Clinical trial NCT01554371
Conditions: Malignant Solid Tumour Breast Cancer Nos Metastatic Recurrent Neuropathy
Keywords: Solid tumor Metastatic breast cancer Unresectable or metastatic carcinoma Neuropathy Eribulin Cyclophosphamide
Sponsor: University of California, San Francisco
Start date: 2012-03-27; Completion date: 2019-12-31
Enrollment: 44 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test the safety of eribulin (Halaven™) and cyclophosphamide (Cytoxan®) given together at different doses. This study will look at what effects, good and/or bad, that these drugs have on solid tumors. Eribulin is a drug that has been approved by the FDA for breast cancer that has spread to other parts of the body. Cyclophosphamide has been approved for different types of cancers (including breast cancer). However, the combination of eribulin and cyclophosphamide is considered experimental; that means this combination has not been approved by the FDA.

The funding for this study is provided by Eisai Inc., the maker of eribulin.

Detailed description:
This is a phase Ib/II trial designed to determine the maximum tolerated dose (MTD) and does limiting toxicities (DLTs) of the combination of eribulin and cyclophosphamide in solid tumors and make preliminary estimates regarding efficacy of this treatment in patients with advanced breast cancer.

The study includes a standard dose-confirmation schema (phase Ib portion) enrolling 3 to 6 patients/subjects, with any solid tumors, per cohort (3+3 design) with a total of 18 patients. The dose-expansion (phase II portion) will enroll 40 patients with advanced breast cancer to detect an effect size of 15% with a power of 80% with endpoints of safety, efficacy, and clinical benefit rate. A maximum of 58 patients will be enrolled on the phase Ib and II portions of this trial combined and will be treated until disease progression or toxicity mandate treatment change.

Eribulin is a non-taxane microtubule inhibitor that is FDA approved as monotherapy for the treatment of taxane and anthracycline resistant metastatic breast cancer. The combination of docetaxel and cyclophosphamide is a well-accepted adjuvant chemotherapy regimen that has become an increasingly common therapeutic choice for intermediate risk early stage breast cancer. Eribulin has a favorable toxicity profile compared to docetaxel with the most common adverse reactions (incidence ≤25%) including neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. Eribulin appears to have activity in taxane resistant disease, making it an attractive partner with cyclophosphamide.

Neuropathy can be a devastating complication from adjuvant chemotherapy and in the metastatic setting, may limit effective therapy and reduce quality of life. Understanding the host factors that predict risk for neuropathy is critical, as these patients may in particular benefit from the lower risk of neuropathy associated with eribulin therapy. In conjunction with this trial, we have included correlative studies to study the proposed pharmacogenomic factors associated with risk of neuropathy. In this way we will potentially be able to identify patients who could preferentially be treated with less neurotoxic microtubule inhibitors.

Arms: arm 1: Dose escalation cohort will include all patients with solid tumors. Eribulin mesylate 1.1 mg/ m2 on days 1 and 8 followed by cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle.The highest dose level at which no more than one of six subjects experience DLT defines the MTD arm 2: Dose escalation cohort will include all patients with solid tumors. Eribulin mesylate 1.4 mg/ m2 on days 1 and 8 followed by cyclophosphamide 600 mg/ m2 on day 1 of a 21-day cycle.The highest dose level at which no more than one of six subjects experience DLT defines the MTD arm 3: Dose-expansion cohort will enroll patients with advanced breast cancer only after Phase Ib enrollment has been concluded. The MTD of Eribulin mesylate will be administered on days 1 and 8 followed by cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle.
Interventions: intervention 1: Eribulin intervention 2: Cyclophosphamide
Intervention descriptions: intervention 1: Given intravenously (IV)

Phase II: Eribulin mesylate (mg/m2) + Cyclophosphamide (mg/ m2) for advanced breast cancer participants only intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Protocol #: 11996 
Page 1 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
Hope S. Rugo, MD 
A Phase Ib/II Study of Eribulin in Combination with Cyclophosphamide 
in Patients with Solid Tumor Malignancies 
Protocol Number: 
11996 
Version:  
6.0 (May 26, 2017) 
Study Drug: 
Eribulin 
IND: 
Exempt 
Coordinating Center: 
University of California, San Francisco 
Helen Diller Family Comprehensive Cancer Center 
Principal Investigator: 
Hope S. Rugo, M.D. 
UCSF Helen Diller Family Comprehensive Cancer Center 
 
 
 
  
Statistician: 
Jimmy Hwang, PhD 
Revision History: 
Version 6.0 (May 26, 2017) 
Version 5.0 (May 31, 2013) 
Version 4.0 (May 29, 1012) 
Version 3.0 (July 1, 2011) 
Version 2.0 (June 27, 2011) 
Version 1.0 (June 13, 2011) 
Version 0.4 (April 18, 2011) 
Version 0.2 (April 1, 2011) 
NCT# 01554371


Protocol #: 11996 
Page 2 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
STUDY SYNOPSIS: 
 
This is a phase Ib/II trial designed to determine the MTD and DLTs of the combination of eribulin and 
cyclophosphamide in solid tumors and make preliminary estimates regarding efficacy of this 
treatment in patients with advanced breast cancer.  Phase 1b will be conducted at UCSF.  Phase 2 
will be conducted at multiple sites to be determined.  UCSF will be the coordinating center.   
 
The study drug in this protocol is intravenous eribulin mesylate. Eribulin will be administered on day 1 
and 8 in combination with cyclophosphamide 600 mg/m2 on day 1. Three weeks will constitute one 
cycle of treatment. 
 
The study includes a standard dose-confirmation schema (phase Ib portion) enrolling 3 to 6 
patients/subjects, with any solid tumors, per cohort (3+3 design) with a total of 18 patients. The dose-
expansion (phase II portion) will enroll 40 patients with advanced breast cancer to detect an effect 
size of 15% with a power of 80% with endpoints of safety, efficacy, and clinical benefit rate. A 
maximum of 58 patients will be enrolled on the phase Ib and II portions of this trial combined and will 
be treated until disease progression or toxicity mandate treatment change. 
 
Eribulin is a non-taxane microtubule inhibitor that is FDA approved as monotherapy for the treatment 
of taxane and anthracycline resistant metastatic breast cancer. The combination of docetaxel and 
cyclophosphamide is a well-accepted adjuvant chemotherapy regimen that has become an 
increasingly common therapeutic choice for intermediate risk early stage breast cancer. Eribulin has a 
favorable toxicity profile compared to docetaxel with the most common adverse reactions (incidence 
≤25%) including neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and 
constipation. Eribulin appears to have activity in taxane resistant disease, making it an attractive 
partner with cyclophosphamide. 
 
Neuropathy can be a devastating complication from adjuvant chemotherapy and in the metastatic 
setting, may limit effective therapy and reduce quality of life. Understanding the host factors that 
predict risk for neuropathy is critical, as these patients may in particular benefit from the lower risk of 
neuropathy associated with eribulin therapy. In conjunction with this trial, we have included correlative 
studies to study the proposed pharmacogenomic factors associated with risk of neuropathy. In this 
way we will potentially be able to identify patients who could preferentially be treated with less 
neurotoxic microtubule inhibitors. 
 
 


Protocol #: 11996 
Page 3 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Table of Contents 
List of Tables and Figures ........................................................................................................... 6 
List of Abbreviations .................................................................................................................... 7 
1.0  BACKGROUND AND RATIONALE ........................................................................................ 8 
1.1 
 Breast Cancer ................................................................................................................. 8 
1.2 
 Breast cancer treatment .................................................................................................. 8 
1.3 
 Toxicity of taxanes .......................................................................................................... 9 
1.4 
 Toxicity of epothilones ..................................................................................................... 9 
1.5 
 Eribulin mesylate and Preclinical data ............................................................................ 9 
1.6 
 Clinical data for eribulin mesylate ................................................................................. 10 
1.7 
 In Vitro and Vivo Activity Studies .................................................................................. 10 
1.7.1 
Nonclinical Pharmacokinetics ................................................................................ 10 
1.7.2 
Clinical Pharmacokinetics ...................................................................................... 11 
1.7.3 
Toxicology .............................................................................................................. 11 
1.7.4 
Developmental/Reproductive Toxicity: ................................................................... 11 
1.8 
 Cyclophosphamide ........................................................................................................ 12 
1.9 
 Rationale ....................................................................................................................... 12 
1.9.1 
Rationale for eribulin in combination with cyclophosphamide ............................... 12 
1.9.2 
Rationale for Dosing ............................................................................................... 12 
1.9.3 
Rationale for Starting Dose .................................................................................... 13 
1.10 
Correlative Studies Background..................................................................................... 13 
1.10.1 
Single-nucleotide polymorphisms .......................................................................... 13 
1.10.2 
Genome Analysis ................................................................................................... 13 
1.10.3 
Circulating Tumor Cells .......................................................................................... 14 
1.10.4 
Archived Tissue Analysis ....................................................................................... 15 
1.10.5 
Quality of life ........................................................................................................... 15 
1.10.6 
Neuropathy measurements .................................................................................... 15 
2.0  OBJECTIVES ....................................................................................................................... 17 
2.1 
 Phase Ib ........................................................................................................................ 17 
2.2 
 Phase II ......................................................................................................................... 17 
3.0  PATIENT SELECTION ......................................................................................................... 18 
3.1 
 Subject Inclusion Criteria .............................................................................................. 18 
3.2 
 Subject Exclusion Criteria ............................................................................................. 19 
3.3 
 Inclusion of Women and Minorities ............................................................................... 19 
4.0  SUBJECT REGISTRATION AND ENROLLMENT ............................................................... 20 
4.1 
 Subject Recruitment & Study Sites ............................................................................... 20 
4.2 
 Registration Procedures ................................................................................................ 20 
4.2.1 
Institutional Registration ......................................................................................... 20 
4.2.2 
Lead Center Registration ....................................................................................... 20 
5.0  STUDY DESIGN AND TREATMENT PLAN ........................................................................ 20 
5.1 
 Dose and schedule ....................................................................................................... 20 
5.2 
 Dose-Limiting Toxicity Phase Ib .................................................................................... 21 
5.2.1 
Hematologic dose-limiting toxicity .......................................................................... 22 
5.2.2 
Non-hematologic dose-limiting toxicity ................................................................... 22 
5.3 
 Duration of Therapy ...................................................................................................... 23 
5.4 
 Conditions for Terminating the Study ............................................................................ 23 
6.0  TOXICITY MANAGEMENT AND DOSE MODIFICATION ................................................... 23 
6.1 
 Removal of patients from study:.................................................................................... 24 
6.2 
 Concomitant Medications .............................................................................................. 24 
6.3 
 Supportive Care Guidelines .......................................................................................... 24 
7.0  DRUG INFORMATION ......................................................................................................... 28 
7.1 
 Eribulin mesylate (Halaven™) ....................................................................................... 28 
7.2 
 Cyclophosphamide (Cytoxan®) .................................................................................... 29 
8.0  CORRELATIVE/SPECIAL STUDIES ................................................................................... 31 
8.1 
 Pharmacokinetic (PK) Studies ...................................................................................... 31 
8.2 
 Circulating Tumor Cells ................................................................................................. 31 


Protocol #: 11996 
Page 4 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
8.3 
 Pharmacogenomic (PG studies) ................................................................................... 32 
8.4 
 Archived Tissue Analysis .............................................................................................. 32 
9.0  STUDY PROCEDURES ....................................................................................................... 33 
9.1 
 Screening assessments ................................................................................................ 33 
9.2 
 Assessments and Procedures During Treatment ......................................................... 33 
9.3 
 Study Termination ......................................................................................................... 34 
9.4 
 Follow-up ....................................................................................................................... 34 
10.0 CRITERIA FOR EVALUATION ............................................................................................. 37 
10.1 
Antitumor Effect – Solid Tumors .................................................................................... 37 
10.1.1 
Response Definitions ............................................................................................. 37 
10.1.2 
Disease Parameters ............................................................................................... 37 
10.1.3 
Methods for evaluation of measurable disease ..................................................... 38 
10.1.4 
Response Criteria................................................................................................... 40 
10.1.5 
Duration of Response ............................................................................................ 41 
11.0 STATISTICAL CONSIDERATIONS ...................................................................................... 42 
11.1 
Study Design/Endpoint Definitions ................................................................................. 42 
11.2 
Accrual Objectives ......................................................................................................... 42 
11.2.1 
Replacement of Patients: ....................................................................................... 42 
11.3 
Stratification Factors ...................................................................................................... 43 
11.4 
Analysis of Secondary Endpoints................................................................................... 43 
11.5 
Reporting and Exclusions .............................................................................................. 43 
11.5.1 
Evaluation of toxicity. ............................................................................................. 43 
11.5.2 
Evaluation of response ........................................................................................... 43 
12.0 MULTI-CENTER GUIDELINES ............................................................................................. 43 
12.1 
Responsibilities of the coordinating/lead center ............................................................. 44 
12.1.1 
Oversight ................................................................................................................ 44 
12.1.2 
Protocol Distribution ............................................................................................... 44 
12.1.3 
Documentation of Distribution ................................................................................ 44 
12.1.4 
Documentation of Protocol Approvals .................................................................... 44 
12.2 
Responsibilities of other participating sites .................................................................... 44 
12.2.1 
Study Initiation ........................................................................................................ 45 
12.2.2 
Patient Enrollment .................................................................................................. 45 
12.2.3 
Study Drug Supply and Accountability ................................................................... 45 
12.2.4 
Approval of Protocol and Amendments.................................................................. 45 
13.0 DATA MANAGEMENT .......................................................................................................... 45 
14.0 ETHICAL ASPECTS AND REGULATORY CONSIDERATIONS ......................................... 46 
14.1 
Conduct of the study ...................................................................................................... 46 
14.2 
Scientific Review ............................................................................................................ 46 
14.3 
Institutional Review Board / Independent Ethics Committee ......................................... 46 
14.4 
Investigational New Drug Application (IND) ................................................................... 46 
14.5 
Additional Reporting Requirements ............................................................................... 46 
15.0 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .................................................. 46 
15.1 
Adverse Event Definitions .............................................................................................. 46 
15.1.1 
Adverse Events ...................................................................................................... 46 
15.1.2 
Serious Adverse Events ......................................................................................... 47 
15.2 
Adverse Event Grading .................................................................................................. 47 
15.3 
Adverse Event Reporting Period .................................................................................... 47 
15.4 
Adverse Event Reporting and Data Safety Monitoring .................................................. 48 
15.4.1 
Oversight and Monitoring Plan ............................................................................... 48 
15.4.2 
Monitoring and Reporting Guidelines ..................................................................... 48 
15.4.3 
Review and Oversight Requirements..................................................................... 48 
16.0 REFERENCES ...................................................................................................................... 50 
APPENDIX A ............................................................................................................................. 54 
APPENDIX B ............................................................................................................................. 55 
APPENDIX C ............................................................................................................................. 56 
APPENDIX D ............................................................................................................................. 58 


Protocol #: 11996 
Page 5 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
APPENDIX E ............................................................................................................................. 60 
APPENDIX F ............................................................................................................................. 61 
 
 


Protocol #: 11996 
Page 6 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
List of Tables and Figures 
Table 3-1. Adequate Organ Function Values ....................................................................................... 18 
Table 5-1. Dose Escalation Schedule .................................................................................................. 20 
Table 6-1. Toxicity management guidelines for eribulin and cyclophosphamide ................................ 26 
Table 9-1  Study Calendar ................................................................................................................... 35 
Table 10-2. Evaluation of Patients with Measurable Disease (i.e., Target Disease) ........................... 41 
Table 10-3. Evaluation of Patients with Non-Measurable Disease (i.e., Non-Target Disease) ........... 41 
 
 
 


Protocol #: 11996 
Page 7 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
List of Abbreviations 
 
AC 
doxorubicin (adriamycin) and cyclophosphamide 
aCGH 
array comparative genomic hybridization 
AE 
adverse event 
ALDH 
aldehyde dehydrogenase 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase 
AUC 
area under the curve 
BID 
twice a day 
BSA 
body surface area 
CAEPR Comprehensive Adverse Event and Potential 
 
Risks 
CALGB 
Cancer and Leukemia Group B 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CGH 
comparative genomic hybridization  
CHR 
UCSF Committee on Human Research 
Cl 
plasma clearance 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CT 
computerized tomography 
CTC 
circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse 
 
Events 
CTMS 
Clinical Trials Management System 
CV 
coefficient of variability 
CYP 
cytochrome P450 
DLT 
dose limiting toxicity 
DFS 
disease free survival 
DNA 
deoxyribonucleic acid 
DSMB 
data safety monitoring board 
E7389 
eribulin mesylate 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor 
ECOG 
Eastern Cooperative Oncology Group 
EORTC European Organization for Research and 
 
Treatment of Cancer 
FACS 
fluorescence-activated cell sorting 
FACT 
Functional Assessment of Cancer Therapy 
FDA 
Food and Drug Administration 
FNA 
Fine needle aspiration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GOG 
Gynecologic Oncology Group 
GWAS 
genome wide association study 
HER-2 
human epidermal growth factor receptor 2 
HIPPA 
The Health Insurance Portability and 
 
Accountability Act 
HGB 
hemoglobin 
HR 
heart rate 
HV 
healthy volunteers 
IC50 
50% inhibitory concentration 
IND 
investigational new drug 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IB 
Investigator’s Brochure  
IV 
intravenous 
KPS 
Karnofsky Performance Status 
MAD 
maximum administered dose 
MBC 
metastatic breast cancer 
MRI 
Magnetic Resonance Imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
no observed adverse effect level 
NSABP 
National Surgical Adjuvant Breast and Bowel 
 
Project 
NYHA 
New York Heart Association 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression free survival 
Pgp 
permeability glycoprotein 
PgR 
progesterone receptor 
PHI 
personal health information 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PO 
by mouth 
PR 
partial response 
PRC 
UCSF Protocol Review Committee 
QD 
once daily 
QID 
four times a day 
QOD 
every other day 
QOL 
Quality of life 
QLQ 
Quality of life questionnaire 
QTc 
QT corrected interval 
RECIST Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RR 
response rate 
SAE 
serious adverse event 
SC 
subcutaneously 
SD 
stable disease 
SiBP 
sitting blood pressure 
t ½  
elimination half-life 
TC 
docetaxel and cyclophosphamide 
TPC 
the physician’s choice 
ULN 
upper limit of normal 
Vdss 
volume of distribution at steady state 
WBC 
white blood cell 
WGA 
whole genome amplification 


Protocol #: 11996 
Page 8 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
1.0  
BACKGROUND AND RATIONALE 
 
1.1  
Breast Cancer 
 
Breast cancer is the most common female cancer in the United States and is estimated to affect 
207,090 women in the United States in 2010, with over 40,000 deaths expected (Jemal, Siegel et al. 
2010). As many as 20% of patients will develop metastatic disease and most will have received prior 
adjuvant and/or neoadjuvant chemotherapy. Despite advances in therapies, the overall long-term 
prognosis of patients with metastatic breast cancer remains poor, with time to progression ranging 
from 6 to 9 months in the first-line setting and median survival overall of approximately 3 years. 
 
