutropenia of <30% 
• 
Incidence of sensory neuropathy (all grades) to <25% 
Exploratory: 
• 
Assess the role of circulating endothelial cell precursors (CEPs) and apoptotic 
CECs, in predicting early response to treatment. 
4. Trial Design 
This is an open-label, multi-center, phase II study of eribulin for patients with 
metastatic breast cancer. 
Patients will receive eribulin 0.9 mg/m2  administered intravenously over 2 to 5 
minutes on Days 1,8 and 15 of a 28-day cycle. Treatment will be continued until 
disease progression, unacceptable toxicity or withdrawal of patient consent. 
5. Subject Selection 
Patients with metastatic breast cancer (MBC) whose disease has progressed following 
at least one prior regimen of chemotherapy in the setting of metastatic breast cancer 
will be recruited from the Seattle Cancer Care Alliance (SCCA), University of Arizona 
and SCCA Network sites. 
5.1 	
Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following 
criteria: 
• 
Ability to provide written informed consent 
• 
Prior exposure to taxane in the adjuvant, neoadjuvant or metastatic setting. 
• 
At least one prior regimen of chemotherapy in the setting of metastatic breast 
cancer; no upper limit on the number of prior endocrine regimens for 
metastatic breast cancer, however no more than 6 chemotherapeutic regimens 
may have been given in the metastatic setting. 
• 
Age > 18 years. 
• 
ECOG performance status of 0, 1, or 2. 
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• 
Patients must have baseline imaging within 30 days prior to the start of therapy 
and satisfy one of the following: 
o 
Measurable disease per RECIST 1.1 criteria [Eisenhauer]. At least one non 
lymph node lesion of 1.0 cm or lymph node > 1.5 cm in short axis by CT 
scan (CT scan thickness no greater than 5 mm which is serially 
measurable according to RECIST 1.1 using either computerized 
tomography (CT) or magnetic resonance imaging (MRI). Lesions that have 
had radiotherapy must show evidence of progressive disease (PD) based 
on RECIST 1.1 to be deemed a target lesion. 
o 
Non-measurable disease by RECIST 1.1 criteria (includes bone only 
disease and lesions < 10 mm or lymph nodes <15 mm in short axis) with 
rising serum CA15-3 or CA 27.29 or CEA documented by two consecutive 
measurements taken at least 14 days apart with the most recent 
measurement being within 42 days prior to registration. The second CA 
15-3 or CA 27.29 value must have at least a 20% increase over the first 
and for CA 15-3 or CA27.29 be greater than or equal to 40 units/mL or 
for CEA be greater than or equal to 4 ng/mL. 
• 
Patients must have normal organ and marrow function as defined below: 
o 
absolute neutrophil count >1,500/mm3  
o 
hemoglobin > 10 g/dL 
o 
platelets >100,000/mm3  
o 
creatinine s 1.5 x ULN 
o 
total bilirubin s 1.5 x ULN 
o 
alkaline phosphatase s 3.0 x ULN Up to 5X ULN is acceptable if due to 
bone metastases in the absence of liver metastases 
o 
AST and ALT s 3.0 x institutional upper limit of normal, unless due to 
liver metastases (< 5 X ULN) 
• 
Women of child-bearing potential (WOCBP) and men must agree to use 
adequate contraception (hormonal or barrier method of birth control or 
abstinence) prior to study entry and for the duration of study participation. 
• 
Life expectancy of > 12 weeks. 
5.2 Exclusion Criteria 
Subjects presenting with any of the following will not be included in the trial: 
• 
Prior treatment with Eribulin 
• 
Plan to administer any other systemic antitumor including endocrine therapy 
except for following standard of care treatment: 
1. Trastuzumab at standard dosing HER2 positive tumors; 
2. Denosumab or bisphosphonates to treat metastatic bone disease. 
• 
Plan to administer concurrent radiation therapy now or for progressive 
symptoms during treatment 
• 
Patients with known CNS metastases must have stable disease off steroids after 
treatment with surgery or radiation therapy 
• 
Second primary malignancy that is clinically detectable or clinically significant 
at the time of consideration for study enrollment 
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• 
Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or 
moderate (CrCl 30-50 mL/min) renal impairment 
• 
Radiotherapy within 14 days of study treatment 
• 
Major surgery within 21 days of study treatment. Minor surgery within 2 weeks 
of study treatment. Placement of vascular access device and biopsies allowed 
and is not considered major or minor surgery. 
• 
Treatment with any systemic chemotherapy or investigational agents within 3 
weeks of the start of study treatment. Endocrine treatment must be stopped 
prior to initiating study treatment. Subjects must have recovered from 
toxicities of prior therapy. 