1.2  
Breast cancer treatment 
 
For breast cancer, anthracyclines are one of the most commonly administered intravenous 
chemotherapy agents and are known to cause cardiac toxicity and rare cases of acute leukemia 
(Patt, Duan et al. 2007) (Du, Xia et al. 2009). The taxanes were introduced in 1990 and quickly 
became an integral part of chemotherapy regimens. Significant side effects include bone marrow 
suppression, peripheral neuropathy, nail changes, epiphora, and, less commonly, permanent 
alopecia (Sparano, Wang et al. 2008). Patients with metastatic disease develop cumulative toxicity 
from multiple lines of chemotherapy as well as chemotherapy resistance which limits efficacy. 
Selection of less toxic regimens with improved efficacy is important to achieve the goal of improved 
outcome without worsening quality of life. Development of agents targeted to the biology that drives 
tumor growth are a critical step in this process, however, chemotherapy remains the backbone of 
breast cancer treatment. New agents and new combinations may not only improve response and 
duration of response, but also could provide an improved backbone for the addition of targeted 
agents.  
 
The combination of doxorubicin and cyclophosphamide (AC) is a standard contemporary adjuvant 
chemotherapy regimen based on data from NSABP-15, NSABP-23 and other studies (Fisher, Brown 
et al. 1990; Fisher, Anderson et al. 2001). Jones and colleagues studied the combination of docetaxel 
and cyclophosphamide (TC) in patients with early stage breast cancer in order to evaluate a non-
anthracycline containing regimen that might avoid the risk of long-term toxicity. 1800 women with 
stage I and II breast cancer were randomized to receive TC every three weeks for 4 cycles or AC on 
the same schedule. At a median follow-up of five years, patients treated with TC had a significantly 
improved disease free survival (DFS) of 86% versus 80% p=0.015, compared to those receiving AC 
(Jones, Savin et al. 2006). Subsequently, 7 year follow-up data demonstrated a significant 
improvement in overall survival (OS) favoring TC, 87% versus 82% p=0.032 (Jones, Holmes et al. 
2009). Grade 3-4 toxicities were evaluated by age group and anemia was highest in the age group ≥ 
65 occurring in 5% of patients who received AC. Febrile neutropenia was 5% with TC and 2.5% with 
AC. Patients treated with TC also experienced more peripheral edema (1% vs. <1%), diarrhea (5% 
vs. 1%), myalgia (2% vs. 1%). The AC group had more asthenia (9% vs. 6%), infections (10% vs. 
7%), nausea (7% vs. 3%) and vomiting (6% vs. 1%). Four late deaths without breast cancer relapse 
and probably related to treatment occurred in the AC group: a 45-year-old woman died of 
cardiomyopathy and congestive heart failure, and two older women died of complications related to 
myelodysplasia and myelofibrosis. One more patient died of acute leukemia 10 years after AC. No 
cardiac toxicities or leukemia were observed in the group receiving TC. 
 
Based on this data, TC has become a generally accepted adjuvant chemotherapy regimen for the 
treatment of lower risk early stage disease. Ongoing or planned studies have incorporated TC as a 
chemotherapy backbone, including two NSABP trials. NSABP B-46 is a three-arm trial and 
randomizes women with node-positive or high-risk node-negative breast cancer to 6 cycles of TAC 
(docetaxel, doxorubicin, and cyclophosphamide), TC, or TC combined with bevacizumab. NSABP 
B47 is studying the impact of trastuzumab in patients with HER2 normal disease when given with 
either TC or AC followed by paclitaxel. 
 


Protocol #: 11996 
Page 9 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
1.3  
Toxicity of taxanes 
 
Despite the success of taxanes in the treatment of early stage breast cancer, toxicity remains an 
issue. Mild to moderate peripheral neuropathy is seen in up to 88% of women, with 3% having severe 
neuropathy, and some suffering from long-term neuropathy (Rowinsky and Donehower 1995). In 
ECOG 1199, a randomized trial of doxorubicin and cyclophosphamide followed by various schedules 
of taxane therapy, 27% of patients who received weekly paclitaxel had Grade 2 or greater 
neuropathy(Sparano, Wang et al. 2008). Other toxicities, such as epiphora, edema, and delayed hair 
growth, among others, limit time to recovery from adjuvant therapy. 
 
1.4  
Toxicity of epothilones 
 
Epothilones also target microtubules and stabilize their polymerization, but differ from taxanes in that 
they demonstrate less susceptibility to Pgp-mediated efflux and retain antitumor activity even in the 
setting of tubulin mutations (Rivera and Gomez 2010). Phase II studies for the mostly widely studied 
epothilone, ixabepilone, when given as monotherapy, has shown overall response rates (ORR) for 
metastatic breast cancer patients not previously treated with taxanes of 41.5 and 57% and in taxane-
pretreated patients ORR of 11.5 to 22% (Denduluri, Low et al. 2007) (Low, Wedam et al. 2005) 
(Perez, Lerzo et al. 2007) (Roche, Yelle et al. 2007) (Thomas, Gomez et al. 2007). In a phase II study 
with 113 patients, grade 3/4 adverse events included 14% of patients with peripheral sensory 
neuropathy, 54% with neutropenia, 14% with fatigue and grade 3 myalgia/arthralgia in 14% (Perez, 
Lerzo et al. 2007).  Based on this toxicity profile, newer, less toxic agents are still needed. 
 
1.5  
Eribulin mesylate and Preclinical data 
 
Eribulin mesylate (E7389) is a nontaxane, microtubule dynamic inhibitor with a novel mechanism of 
action. Eribulin suppresses polymerization, has no effect on microtubule depolymerization, and 
sequesters tubulin into nonfunctional aggregates (Kuznetsov, Towle et al. 2004; Jordan, Kamath et 
al. 2005; Okouneva, Azarenko et al. 2008) (Towle, Salvato et al. 2001).  
 
Results of in vitro studies demonstrate that eribulin inhibits cell growth with sub- to low-nmol/L half-
maximal inhibitory concentration (IC50) values in a wide range of established human cancer cell 
lines, including breast, colon, prostate, ovarian, small cell lung, and non-small cell lung cancers, 
histiocytic lymphoma, promyelocytic leukemia, head and neck carcinoma, melanoma, and uterine 
sarcoma.  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 after prolonged mitotic blockage. Among 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. 
 
Preclinical studies have also demonstrated antitumor activity in cell lines that are taxane resistant as 
a result of β-tubulin mutations (Cortes and Lorca 2011) (Kuznetsov et al. abstract ESMO 2007). In 
addition, eribulin appears to have less neurotoxicity than other microtubule antagonists. A murine 
model compared the effect on nerve conduction of paclitaxel and ixabepilone to eribulin. This data, 
presented at the annual European Society for Medical Oncology found that treatment with paclitaxel 
and ixabepilone resulted in a reduction in caudal nerve conduction velocity as well as caudal and 
digital amplitude, but eribulin had no deleterious effect on these endpoints. Eribulin also caused less 
severe morphological changes in dorsal root ganglion and sciatic nerves on pathological assessment 
(Wozniak, Lapidus et al. 2010). 
 
 
 
 


Protocol #: 11996 
Page 10 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
1.6  
Clinical data for eribulin mesylate 
 
In two phase II studies, eribulin has demonstrated efficacy in patients with heavily pre-treated 
metastatic breast cancer. E7389-A001-201 evaluated the safety and efficacy of eribulin in subjects 
with locally advanced or metastatic breast cancer who had been previously treated with an 
anthracycline and taxane and had documented progression during or within 6 months following the 
last dose of chemotherapy. 103 patients with a median of 4 prior chemotherapy regimens for 
advanced disease enrolled (Vahdat, Pruitt et al. 2009). 70 subjects received 1.4 mg/m2 eribulin 
administered as an IV bolus on days 1, 8, and 15 of a 28-day cycle; another 33 subjects received 
eribulin administered as an IV bolus on days 1 and 8 of a 21-day cycle. The 21-day cycle cohort was 
added because 63% of subjects in the 28-day cycle cohort experienced dose delays, reductions, or 
omissions due to neutropenia; in most cases the day 15 dose was being omitted. The response rate 
(RR) was 11.5% (all PR), the clinical benefit rate (CBR) was 17.2%, and progression free survival 
(PFS) was 2.6 months. The second phase II trial, E7389-A001-211, enrolled 299 patients with locally 
advanced or metastatic breast cancer who had received anthracycline, taxane, and capecitabine as 
prior therapy, and were refractory to their last chemotherapy regimen as documented by progression 
on or within 6 months of therapy (Cortes, Vahdat et al. 2010). All patients received 1.4 mg/ m2 on day 
1 and 8 every 21 days. Results were similar by independent review, with RR of 9.3%, CBR of 17.1% 
and PFS of 2.6 months. Between the two trials, OS ranged from 9 to 10.4 months.  The most 
common drug-related grades 3/4 toxicities were neutropenia (54-64%), fatigue (5-10%), peripheral 
neuropathy (5-6.9%), and febrile neutropenia (4-5.5%). 
 
The results of a phase III trial comparing eribulin to treatment of physician’s choice (TPC) in patients 
with anthracycline and taxane pre-treated MBC and at least two prior chemotherapy regimens for 
advanced disease recently led to FDA approval of this novel chemotherapy agent (Twelves, Cortes et 
al. 2010). The EMBRACE trial randomized 508 women to single agent eribulin and 254 women to 
TPC; the primary endpoint of OS was 13.12 months in the eribulin arm versus 10.65 months in the 
TPC arm (HR 0.81, p=0.041). The RR was also greater in the eribulin arm (12.2 versus 4.7%, 
p=0.002), and although PFS was significantly longer by investigator assessment, by central review 
this was not significantly different, likely due to the inclusion of patients with evaluable rather than 
solely measurable disease (3.7 versus 2.2 months, HR 0.87, p=0.14). Subset analysis suggested 
benefit from eribulin across identified risk groups. 144 patients were identified with ER/PgR/HER2 
negative disease, determined locally, and in this group the PFS for eribulin was 2.23 months, 
compared to 1.9 months for TPC. In the overall study, grade 3/4 toxicities that were higher in the 
eribulin arm included higher rates of neutropenia (21% versus 14%) and leukopenia (11.7% versus 
5%) as well as febrile neutropenia (3% versus 0.8%). However, anemia (1.8 vs 3.2%), 
asthenia/fatigue (8.2 vs 10.1%), nausea (1.2 vs 2.4%), mucositis (1.4 vs 2%) and hand-foot syndrome 
(0.4 vs 3.6%) were more prevalent in the TPC arm. 
 
1.7  
In Vitro and Vivo Activity Studies 
 
1.7.1 
Nonclinical Pharmacokinetics  
 
The pharmacokinetics (PK) of eribulin were examined after single IV administrations in male mice 
(0.5 or 2 mg/kg), male rats (0.5 or 1 mg/kg), and male dogs (0.08 mg/kg). The PK of eribulin can be 
characterized by an extensive volume of distribution (7.45 – 12.2 l/kg in mice, 36.3 – 44.1 l/kg in rats, 
and 18.8 – 20.4 l/kg in dogs), a moderate clearance (2.03 – 2.79 l/hr/kg in mice, 1.61 – 2.04 l/hr/kg in 
rats, and 0.688 – 1.06 l/hr/kg in dogs), and a relatively slow elimination (t½, 3.55 - 6.88 hours in mice, 
15.9 - 27.9 hours in rats, 21.9 - 28.2 hours in dogs). In multiple dose PK studies in which eribulin was 
administered every four days for three courses no accumulation was observed in both rats and dogs. 
 
The protein binding of eribulin in mouse, rat, dog and human plasma in vitro was investigated. 
Between 100 and 1000 ng/mL, eribulin was not strongly bound to plasma protein in vitro: mouse 
(28.47%-35.94%), rat (23.01%-34.09%), dog (15.41%-26.37%), and human plasma (48.92%-
65.07%). Cytochrome 3A4 (CYP3A4) appears to be the major enzyme responsible for the human 
hepatic metabolism of eribulin, and forms mainly isomeric monohydroxylates in vitro. 


Protocol #: 11996 
Page 11 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 was detected with 
eribulin at concentrations up to 5 μmol/L. Eribulin inhibited CYP3A4-mediated R-warfarin 10-
hydroxylation, testosterone 6-β hydroxylation, nifedipine dehydration (Ki: 3-17 μmol/L), and exhibited 
weak inhibitions on the metabolism of carbamazepine, diazepam, paclitaxel, tamoxifen, midazolam, 
and terfenadine. Eribulin did not alter the activities or the protein expressions of CYP1A, CYP3A, 
CYP2C9, and CYP2C19 in the primary cultures of human hepatocytes (up to 5 or 10 μmol/L).  It is 
unlikely that eribulin would cause metabolic inhibition of concurrent drugs based on anticipated low 
therapeutic dose in humans. However, caution will be taken for patients who are taking drugs that are 
metabolized by CYP3A4 since CYP3A4 was substrate dependant and appears to be the major 
enzyme responsible for human hepatic metabolism of eribulin in vitro. 
 
1.7.2 
Clinical Pharmacokinetics 
 
The pharmacokinetics of eribulin in human subjects is characterized by a rapid distribution phase, 
with a prolonged elimination phase after intravenous infusion. Plasma concentrations of drug are 
sufficiently low during the elimination phase to preclude significant accumulation at the dosing 
intervals being tested. The disposition of eribulin follows linear kinetics over the dose range studied, 
as shown by consistent dose-independent pharmacokinetic parameters (t½, CI, Vdss) and similar 
dose-normalized parameters (Cmax/Dose, AUC0-t/Dose and AUC0-∞/Dose) between eribulin doses 
ranging from 0.25 to 1.4 mg/ m2 (E7389-A001-101) and from 0.25 to 4.0 mg/ m2 (E7389-A001-102). 
 
1.7.3 
Toxicology  
 
The toxicity of eribulin has been evaluated in rats and dogs with the drug administered in 5% ethanol 
in 0.9% sodium chloride (NaCl) as a slow IV bolus to rats or as a 1-hour IV infusion to dogs once a 
day on days 1, 5, 9. In range-finding studies, single doses of 0.75 mg/kg/day (4.5 mg/ m2/day) were 
lethal to rats and two doses of 0.075 mg/kg/day (1.5 mg/ m2/day) were lethal to dogs.  Bone marrow 
toxicity appeared to be dose-limiting in both rats and dogs.  In the Investigational New Drug 
Application (IND)-directed, Good Laboratory Practices (GLP) toxicity studies, doses of 0.08 mg/ 
m2/day produced no toxicity in dogs or rats, while doses of 0.6 to 0.8 mg/ m2/day produced reversible 
bone marrow toxicity in both species. Other toxicities that were considered to be drug-related 
occurred in the lymphoid tissue, testes, and skeletal muscle. All observed toxicities (except testicular 
toxicity) were reversible in both dogs and rats. Based on these studies, the recommended starting 
dose for phase I clinical trials is 0.12 mg/ m2/day, as dose less than 1/10th the maximum tolerated 
dose (MTD) in rats (1.2-1.5 mg/ m2/day) and 1/6th the Toxic Dose Low (0.4 mg/ m2/day) in dogs. 
 
In vitro bone marrow assays did not demonstrate significant species difference between human, dog, 
and mouse CFU-G/M cell sensitivity to eribulin. Based on the ratios of human to murine and human to 
canine IC90S and in vivo MTDs, the calculated human MTD was projected to be 0.9 mg/ m2/day 
(based on canine data) and 3.1 mg/ m2/day (based on murine data.) Similar bone marrow effects 
were also confirmed by in vitro assays using multipotential stem cells (CFC-GEMM) from mouse, dog 
and human. The murine CFC-GEMM cells appeared to be less sensitive to the toxic effects, whereas 
human and canine cells appeared to be equally sensitive.  In in vitro genotoxicity studies, eribulin was 
negative in the Ames test with or without S9, but was weakly positive in the L5178Y/TK+/- mouse 
lymphoma mutagenesis assay. 
 
1.7.4 
Developmental/Reproductive Toxicity: 
 
Developmental and reproductive toxicity studies of eribulin have not been performed thus far. Eribulin 
was not tested in pregnant or breast-feeding women. Women of child-bearing potential and men 
participating in clinical studies of eribulin must use appropriate contraception, including abstinence 
and double-barrier methods, throughout eribulin therapy. In preclinical mutagenicity studies, eribulin 
was neither genotoxic or mutagenic. 
 


Protocol #: 11996 
Page 12 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
1.8  
Cyclophosphamide 
 
Cyclophosphamide (Endoxan, Cytoxan, Neosar, Procytox, Revimmune) is a prodrug nitrogen 
mustard alkylating agent, from the oxazophorines group. It is converted by oxidase enzymes in the 
liver to active toxic metabolites, 4-hydroxycyclophosphamide and aldophosphamide. Most of the 
aldophosphamide is oxidized by the enzyme aldehyde dehydrogenase (ALDH) to make 
carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide 
mustard and acrolein. Phosphoramide mustard forms DNA crosslinks between (interstrand 
crosslinkages) and within (intrastrand crosslinkages) DNA strands at guanine N-7 positions. This is 
irreversible and leads to cell death(Cohen and Jao 1970) (Brock 1989) (Brock 1996). 
 
Phosphoramide mustard is only formed in cells that have low levels of ALDH. Cyclophosphamide has 
relatively little typical chemotherapy toxicity as ALDH is present in relatively large concentrations in 
bone marrow stem cells, liver and intestinal epithelium. ALDH protects these actively proliferating 
tissues against toxic effects phosphoramide mustard and acrolein by converting aldophosphamide to 
carboxyphosphamide that does not give rise to the toxic metabolites (phosphoramide mustard and 
acrolein). 
 
Cyclophosphamide has activity in a broad range of human cancer types and has emerged as front 
line therapy for many advanced cancers including breast cancer. Phase III clinical trials have shown 
that cyclophosphamide in combination with adriamycin prolongs survival in patients with breast 
cancer (Fisher, Brown et al. 1990). In early stage breast cancer patients, the regimen of 
cyclophosphamide and docetaxel has recently been adopted since it is a less toxic regimen and data 
shows that it improves DFS and OS (Jones, Holmes et al. 2009). 
 
The most common toxicities associated with cyclophosphamide include bone marrow suppression, 
nausea, vomiting, anorexia, diarrhea, abdominal discomfort, alopecia, mucositis, infertility; and rare 
cases of hemorrhagic cystitis due to the metabolite acrolein, hemorrhagic colitis, Stevens-Johnson 
syndrome or interstitial pneumonitis. 
 
1.9  
Rationale 
 
1.9.1 
Rationale for eribulin in combination with cyclophosphamide 
 
Docetaxel or paclitaxel are well-established active and effective treatments for advanced breast 
cancer in both the front-line and pre-treated setting. In vitro data with taxane resistant cell lines offers 
a biological basis for the efficacy of eribulin in this setting.  Due to the favorable toxicity profile and 
efficacy seen with the use of eribulin as a single agent, it is feasible to study combinations of eribulin 
with standard chemotherapeutic agents given in breast cancer. The success of docetaxel combined 
with cyclophosphamide in the adjuvant setting has led to considerable interest in anthracycline-free 
chemotherapy options. Given the advantages of eribulin in both toxicity and efficacy, the combination 
of eribulin and cyclosphosphamide is intriguing. If both efficacy and safety is demonstrated in the 
metastatic setting, this could be an important combination therapy to test as adjuvant therapy for early 
stage breast cancer. 
 
1.9.2 
Rationale for Dosing 
 
On November 15, 2010, the U. S. Food and Drug Administration granted approval for eribulin 
mesylate for the treatment of patients with metastatic breast cancer who have previously received an 
anthracycline and a taxane in either the adjuvant or metastatic setting, and at least two 
chemotherapeutic regimens for the treatment of metastatic disease.  In the phase III trial which led to 
this approval, eribulin was administered as an intravenous dose of 1.4 mg/ m2 on days 1 and 8 of a 
21-day cycle, with dose delays and reductions for pre-specified toxicities. 
 
 


Protocol #: 11996 
Page 13 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
1.9.3 
Rationale for Starting Dose 
 
We anticipate the possibility of increased toxicity, including bone marrow suppression, when eribulin 
is combined with standard dose cyclophosphamide (600 mg/m2 on day 1 of a 21-day cycle.)  
Therefore we plan to test this combination initially with a reduced dose of eribulin (1.1 mg/m2 days 1 
and 8 of a 21-day cycle). 
 
1.10 
Correlative Studies Background 
 
1.10.1 Single-nucleotide polymorphisms  
 
Chemotherapy-associated toxicity is highly variable. This may be largely due to host factors such as 
differences in absorption, distribution, and particularly metabolism and clearance. Sources of 
variability may be compounded by the presence of vomiting and diarrhea, poor nutritional status, 
concomitant medications, prior therapies, and liver metastases or effusions (Ratain 1992). Response 
to chemotherapy is also highly variable and may be influenced by both host and tumor specific 
factors. Variability in hepatic metabolism and membrane transport has been the focus of many 
studies addressing the sources of interindividual differences in response to medications, particularly 
chemotherapy. Several CALGB studies have included correlative pharmacogenetics studies to 
investigate genetic contributions to toxicity and response.  The most mature of these studies in breast 
cancer, CALGB 40101, has recently identified novel genetic predictors of paclitaxel-induced 
peripheral neuropathy. Surprisingly, polymorphisms in known candidate genes for metabolism and 
transport did not contribute significantly to toxicity. Results from a genome-wide scan of over 500,000 
single nucleotide polymorphisms (SNPs) identified three novel candidate genes, FZD3, FGD4 and 
EPHA5. 
 
FZD3 encodes a Wnt receptor with a known role in neurite outgrowth (Endo, Beauchamp et al. 2008), 
suggesting that altered function in individuals carrying the variant allele of this gene may protect 
against paclitaxel-induced peripheral nerve injury. A COX model was also used to identify genetic 
predictors of time to developing peripheral neuropathy.  Although not reaching genome-wide 
significance, the two top hits were in genes of biological interest.  One SNP was in EPHA5 (p = 9.6 x 
10-7; HR = 1.63) and another in FGD4 (p = 2.6 x 10-6; HR = 1.57). EPHA5 encodes an ephrin 
receptor involved in axon guidance. Studies in mice have shown that EPHA5 is important for neuronal 
regeneration following injury (Barrette, Calvo et al. 2010). Patients carrying a reduced function 
EPHA5 allele may have an attenuated repair response following paclitaxel-induced injury.  FGD4 
encodes a Rho GTPase that is critical for proper myelination of peripheral nerves. Rare mutations in 
FGD4 are associated with the congenital peripheral neuropathy Charcot-Marie-Tooth disease 
(Stendel, Roos et al. 2007).  The more common FGD4 polymorphisms identified in CALGB 40101 
may be associated with demyelination of peripheral nerves following paclitaxel treatment. The 
molecular bases for each of these three genes in paclitaxel-induced peripheral neuropathy are 
currently under study at Dr. Kroetz’ laboratory at USCF. Therefore, in addition to specific hypothesis 
testing for the above candidate genes, this study will also provide the framework for hypothesis 
generation investigations of genotype and/or haplotype in additional candidate genes of putative 
importance to response and toxicity of the agents being evaluated in this study.  
 
For patients who consent, whole blood will be collected prior to the start of treatment. DNA extraction 
will occur at UCSF Genomics Core Facility, the Cancer Center Genome Analysis Core, the Cancer 
Center Tissue Core or within the laboratory of Dr. Kroetz. Exploratory SNP analysis will then be 
performed in Dr. Kroetz laboratory. Data from this trial will be combined with other SNP data for 
separate larger analysis of pooled patients. 
 
1.10.2 Genome Analysis 
 
In genetic epidemiology, a genome-wide association study (GWA study, or GWAS), also known as 
whole genome association study (WGA study, or WGAS), is an examination of all or most of the 
genes (the genome) of different individuals of a particular species to see how much the genes vary 


Protocol #: 11996 
Page 14 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
from individual to individual.  Different variations can then be associated with different traits, for 
example diseases or toxicity from treatment.  One challenge for successful GWAS in the future will be 
to apply the findings in a way that accelerates drug and diagnostics development, including better 
integration of genetic studies into the drug-development process and a focus on the role of genetic 
variation.  One such success was found relating genetic variant with response to anti-hepatitis C virus 
treatment.  For genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated 
interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin, a GWAS study 
has shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, 
are associated with significant differences in response to the treatment.  A later report demonstrated 
that the same genetic variants are also associated with the natural clearance of the genotype 1 
hepatitis C virus (Ge, Fellay et al. 2009). 
 
For purposes of hypothesis generation, we plan to collect whole blood on patients prior to the start of 
treatment and perform a genome scan in the Genome Analysis Core or the UCSF Genomics Core. 
Data from this trial will be combined with other genome scan data from UCSF for a separate larger 
analysis of pooled patients.  These samples will not be sent to the National Institutes of Health (NIH) 
and will not be part of the NIH GWAS database. 
 
1.10.3 Circulating Tumor Cells  
 
The development of techniques to detect circulating tumor cells (CTCs) or micrometastases in the 
blood of cancer patients provides a new approach to monitoring cancer activity and response to 
therapy.  Numerous studies have demonstrated the utility of using CTC enumeration as a prognostic 
marker in advanced breast cancer (Cristofanilli, Budd et al. 2004; Cristofanilli, Hayes et al. 2005). 
More recently, considerable attention has turned to the development of more sophisticated assays to 
better understand the biology and molecular nature of CTCs. Current models suggest that CTCs may 
represent tumor cells with metastatic potential, and therefore gene-expression profiling of CTCs may 
be a rich resource for the identification of biomarkers with therapeutic relevance to micrometastatic 
disease. In addition, as molecular targeted therapies are being developed, it is imperative that we 
have strategies to assess target levels in patients, as well as changes in target status during 
treatment. CTCs offer an ideal focus for such strategies, as they are readily obtainable and can be 
subjected to further molecular analysis. 
 
Molecular profiling of CTCs is challenging because CTCs are a rare cell population. Isolating CTCs 
and handling picogram levels of RNA and DNA is extremely difficult and can be wrought with 
technical complications (Racila, Euhus et al. 1998). Efforts to detect CTCs have involved the use of 
antibody-based capture methods which greatly enrich the tumor cell component relative to 
hematopoetic cells, however these current methods still retain a considerable fraction of leukocytes 
which results in a heterogeneous sample that prevents accurate characterization of isolated CTCs.  
Dr. John Park’s laboratory at UCSF has developed a novel approach using sequential 
immunomagnetic enrichment and FACS (Fluorescence-activated cell sorting) for CTC 
isolation.  Using this protocol, the Park laboratory has successfully isolated small pools of highly 
purified CTCs from breast cancer patients. Genomic DNA from these CTCs were subjected to whole 
genome amplification (Howgate, Gamie et al.) followed by array comparative genomic hybridization 
(aCGH ) for copy number analysis. Their results demonstrate that CTCs can be isolated from 
hematopoietic cells with high enough purity to perform molecular profiling. 
 
We plan to utilize this novel isolation strategy to perform the following exploratory CTC analyses: 1) 
enumeration of CTCs prior to starting therapy and if ≥5 CTC/mL, a second sample at cycle 2 day 1; 2) 
whole genome amplification (Howgate, Gamie et al.) followed by aCGH of isolated CTCs 3) 
sequencing analysis for beta tubulin mutations as indicated; and 4) gene expression using a 64 gene 
panel including beta 3 tubulin (#2, 3, will be performed only if an adequate number of CTCs are 
available.) 
 


Protocol #: 11996 
Page 15 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
1.10.4 Archived Tissue Analysis 
 
Over the past several years, advances in molecular technology have allowed scientists to perform 
genome-wide queries using oligonucleotide arrays to identify genes that are differentially expressed 
in tumor metastases, as well as in pre- and post-treatment tissue samples (Ramaswamy and Perou 
2003; Weigelt, Glas et al. 2003). 
 
Archived tumor tissue will be collected for the analysis of biomarkers predictive of clinical response to 
eribulin. This may include, but is not limited to, proteins, phosphoproteins, and RNA expression 
related to the activity of eribulin may be assessed in this tissue.  DNA will be extracted from tissue 
specimens in order to sequence and genotype the samples, to evaluate the prevalence of genetic 
polymorphisms of all membrane transporters as well as all other genes of interest which could 
potentially be interacting with the membrane transporters or having a effect on the expression levels 
of the membrane transporter genes. Sequencing and genotyping of the tissue samples will be carried 
out using traditional sequencing methods, or using the genomewide association array chip (Illumina, 
Affymetrix or others) and/or using the high-throughput DNA sequencing technologies (Illumina 
Genome Analyzer, 454 technologies and SOLiD) mRNA levels of all membrane transporters and 
other potential genes of interest will be measured by quantitative PCR, microarray analysis or other 
cutting edge technologies such as high-throughput RNA sequencing technologies (Illumina Genome 
Analyzer, 454 technologies and SOLiD). The protein levels of the interested genes in the tissue 
specimens will be determined by immunohistochemistry and Western Blot analyses using targeted 
antibodies. RNA/protein levels will be associated with various genotypes to identify genetic variants 
that have an impact on RNA/protein concentration. Other analysis of tumor tissue may include, but is 
not limited to, markers of response to treatment or potential for metastasis including, but not limited 
to, proteins, phosphoproteins, and other biological markers. 
 
1.10.5 Quality of life 
 
We plan to evaluate quality of life endpoints using the standard assessment tool EORTC QLQ-C30.  
QLQ-30 is a copyrighted instrument, which has been translated and validated into 81 languages and 
is used in more than 3,000 studies worldwide (Groenvold, Klee et al. 1997; Taenzer, Speca et al. 
1997; Apolone, Filiberti et al. 1998; McLachlan, Devins et al. 1998).   
 
This questionnaire will be administered at baseline (within 7 days of cycle 1 day 1), and thereafter at 
6 weeks, 3 months, 6 months, 12 months, 18 months and 24 months after the start of treatment, 
before drug administration and before any tumor assessments are communicated to the patient.  
Questionnaires should continue to be completed at the scheduled time-points (including beyond study 
termination), until the patient has progressive disease or starts a different course of anti-tumor 
treatment, whichever comes first.  One person in each center will be designated to take responsibility 
for the administration, collection, and verification of the QLQ forms.  Further details regarding QLQ 
administration are provided separately to on-site staff.  An online questionnaire may also be available. 
 
1.10.6 Neuropathy measurements 
 
Cellular functions that rely on tubulin, such as axonal transport and cytoskeletal support of 
transmembrane proteins, may also be affected when cells are treated with microtubule inhibitors. In 
paclitaxel induced neuropathy, these disruptions lead to axonal atrophy of large diameter peripheral 
nerve axons (Sahenk, Barohn et al. 1994; Persohn, Canta et al. 2005). Patients with taxane-induced 
neuropathy present with neuropathic pain, dyesthesias, parathesias in a stocking-and-glove pattern, 
decreased deep tendon reflexes, increased vibration thresholds, decreased sensory nerve action 
potential amplitudes, and distal muscle weakness (Lipton, Apfel et al. 1989; Chaudhry, Rowinsky et 
al. 1994; New, Jackson et al. 1996; Forsyth, Balmaceda et al. 1997). 
 
Investigators at UCSF have developed a 10-point Modified Total Neuropathy Score (mTNS) and 
validated the measure in a group of 40 patients (Wampler, Miaskowski et al. 2006). It is inexpensive, 
noninvasive, and can be performed by a health care provider in less than ten minutes. 


Protocol #: 11996 
Page 16 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
 
The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 
(FACT/GOG-Ntx) questionnaire is an eleven-item subscale (Ntx subscale) that evaluates symptoms 
and concerns associated specifically with chemotherapy-induced neuropathy. It assesses levels of 
patient neuropathy, severity of toxicity, and patient quality of life and has been validated (Calhoun, 
Welshman et al. 2003). 
 
The mTNS and FACT/GOG-NTX assessments will take place by a health care provider at baseline 
(within 7 days of cycle 1 day 1), and at the start of each cycle and study termination. It will be 
performed before drug administration and before any tumor assessments are communicated to the 
patient. Assessments will take place until the patient has progressive disease, starts a different 
course of anti-tumor treatment, or until 12 months from time of enrollment on study, whichever comes 
first. One person in each center will be designated to take responsibility for the collection and 
verification of the mTNS and FACT/GOG-Ntx forms. Further details regarding mTNS and 
FACT/GOG-Ntx administration are provided separately to on-site staff. 
 
 


Protocol #: 11996 
Page 17 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
2.0  
OBJECTIVES 
 
2.1  
Phase Ib 
 
Primary Objective: 
1. Determine the maximum tolerated dose (MTD) of eribulin in combination with cyclophosphamide 
in patients with any solid tumor. 
 
Secondary Objectives: 
1. Evaluate the safety of treatment with the combination of eribulin and cyclophosphamide in 
patients with any solid tumor. 
2. Determine the dose-limiting toxicities (DLTs) of eribulin in combination with cyclophosphamide in 
this cohort.  
3. Characterize the pharmacokinetics (Bettmann, Dake et al.), including evaluating the potential for 
drug-drug interaction of eribulin and cyclophosphamide. 
4. Evaluate quality of life endpoints using assessment tools EORTC QLQ-C30, FACT/GOG-Ntx and 
10-point Modified Neuropathy Score. 
5. Explore the relationships between the combination of eribulin/cyclophosphamide 
pharmacodynamic, pharmacogenomic and response prediction biomarkers. 
a. Explore single-nucleotide polymorphism (SNP) variations evaluating potential toxicities 
including peripheral neuropathy and bone marrow suppression. 
b. Perform circulating tumor cell (CTC) analysis to enumerate and sort CTCs, and perform 
exploratory analyses evaluating WGA and β-tubulin expression in CTCs. 
c. Evaluate archival tumor specimens for exploratory markers of target validation and response, 
including, but not limited to tubulin mutations and comparative analysis with CTC aCGH 
analysis. 
 
2.2  
Phase II 
 
Primary Objective: 
1. Estimate the clinical benefit rate (complete response, partial response, and stable disease) of the 
combination of eribulin and cyclophosphamide in patients with advanced breast cancer. 
 
Secondary Objectives: 
1. Make a preliminary assessment of efficacy of this combination in patients with advanced breast 
cancer including response rate, duration of response and time to progression.  
2. Evaluate the safety of this combination in an expanded cohort of patients. 
3. Evaluate quality of life endpoints using assessment tools EORTC QLQ-C30, FACT/GOG-Ntx and 
10-point Modified Neuropathy Score. 
4. Explore the relationships between the combination of eribulin/cyclophosphamide 
pharmacodynamic, pharmacogenomic and response prediction biomarkers. 
a. Explore single-nucleotide polymorphism (SNP) variations evaluating potential toxicities 
including peripheral neuropathy and bone marrow suppression. 
b. Perform circulating tumor cell (CTC) analysis to enumerate and sort CTCs, and perform 
exploratory analyses evaluating WGA and β-tubulin expression in CTCs. 
c. Evaluate archival tumor specimens for markers of target validation and response, including, 
but not limited to tubulin mutations and comparative analysis with CTC aCGH analysis. 


Protocol #: 11996 
Page 18 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
3.0  
PATIENT SELECTION 
 
3.1  
Subject Inclusion Criteria 
 
1. Phase Ib:  Patient must have histologically or cytologically documented solid tumor 
malignancies. 
Phase II:  Patients must have histologically or cytologically confirmed locally advanced, 
unresectable or metastatic carcinoma of the breast. 
 
2. Patient is male or female and ≥18 years of age on the day of signing informed consent. 
 
3. Patient must have performance status of 0-2 on the ECOG Performance Scale and life 
expectancy > 3 months. 
 
4. Patients with ≤ grade 1 peripheral neuropathy are eligible for this trial using the CTCAE v4.0, 
regardless of use of therapy for neuropathy including gabapentin. 
 