• 
Patients with peripheral neuropathy > grade 2 regardless of etiology 
• 
Significant cardiovascular impairment: congestive heart failure >Class II 
according to the New York Heart Association (NYHA), unstable angina or 
myocardial infarction within 6 months of enrollment, or serious cardiac 
arrhythmia (> grade 2). 
• 
Concomitant severe or uncontrolled medical disease 
• 
Significant psychiatric or neurologic disorder which would compromise 
participation in the study 
• 
Pregnant or breast-feeding females 
6. Trial Treatments 
All patients enrolled will receive treatment with eribulin. 
6.1 	
Drug Supplies 
6.1.1 Formulation and Packaging 
Eribulin mesylate will be supplied by Eisai in single-use vials at a concentration of 1 
mg/2 mL (0.5 mg/mL) solution in ethanol: water (5:95). Eribulin is a clear, colorless, 
sterile solution for intravenous administration. 
6.1.2 Preparation and Dispensing 
Aseptically withdraw the required amount of eribulin mesylate from the single-use 
vial and administer undiluted. 
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. 
Store undiluted eribulin mesylate in the syringe for up to 4 hours at room temperature 
or for up to 24 hours under refrigeration (40°F or/ 4°C). 
Discard unused portions of the vial. 
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6.2 Treating the Patient 
6.2.1 Conditions patients must meet prior to administering any treatment on any 
week. 
Prior to receiving any study treatment on Day 1,8 or 15 of each cycle, the patient 
must meet all of the following criteria: 
• 
Neutrophils are > 1,000/mm3  
• 
Hemoglobin > 8.0 g/dL 
• 
Platelets > 50,000/mm3  
• 
No grade 3 or 4 non-hematological toxicities. 
If any of these criteria are not met the dose for that treatment day should be 
omitted. 
Blood tests must be performed prior to resuming treatment with toxicities resolved or 
improved to < grade 2 severity. Treatment should resume according to these criteria 
at the appropriate dose reduction outlined in Table 6-1. 
There should always be a two week treatment free interval between cycles when the 
patient criteria is not met (as above) and the dose is omitted. 
Non toxicity related treatment delays/omissions will be considered on a case by case 
basis in consultation with the P.I. 
If a delay of > 3 weeks is required, the patient should be removed from study 
treatment and continue to be treated in accordance with the Investigator's standard 
clinical practice. 
6.2.2 Eribulin administration 
Eribulin will be administered at 0.9 mg/m2  on days 1, 8 and 15 every 4 weeks. 
Treatment will continue until patient develops disease progression, unacceptable 
toxicity or chooses to stop study treatment. 
Guidelines for dose modification and dose interruption of study drug are described in 
Table 6-1. 
6.2.3 Dose Modifications 
Any dose reduction or dose delay of study drug is based upon the severity of toxicity 
as graded by NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE, 
version 4.0). Once a dose has been reduced during a treatment cycle, re-escalation 
will not be permitted during any subsequent cycles. 
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All toxicity-related causes for dose reductions or dose delays must be recorded as 
adverse events. Please refer to Table 6-1 for recommended study drug dose 
adjustments. Patients requiring a delay in study treatment of greater than 3 weeks or 
greater than 3 dose reductions will be discontinued from study treatment. 
Table 6-1 Recommended Dose Reductions of Eribulin 
Event Description 
Recommended 
Dose 
Hold treatment and reduce to recommended dose for 
subsequent treatments for any of the following: 
• 
Grade 3 neutropenia (ANC <1,000/mm3) 
• 
Grade 3 anemia (Hgb < 8.0 g/dL) 
• 
Grade 3 thrombocytopenia (platelets 
<50,000/mm3) 
• 
Non-hematologic Grade 3 or 4 toxicities 
• 
Omission or delay of Day 8 or 15 dose in previous 
cycle for toxicity 
0.7 mg/mi 
 
Occurrence of any of the above events while receiving 
0.7 mg/m2 dose 
0.6 mg/m2  
Occurrence of any of the above events while receiving 0.6 
mg/m2 dose 
0.5 mg/mz  
Occurrence of any of the above events while receiving 0.5 
mg/m2 dose 
Discontinue eribulin 
GCS-F may be used according to NCCN Guidelines 
(http://www.nccn.org/professionals/phvsician gls/pdf/rnyeloid Rrowth.pdf) and the 
treating physician's clinical judgment. When G-CSF is given, it should begin the day 
after administration of eribulin and stop at least 24 hours prior to the next dose of 
eribulin. G-CSF dates of administration and doses must be documented in source 
documents. 
6.3 	
Concomitant Medications 
Other systemic antitumor therapy is not allowed except for: 
a. Trastuzumab, at standard doses, as this is standard of care for HER2 positive 
tumors. 
b. Denosumab or bisphosphonates to treat metastatic bone disease, as these are 
also standard of care. 
Radiation therapy may have been administered previously. However, concurrent 
radiation therapy or its institution to treat progressive symptoms during treatment is 
not permitted. Patients who require palliative radiation must discontinue eribulin for 
7-14 days and wait 7-14 days after completing radiation before resuming eribulin 
therapy. 
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Endocrine therapy is not permitted during the study. However, good clinical practice 
would imply that for ER+ patients, endocrine therapy will previously have been given 
unless contraindicated in the judgment of the treating physician (e.g., for significant 
visceral involvement). 
Patients should also be screened for concomitant use of drugs that prolong QT 
interval. If identified, these drugs should be discontinued. A list of drugs that prolong 
QT interval is available at http:/ /www.azcert.org/medical-pros/drug-lists/printable-
drug-list.cfm. Please note that low dose Zofran is allowed because QT safety issues 
are associated with high dose Zofran. The expectation is that sites will use the list 
together with the same good medical practice procedures used for patients who are 
not on a study. This may involve consultation with the site's pharmacist. 
7. Trial Procedures 
Prior to undergoing any study-specific procedure, patients must read and sign 
the current Institutional Review Board (IRB)-approved informed consent form. 
The schedule of assessments is presented in Appendix 1 (Visit Schedule). 
Assessments outlined in the visit schedule include the following components: 
7.1 	
Screening Visit 
The screening visit will occur within 30 days prior to initiating study treatment. 
Laboratory tests must be done within 14 days prior to cycle 1 day 1. 
• 
Medical History - metastatic breast cancer diagnosis, prior treatment history, 
and demographics. 
• 
Physical Examination - examination of major body systems, ECOG performance 
status, body weight and vital signs (i.e., blood pressure, heart rate). 
• 
Laboratory Evaluations must be obtained up to 14 days prior the first dose of 
eribulin 
o 
Hematology (CBC with platelets and absolute neutrophil count) 
o 
Blood chemistry (sodium, potassium, chloride, carbon dioxide, 
creatinine, BUN, glucose, calcium, LDH, albumin, bilirubin, AST, ALT, 
total protein, alkaline phosphatase, magnesium) 
o 
Pregnancy test - serum or urine pregnancy test performed for all women 
of childbearing potential 
o 
Tumor markers - CEA and either CA 27.29 or CA 15-3 
o 
Research blood sample 
• 
CT scan or PET with diagnostic CT of chest, abdomen and pelvis to determine 
areas of involvement. With principal investigator approval, ultrasound or MRI 
may be substituted for CT or PET with diagnostic CT. 
7.2 	
Prior to Each Cycle 
Evaluations and procedures required for screening may be used for cycle 1 day 1 and 
do not need to be repeated. 
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In the absence of adverse events requiring dose delays, day 1 will occur 
approximately every 28 days (+/- 4 days or as determined by consultation with 
principal investigator). Procedures to be completed after recovery from the previous 
cycle and prior to the start of each subsequent cycle include: 
• 
Physical examination - monthly clinical evaluation of major body systems, 
assessment of toxicity and clinical assessment of disease response, ECOG 
performance status, body weight and vital signs (i.e. blood pressure, heart 
rate). 
• 
Laboratory Evaluations 
o 
Hematology (CBC with platelets and absolute neutrophil count) 
o 
Blood chemistry (sodium, potassium, chloride, carbon dioxide, 
creatinine, BUN, glucose, calcium, LDH, albumin, bilirubin, AST, ALT, 
total protein, alkaline phosphatase, magnesium) 
o 
Tumor markers if elevated at baseline 
o 
Research blood sample- prior to day 1 of cycles 2, 4 and 6 
• 
Adverse Event Assessment 
• 
Disease reassessment of known sites of disease by same method used at 
baseline should be repeated approximately every 12 weeks (i.e. after 
completing cycles 3, 6, 9, etc. and before beginning the next cycle.) 
7.3  Day 8 (+/- 1 Day) and Day 15 (+/- 1 Day) of Each Cycle. 
• 
CBC with differential and platelet count - to be done prior to each dose of 
chemotherapy 
• 
Adverse event assessment. 
7.4  End of Treatment Visit 
Patients should undergo the following assessments when all study treatment is 
discontinued. If it is not feasible for a patient to come to the clinic for an end of 
treatment visit the patient may be contacted by phone to assure any serious and 
ongoing adverse events are managed and reported appropriately. 
• 
Physical Examination - examination of major body systems, ECOG performance 
status, body weight and vital signs (i.e., blood pressure, heart rate). 
• 
Laboratory Evaluations 
o 
Hematology (CBC with platelets and absolute neutrophil count) 
o 
Blood chemistry (sodium, potassium, chloride, carbon dioxide, 
creatinine, BUN, glucose, calcium, LDH, albumin, bilirubin, AST, ALT, 
total protein, alkaline phosphatase, magnesium) 
o 
Tumor markers if elevated previously 
o 
Research blood sample (unless patient has started a new treatment 
regimen). 