5. Patient must have evaluable disease. Measureable disease is not required 
 
6. Patient must have adequate organ function as indicated by the following laboratory values: 
 
Table 3-1. Adequate Organ Function Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC6 
≥1,000/μL 
Platelets 
≥100,000/μL 
Hemoglobin 
≥9 g/dL  
Renal 
 
Serum creatinine  
or calculated creatinine clearance† 
≤1.5 x upper limit of normal (ULN) OR 
≥60 mL/min for patients with creatinine levels >1.5 x 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤1.5 x ULN  OR direct bilirubin ≤ ULN for patients with 
total bilirubin levels >1.5 x ULN 
AST (SGOT) and ALT (SGPT) 
≤3 x ULN or ≤5 x ULN in patients with known liver 
metastasis 
Metabolic 
 
Potassium§ 
in normal range 
 
† 
Creatinine clearance should be calculated per institutional standard. 
§ 
Patients with hypokalemia at screening must be corrected prior to initiating treatment. 
 
7. Female patient of childbearing potential must have a negative serum or urine pregnancy test 
β-hCG within 72 hours prior to receiving the first dose of study medication and agree to the 
use of effective methods of contraception while on study. 
 
8. Any number of prior lines of chemotherapy in the metastatic setting is allowed. 
 
9. Concomitant use of bisphosphonates is allowed. 
 
10. Patients with stable and clinically insignificant CNS disease are allowed. Patients must be off 
steroids with no new CNS symptoms or findings on radiographic imaging for 1 month. 
 
11. Patients willing and able to complete the questionnaires. 
 


Protocol #: 11996 
Page 19 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
12. Patients willing and able to comply with the study protocol for the duration of the study. 
 
13. Written informed consent prior to any study-specific screening procedures with the 
understanding that the patient may withdraw consent at any time without prejudice. 
 
3.2  
Subject Exclusion Criteria 
 
A patient meeting any of the following criteria is not eligible to participate in this study: 
 
1. Patients who have had chemotherapy or radiotherapy within two weeks, 4 weeks for 
nitrosoureas, mitomycin C, pegylated-doxorubicin and one half-life for bevacizumab, 
hormone therapy within one week, trastuzumab within 2 weeks or lapatinib within one week 
of study Day 1.  
 
2. If the patient has residual toxicity from prior treatment, toxicity must be ≤ Grade 1. 
 
3. Patients with non-healing surgical wounds. Patients must be at least two weeks from a major 
surgical procedure, and surgical wounds must be completely healed. 
 
4. Patients with known active CNS metastases and/or carcinomatous meningitis. However, 
patients with CNS metastases who have completed a course of therapy would be eligible for 
the study provided they are clinically stable for at least 1 month prior to entry as defined as: 
a. no evidence of new or enlarging CNS metastasis 
b. off steroids that are used to minimize surrounding brain edema. Patients with clinically 
insignificant brain metastases that do not require treatment are eligible. 
 
5. Patients with known hypersensitivity to the components of study drug or its analogs. 
 
6. Significant cardiovascular impairment: 
a. Congestive heart failure, Clinically significant cardiac arrhythmia, history or current 
evidence of a myocardial infarction during the last 6 months, and/or a current ECG 
tracing that is abnormal in the opinion of the treating Investigator, or unstable angina 
b. QTc prolongation >480 msec (Bazett's Formula) or congenitally long QT syndrome 
 
7. Severe/uncontrolled concurrent illness/infection 
 
8. Patients with other active, current primary malignancies, other than carcinoma in situ of the 
cervix or non-melanoma skin cancer 
 
 
9. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative 
 
10. Patient is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study. 
 
11. Patients with other significant disease or disorders that, in the Investigator’s opinion, would 
exclude the patient from the study 
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 


Protocol #: 11996 
Page 20 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
4.0  
SUBJECT REGISTRATION AND ENROLLMENT 
 
4.1  
Subject Recruitment & Study Sites 
 
Patients will be screened by the medical oncologists in the oncology practice clinics at participating 
sites.  Patients to be screened will include those currently followed in these practices, as well as 
those referred from outside providers. 
 
4.2  
Registration Procedures 
 
After eligibility screening, patients selected to participate will be registered with the local study 
site/institution first, then with the lead/coordinating center at University of San Francisco-California 
Helen Diller Family Comprehensive Cancer Center.  
 
4.2.1 
Institutional Registration 
 
Patient registration at each study site/institution will be conducted according to the institution’s 
established policies. Prior to registration, patients will be asked to sign and date an Institutional 
Review Board (IRB)-approved consent form and a research authorization form/Heath Insurance 
Portability and Accountability Act (HIPAA) authorization form. Patients must be registered with the 
institution before beginning any treatment or study activities. 
 
4.2.2 
Lead Center Registration 
 
To initiate lead center registration, local study sites/institutions should forward copies of the signed 
informed consent, research authorization/HIPAA forms, and the completed and signed eligibility 
checklist and any supporting source documentation to clinical research coordinator (CRC) at the lead 
center by fax to the number on Page 1. The CRC will check the forms for completeness and contact 
the site regarding any discrepancies 
 
The lead center will then assign a unique patient study identification number, and send a confirmation 
of patient registration to the local CRC via electronic mail. A copy of this confirmation will be retained 
by both the lead center and local institution. All future study documentation related to that patient 
should include the assigned patient ID number. 
 
A patient cannot be treated until confirmation of enrollment is received. 
 
 
5.0  
STUDY DESIGN AND TREATMENT PLAN 
 
5.1  
Dose and schedule 
 
Table 5-1. Dose Escalation Schedule 
 
Dose Level 
Dose* 
Eribulin mesylate 
(mg/m2) 
Cyclophosphamide 
(mg/ m2) 
Number of patients 
Phase Ib 
Level -1 
0.7 day 1, 8 
600 day 1 
3-6 
Level 0 (start) 
1.1 day 1, 8 
600 day 1 
3-6 
Level 1 
1.4 day 1, 8 
600 day 1 
3-6  
Phase II 
 
MTD determined in 
phase I 
600 day 1 
40 
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. 


Protocol #: 11996 
Page 21 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Phase Ib: The study will follow a standard dose-confirmation schema (phase Ib portion) with 3 to 6 
patients per cohort (3+3 design) for a total of 9-18 patients with any solid tumor malignancy. The 
starting dose level will consist of eribulin mesylate 1.1 mg/ m2 on days 1 and 8 followed by 
cyclophosphamide 600 mg/ m2 on day 1 of a 21-day cycle.  
 
If no DLTs are observed in the first three patients, the dose of eribulin will be escalated to the 
next dose level for the subsequent patients. 
 
If one of three patients experiences a DLT, three additional subjects will be enrolled in that 
expanded cohort for a total of no more than 6 patients in each cohort. 
 
If no additional DLT is observed at the expanded dose level, i.e. 5 of 6 do not experience DLT 
during the first cycle, the dose of eribulin will be escalated to the next level. 
 
If 2 or more dose-limiting toxicities (DLTs) during the first cycle of therapy at any dose level 
occur, escalation will cease and cohort expansion will continue at the next lower dose level.  
 
All patients at a given dose level will be followed on treatment for at least 3 weeks (one cycle) 
before accrual to the next cohort can commence.  
 
There will be no intra-patient dose escalation allowed.  
 
For any dose cohort, if a patient is removed from study for reasons that are clearly not 
treatment-related, then an additional patient will be accrued to that dose level.  
 
For the purposes of Phase Ib dose escalation, DLTs will be defined as any treatment-related 
toxicity occurring within the first 21 days of combination therapy as grade 3 or 4 clinically 
evident non-hematologic toxicity; grade 4 neutropenia or thrombocytopenia lasting > 7 days 
or febrile neutropenia; or any clinically significant toxicity grade 2 or higher that requires more 
than 14 days to resolve.  
 
The highest dose level at which no more than one of six subjects experience DLT defines the 
MTD. Once the MTD has been defined, enrollment of subjects into the dose-expansion 
(Phase II) study in advanced breast cancer patients will commence. 
 
Phase 1b will be conducted at UCSF. 
 
Phase II: The dose-expansion (phase II portion) will enroll 40 patients with advanced breast cancer to 
detect a clinically meaningful benefit rate (efficacy and response) of at least 25% in the study cohort.  
Phase 2 will be conducted at multiple sites, to be determined. Using a two-stage Simon’s minimax 
design, the null and alternative hypothesis will be H0: p0 < 10% versus Ha: p1 > 25% for proportion of 
patients with complete or partial response by RECIST criteria. Based on defined p0=10% and 
p1=25% under the type I error of 5% and the type II error rate of 20%, the sample size for the first 
stage will be 22 patients. If 2 or fewer responses are observed in the first 22 patients (after all patients 
in the first stage have completed at least 2 months of treatment), the study will be terminated in the 
first stage; otherwise, the study will be expanded by additional 18 patients. If there are 7 or fewer 
responses are observed by the end of the second stage, no further investigation of the drug is 
warranted. If the clinical benefit rate is less than 10%, the probability of ending the study during the 
first stage is 62%. If the clinical benefit rate is greater than 25%, the probability that the study will be 
stopped in the first stage is 6%. 
 
5.2  
Dose-Limiting Toxicity Phase Ib 
 
Toxicities will be graded in severity according to the guidelines outlined in the NCI-CTCAE version 
4.0, published date 28-May-2009. Dose-limiting hematologic and non-hematologic toxicities will be 
defined differently, and will be based on events occurring during the first cycle of study drug 
administration (weeks 1-3). To be considered a dose-limiting toxicity (DLT), an adverse experience 
must be related to study drug, and must not be related to disease progression or intercurrent 
illnesses. 
 


Protocol #: 11996 
Page 22 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Patients must receive ≥1 of 2 weekly treatments of eribulin during the first cycle in order to be 
evaluable for DLT. If therapy is delayed >14 days during the first cycle attributable to study drug, this 
is considered a DLT and the patient will not be replaced. If therapy is delayed due to another reason, 
the patient will be replaced. 
 
5.2.1 
Hematologic dose-limiting toxicity 
 
 
Grade 4 neutropenia lasting for ≥7 days in duration despite growth factor support. GCSF 
(Filgrastim) or Pegylated-GCSF (Neulasta) may be administered.  Filgrastim may be 
used for ANC < 1000 at any time, or as prophylaxis in patients at risk for neutropenia.    
GCSF may not be administered within 24 hours of a chemotherapy infusion. When 
administered, this does not constitute a DLT. 
 
 
Grade 4 neutropenia with fever >38.5° C and/or infection requiring antibiotic or anti-fungal 
treatment 
 
 
Grade 4 thrombocytopenia (≤25.0 x 109/L) 
 
 
Grade 3 thrombocytopenia complicated by bleeding and/or requiring platelet or blood 
transfusion 
 
5.2.2 
Non-hematologic dose-limiting toxicity 
 
This will be defined as any Grade ≥3 non-hematologic toxicity, with the specific exception of: 
 
 
Grade 3 nausea or Grade 3 vomiting that in the opinion of the investigator/sponsor 
occurs in the setting of inadequate compliance with supportive care measures and lasts 
for less than 48 hours. 
 
 
Grade 3 diarrhea that in the opinion of the investigator/sponsor occurs in the setting of 
inadequate compliance with supportive care measures and lasts for less than 48 hours.  
 
 
Grade 3 dehydration that in the opinion of the investigator/sponsor occurs in the setting of 
inadequate compliance with supportive care measures and lasts for less than 48 hours. 
 
 
Alopecia 
 
 
Asthenia 
 
 
Inadequately treated (in the opinion of the investigator/sponsor) hypersensitivity reactions 
 
 
Grade 3 elevated transaminases of ≤1 week in duration. In patients with known liver 
metastases and abnormal LFTs at baseline, grade 3 elevated transaminases of ≤1 week 
in duration must be ≥2x baseline to meet criteria for DLT. 
 
 
Grade 3 total hyperbilirubinemia if <35% is direct component 
 
 
Hyperglycemia: isolated non-fasting Grade 3 glucose values or Grade 3 hyperglycemia 
that in the opinion of the investigator/sponsor occurs in the setting of inadequate 
compliance with supportive care measures. 
 
The following will be considered DLT: 
 
 
≥ Grade 3 electrolyte (Na, K, Ca, Mg, Cl, phosphate, and bicarbonate) abnormalities due 
to glucose intolerance and not attributable to another cause 


Protocol #: 11996 
Page 23 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
 
 
Symptomatic bradycardia 
 
 
Persistent increases in QTc interval (>60 milliseconds from baseline and/or >500ms) 
 
 
Treatment delay of greater than 14 days  
 
 
Failure to administer ≥75% of the planned study drugs during cycle 1 as a result ≥ Grade 
2 treatment-related toxicity 
 
Subjects who fail to complete the first cycle due to reasons other than toxicity will be classified as not 
evaluable for toxicity, and will be replaced as in Section 5.1. No dose reductions can occur within the 
DLT window, see Table 6-1. 
 
5.3  
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies: 
 
Disease progression 
 
Need for exclusionary concurrent treatment 
 
Unacceptable toxicity 
 
Patient decides to withdraw from the study 
 
Protocol non-compliance 
 
Study is completed or terminated 
 
The reason for study removal and the date the patient was removed must be documented in the data 
management system. 
 
5.4  
Conditions for Terminating the Study 
 
The Principal Investigator may terminate the study for any of the following reasons: 
 
Significant toxicities 
 
The study treatment is less effective than standard treatment 
 
Completion of all study data. 
 
 
6.0  
TOXICITY MANAGEMENT AND DOSE MODIFICATION 
 
Toxicities will be graded for management according to NCI-CTCAE version 4.0. Eribulin and 
cyclophosphamide dose-modification guidelines are outlined in Table 6-1. 
 
Both agents should be held for all instances of febrile neutropenia (ANC < 1000/μL). GCSF 
(Filgrastim) or Pegylated-GCSF (Neulasta) growth factor support is encouraged for ANC < 1500/ μL 
and may be used at the discretion of the treating physician in order to maintain adequate blood 
counts.  Filgrastim may be used for ANC < 1000 at any time, or as prophylaxis in patients at risk for 
neutropenia.  Growth factor support is not permitted within 24 hours prior to or following any infusion. 
 
How to administer eribulin and cyclophosphamide when a delay is required: the goal is to administer 
the agents on the same day whenever possible. See table 6-1 for full details. 
 


Protocol #: 11996 
Page 24 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
6.1  
Removal of patients from study: 
 
If toxicity occurs in a patient at the 0.7 mg dose of eribulin, no further reduction will occur and the 
patient will be discontinued from the study. The dose of cyclophosphamide will not be reduced. 
 
If any treatment is held for >3 weeksdue to delayed toxicity recovery from any of the therapies, the 
patient will be removed from the study. 
 
After the first cycle, patients are allowed to miss 1 out of every 2 weeks of treatment due to 
hematologic or non-hematologic toxicity. Treatment delays are made at the discretion of the treating 
physician.  Treatment or visit delays due to public holidays, weather conditions, or natural disasters, 
do not constitute protocol violations.  The following treatment delays are allowable for patient 
coordination: 
 
Cycle 1, Day 8 – delay eribulin administration up to 1 day 
 
Cycle 2+, Day 1 – delay treatment up to 14 days 
 
Cycle 2+, Day 8 – delay treatment up to 3 days 
 
If a delay of >3 weeks in subsequent cycles (after Cycle 1) is required, the patient must discontinue 
permanently from the study protocol. 
 
6.2  
Concomitant Medications 
 
Concomitant treatments permitted: anti-emetics, anti-diarrheals, anti-allergic medications including 
antihistamines and steroids, granulocyte colony-stimulating factor/granulocyte-macrophage colony-
stimulating factor/erythropoietin is allowed in response to cytopenias, palliative radiotherapy, 
bisphosphonate treatment, weak inhibitors of CYP3A4. 
 
For patients receiving study treatment, any medication (including over-the-counter medications) will 
be recorded on the CRF (case report form).  
 
Concomitant treatments not permitted: other investigational drugs; anti-tumor therapies including 
chemotherapy, hormone therapy, radiation therapy (other than required for palliation), gene therapy, 
biologics, or immunotherapy. 
 
Use of strong CYP3A4 inhibitors should be avoided: ketoconazole, itraconazole, clarithromycin, 
nefazadone, saquinavir, telithromycin, ritonavir, indinavir, nefinavir. See Appendix B. Grapefruit juice 
may also increase plasma concentrations of eribulin and should be avoided. 
 
Caution should be used when administering mild or moderate CYP3A4 inhibitors during treatment, 
and alternative therapeutic agents that do not inhibit CYP3A4 should be considered. Patients 
receiving CYP3A4 inhibitors during treatment should be monitored closely for acute toxicities (e.g 
blood counts in between cycles.) See Appendix B. 
 
Caution should be used for CYP3A4 substrates with a narrow therapeutic index.See Appendix B.  
 
6.3  
Supportive Care Guidelines 
 
Patients should be treated with supportive care measures at the discretion of the treating physician 
according to standard practices guidelines. 
 
Diarrhea:  Anti-diarrheal agents should not be taken prophylactically. Patients should be instructed to 
begin taking anti-diarrhea medication at the first sign of poorly formed or loose stool, occurrence of 
more bowel movements than usual in one day, or unusually high volume of stool. Anti-diarrheal 
agents should be deferred if blood or mucus is present in the stool or if diarrhea is accompanied with 
fever.  In this setting, an infectious etiology must be considered and excluded. 


Protocol #: 11996 
Page 25 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
 
Rash:  Skin rash and can be treated with standard topical steroids and/or oral antibiotics, 
antihistamines, sulfadiazine, or even a short course of oral steroids (less than 7 days) if clinically 
indicated. 
 
Nausea/Vomiting:  Anti-emetic therapy beyond routine premedication is not necessary, but 
symptomatic patients should be treated with standard anti-emetic medications including a 5HT3 
receptor antagonist.  
 
Anemia:  Transfusions and/or erythropoietin may be utilized as clinically indicated for the treatment of 
anemia after the first cycle. 
 
Neutropenia:  GCSF (Filgrastim) or Pegylated-GCSF (Neulasta) may be administered to treat ANC < 
1000 at any time, or as prophylaxis in patients at risk for neutropenia. GCSF may not be administered 
within 24 hours of a chemotherapy infusion. 
 