• 
Adverse Event Assessment 
• 
Disease reassessment of known sites of disease by the same method used at 
baseline if not done within the last 12 weeks (+/-1 week). 
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7.5 	
Subject Withdrawal 
Patients will be removed from study treatment if • they present with disease 
progression, as defined by RECIST version 1.1 criteria. Subjects will also be 
removed from study treatment if they require more than three dose level 
reductions or more than three weeks to recover from treatment related adverse 
events. Patients may withdraw consent at any time. 
Patients will be followed for survival until one year after the last patient is registered 
to the study. Follow up testing will be performed according to standard of care. 
8. Assessments 
The schedule of assessments is presented in Appendix 1. The description of 
assessments is provided in Section 7. 
8.1 	
Efficacy Assessments 
Patients will have their disease assessed for response by conventional imaging 
methods. This will most often include a CT scan of the chest, abdomen and pelvis for 
baseline tumor burden. Bone scan or other appropriate imaging may also be used as 
clinically indicated. All baseline imaging must be obtained no more than 30 days prior 
to the first study drug dose and after all previous treatment has been discontinued. 
Imaging will be repeated every 12 weeks + / - 1 week (i.e. after completing 
treatment on cycles 3, 6, 9, etc. and before beginning the next treatment cycle) by 
the same methods used at baseline unless clinically indicated sooner as part of 
standard of care. 
8.1.1 Definition of Measurable and Non-Measurable Disease 
Measurable disease: The presence of at least one lesion (non-lymph node) that is 
>10mm in longest diameter on an axial image on CT or MRI with < 5 mm 
reconstruction interval (if slice thickness is > 5mm, the longest diameter must be at 
least two times the thickness) or a lymph node that is > 15 mm in short axis. Skin 
lesions > 10 mm in longest diameter on clinical exam (photo) are considered 
measurable. The photo should include a ruler. 
Non-measureable disease by RECIST 1.1 criteria (includes bone only disease and 
lesions < 10 mm or lymph nodes < 15 mm in short axis) with rising serum CA15-3 or CA 
27.29 or CEA documented by two consecutive measurements taken at least 14 days 
apart with the most recent measurement being within 42 days prior to registration. 
The second CA 15-3 or CA 27.29 or CEA value must have at least a 20% increase over 
the first and for CA 15-3 or CA 27.29 be greater than or equal to 40 units/mL or for 
CEA be greater than or equal to 4 ng/mL. 
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8.1.2 Baseline Documentation of Tumor Burden 
• 
Target lesions: A maximum of five target lesions in total (up to two per organ) 
will be identified. Target lesions should be selected on the basis of their size 
(those with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest 
diameter for all target lesions will be calculated and reported as the baseline 
sum longest diameter (SLD). The baseline SLD will be used as the reference by 
which to characterize the objective tumor response. 
• 
Nontarget lesions: All other lesions (or sites of disease) should be identified as 
nontarget 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. 
8.1.3 Response Criteria 
Radiological response will be defined as per the RECIST 1.1 criteria. Treatment 
outcomes will be defined as: 
• 
Complete response (CR): complete disappearance of all extranodal target and 
non-target lesions. All pathological lymph nodes must have decreased to <1mm 
in short axis. 
• 
Partial response (PR): at least a 30% decrease in the sum of diameters of target 
lesions taking as a reference the baseline sum of diameters. 
• 
Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient 
increase to qualify for PD. 
• 
Progressive disease (PD): Sum of diameters increased by at least 20% from the 
smallest value on study (including baseline if that is the smallest). The sum of 
diameters must also demonstrate an absolute increase of at least 5 mm. (Two 
lesions increasing from 2mm to 3mm, for example, does not qualify). 
Unequivocal progression of existing non-target lesions also constitutes disease 
progression as does the appearance of one or more new lesions. 
FDG-PET can be used to complement CT scanning. A positive FDG-PET scan is one 
which is FDG avid with an uptake greater than twice that of the surrounding tissue on 
the attenuation corrected images. Progressive disease by FDG-PET: Negative FDG-PET 
at baseline, with a positive FDG-PET at follow-up based on a new lesion, or No FDG-
PET at baseline and a positive FDG-PET at follow-up. Either of these findings should 
be correlated with CT scan imaging as described in RECIST 1.1 but date of progression 
is assigned to the date of the initial abnormal FDG-PET scan. 
Tumor Marker (CEA and either CA 27.29 or CA 15-3) Response:  
• 
Tumor Marker Complete Response: Reduction in CEA and CA 15-3 or CA 27.29 to 
ULN 
Tumor Marker Partial Response: Greater than or equal to a 50% reduction in 
CEA and CA 15-3 or CA 27.29 from baseline, but not qualifying as CR. 