Hypersensitivity/Allergic reaction:  Hypersensitivity reactions will be managed by the treating 
physician per standard protocols. Whether to rechallenge the patient or discontinue the offending 
agent will be decided by the treating physician. Dose reductions will not be made for hypersensitivity 
reactions. 
 
 
 


Protocol #: 11996 
Page 26 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
 
Table 6-1. Toxicity management guidelines for eribulin and cyclophosphamide 
Toxicity 
NCI-CTC grade, 
unless otherwise 
specified 
management of 
eribulin 
eribulin dose 
upon resumption 
management of 
cyclophosphamide 
cyclophosphamide 
dose upon 
resumption 
Neutropenia (ANC <1000) 
+/- fever (T>38) 
1st episode 
hold until afebrile and 
ANC ≥ 1000 
no change and 
add filgrastim 
hold until afebrile and 
ANC ≥ 1000 
no change and add 
filgrastim  
  
2nd episode 
hold until afebrile and 
ANC ≥ 1000 
no change 
hold until afebrile and 
ANC ≥ 1000 
reduce to 500 mg/m2 
and continue 
filgrastim 
  
3rd episode 
hold until afebrile and 
ANC ≥ 1000 
reduce by one 
dose level 
hold until afebrile and 
ANC ≥ 1000 
continue 500 mg/m2; 
continue filgrastim 
  
4th episode 
remove from study 
remove from 
study 
remove from study 
remove from study 
Thrombocytopenia 
Grade 2 or 
greater (<75K) 
hold until ≥ 75K 
no change 
hold until ≥ 75K 
reduce to 500 mg/m2 
  
Recurrent grade 2 
or greater 
 hold until ≥75K 
reduce by one 
dose level 
hold until ≥ 75K 
no change 
  
3rd occurrence 
grade 2 or greater 
hold until ≥ 75K 
no change 
hold until ≥ 75K 
reduce to 400 mg/m2 
  
4th occurrence 
grade 2 or greater 
remove from study 
remove from 
study 
remove from study 
remove from study 
Rash 
1 or 2 
continue treatment; 
supportive care 
no change** 
continue treatment 
no change 
  
3 
Hold until grade 1 or 
less; supportive care 
no change** 
Hold until grade 1 or less 
no change 
  
Recurrent grade 3 
Hold until grade1 or 
less; 
supportive care 
reduce by one 
dose level  
Hold until grade 1 or less 
no change 
  
3rd occurrence  
grade 3 
remove from study; 
supportive care 
remove from 
study 
remove from study 
remove from study 
 
 
 


Protocol #: 11996 
Page 27 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Toxicity 
NCI-CTC grade, 
unless otherwise 
specified 
management of 
eribulin 
eribulin dose 
upon resumption 
management of 
cyclophosphamide 
cyclophosphamide 
dose upon 
resumption 
GI toxicity: diarrhea, 
nausea, vomiting 
1, 2 
Continue treatment 
no change; 
maximize 
supportive 
treatment 
no change; maximize 
supportive treatment 
no change; 
maximize 
supportive 
treatment 
  
3 
Hold until grade 1 
or less  
no change 
hold until grade 1 or less 
no change 
  
recurrent 3  
Hold until grade 1 
or less  
no change 
hold until grade 1 or less 
reduce to 500 mg/ 
m2 
  
3rd occurrence  
Hold until grade 1 
or less  
reduce by one 
dose level 
hold until grade 1 or less  
no change 
  
4th occurrence 
grade 3 or 4 
remove from study 
remove from 
study 
remove from study 
remove from study 
Liver function abnormalities 
(ALT, AST, Alk Phos only) 
1, 2 
Continue treatment 
no change 
Continue treatment 
no change 
 
3 and > 2x baseline 
Hold until less than 
grade 3 
no change 
Hold until less than grade 
3 
Reduce to 500 mg/ 
m2 
 
recurrent 3 and > 
2x baseline 
 Hold until less than 
grade 3 
reduce by one 
dose level 
Hold until less than grade 
3 
no change 
  
4th occurrence 
grade 3 or 4 
remove from study 
remove from 
study 
remove from study 
remove from study 
Neuropathy (motor and 
sensory) 
1, 2 
continue treatment 
no change 
continue treatment 
no change 
 
3  
Hold until less than 
grade 3 
 no change 
Hold until less than grade 
3 
no change 
 
Recurrent 3 
Hold until less than 
grade 3 
 reduce by one 
dose level 
Hold until less than grade 
3 
no change 
 
3rd occurrence 3 
remove from study 
remove from 
study 
remove from study 
remove from study 
* A cycle is a 3-week course. If treatment needs to be held for >48 hours, the dose should be held for that week and resumed the following 
week. If doses are held for more than 3 weeks, the patients must be removed from study. 
** If Grade 2 rash develops but resolves to grade ≤ 1 within 7 days allowing the patient to resume treatment, the patient should be restarted at 
the same dose. 


Protocol #: 11996 
Page 28 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
7.0  
DRUG INFORMATION 
 
7.1  
Eribulin mesylate (Halaven™) 
 
(Source: FDA-approved product insert, dated 11/2010) 
 
Classification: microtubule inhibitor 
 
Mode 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. 
 
Metabolism: Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to 
patients, approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin 
accounted for approximately 88% and 91% of the dose in feces and urine, respectively. 
 
Storage and Stability: 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 eribulin 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 eribulin for up to 4 hours at room 
temperature or up to 24 hours under refrigeration. 
 
Discard unused portions of the vial. 
 
Preparation and administration: Eribulin 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).  
 
Aseptically withdraw the required amount of eribulin from the single-use vial and administer undiluted 
or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP as IVP over 2-5 minutes. 
 
Patient care implications:  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. 
 
Incompatibilities/Contraindication: No drug-drug interactions are expected P-gp inhibitors.  
Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro. Eribulin inhibits CYP3A4 
activity in human liver microsomes, but it is unlikely that eribulin will substantially increase the plasma 
levels of CYP3A4 substrates. However, strong CYP3A4 inhibitors and inducers will be prohibited in 
this study, see Appendix B. 
 
Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or 
induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. Eribulin 
is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes 
 
There are no known contraindications. 
 
Side Effects: 
 
Common side effects: 
Neutropenia 
Anemia 
asthenia/fatigue 
alopecia 
peripheral neuropathy 
nausea 
constipation 


Protocol #: 11996 
Page 29 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
 
Less common side effects: 
lacrimation 
dyspepsia 
abdominal pain 
stomatitis 
dry mouth  
peripheral edema 
upper respiratory tract infection 
hypokalemia  
muscle spasms, muscular weakness  
dysgeusia, dizziness  
insomnia, depression  
rash 
liver function test changes 
 
Cardiac toxicity: 
QT prolongation has rarely been observed.  ECG and electrolyte (potassium and magnesium) 
monitoring is recommended in patients with history of heart failure or bradyarrhythmias and in 
patients using drugs known to prolong the QT interval.  Eribulin should be avoided in patients with 
congenital long QT syndrome. 
 
Availability: Eribulin mesylate injection, 1 mg/2 mL, in a single-use vial. One vial per carton.  Drug will 
be provided by Eisai, Inc and will investigationally labeled, but is identical in formulation to the 
commercial product. 
 
Accountability: Drug accountability records will be maintained by the investigational pharmacy as per 
standard pharmacy practice.  Eisai will request drug accountability confirmation on a periodic basis. 
Standard information such as drug supply utilized and supply remaining will be requested. 
 
Unused or expired drug will be destroyed by USCF per standard operating procedures and a 
certificate of destruction (including product lot and expiry, amount destroyed and method of 
destruction) will be provided to Eisai. 
 
7.2  
Cyclophosphamide (Cytoxan®) 
 
Product description:  Lyophilized CYTOXAN® (cyclophosphamide for injection, USP) is a sterile white 
lyophilized cake, or partially broken cake, containing 75 mg mannitol per 100 mg cyclophosphamide 
(anhydrous).  Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen 
mustards. Cyclophosphamide is a white crystalline powder with the molecular formula 
C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. The chemical name for cyclophosphamide 
is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate. 
Cyclophosphamide is soluble in water, saline, or ethanol and has the following structural formula.  
Please refer to the package insert for complete product details.  
 
Classification: Alkylating agent 
 
Mode of Action: Cyclophosphamide is biotransformed principally in the liver to active alkylating 
metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the 
growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to 
involve cross-linking of tumor cell DNA. 
 
Metabolism: Cyclophosphamide is well absorbed after oral administration with a bioavailability greater 
than 75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated primarily 
in the form of metabolites, but from 5 to 25% of the dose is excreted in urine as unchanged drug. 
Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma. 
Concentrations of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose. 
 
Storage and Stability: Storage at or below 77°F (25°C) is recommended; this product will withstand 
brief exposure to temperatures up to 86°F (30°C) but should be protected from temperatures above 
86°F (30°C). 
 


Protocol #: 11996 
Page 30 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Reconstituted Lyophilized CYTOXAN are chemically and physically stable for 24 hours at room 
temperature or for six days in the refrigerator; it does not contain any antimicrobial preservative and 
thus care must be taken to assure the sterility of prepared solutions. 
 
Preparation: Refer to the package insert for standard preparation instruction.  Parenteral drug 
products should be inspected visually for particulate matter and discoloration prior to administration, 
whenever solution and container permit. 
 
Lyophilized CYTOXAN should be prepared for parenteral use by adding Sterile Water for Injection, 
USP, to the vial and shaking to dissolve. Use the quantity of diluent shown in the package insert. 
 
Administration: Route of administration:  Cyclophosphamide will be administered as an IV infusion 
over 60-120 minutes. 
 
Solutions of Lyophilized CYTOXAN will be infused intravenously in the following: Dextrose Injection, 
USP (5% dextrose); Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sodium 
chloride); 5% Dextrose and Ringer’s Injection; Lactated Ringer’s Injection, USP; Sodium Chloride 
Injection, USP (0.45% sodium chloride); Sodium Lactate Injection, USP (1/6 molar sodium lactate). 
 
Patient care implications: To minimize the risk of dermal exposure, always wear impervious gloves 
when handling vials containing CYTOXAN sterile powder for injection.  This includes all handling 
activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during 
unpacking and inspection, transport within a facility, and dose preparation and administration. 
 
Incompatibilities/Contraindications: Continued use of cyclophosphamide is contraindicated in patients 
with severely depressed bone marrow function. Cyclophosphamide is contraindicated in patients who 
have demonstrated a previous hypersensitivity to it. 
 
Side Effects: 
 
Myelosuppression 
Liver function test abnormalities 
Impairment of fertility 
Rash  
Skin pigmentation changes 
Nail changes 
Stevens-Johnson syndrome 
Congestive heart failure 
Infusion-related symptoms such as fever, chills, 
rigors, headache 
Abdominal discomfort 
Nausea 
Vomiting 
Diarrhea 
Mucositis, oral ulceration 
Alopecia 
Anorexia 
Pain 
Hemorrhagic cystitis  
Hemorrhagic ureteritis  
Urinary bladder fibrosis 
Renal tubular necrosis  
Hemorrhagic colitis 
Intersitital pnemonitis 
Intersitital pulmonary fibrosis 
Jaundice 
Infections 
Secondary malignancy 
Anemia, thrombocytopenia, leukopenia, 
neutropenia 
Anaphylaxis 
SIADH 
Malaise 
Asthenia 
 
Availability: CYTOXAN® (cyclophosphamide for injection, USP) contains cyclophosphamide 
monohydrate and is supplied in vials for single-dose use. 
 
Accountability: Drug accountability records will be maintained by the investigational pharmacy as per 
standard pharmacy practice. 
 
 
 


Protocol #: 11996 
Page 31 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
8.0  
CORRELATIVE/SPECIAL STUDIES 
 
8.1  
Pharmacokinetic (PK) Studies 
 
Whole blood for pharmacokinetic assessments of eribulin and cyclophosphamide will be drawn in 6  
mL tubes on Cycle 1 Day 1 pre-dose, at the end of eribulin infusion, and at 15 min, 30 min, hour 1, 2, 
3, 4, 6 and 8 after the end of eribulin.  Participation in the pharmacokinetic assessment portion of the 
protocol, i.e. recruitment during dose-escalation will be limited to patients enrolled in the Phase Ib 
portion of the trial. 
 
Description of collection, handling and shipping procedures of PK samples will be provided in 
Appendix F. 
 
Handling of Specimens(s) – Standard phlebotomy handling 
 
Site(s) Performing Correlative Study – XenoBiotic Laboratories, Inc. 
 
Shipping of Specimen(s) –  
Blood will be processed and shipped on dry ice by overnight mail on Monday-Wednesday to: 
 
 
 
 
 
 
 
Notification on the day of shipping should be sent to: 
 
 
8.2  
Circulating Tumor Cells  
 
Collection of Specimen(s) 
Three tubes of blood will be collected at baseline, either during screening assessments or Cycle 1 
Day 1 prior to treatment (2 CellSave tubes and 1 purple top tube) in each patient. 7.5 mL of blood is 
required per CellSave tube, it is critical that the tube be completely filled. 10mL is required in each 
purple top tube. One CellSave tube will be used for CTC enumeration, the second CellSave tube will 
be used for sorting and WGA with CGH/sequencing. The purple top tube will be used for gene 
expression if there is adequate sample.  If the first sample has ≥ 5 CTC/mL, on Cycle 2 Day 1, 1 
CellSave and 1 purple top tube will be collected for CTC enumeration and aCGH/gene expression. 
 
2 CellSave tubes and 1 purple top tube should be obtained at end of study if at all possible. 
 
Handling of Specimens(s) – Standard phlebotomy handling 
 
Site(s) Performing Correlative Study – John Park MD laboratory, UCSF 
 
Shipping of Specimen(s) –  
UCSF:  No shipment is required.  Samples will be hand-delivered at room temperature to the Park 
laboratory immediately after they are obtained and processed immediately. 
 
Outside sites:  Blood will be shipped at room temperature by overnight mail to: 
 
  
 
 


Protocol #: 11996 
Page 32 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Notification on the day of shipping should be sent to: 
  
 
Special instructions will be provided for Friday shipping. 
 
8.3  
Pharmacogenomic (PG studies)  
 
One 7.5 mL purple top tube will be collected at baseline, either during screening assessments or 
Cycle 1 Day 1 prior to treatment. DNA extraction and analysis for three novel candidate genes which 
may relate to development of peripheral neuropathy, FZD3, FGD4 and EPHA5 will be performed. 
Other exploratory analysis may also be performed. If adequate sample remains, a genome scan at 
UCSF may also be performed. 
 
Handling of Specimens(s) – Standard phlebotomy handling 
 
Site(s) Performing Correlative Study – Deanna Kroetz laboratory, UCSF 
 
Shipping of Specimen(s) –  
UCSF:  No shipment is required.  Samples will be sent by courierat room temperature to the Kroetz 
laboratory immediately after they are obtained and processed immediately. 
 
Outside sites:  Blood will be shipped at room temperature by overnight mail to: 
 
 
 
 
8.4  
Archived Tissue Analysis 
 
Collection of Specimen(s) 
FFPE (formalin-fixed paraffin embedded) archived tumor blocks from prior surgery or biopsies with 
corresponding H&E slides, will be requested for all patients, although they are not required and 
should not delay enrollment. If necessary, the research team will contact outside institutions to obtain 
specimens.  
 
All patients consenting to this protocol will be presented with a Tumor Specimen Release Form. 
These specimens will become the property of UCSF Cancer Center and will be stored at the Cancer 
Center Tissue Core at UCSF 
. 
 
Mutational analyses will be performed on tumor tissue and correlated with results from CTC studies 
described above. 
 


Protocol #: 11996 
Page 33 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
9.0  
STUDY PROCEDURES 
 
9.1  
Screening assessments 
 
Screening radiographic studies, EKG, and laboratory studies must be performed within 30 days of 
starting protocol therapy. 
 
If laboratory studies are performed within 14 days of starting protocol therapy, these can serve as day 
one values. 
 
 
CT scan of chest/abdomen/pelvis 
 
Bone scan for patients with known or suspected bone metastases 
 
PET/CT scan with a diagnostic CT may be substituted for the above two scans 
 
Additional radiographic studies for known sites of disease not evaluated by the above scans 
 
EKG 
 
CBC with differential 
 
Serum biochemical panel including Na, K, HC03-, Cl-, Ca, Mg, Phos, BUN, creatinine, 
glucose, total bilirubin, AST, ALT, alkaline phosphatase 
 
Negative serum pregnancy test for females of child-bearing potential 
 
Concomitant medication review 
 
9.2  
Assessments and Procedures During Treatment 
 
Once the patient is confirmed to be eligible based on screening assessments, the following study 
assessments will be performed (see also study calendar below). 
 
Each cycle will be 21 days (3 weeks). Patients will receive eribulin on day 1 and 8 and 
cyclophosphamide on day 1 of each cycle. Treatment delay of greater than 7 days or missing >1 out 
of the 2 weekly doses in the first cycle due to toxicity will be considered a DLT. If a dose is held a 
week, then that week’s dose is omitted and treatment resumes at the next scheduled infusion without 
prolongation of the 3 week cycle. 
 
Cycle 1 (Day 1) 
 
The following assessments will be performed prior to receiving treatment on Cycle 1 Day 1: 
 
Medical history, physical examination including vital signs, ECOG performance status 
 
Adverse event and con-med review 
 
CBC with differential, serum biochemical panel (labs performed for screening within 14 days 
of treatment start can be used for baseline values) 
 
EKG – to be read by a cardiologist 
 
Pharmacokinetic blood work – day 1 only 
 
Research blood work – at baseline and per schema  
 
EORTC QLQ-C30 
 
10-point Modified Total Neuropathy Score (mTNS) 
 
FACT/GOG-Ntx 
 
Cycle 1 Day 8  
 
 
CBC with differential, serum biochemical panel 
 
EKG – to be read by clinician.  If there is an unanticipated abnormal EKG, a cardiologist will 
be consulted prior to patient treatment 
 


Protocol #: 11996 
Page 34 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Cycle 2 and every cycle thereafter 
 
The following assessments will be performed on day 1 and day 8 (or within 24 hours prior) of every 
cycle: 
 
CBC with differential, serum biochemical panel 
 
For Phase 2, Day 8 visits will only occur in Cycle 2.   
 