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• 
Tumor Marker Progression: Greater than or equal to a 50% increase in CEA and 
CA 15-3 or CA 27.29 from baseline. 
• 
Tumor Marker Stable Disease: or CEA and CA 15-3 or CA 27.29 response not 
qualifying as CR, PR, or Progression. 
• 
Tumor Marker Inadequate Assessment, response unknown: CEA and CA 15-3 or 
CA 27.29 response has not been adequately assessed. 
8.2 Time-to-Event Measures 
The following definitions for time-to-event measures will apply: 
• 
Duration of Tumor Response is measured from the date of the first objective 
assessment of PR or CR to the first date of disease relapse or death from any 
cause. 
• 
Progression-free survival is measured from the date of enrollment to the first 
date of radiographic progression of disease per RECIST 1.1 criteria or death. 
8.3 Correlative Science 
Research blood samples will be collected to explore markers that may be related to 
eribulin's antitumor and antiangiogenic activity. Circulating endothelial cell (CEC), 
circulating endothelial precursor cell (CEP) and apoptotic CEC assays are among the 
markers that will be assessed. Other markers may also be explored. 
The role of CEPs in predicting early response will be examined by serial measurements 
in the laboratory of Dr. Alison Stopeck at the University of Arizona Cancer Center. 
CECs have been shown to decrease in response to anti-angiogenic therapies (11, 12). 
CEPs have also been shown to correlate with increased angiogenesis and can increase 
in response to growth factor use with G-CSF (13, 14). One mechanism by which 
metronomic therapy is hypothesized to be more effective is by specifically acting on 
endothelial cells resulting in increased apoptosis and antiangiogenic effects as well as 
decreasing or eliminating G-CSF use to prevent increases in CEPs, a precursor for 
tumor induced angiogenesis. In advanced breast cancer patients receiving metronomic 
chemotherapy, an increase in apoptoic CECs after 2 months of therapy was associated 
with prolonged progression-free and overall survival with follow up of greater than 2 
years (15). In this trial we propose to measure levels of CEPs, and apoptotic CECs, at 
baseline and in response to eribulin therapy in an effort to validate metronomic 
dosing as having both antitumor as well as antiangiogenic effects. 
Instructions for collecting, processing and shipping research specimens are included in 
the Laboratory Section of the Study Manual. 
9. 	
Adverse Event Reporting 
9.1 	
Adverse Events 
Investigators are responsible for monitoring the safety of patients who have entered 
this study. Any unanticipated problem (incident, experience or outcome) that 
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involves risk to a study patient must be reported to the Coordinating Center in an 
expedited manner within 24 hours of awareness of the event and to the IRB of record 
in accordance with the IRB policy. Examples of unanticipated events are (1) adverse 
events, (2) breach of confidentiality, (3) accidental or unintentional change to the IRB 
approved protocol that harmed participants, (4) incarceration of a study patient, (5) 
study patient complaint. 
The investigator is responsible for the appropriate medical care of patients during the 
study. The investigator remains responsible to follow, through an appropriate health 
care option, adverse events that are serious or that caused the patient to discontinue 
study treatment. The patient should be followed until the event resolves or stabilizes. 
Safety measurements that will be used in the study include physical examinations and 
clinical laboratory tests. Clinical exam by the provider with CBC, absolute neutrophil 
count, platelet count and serum chemistry to include sodium, potassium, chloride, 
carbon dioxide, creatinine, BUN, glucose, calcium, LDH, albumin, bilirubin, AST, ALT, 
total protein, alkaline phosphatase and magnesium will be performed after recovery 
from the previous cycle and prior to the start of each subsequent treatment cycle. 
CBC, absolute neutrophil count and platelet count will be done prior to each dose of 
planned chemotherapy (days 1, 8, 15 of each cycle). 
Adverse events will be graded for toxicity using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. Toxicity assessments will be performed based 
on procedures outlined in the Schedule of Assessments. Any adverse events leading to 
a treatment interruption or dose reduction along with all adverse events that are 
grade 3 and higher will be recorded in the CRF. 
9.2  Definition of an Adverse Event 
The definitions of adverse events (AEs) and serious adverse events (SAEs) are given 
below. 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. 
An undesirable medical condition can be a symptom (e.g., nausea, chest pain), or a 
sign (e.g., tachycardia, enlarged liver). 
9.3  Serious Adverse Events 
An event that fulfills at least one of the following criteria will be designated a serious 
adverse event (SAE). SAEs will be reported to the Coordinating Center, Eisai and the 
IRB of record according to the IRB's policy/procedure. 
• 
Results in death 
• 
Requires initial inpatient hospitalization or prolongation of existing 
hospitalization 
• 
Is immediately life-threatening 
• 
Results in severe or permanent disability or incapacity 
• 
Is a congenital abnormality or birth defect 
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• 
Any other important medical event that may jeopardize the subject or requires 
medical intervention to prevent one of the outcomes listed above. 
Reportable Serious Adverse Event (SAE) - Any event that is unequivocally 
unrelated to study drug or is due to progression of disease should not be reported 
as an SAE. 
9.4 	
Adverse Event Reporting Requirements 
Adverse events will be collected after the patient has taken the first dose of study 
drug. After discontinuation from treatment, patients must be followed for all existing 
AEs for 30 calendar days after the last dose of study drug or until another anti-cancer 
therapy is initiated. 
Prior to beginning study treatment, study site personnel will note the occurrence and 
nature of each patient's medical condition(s). During the study, site personnel will 
again note any change in the condition(s) and/or the occurrence and nature of any 
adverse events. Adverse events are to be graded according to the NCI CTCAE version 
4.0. 
A description of the event, including its date of onset, date of resolution and any 
action taken should be provided along with the investigator's assessment of causality. 
An event that is due to unequivocal progression of disease should not be reported as 
an AE. Any adverse events leading to a treatment interruption or dose reduction along 
with all grades 3 and higher adverse events must be recorded on a case report form 
(CRF). 
Any SAE that is NOT unequivocally unrelated to study drug or due to progression of 
disease must be reported to EISAI and the appropriate IRB. Reportable SAEs 
experienced within 30-days after the patient has stopped study treatment must be 
reported. For enrollments from SCCA main campus, SCCA at Evergreen and the SCCA 
Network sites SAE reports should be submitted to the Consortium IRB. Reportable 
SAEs occurring at Arizona Cancer Center (AZCC) will be reported to their IRB. 
10. Data Analysis/Statistical Methods 
Patients must meet all eligible criteria and receive at least one full cycle of protocol 
directed therapy to be included in the efficacy analysis. All treated patients will be 
included in the assessment of adverse events. 
10.1 Efficacy Analysis 
The primary endpoint is progression free survival. 
Progression free survival (PFS) will be measured as the time from study enrollment 
until the earliest date of disease progression or death. PFS will be censored at last 
radiographic assessment for patients who discontinue study therapy for reasons other 
than disease progression. 	
Kaplan-Meier survival curves will be used to describe 
progression-free survival, overall and stratified by number of prior metastatic 
treatment regimens. A 95% confidence interval for the median PFS will be calculated 
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using the method of Brookmeyer and Crowley. The sample size of 60 eligible and 
evaluable patients has 99% power for the lower bound of the confidence interval to be 
greater than 2.2 months (the median PFS in the physician's discretion arm of the 
EMBRACE trial), assuming that the true median PFS is 4 months, comparable to or an 
incremental improvement over the median PFS for the eribulin arm of the EMBRACE 
trial (3.7 months). 
Based on the eribulin arm of the EMBRACE trial, median progression free survival is 
expected to be approximately 3.7 months. Approximately 4 years of accrual and 1 
year of follow up will be necessary to detect an improvement in median progression 
free survival from 3.7 to 4 months. 
10.2 Analysis of Other Endpoints 
Demographic characteristics such as patient age, gender, tumor type, and [COG 
performance status will be tabulated. All continuous data will be summarized using 
descriptive statistics (mean, standard deviation, median, minimum and maximum 
values). All categorical data will be summarized using frequencies and percentages. 
The prevalence of key adverse events will be calculated and 95% Wilson (score) 
confidence intervals reported for each. 	
With a sample size of n=60, power is 
approximately 88% to produce confidence intervals with an upper bound lower than 
the rate reported in the EMBRACE trial, assuming that the rate of the adverse event is 
20 percentage points lower under the metronomic schedule of delivery. 
Dose delivery, use of cytokine support and reasons for discontinuing therapy will be 
described for all enrolled patients. 
Case report forms and an electronic database using the Redcap system from 
Vanderbilt University will be created during start up. Study data will be extracted 
from the medical record by the Coordinating Center. Response evaluations according 
to RECIST criteria will be provided by the University of Washington Tumor Imaging 
Metrics Core service. 
11. Registration Guidelines 
Before a subject participates in the trial, the investigator or delegate (as allowed by 
the IRB of record) is responsible for obtaining written informed consent after 
adequate explanation of the aims, methods, anticipated benefits, subject 
responsibilities including the use of adequate methods to prevent pregnancy, and 
potential hazards of the study and before any protocol-specific screening procedures 
or any study medications are administered. 
All patients must be registered before the start of treatment. To register a patient, 
call the Coordinating Center at the Seattle Cancer Care Alliance (288-7232 or, toll 
free, (888) 201-0060) between the hours of 8:00 AM and 5:00 PM Pacific time, Monday 
through Friday. Materials required to complete the registration may be faxed (206 
288-1310) or scanned/e-mailed (sccanetresearch@seattlecca.org) and include: 
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• 
Consent Form 
• 
HIPAA Authorization 
• 
Registration Form and all supporting documentation 
• 
Eligibility Checklist 
• 
Race and Ethnicity Form. 