The following assessments will be performed on day 1 of (or within 72 hours prior to) every cycle: 
 
Medical history and physical exam 
 
Adverse event and con-med review 
 
10-point Modified Total Neuropathy Score (mTNS) 
 
FACT/GOG-Ntx 
 
Imaging: 
Phase 1b (all solid malignancies) 
At 6 weeks after study start, then every 6 weeks until end of study therapy  
 
CT scan of chest/abdomen/pelvis  
 
Bone scan should be performed as indicated to evaluate change in symptoms 
 
PET/CT with diagnostic CT scan can substitute for the two above studies 
 
Additional radiographic studies for known sites of disease not evaluated by the above scans 
 
Pertinent tumor markers per treating physician’s discretion 
 
Phase II (breast cancer only) 
At 6 weeks after study start, then every 9 weeks until end of study therapy  
 
CT scan of chest/abdomen/pelvis  
 
Bone scan should be performed as indicated to evaluate change in symptoms 
 
PET/CT with diagnostic CT scan can substitute for the two above studies 
 
Additional radiographic studies for known sites of disease not evaluated by the above scans 
 
Pertinent tumor markers per treating physician’s discretion 
 
EORTC QLQ-C30 
6 weeks, 3 months, 12 months, 18 months, 24 months, and/or at study termination. 
 
9.3  
Study Termination 
 
The following assessments will be performed when the patient goes off-study: 
 
Physical exam 
 
Adverse event and con-med review 
 
CBC with differential, serum biochemical panel 
 
EORTC QLQ-C30  
 
10-point Modified Total Neuropathy Score (mTNS) 
 
FACT/GOG-Ntx 
 
Radiographic imaging of evaluable and measurable disease  
 
9.4  
Follow-up 
 
Patients’ clinical data will be collected monthly for the first 3 months after completion of the clinical 
trial, then every 6 months. These biennial assessments will continue until death or for duration of up 
to at least ten years. Patients removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event and then for at least ten years to obtain 
recurrence/survival data. 


Protocol #: 11996 
Page 35 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Table 9-1  Study Calendar 
 
Test/Study 
Pre-
study 
Cycle 1 
(Days 1-21) 
Cycle 2 
Cycle 3 and 
subsequent 
cycles 
Off 
study 
D1 
D8 
D12 
D8 
D12 
D8 
 
Medical History 
X1 
X 
 
X2 
 
X2 
 
X 
Physical Exam3 
X1 
X 
 
X2 
 
X2 
 
X 
Informed consent 
X1 
 
 
 
 
 
 
 
Inclusion/exclusion 
X1 
 
 
 
 
 
 
 
Toxicity assessment 
(including weight) 
 
 
X 
X 
X 
X 
X18 
X 
PK4 
 
X 
 
 
 
 
 
 
PG5 
X 
 
 
 
 
 
 
 
EKG6 
X1 
 
X 
 
 
 
 
 
CBC, Diff.7 
X1 
X1 
X 
X 
X 
X 
X18 
X 
Chemistry8 
X1 
X1 
X 
X 
X 
X 
X18 
X 
CTC enumeration and 
analysis9 
X 
 
 
X 
 
 
 
X 
Genome scan10 
X 
 
 
 
 
 
 
 
Archival tumor tissue 
collection11 
X 
 
 
 
 
 
 
 
Eribulin administration12 
 
X 
X 
X 
X 
X 
X 
 
Cyclophosphamide 
administration 
 
X 
 
X 
 
X 
 
 
Pregnancy Test13 
X1 
 
 
 
 
 
 
 
Staging Studies 
(RECIST)14 
X 
 
 
 
X 
 
 
X 
EORTC QOL-C30 
questionnaire15 
X 
 
 
 
X 
 
 
X 
Neuropathy 
assessment16 
X 
 
 
X 
 
X 
 
X 
FACT-GOG Ntx17 
X 
 
 
X 
 
X 
 
X 
Evaluations should continue as noted for all subsequent cycles.  Day 1 visit procedures for any cycle of therapy 
are allowed a window of ± 3 days unless otherwise noted. 
 
X1 
Pre-study tests may be used for Day 1 tests if within 2 weeks and no significant changes have occurred.  
X2 
D1 physical exam and history in subsequent cycles may be done within 72 hours prior to next cycle. 
X3 
Physical Exam includes ECOG status, vital signs, height and weight. 


Protocol #: 11996 
Page 36 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
X4 
Pharmacokinetic samples to be collected from patient at study site Day 1 pre-dose, at the end of eribulin 
infusion, and at 15 min, 30 min, 1, 2, 3, 4, 6 and 8 hours after the end of eribulin in phase Ib and analyzed 
by an outside vendor. 
X5 
Pharmacogenomic samples to be collected from patient at study site will be collected at baseline, either 
during screening assessments or Cycle 1 Day 1 prior to treatment and analyzed by Dr. Deanna Kroetz’ 
laboratory at UCSF. 
X6  
EKG will be performed at baseline and analyzed by a cardiologist.  EKG performed on cycle 1 day 8 will 
be analyzed by the clinician.  If there is an unanticipated abnormal EKG, a cardiologist will be consulted 
prior to patient treatment. 
X7 
Hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and differential.  
X8 
BUN, creatinine, sodium, potassium, chloride, CO2 (HCO3), glucose, calcium, albumin,    total protein, total 
bilirubin, alkaline phosphatase, LDH (melanoma only), AST/SGOT, ALT/SGPT, phosphorous, 
magnesium.  If total bilirubin is greater than the upper limit of normal, direct and indirect bilirubin should be 
performed. Biochemistry tests should be obtained after patient has fasted, if possible. 
X9 
CTC (circulating tumor cells) will be collected using whole blood by study site and enumerated by Dr. John 
Park’s lab at UCSF using either CellSearch or IE/FACS. The first sample will be collected on cycle 1 day 1 
collected at baseline, either during screening assessments or Cycle 1 Day 1 prior to treatment. 
Baseline/cycle 1 analysis will include genomic profiling and gene expression for tubulin mutations and 
others. If initial sample shows CTC ≥ 5/mL, a second sample with be enumerated and aCGH/gene 
expression may be performed on cycle 2 day 1. 
X10 
Genome scan to be collected by study site, processed by the DNA bank at UCSF and then analyzed at 
Dr. Kwok’s laboratory at UCSF. 
X11 
If available, archival tumor tissue will be collected from the pathology department and  analyzed for 
expression profiling including tubulin mutations and proteomics. 
X12 
Treatment delays due to patient coordination are allowed for the following:  Cycle 1, Day 8 (eribulin delay 
up to 1 day), Cycle 2+, Day 1 (treatment delay up to 14 days), and Cycle 2+, Day 8 (delay treatment up to 
3 days).  Note – treatment or visit delays due to public holidays, weather conditions, or natural disasters, 
do not constitute protocol violations.     
X13 
Pregnancy test is for women of child bearing potential and will be assessed by serum hcg. 
X14 
Baseline evaluations should be performed not more than 30 days prior to the beginning of the treatment. 
Scans should be performed as detailed in section 9.2 every 6 weeks (2 cycles) for phase Ib, and at 6 
weeks, then every 9 weeks for phase II until disease progression or end of study therapy for any reason.  
A 7 day variation in timing before or after the scheduled scan date is allowed to facilitate scheduling.If 
patients remain on study for more than one year from study start, these assessments will be optional. 
X15 
EORTC QLQ-C30 questionnaire will be performed at baseline (within 7 days of cycle 1 day) and thereafter 
at 6 weeks, 3 months, 12 months, 18 months, 24 months, and/or at study termination. Questionnaires will 
be completed prior to drug administration. 
X16 
Neuropathy will be assessed using the 10-point Modified Total Neuropathy Score (mTNS) at the start of 
each cycle and at study termination. 
X17 
Patient assessment of neuropathy will be assessed using the FACT-GOG-Ntx 11 point questionnaire at 
the start of each cycle and at study termination. 
X18 
Cycle 3+, Day 8 visits are only required for Phase 1.  For Phase 2, toxicity assessment will only be done 
on Day 1 of cycles 3 and beyond.  
 
 


Protocol #: 11996 
Page 37 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
10.0 
CRITERIA FOR EVALUATION 
 
10.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response at 6 weeks (after 2 
cycles), then every 6 weeks (phase Ib) or 9 weeks (phase II) until end of study therapy.  A one week 
window in scans is allowable to facilitate scheduling of scans; however every effort should be made to 
keep the scans on schedule. Confirmatory scans will not be performed since this is a Phase I/II trial 
and the primary endpoints are safety, toxicity, and clinical benefit rate. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 
1.1) (Eisenhauer, Therasse et al. 2009). Changes in the largest diameter (uni-dimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST 1.1 criteria. 
 
10.1.1 Response Definitions 
 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first study 
treatment. 
 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response. These patients will have their response classified according to the 
definitions stated below. (Note:  Patients who exhibit objective disease progression prior to the end of 
cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. 
The response assessment is based on the presence, absence, or unequivocal progression of the 
lesions. 
 
10.1.2 Disease Parameters 
 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter for non-nodal lesions and short axis for nodal lesions to be 
recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical 
exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 


Protocol #: 11996 
Page 38 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum. The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up. 
 
10.1.3 Methods for evaluation of measurable disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred 
to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin 
nodules). In the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. 
As with CT, if an MRI is performed, the technical specifications of the scanning sequences used 
should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the 
modality used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 1.1 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and 
diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should 
be followed as closely as possible to prior scans. Body scans should be performed with breath-hold 
scanning techniques, if possible. 


Protocol #: 11996 
Page 39 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST 1.1 measurements. If the CT performed 
as part of a PET-CT is of identical diagnostic quality to a diagnostic CT, then the CT portion of the 
PET-CT can be used for RECIST 1.1 measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised.  
 
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete clinical 
response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA 
response (in recurrent prostate cancer) have been published (Bubley, Carducci et al. 1999; Rustin, 
Quinn et al. 2004; Scher, Halabi et al. 2008).   In addition, the Gynecologic Cancer Intergroup has 
developed CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer (Vergote, Rustin et al. 2000). 
 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible new sites of disease). New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new 
lesion. 
 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at follow-up 
corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-
up is not confirmed as a new site of disease on CT, additional follow-up CT  scans are needed to 
determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. Both 
approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 


Protocol #: 11996 
Page 40 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
10.1.4 Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 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. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase. 
 
Note:  Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the Principal Investigator. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 
 


Protocol #: 11996 
Page 41 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Table 10-2. Evaluation of Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on evidence of a new 
lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression 
at that time should be reported as “symptomatic deterioration.”  Every effort 
should be made to document the objective progression even after 
discontinuation of treatment. 
 
 
Table 10-3. Evaluation of Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so 
to assign this category when no lesions can be measured is not advised 
 
10.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that progressive disease is objectively documented. 


Protocol #: 11996 
Page 42 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
Response Review:  N/A 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design/Endpoint Definitions 
 
The study will follow a standard dose-confirmation schema (phase Ib portion) with 3 to 6 patients per 
cohort (3+3 design) for a total of 9-18 patients. The starting dose level will consist of eribulin mesylate 
1.1 mg/ m2 on days 1 and 8 followed by cyclophosphamide 600 mg/ m2 on day 1 of a 21-day cycle. 
Enrollment to successive cohorts up to dose level +1 will be performed according to the table shown 
below, to establish the MTD. If 2 or more dose-limiting toxicities (DLTs) are observed at level 0, one 
dose reduction (to level -1) is built in to the study design. All patients at a given dose level will be 
followed on treatment for at least 3 weeks before accrual to the next cohort can commence. There will 
be no intra-patient dose escalation allowed. For any dose cohort, if a patient is removed from study 
for reasons that are clearly not treatment-related, then an additional patient will be accrued to that 
dose level. For the purposes of Phase I dose escalation, DLTs will be defined as any treatment-
related toxicity occurring within the first 21 days of combination therapy as grade 3 or 4 clinically 
evident non-hematologic toxicity; grade 4 neutropenia or thrombocytopenia lasting > 7 days or febrile 
neutropenia; or any clinically significant toxicity grade 2 or higher that requires more than 14 days to 
resolve. 
 
The dose-expansion (phase II portion) will enroll 40 patients to detect a clinically meaningful benefit 
rate (efficacy and response including complete response, partial response and stable disease) of at 
least 25% in the study cohort. Using a two-stage Simon’s minimax design, the null and alternative 
hypothesis will be H0: p0 < 10% versus Ha: p1 > 25% for proportion of patients with complete or 
partial response or stable disease by RECIST criteria. Based on defined p0=10% and p1=25% under 
the type I error of 5% and the type II error rate of 20%, the sample size for the first stage will be 22 
patients. If 2 or fewer responses are observed in the first 22 patients (after all patients in the first 
stage have completed at least 2 months of treatment), the study will be terminated in the first stage; 
otherwise, the study will be expanded by additional 18 patients. If there are 7 or fewer responses are 
observed by the end of the second stage, no further investigation of the drug is warranted. If the 
clinical benefit rate is less than 10%, the probability of ending the study during the first stage is 62%. 
If the clinical benefit rate is greater than 25%, the probability that the study will be stopped in the first 
stage is 6%. 
 
The circulating tumor cell data, pharmacodynamic and pharmacogenomic exploratory analysis will be 
reported using descriptive statistics only.   
 
11.2 
Accrual Objectives 
 
Maximum of 18 patients in phase Ib, 40 in phase II. 
 
11.2.1 Replacement of Patients: 
 
For dose escalation decisions in Cycle 1, each cohort must have at least 3 patients evaluable for 
toxicity (unless the first 2 patients in the cohort experience a DLT). In Cycle 1, patients are considered 
non-evaluable and will be replaced if they do not receive at least one dose of eribulin (unless due to a 
DLT), or if they discontinue from the study prior to completing all safety and toxicity evaluations for 3 
weeks. These patients must be replaced unless accrual to the cohort has stopped due to a DLT. Non-
evaluable patients will not be included in the cohort total for DLT evaluation.  


Protocol #: 11996 
Page 43 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
 
11.3 
Stratification Factors 
 
This is a Phase I/II trial.  There will be no planned patient stratification factors.  
 
11.4 
Analysis of Secondary Endpoints 
 
Efficacy – Although disease response is not a primary endpoint of the study, it will be assessed by 
clinical exam at defined time points (see table 9-1) and imaging after 6 weeks on study and then 
every 9 weeks until end of study treatment. Overall tumor response and time to progression will be 
assessed using RECIST 1.1 as described in Section 11. Response data will be correlated with dose 
as well as PD data in a descriptive manner. 
 
Correlative studies – The CTC studies, pharmacogenomics, and evaluation of archived tissue are 
exploratory.  Results will be reported using descriptive statistics only. 
 
11.5 
Reporting and Exclusions 
 
11.5.1 Evaluation of toxicity.  
 
All patients will be evaluable for toxicity from the time of their first treatment with eribulin. 
 
11.5.2 Evaluation of response 
 
All patients included in the study must be assessed for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the 
following categories:  1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of 
other cause, or 9) unknown (not assessable, insufficient data). [Note:  By arbitrary convention, 
category 9 usually designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who received no 
study medication) should be included in the main analysis of the response rate. Patients in response 
categories 4-9 should be considered to have a treatment failure (disease progression). Thus, an 
incorrect treatment schedule or drug administration does not result in exclusion from the analysis of 
the response rate. Precise definitions for categories 4-9 will be protocol specific. 
 
All conclusions will be based on all eligible patients.  Sub analyses may then be performed on the 
basis of a subset of patients, excluding those for whom major protocol deviations have been identified 
(e.g., early death due to other reasons, early discontinuation of treatment, major protocol violations, 
etc.).  However, these sub analyses will not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis will be clearly reported.  
The 95% confidence intervals will also be provided. 
 
 
12.0 
MULTI-CENTER GUIDELINES 
 
This study is a multiple-institution, investigator- sponsored trial (IST) coordinated by UCSF.  Phase 1 
will be conducted at UCSF.  Phase 2 will be conducted at multiple-institutions.  The UCSF 
Coordinating Center provides administration, data management, and organizational support for the 
participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also 
coordinate quarterly conference calls with the participating sites to communicate the review of 
adverse events, safety data, and other study matters.  
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The 
Study Chair is responsible for the overall conduct of the study and for monitoring its safety and 


Protocol #: 11996 
Page 44 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
progress at all participating sites. The Study Chair will conduct continuous review of data and subject 
safety and discuss each subject’s treatment at monthly UCSF Site Committee meetings. The 
discussions are documented in the UCSF Site Committee meeting minutes. 
 
12.1 
Responsibilities of the coordinating/lead center 
 
The purpose of this section is to provide the regulatory guidelines needed for the conduct of 
multicenter investigator-initiated clinical trials where UCSF is the coordinating center. It is the Study 
Chair’s responsibility to ensure that these guidelines are followed. 
 
12.1.1 Oversight 
 
The lead center will coordinate conference calls with participating sites approximately every 1 to 2 
weeks to review adverse events, enrollment, safety data, cohort dose escalation, and other study 
matters. The dose level for ongoing enrollment will be confirmed for new patients scheduled at each 
site (see section 11 for more information). 
 
The lead center CRC will insure that participating sites are notified of safety events. 
 
Questions regarding the study or reporting of adverse events may be directed to the lead center CRC 
listed on Page 1 of this protocol. 
 
12.1.2 Protocol Distribution 
 
Upon approval by the coordinating center’s IRB, the protocol will be distributed by the Study Chair or 
designee to the other participating sites via e-mail or private courier. The correspondence will include 
a description of changes made to the protocol and what action must be taken by the participating site. 
 
If necessary, the Study Chair will forward a copy of the protocol to the drug manufacturer (Eisai) in 
accordance with the manufacturer’s submission requirements. 
 
12.1.3 Documentation of Distribution 
 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution of 
study documents as well as their receipt (when possible). The UCSF-HDFCCC recommends that the 
Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, drug 
manufacturer, participating sites, etc.). 
 
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt. 
 
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received. 
 
At a minimum, the Study Chair must keep documentation of when and to whom the protocol and its 
updates and safety information are distributed. 
 
12.1.4 Documentation of Protocol Approvals 
 
Documentation of protocol approval at each participating sites will be maintained in a file by the Study 
Chair or designee; copies must also be provided to the centralized regulatory staff of the UCSF-
HDFCCC.  It is the responsibility of the Study Chair to review these documents to ensure that 
participating sites are using the current protocol version. 
12.2 
Responsibilities of other participating sites 
 


Protocol #: 11996 
Page 45 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
12.2.1 Study Initiation 
 
Before the start of this study, the following documents must be submitted by the each site to the lead 
center CRC: 
 
U.S. Food and Drug Administration (FDA) Form 1572, signed by the site’s Principal 
Investigator. 
 