After eligibility has been confirmed, a patient identification number will be assigned. 
The patient will be considered registered, and study treatment may then begin. 
12. Data Submission Schedule 
Staff of the Seattle Cancer Care Alliance Network Research Office (NRO) will monitor 
compliance and complete data forms for all enrollments from SCCCA Network sites 
and the Arizona Cancer Center (AZCC). SCCA Breast Program research staff will 
monitor and complete the data forms for patients enrolled at the SCCA main campus 
and SCCA at Evergreen research staff will monitor and complete the data forms for 
patients enrolled at that facility. 
13. Study Monitoring 
Continuous Monitoring 
Protocol implementation will be reviewed and summarized in an on-going manner. 
The principal investigator will review (1) all serious adverse events and (2) data 
concerning disease progression. 
Teleconferences between investigators at the University of Washington and University 
of Arizona will occur regularly to discuss the progress of the study. The following 
topics will be discussed: 
• 
Reports of serious, unexpected adverse events occurring on the study that are 
related to study drug 
• 
IND safety reports of serious, unexpected adverse events that are related to study 
drug 
• 
Instances of disease progression 
• 
Pending protocol or consent form changes 
• 
Other issues related to accrual or protocol implementation as necessary. 
Written summaries of serious, unexpected adverse events occurring on the study that 
are related to study drug and IND safety reports received from Eisai will be 
distributed by the SCCA NRO to the lead investigator at each performance site as 
they are reported. 	
Similarly protocol modifications and consent form changes will 
be distributed to each performance site as they are approved with instructions as to 
whether subjects must be re-consented. 
Annual Monitoring 
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Data and safety monitoring for the study will be performed according to the Fred 
Hutchinson / University of Washington Cancer Consortium Institutional Data and 
Safety Monitoring Plan every 12 - 24 months. Enrollments from the Seattle Cancer 
Care Alliance main campus and SCCA at Evergreen will be monitored by the Clinical 
Research Support Office of the Fred Hutchinson/University of Washington Cancer 
Consortium which has primary oversight of the study. Enrollments from Seattle 
Cancer Care Alliance Network sites or the University of Arizona will be monitored by 
the Seattle Cancer Care Alliance NRO . Additional study monitoring may occur at 
each performance site according to the site's institutional policy. 	
Copies of 
monitoring reports should be submitted to the Coordinating Center. 
The purpose of the monitoring is to verify the accuracy of the study data, assess 
compliance with the protocol and with Good Clinical Practice (GCP) regulations, and 
assure the timely and complete reporting of safety (adverse event) data. The 
significant elements of the plan are summarized below. 
At each monitoring visit the following documents will be reviewed in accordance with 
the current Consortium monitoring plan: 
• 
Informed consent 
• 
Eligibility 
• 
Data review - (safety, dosing, efficacy, etc.) 
• 
Critical Document Review. 
• 
Test Article Inventory. 
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14. References 
1. 
Livingston RB, Ellis GK, Gralow JR, Williams MA, White R, McGuirt C, 
Adamkiewicz BB, Long CA: Dose-intensive vinorelbine with concurrent 
granulocyte colony-stimulating factor support in paclitaxel-refractory 
metastatic breast cancer. J Clin Oncol 1997, 15(4):1395-1400. 
2. 
Chew HK, Somlo G, Mack PC, Gitlitz B, Gandour-Edwards R, Christensen S, 
Linden H, Solis LJ, Yang X, Davies AM: Phase I study of continuous and 
intermittent schedules of lapatinib in combination with vinorelbine in solid 
tumors. Ann Oncol. 
3. 
Weide R, Mergenthaler U, Pandorf A, Arndt H, Heymanns J, Thomalla J, 
Koppler H: Improved survival of patients with metastatic breast cancer in 
routine care: results of a retrospective study in a community-based oncology 
group practice 1995-2005. Onkologie 2009, 32(3):107-113. 
4. 
Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, 
Choilet P, Manikas A, Dieras V, Delozier T et al: Eribulin monotherapy versus 
treatment of physician's choice in patients with metastatic breast cancer 
(EMBRACE): a phase 3 open-label randomised study. Lancet, 377(9769):914-
923. 
5. 
Stockier MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van 
Hazel G, Wilcken NR, Grimison PS, Nowak AK et al: Capecitabine versus 
classical cyclophosphamide, methotrexate, and Fluorouracil as first-line 
chemotherapy for advanced breast cancer. J Clin Oncol, 29(34):4498-4504. 
6. 