Current curricula vitae and medical licenses of the site’s Principal Investigator and all co-
investigators. 
 
All investigators must also complete all regulatory documentation as required by local 
regulations. 
 
Written documentation of local IRB approval. 
 
Contact information (email, phone number, address) for the research pharmacist and 
designated contact person(s) (CRC and/or nurse) assigned to this study. 
 
12.2.2 Patient Enrollment 
 
Refer to section 4.0 
 
12.2.3 Study Drug Supply and Accountability 
 
Study drugs will be shipped from the drug manufacturer directly to the site.  Each site will be 
responsible for drug accountability at their site.  See Section 7.1 for specific instructions regarding 
study drug availability. 
 
12.2.4 Approval of Protocol and Amendments 
 
All protocol amendments must be approved by the participating site’s IRB within 90 days of receipt. 
Failure to do so may result in the suspension of study activities at that site. 
 
Upon approval of the protocol or amendment by a participating site’s IRB, a copy of the approval 
documentation must be submitted (electronic or hardcopy) to the Study Chair. 
 
 
13.0 
DATA MANAGEMENT 
 
Case Report Form (CRF) and Source Documentation 
 
Study data will be entered into OnCore via electronic CRFs and electronic signatures.  
OnCore meets HIPAA guidelines. 
 
Source documentation will be kept in separate file folders for each subject. 
 
All source documentation and CRF data will be made available for monitoring/auditing. 
 
Regulatory Files 
 
Regulatory files will be maintained by the centralized regulatory office of the UCSF Helen 
Diller Family Comprehensive Cancer Center. 
 
Record Retention 
 
All study documentation will be archived as per sponsor/grantor requirements or as per 
institutional guidelines, whichever is greater. 
 
The University of California Office of the President (UCOP) recommends that study-related 
documents be maintained for at least 3 years after completion of the study. 


Protocol #: 11996 
Page 46 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
14.0 
ETHICAL ASPECTS AND REGULATORY CONSIDERATIONS 
 
14.1 
Conduct of the study 
 
This study will be conducted in accordance with ICH GCP guidelines and the Declaration of Helsinki. 
 
14.2 
Scientific Review 
 
This study will be reviewed by the UCSF Comprehensive Cancer Center Protocol Review Committee 
(PRC) for scientific merit.  After initial review and approval, the study will be reviewed at least once a 
year for scientific progress.  Any changes to the protocol are to be reviewed and approved by the 
PRC. 
 
14.3 
Institutional Review Board / Independent Ethics Committee 
 
The study will be reviewed by the Committee on Human Research (CHR), UCSF’s IRB.  After initial 
review and approval, the study will be reviewed at least once a year as per FDA regulations (21 CFR 
56.109).  Any changes to the protocol, consent form, and other associated documents are to be 
reviewed and approved by the CHR. 
 
It is the responsibility of the Principal Investigator to keep the CHR informed of the progress of the 
study, including changes to the protocol or consent form, exceptions or deviations from the protocol, 
and any new developments which may affect subject safety or willingness to participate. 
 
14.4 
Investigational New Drug Application (IND) 
 
An IND will be filed with the FDA.  For non-exempt studies, annual reports will be submitted to the 
FDA within 60 days of the anniversary date that the IND went into effect, as per FDA regulations (21 
CFR 312.33). 
 
14.5 
Additional Reporting Requirements 
 
Reporting of Pregnancy to Eisai: 
Although not considered an adverse experience, it is the responsibility of investigators or their 
designees to report any pregnancy in a patient or a male patient(s) partner (spontaneously reported 
to them) which occurs during the study or within 30 days of completing the study. Women who 
become pregnant must be followed to the completion/termination of the pregnancy. If the pregnancy 
continues to term, the outcome (health of infant) must also be reported to Eisai. 
 
 
15.0 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
15.1 
Adverse Event Definitions 
 
15.1.1 Adverse Events 
 
Any unfavorable or unintended sign, symptom, or illness that develops or worsens during the course 
of the study (treatment and follow-up) regardless of causality.  This includes abnormal clinical or 
laboratory findings. 
 
Laboratory AEs:  Laboratory test value abnormalities are recorded as adverse events if they 
are clinically significant.  Laboratory AEs are clinically significant if they are designated as 
serious, require treatment, cause dose modification/delay or premature withdrawal from the 
study, or place the subject at risk for other toxicity. 
 


Protocol #: 11996 
Page 47 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Unexpected AEs:  An AE is unexpected if it is not listed in the current labeling for the study 
drug (Investigator’s Brochure, Package Insert, etc.), whether or not it has been previously 
reported.  An unexpected AE may also be one that, although listed in the labeling, is greater 
in severity or occurs more frequently than expected. 
 
15.1.2 Serious Adverse Events 
 
 A serious adverse event (SAE) is one that results in any of the following outcomes regardless of dose 
(including overdose): 
 
Death 
 
Life-threatening (places the subject, in the view of the investigator, at immediate risk of death 
from the reaction as it occurred) 
 
Inpatient hospitalization or prolongs existing hospitalization, 
 
Persistent or significant disability/incapacity (a substantial disruption of a person’s ability to 
conduct normal life functions), 
 
Birth defect/congenital anomaly, 
 
Any important medical event that may not result in prior listed outcomes but, based upon 
appropriate medical judgment, may jeopardize the subject, and may require medical or 
surgical intervention to prevent one of the prior listed outcomes. 
 
15.2 
Adverse Event Grading 
 
Severity of AEs will be graded as follows: 
 
Grade 1 – Mild (no limitations) 
 
Grade 2 – Moderate (some limitations) 
 
Grade 3 – Severe (requires medical attention; usual activities stop) 
 
Grade 4 – Life-threatening/disabling (requires immediate medical help) 
 
Grade 5 - Death 
 
Causality of AEs will be graded as follows: 
 
Unrelated 
 
Unlikely related 
 
Possibly related 
 
Probably related 
 
Definitely related 
 
AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. 
 
15.3 
Adverse Event Reporting Period 
 
Reportable AEs are normally those that occur at initiation of study drug and within 6 weeks after the 
last administration of study drug.  Unresolved AEs (those that begin during the reporting period and 
extended past the 6 week period) should continue to be reported on if the condition worsens or 
results in death. 
 
AEs that begin after the end of the reporting period (after the 6 week period) are normally not 
reported, unless they are serious AND the primary investigator has reason to believe the event(s) 
might be related to study participation.  During the last scheduled visit, the investigator should instruct 
the subject to report any event that the subject or the subject’s referring physician believes might 
reasonably be related to study participation. 
 


Protocol #: 11996 
Page 48 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
15.4 
Adverse Event Reporting and Data Safety Monitoring 
 
15.4.1 Oversight and Monitoring Plan 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (UCSF-HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UCSF-HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes: 
 
Review of subject data in each cohort  
 
Chairman will issue the approval to continue to the new dose level 
 
Monitoring every six months (depending on patient accrual) 
 
Review of all serious adverse events  
 
Minimum of a yearly audit 
 
15.4.2 Monitoring and Reporting Guidelines 
 
Investigators will conduct continuous review of data and patient safety at weekly study group or site 
committee meetings where the results of each patient’s treatment are discussed and the discussion is 
documented in the minutes. The discussion will include for each dose level the number of patients, 
significant toxicities as described in the protocol, doses adjustments, and observed responses. 
 
The study coordinator will keep a log of subject(s) at each dose level in the UCSF-HDFCCC clinical 
trials management system (CTMS).  DLTs will be documented in the CTMS.  At the time of dose 
escalation, a written report will be submitted to the DSMC Chair outlining the cohort’s dose, grade 3-5 
AEs and SAE reports, and DLTs (if any) as described in the protocol. The report will be reviewed by 
the chairman or designee (maximum time 5 working days) and written authorization to proceed or a 
request for more information will be issued. 
 
15.4.3 Review and Oversight Requirements 
 
Adverse Event Monitoring 
 
Adverse Events (AEs) will be recorded on the CTMS.  All grade 3-5 expected and unexpected AEs 
will be recorded and updated at each visit. 
 
Serious Adverse Event Reporting 
 
Serious Adverse Event reporting will be in accordance with the UCSF Committee on Human 
Research (CHR) Regulations and Code of Federal Regulation (CFR) Title 21 Volume 5 Part 312.32. 
 
UCSF CHR website for guidance in reporting serious adverse events: 
http://www.research.ucsf.edu/chr/Guide/Adverse_Events_Guidelines.pdf 
 
FDA website for guidance in reporting serious adverse events: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32 
 
MedWatch forms and information: 
http://www.fda.gov/medwatch/getforms.htm 
 
For studies conducted under an IND:  Adverse events that are at least possibly related to the study 
and that are both serious and unexpected will be reported in writing to the FDA as soon as possible 
but no later than 15 days after first becoming aware of the event (21 CFR 312.32(c)).  The sponsor-
investigator will use MedWatch FDA Form 3500A for mandatory reporting. 
 


Protocol #: 11996 
Page 49 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Serious Adverse events will be reported on the MedWatch form. A copy of the MedWatch report and 
CHR forms must be sent to the DSMC 
.  The date the SAE was sent to all required 
reporting agencies will be documented on the CTMS; hard copies of the report will be maintained in 
the regulatory files. 
 
All subjects/patients with serious adverse experiences must be followed up for outcome. 
 
If the SAE is death, and is determined to be possibly, probably or definitely related to the 
investigational drug or any research related procedure, the event must be reported to the DSMC 
Chair or his designee via phone or in person within 24 business hours of the Principal Investigator’s 
awareness of the event. The reporting investigator or designee will confirm all verbal communication 
via e-mail and will copy the email to the DSMC Administrator and DSMC Coordinator. 
 
If any of the above actions occur in a multiple-institutional clinical trial coordinated by the UCSF-
HDFCCC, the CRC will ensure that all participating sites are notified. 
 
Review of Adverse Event Rates 
 
If the study has an increase of grade 3 or 4 expected or unexpected AEs above the rate reported in 
the Investigational brochure or package insert, this will be reported to the DSMC at the time of 
identifying the increased rate. 
 
If at any time the Investigator stops enrollment or stops the study due to safety issues the DSMC 
Chair and DSMC Administrator must be notified within 24 business hours via e-mail.  The DSMC 
must receive a formal letter within 10 business days and the CHR must be notified. 
 
If any of the above actions occur in a multiple-institutional clinical trial coordinated by the UCSF-
HDFCCC, the CRC will ensure that all participating sites are notified. 
 
 
Data Safety Monitoring Committee Contacts: 
 
DSMC Chair:  
 
Phone  
 
Email 
 
 
Box 
 
 
 
DSMC Monitors  
  
UCSF Helen Diller Family Comprehensive Cancer Center 


Protocol #: 11996 
Page 50 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
16.0 
REFERENCES 
 
Apolone, G., A. Filiberti, et al. (1998). "Evaluation of the EORTC QLQ-C30 questionnaire: a 
comparison with SF-36 Health Survey in a cohort of Italian long-survival cancer patients." 
Ann Oncol 9(5): 549-557. 
Barrette, B., E. Calvo, et al. (2010). "Transcriptional profiling of the injured sciatic nerve of mice 
carrying the Wld(S) mutant gene: identification of genes involved in neuroprotection, 
neuroinflammation, and nerve regeneration." Brain Behav Immun 24(8): 1254-1267. 
Bettmann, M. A., M. D. Dake, et al. (2004). "Atherosclerotic Vascular Disease Conference: Writing 
Group VI: revascularization." Circulation 109(21): 2643-2650. 
Brock, N. (1989). "Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award 
lecture." Cancer Res 49(1): 1-7. 
Brock, N. (1996). "The history of the oxazaphosphorine cytostatics." Cancer 78(3): 542-547. 
Bubley, G. J., M. Carducci, et al. (1999). "Eligibility and response guidelines for phase II clinical trials 
in androgen-independent prostate cancer: recommendations from the Prostate-Specific 
Antigen Working Group." J Clin Oncol 17(11): 3461-3467. 
Calhoun, E. A., E. E. Welshman, et al. (2003). "Psychometric evaluation of the Functional 
Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) 
questionnaire for patients receiving systemic chemotherapy." Int J Gynecol Cancer 13(6): 
741-748. 
Chaudhry, V., E. K. Rowinsky, et al. (1994). "Peripheral neuropathy from taxol and cisplatin 
combination chemotherapy: clinical and electrophysiological studies." Ann Neurol 35(3): 304-
311. 
Cohen, J. L. and J. Y. Jao (1970). "Enzymatic basis of cyclophosphamide activation by hepatic 
microsomes of the rat." J Pharmacol Exp Ther 174(2): 206-210. 
Cortes, J. and R. Lorca (2011). "Eribulin mesylate: a promising new antineoplastic agent for locally 
advanced or metastatic breast cancer." Future Oncology 7(3): 355-364. 
Cortes, J., L. Vahdat, et al. (2010). "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. 
Cristofanilli, M., G. T. Budd, et al. (2004). "Circulating tumor cells, disease progression, and survival 
in metastatic breast cancer." N Engl J Med 351(8): 781-791. 
Cristofanilli, M., D. F. Hayes, et al. (2005). "Circulating tumor cells: a novel prognostic factor for newly 
diagnosed metastatic breast cancer." J Clin Oncol 23(7): 1420-1430. 
Denduluri, N., J. A. Low, et al. (2007). "Phase II trial of ixabepilone, an epothilone B analog, in 
patients with metastatic breast cancer previously untreated with taxanes." J Clin Oncol 
25(23): 3421-3427. 
Du, X. L., R. Xia, et al. (2009). "Cardiac toxicity associated with anthracycline-containing 
chemotherapy in older women with breast cancer." Cancer 115(22): 5296-5308. 


Protocol #: 11996 
Page 51 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Eisenhauer, E. A., P. Therasse, et al. (2009). "New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1)." Eur J Cancer 45(2): 228-247. 
Endo, Y., E. Beauchamp, et al. (2008). "Wnt-3a and Dickkopf-1 stimulate neurite outgrowth in Ewing 
tumor cells via a Frizzled3- and c-Jun N-terminal kinase-dependent mechanism." Mol Cell 
Biol 28(7): 2368-2379. 
Fisher, B., S. Anderson, et al. (2001). "Tamoxifen and chemotherapy for axillary node-negative, 
estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast 
and Bowel Project B-23." J Clin Oncol 19(4): 931-942. 
Fisher, B., A. M. Brown, et al. (1990). "Two months of doxorubicin-cyclophosphamide with and 
without interval reinduction therapy compared with 6 months of cyclophosphamide, 
methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-
nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project 
B-15." J Clin Oncol 8(9): 1483-1496. 
Forsyth, P. A., C. Balmaceda, et al. (1997). "Prospective study of paclitaxel-induced peripheral 
neuropathy with quantitative sensory testing." J Neurooncol 35(1): 47-53. 
Ge, D., J. Fellay, et al. (2009). "Genetic variation in IL28B predicts hepatitis C treatment-induced viral 
clearance." Nature 461(7262): 399-401. 
Groenvold, M., M. C. Klee, et al. (1997). "Validation of the EORTC QLQ-C30 quality of life 
questionnaire through combined qualitative and quantitative assessment of patient-observer 
agreement." J Clin Epidemiol 50(4): 441-450. 
Howgate, D. J., Z. Gamie, et al. (2009). "The potential adverse effects of aromatase inhibitors on 
wound healing: in vitro and in vivo evidence." Expert Opin Drug Saf 8(5): 523-535. 
Jemal, A., R. Siegel, et al. (2010). "Cancer statistics, 2010." CA Cancer J Clin 60(5): 277-300. 
Jones, S., F. A. Holmes, et al. (2009). "Docetaxel With Cyclophosphamide Is Associated With an 
Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-
Up of US Oncology Research Trial 9735." J Clin Oncol 27(8): 1177-1183. 
Jones, S. E., M. A. Savin, et al. (2006). "Phase III trial comparing doxorubicin plus cyclophosphamide 
with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer." J Clin 
Oncol 24(34): 5381-5387. 
Jordan, M. A., K. Kamath, et al. (2005). "The primary antimitotic mechanism of action of the synthetic 
halichondrin E7389 is suppression of microtubule growth." Mol Cancer Ther 4(7): 1086-1095. 
Kuznetsov, G., M. J. Towle, et al. (2004). "Induction of morphological and biochemical apoptosis 
following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389." 
Cancer Res 64(16): 5760-5766. 
Lipton, R. B., S. C. Apfel, et al. (1989). "Taxol produces a predominantly sensory neuropathy." 
Neurology 39(3): 368-373. 
Low, J. A., S. B. Wedam, et al. (2005). "Phase II clinical trial of ixabepilone (BMS-247550), an 
epothilone B analog, in metastatic and locally advanced breast cancer." J Clin Oncol 23(12): 
2726-2734. 