Towle MJ, Salvato KA, Weis BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis 
BM, Kishi Y, Yu MJ et al: Eribulin induces irreversible mitotic blockade: 
implications of cell-based pharmacodynamics for in vivo efficacy under 
intermittent dosing conditions. Cancer Res, 71(2):496-505. 
7. 
Smith JA, Wilson L, Azarenko 0, Zhu X, Lewis BM, Littlefield BA, Jordan MA: 
Eribulin binds at microtubule ends to a single site on tubulin to suppress 
dynamic instability. Biochemistry, 49(6):1331-1337. 
8. 
Vahdat LT, Pruitt B, Fabian CJ, Rivera RR, Smith DA, Tan-Chiu E, Wright J, 
Tan AR, Dacosta NA, Chuang E et al: Phase II study of eribulin mesylate, a 
halichondrin B analog, in patients with metastatic breast cancer previously 
treated with an anthracycline and a taxane. J Clin Oncol 2009, 27(18):2954-
2961. 
9. 
Cortes J, Vahdat L, Blum JL, Twelves C, Campone M, Roche H, Bachelot T, 
Awada A, Paridaens R, Goncalves A et al: Phase II study of the halichondrin B 
analog eribulin mesylate in patients with locally advanced or metastatic 
breast cancer previously treated with an anthracycline, a taxane, and 
capecitabine. J Clin Oncol, 28(25):3922-3928. 
10. 
Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, 
Gelman R, Winer EP: Trastuzumab plus vinorelbine or taxane chemotherapy 
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for HER2-overexpressing metastatic breast cancer: the trastuzumab and 
vinorelbine or taxane study. Cancer 2007, 110(5):965-972. 
11. 
Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M, 
Daenen LG, Man S, Xu P, Emmenegger U et al: Rapid chemotherapy-induced 
acute endothelial progenitor cell mobilization: implications for antiangiogenic 
drugs as chemosensitizing agents. Cancer Cell 2008, 14(3):263-273. 
12. 
Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, 
Chaplin D, Foster FS, Benezra R et al: Therapy-induced acute recruitment of 
circulating endothelial progenitor cells to tumors. Science 2006, 
313(5794):1785-1787. 
13. 
Shaked Y, Tang T, Woloszynek J, Daenen LG, Mari S, Xu P, Cai SR, Arbeit JM, 
Voest EE, Chaplin DJ et al: Contribution of granulocyte colony-stimulating 
factor to the acute mobilization of endothelial precursor cells by vascular 
disrupting agents. Cancer Res 2009, 69(19):7524-7528. 
14. 
Bertolini F, Mancuso P, Braidotti P, Shaked Y, Kerbel RS: The multiple 
personality disorder phenotype(s) of circulating endothelial cells in cancer. 
Biochim Biophys Acta 2009, 1796(1):27-32. 
15. 
Mancuso P, Colleoni M, Called A, Orlando L, Maisonneuve P, Pruneri G, 
Agliano A, Goldhirsch A, Shaked Y, Kerbel RS et al: Circulating endothelial-
cell kinetics and viability predict survival in breast cancer patients receiving 
metronomic chemotherapy. Blood 2006, 108(2):452-459. 
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ADDendix 1: Schedule of Assessments 
Procedure 
Screening evaluations Et 
procedures may be used 
for Cl Dl 
Subsequent cycle day 1 will occur 
approximately every 28 days +/- 4 days or as 
determined by consultation with principal 
investigator 
End of 
Treatment 
within 30 
days of day 
1 cycle 1 
within 14 
days of day 
1 cycle 1 
Day 1 
Day 8 
(+/- 1 day) 
Day 15 
(+/- 1 day) 
Medical History 
X 
Physical Exam 
X 
X 
X 
Pregnancy Test 
X 
Hematology' 
X 
X 
X 
X 
X 
Serum Chemistries2  
X 
X 
X 
Tumor markers3  
X 
X 
X 
Research Labs4  
X 
X 
X 
Disease Assessmene 
X 
X 
X6  
Adverse Event 
Assessment 
X 
X 
X 
X 
Eribulin 
X 
X 
X 
1 To include CBC with platelet count and absolute neutrophil count 
2 To include sodium, potassium, chloride, carbon dioxide, creatinine, BUN, glucose, calcium, LDH, albumin, bilirubin, 
AST, ALT, total protein, alkaline phosphatase, magnesium 
3 To include CEA and either CA 27.29 or CA 15-3 at baseline and then monthly if elevated at baseline 
4  Research blood sample at baseline (prior to the start of treatment) and before cycles 2, 4, 6 and end of treatment. 
5 Disease assessment of known sites of disease by same method used at baseline (to include chest, abdomen and pelvis) 
approximately every 12 weeks (i.e. after cycles 3, 6, 9, etc.) 
6  Within 1 week of end of treatment if not done within the last 12 weeks. 
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