Protocol #: 11996 
Page 52 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
McLachlan, S. A., G. M. Devins, et al. (1998). "Validation of the European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) as a measure of 
psychosocial function in breast cancer patients." Eur J Cancer 34(4): 510-517. 
New, P. Z., C. E. Jackson, et al. (1996). "Peripheral neuropathy secondary to docetaxel (Taxotere)." 
Neurology 46(1): 108-111. 
Okouneva, T., O. Azarenko, et al. (2008). "Inhibition of centromere dynamics by eribulin (E7389) 
during mitotic metaphase." Mol Cancer Ther 7(7): 2003-2011. 
Patt, D. A., Z. Duan, et al. (2007). "Acute myeloid leukemia after adjuvant breast cancer therapy in 
older women: understanding risk." J Clin Oncol 25(25): 3871-3876. 
Perez, E. A., G. Lerzo, et al. (2007). "Efficacy and safety of ixabepilone (BMS-247550) in a phase II 
study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and 
capecitabine." J Clin Oncol 25(23): 3407-3414. 
Persohn, E., A. Canta, et al. (2005). "Morphological and morphometric analysis of paclitaxel and 
docetaxel-induced peripheral neuropathy in rats." Eur J Cancer 41(10): 1460-1466. 
Racila, E., D. Euhus, et al. (1998). "Detection and characterization of carcinoma cells in the blood." 
Proc Natl Acad Sci U S A 95(8): 4589-4594. 
Ramaswamy, S. and C. M. Perou (2003). "DNA microarrays in breast cancer: the promise of 
personalised medicine." Lancet 361(9369): 1576-1577. 
Ratain, M. J. (1992). "Therapeutic relevance of pharmacokinetics and pharmacodynamics." Semin 
Oncol 19(4 Suppl 11): 8-13. 
Rivera, E. and H. Gomez (2010). "Chemotherapy resistance in metastatic breast cancer: the evolving 
role of ixabepilone." Breast Cancer Res 12 Suppl 2: S2. 
Roche, H., L. Yelle, et al. (2007). "Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B 
analog, as first-line therapy in patients with metastatic breast cancer previously treated with 
anthracycline chemotherapy." J Clin Oncol 25(23): 3415-3420. 
Rowinsky, E. K. and R. C. Donehower (1995). "Paclitaxel (taxol)." N Engl J Med 332(15): 1004-1014. 
Rustin, G. J., M. Quinn, et al. (2004). "Re: New guidelines to evaluate the response to treatment in 
solid tumors (ovarian cancer)." J Natl Cancer Inst 96(6): 487-488. 
Sahenk, Z., R. Barohn, et al. (1994). "Taxol neuropathy. Electrodiagnostic and sural nerve biopsy 
findings." Arch Neurol 51(7): 726-729. 
Scher, H. I., S. Halabi, et al. (2008). "Design and end points of clinical trials for patients with 
progressive prostate cancer and castrate levels of testosterone: recommendations of the 
Prostate Cancer Clinical Trials Working Group." J Clin Oncol 26(7): 1148-1159. 
Sparano, J. A., M. Wang, et al. (2008). "Weekly paclitaxel in the adjuvant treatment of breast cancer." 
N Engl J Med 358(16): 1663-1671. 
Stendel, C., A. Roos, et al. (2007). "Peripheral nerve demyelination caused by a mutant Rho GTPase 
guanine nucleotide exchange factor, frabin/FGD4." Am J Hum Genet 81(1): 158-164. 


Protocol #: 11996 
Page 53 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Taenzer, P. A., M. Speca, et al. (1997). "Computerized quality-of-life screening in an oncology clinic." 
Cancer Pract 5(3): 168-175. 
Thomas, E. S., H. L. Gomez, et al. (2007). "Ixabepilone plus capecitabine for metastatic breast 
cancer progressing after anthracycline and taxane treatment." J Clin Oncol 25(33): 5210-
5217. 
Towle, M. J., K. A. Salvato, et al. (2001). "In vitro and in vivo anticancer activities of synthetic 
macrocyclic ketone analogues of halichondrin B." Cancer Res 61(3): 1013-1021. 
Twelves, C., J. Cortes, et al. (2010). "Phase III trials of eribulin mesylate (E7389) in extensively 
pretreated patients with locally recurrent or metastatic breast cancer." Clin Breast Cancer 
10(2): 160-163. 
Vahdat, L. T., B. Pruitt, et al. (2009). "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 27(18): 2954-2961. 
Vergote, I., G. J. Rustin, et al. (2000). "Re: new guidelines to evaluate the response to treatment in 
solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup." J Natl Cancer Inst 92(18): 
1534-1535. 
Wampler, M. A., C. Miaskowski, et al. (2006). "The modified total neuropathy score: a clinically 
feasible and valid measure of taxane-induced peripheral neuropathy in women with breast 
cancer." Supportive Oncology 4(8): W9-W16. 
Weigelt, B., A. M. Glas, et al. (2003). "Gene expression profiles of primary breast tumors maintained 
in distant metastases." Proc Natl Acad Sci U S A 100(26): 15901-15905. 
Wozniak, K. M., R. G. Lapidus, et al. (2010). "Assessment of neuropathy-inducing effects of eribulin 
mesylate versus paclitaxel and ixabepilone." European Society of Medical Oncology Annual 
Meeting. 
 
 
 


Protocol #: 11996 
Page 54 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
APPENDIX A 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities. Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 


Protocol #: 11996 
Page 55 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
APPENDIX B 
 
Strong CYP3A4 Inhibitors that are prohibited during the study 
Amprenavir 
Atazanavir 
Clarithromycin 
Conivaptan 
Delavirdine 
 
Fosamprenavir 
Grapefruit juice 
Imatinib 
Indinavir 
Isoniazid 
 
Itraconazole 
Ketoconazole (oral) 
Nefazodone 
Nelfinavir 
Nevirapine 
 
Nicardipine 
Posaconazole 
Ritonavir 
Telithromycin 
 
 
 
Strong CYP3A4 Inducers that are prohibited during the study 
Barbiturates 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital  
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort 
 
 
CYP3A4 Substrates (caution is advised) 
Astemizole 
Cisapride 
Opioid analgesics 
Pimozide 
Quinidine 
Tacrolimus 
 
 
 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, 
Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; 
LexiComp Inc. 2007: 1899-1912.  
 
This list is not comprehensive. 
 
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at: 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol #: 11996 
Page 56 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
APPENDIX C 
 
Modified Total Neuropathy Score Sheet 
 
Sensory Symptoms: 
0=no symptoms 
1=symptoms limited to the tips of fingers or toes 
2=symptoms extend to ankle or wrist 
3=symptoms extend to above ankle or above wrist to the level of knee or elbow 
4=symptoms above knee or elbow and /or severe disabling symptoms that affect normal functioning 
and/or neuropathic pain that requires narcotic analgesia 
If symptoms are asymmetrical from side-to-side, grade the worst side (L/R). 
 
A. Paresthesias (tingling): _______________ 
B. Numbness (“dental work anesthesia”): ________________ 
C. Neuropathic pain (aching, burning, stabbing): __________________ 
D. Myalgias or Cramps: _________________  
  
TOTAL SENSORY SYMPTOM SCORE (0-4) 
Use average score from A-D, round up to next whole number 
 
Motor Symptoms: 
0=no difficulty 
1=with slight difficulty 
2=with moderate difficulty 
3=require some help or an assistive device 
4=total loss of function 
 
A. Hand Dexterity (buttoning, writing, tying shoe laces, opening tight jars, or inserting key in lock) 
____________ 
B. Foot Walking (unsteady on feet, walking on tip toes or on heels, or operating pedals in car) 
________________ 
C. Legs Climbing steps, or standing up from a chair ____________ 
D. Arms Combing hair, or reaching up to a high shelf ___________ 
TOTAL MOTOR SYMPTOM SCORE (0-4) 
Use average score from A-D, round up to next whole number 
 
Neurological Examination: 
 
SENSORY 
0=normal 
1=absent/decreased in index finger or great toe 
2=absent/decreased up to ankle or wrist 
3=absent/decreased up to elbow or knee 
4=absent/decreased above the level of knee or elbow 
If symptoms are asymmetrical from side-to-side, grade the worst side (L/R). 
 


Protocol #: 11996 
Page 57 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
A. Pin level 
__________ 
B. Vibration 
__________(From quantitative vibration testing compared to norms in Bloom paper) 
 
 
TOTAL SENSORY SCORE (0-8) 
 
MOTOR 
0=normal (MMT ≥4+) 
1=mild weakness, but can overcome some resistance (MMT 3+ to 4) 
2=moderate weakness, can overcome gravity (MMT 3) 
3=severe weakness with gravity eliminated (MMT 1 to 2) 
4=paralysis (MMT 0) 
If symptoms are asymmetrical from side-to-side, grade the worst side (L/R). 
 
A. Ankle DF 
__________ 
B. Finger spread __________ 
C. Wrist EXT 
__________ 
 
TOTAL MOTOR SCORE (0-4) 
Use score from weakest muscle group 
 
REFLEXES 
 
L 
R 
Biceps 
__________ 
__________ 
P=present 
Triceps 
__________ 
__________ 
PR=present with reinforcement 
Brachioradialis __________ 
__________ 
A=absent 
Knee 
__________ 
__________ 
Ankle 
__________ 
__________ 
 
0=all reflexes normal (Biceps, Triceps, Brachioradialis, Knee, and ankle)  
1=ankle reflex reduced 
2=ankle reflex absent 
3=ankle reflex absent, others reduced 
4=all reflexes absent 
TOTAL REFLEX SCORE (0-4) 
 
 
 
 
 
 TOTAL mTNS SCORE (0-24) 
 
 
 
 
 
See reference 51, Wampler et al. 
 
 
 


Protocol #: 11996 
Page 58 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
APPENDIX D 
EORTC QLQ-30 
 


Protocol #: 11996 
Page 59 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
 
 


Protocol #: 11996 
Page 60 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
APPENDIX E 
 
FACT-GOG NTX questionnaire 
 
 
 
 
 
 
 
 
 


Protocol #: 11996 
Page 61 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
APPENDIX F 
 
Correlative Studies 
All specimens will be de-identified prior to sending. Only a study ID # will be on the collection tubes. 
 
Pharmacokinetics-Phase Ia only 
Whole blood for pharmacokinetic assessments of pazopanib and PCI24781 will be drawn in 6 mL 
tubes on the following schedule: 
 
Phase Ia: Cycle 1 Day 1: pre-dose, at the end of eribulin infusion, and at 15 min, 30 min, hour 1, 2, 3, 
4, 6 and 8 
 
Handling of Specimens(s) – Standard phlebotomy handling 
ALL required labels will be provided by a third-party vendor contracted by the sponsor.  Labels will 
come pre-filled with the following information: 
 
Protocol No.: 11996 
 
Treatment: Cohort/Dose level  
 
Nominal Time Point: Predose, 1, 2 hr, etc. 
 
Sample Type: Blood, Plasma (Primary), Plasma (Secondary)  
 
The SITE is then responsible for entering the following information on each sample label: 
 
Patient ID Number 
 
Patient Initials 
ALL blood and plasma collection and storage tubes should be labeled PRIOR to sample collection. 
1. Fill an ice bucket with a sufficient amount of ice to completely immerse all tubes before blood 
draw. 
2. Collect approximately 6 mL of whole blood into a pre-chilled 6-mL Na-Heparin tube. 
3. Gently invert the tube 3-5 times and immerse it into the ice immediately to prevent possible 
compound degradation at room temperature. 
4. Record drawing time immediately before proceeding to the next step. 
5. Within 15 min. of blood collection, the sample must be processed by centrifuging at 1,500 g 
(3,000 rpm) for 10 min to obtain plasma.   
6. Transfer approximately 1.5 mL plasma into each of the two clean, pre-labeled polypropylene 
tubes (primary and secondary). Immerse both tubes into the ice immediately to prevent 
possible compound degradation at room temperature. Note, if short on plasma, ensure that 
the primary sample tube contains 1.5 mL 
7. Transfer both polypropylene tubes into a –70oC/–80oC freezer (within 1 hour of collection), 
where they will remain stored until shipping. 
8. Immediately record time of samples’ entry into the freezer. 


Protocol #: 11996 
Page 62 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
NOTE: All secondary (backup) samples will be maintained at the collecting site until they are 
requested by the sponsor to be sent to the bioanalytical laboratory. 
 
Site(s) Performing Correlative Study – XenoBiotic Laboratories, Inc. 
 
Shipping of Specimen(s) –  
Blood will be processed as above, frozen and shipped on dry ice by overnight mail on Monday-
Wednesday to: 
 
 
 
 
 
 
 
Notification on the day of shipping should be sent to: 
 
 
 
Do not ship samples the day before a holiday. 
 
Always ship the primary sample set to the bioanalytical lab first per pre-agreed shipping 
schedule. 
 
All secondary (used as backup) samples will be stored in a –70oC/–80oC freezer at the 
collecting site until shipping is requested by the sponsor. 
 
Arrange sample pick-up(s) (e.g., World Courier) 
 
XBL must be contacted via email at least one working day prior to shipment and 
confirmation of receipt by XBL must be documented at the clinical site. 
 
If you do not hear from XBL within 2-3 working days of shipping, please contact the 
person listed in above immediately to ascertain the delivery status of the samples. 
Shipping Process 
1. Obtain 20 lbs of dry ice pellets.  Use as much dry ice as possible to help safeguard 
against any possible delays. 
2. Use a Styrofoam box, for example, a 19” x 19” x 12”. Use a larger one if multiple 
samples are being shipped. 
3. Place a 4” layer of dry ice in the bottom of the Styrofoam box.  Package the samples 
the day of shipping to maximize the effectiveness of the dry ice pellets. 
4. Wrap the frozen samples in bundles using an elastic band and place the sample 
bundles in a plastic freezer bag.  
5. Use newspaper or other similar material to insulate the bagged sample bundles from 
direct contact with the dry ice.  
6. Place the sample bundles in the Styrofoam box and fill the excess space with the 
remaining dry ice pellets. 
7. Record the estimated weight of the dry ice used per box.  


Protocol #: 11996 
Page 63 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
8. Place the lid on the Styrofoam box and seal around the edges completely with tape.  
9. Place the Styrofoam box in a larger cardboard shipping carton. Tape the plastic bag 
or plastic sleeve that contains essential sample documents from the site on top of the 
Styrofoam box.  
10. Seal the shipping carton securely with tape. 
Labeling the Cardboard Box 
1. Indicate return address and contact person on each carton. 
2. Mark the outside of the shipping cartons with tally number e.g., – Box 1 of 3 boxes, 
Box 2 of 3 boxes, and Box 3 of 3 boxes.  
3. Affix the Biological Substance B label with the information below to the outside of 
each box: 
- One (1) carbon dioxide label with the weight included. Example:  
Carbon Dioxide Solid UN-1845  
Class 9 PKG GR III  
KG _______________________  
- Two (2) internationally recognized dry ice symbols (Class 9) - one on either side of 
the box. Example:  
                                                    
 
 
- One (1) KEEP FROZEN label  
                                                        
 
 
- One (1) PERISHABLE GOODS label  
PERISHABLE 
GOODS 
 


Protocol #: 11996 
Page 64 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Sample Collection Documents to Accompany Shipment(s) 
The following documentation/information must accompany ALL shipments:  
 
A copy of the completed specimen inventory log(s) (i.e., a copy of the completed CRF 
Specimen Collection page). 
 
Sponsor Name: Eisai  
Any missing information may cause a delay in analysis. 
Please notify XBL by email or fax immediately after the samples have been collected by the courier.  
Provide the following information to XBL:  
 
Name of courier or transport company (i.e., World Courier) 
 
Date and time the shipment left your premises 
 
The airway bill number 
 
Single-nucleotide polymorphisms 
One 10 mL purple top tube will be collected at baseline, either during screening assessments or 
Cycle 1 Day 1 prior to treatment.  
 
DNA extraction and analysis for three novel candidate genes which may relate to development of 
peripheral neuropathy, FZD3, FGD4 and EPHA5 will be performed. Other exploratory analysis may 
also be performed. 
 
Handling of Specimens(s) – Standard phlebotomy handling 
 
Sites Performing Correlative Study – Deanna Kroetz laboratory, UCSF 
 
Shipping of Specimen(s) –  
UCSF:  No shipment is required.  Samples will be hand-delivered by courier at 4C and shipped on 
cold packat room temperature to the Kroetz laboratory in batches. 
 
 
 
 
 
Outside sites: Samples will be stored at 4C and shipped on cold pack at room temperature to the 
Kroetz laboratory: 
 
 
 
 
 
 
Genome Scan 
One 10 mL purple top tube will be collected at baseline, either during screening assessments or 
Cycle 1 Day 1 prior to treatment. 
 
DNA extraction and analysis will be done by the DNA bank at UCSF, and then samples will be sent to 
Dr. Pui-Yan Kwok’s laboratory for genomic profile. 
 
Handling of Specimens(s) – Standard phlebotomy handling 
 


Protocol #: 11996 
Page 65 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
Sites Performing Correlative Study – Pui-Yan Kwok laboratory, CVRI, UCSF 
 
 
 
Shipping of Specimen(s) –  
UCSF:  No shipment is required.  Samples will be hand-delivered by courier at room temperature to 
the DNA bank laboratory immediately after they are obtained and processed immediately. If unable to 
be sent immediately, samples will be frozen and shipped on dry ice. 
 
  
 
 
 
Outside sites:  Samples will be frozen and will be on shipped on dry ice by overnight mail to: 
Shigeshi "Shag" Yamamoto 
 
  
 
 
 
 
Circulating Tumor Cells 
2 CellSave tubes and 1 purple top tube will be collected at baseline, either during screening 
assessments or Cycle 1 Day 1 prior to treatment.  
If this first sample has ≥ 5 CTC/mL, then on Cycle 2 Day 1, 1 CellSave and 1 purple top tube will be 
collected for CTC enumeration and aCGH/gene expression.  
2 CellSave tubes and 1 purple top tube should be obtained at end of study if at all possible. 
 
7.5 mL of blood is required per CellSave tube, it is critical that the tube be completely filled.  
10mL is required in each purple top tube.  
 
One CellSave tube will be used for CTC enumeration, the second CellSave tube will be used for 
sorting and WGA with CGH/sequencing. The purple top tube will also be used for gene expression if 
there is adequate sample.   
 
Handling of Specimens(s) – Standard phlebotomy handling 
 
Site(s) Performing Correlative Study – John Park MD laboratory, UCSF 
 
Shipping of Specimen(s) –  
UCSF:  No shipment is required.  Samples will be hand-delivered at room temperature to the Park 
laboratory immediately after they are obtained and processed immediately. 
Outside sites:  Blood will be shipped at room temperature by overnight mail to: 
Park Lab 
  
 
 
Notification on the day of shipping should be sent to: 
  
 
Special instructions will be provided for Friday shipping. 
 
Archived Tissue Analysis 
Once a patient is consented for this study, they will also sign a Tumor Specimen Release Form. 
Clinical research coordinators will request FFPE (formalin-fixed paraffin embedded) archived tumor 
blocks from prior surgery or biopsies along with stained H&E slides, for all patients. These specimens 


Protocol #: 11996 
Page 66 of 66 
Protocol Version:  6.0 (05/26/2017) 
Experimental Agent: Eribulin 
 
Hope S. Rugo, MD 
are not required and should not delay enrollment. These specimens will become the property of 
UCSF Cancer Center and will be stored at the Cancer Center Tissue Core at UCSF under direction of 
Dr. Stöppler. 
 
 
 
 
 
 
 
 
Quality of life 
EORTC QLQ-30, found in Appendix C, will be self-administered to each patient on the following 
schedule: 
Prior to starting treatment (within 7 days of cycle 1 day 1), then at 6 weeks, 3 months, 12 months, 18 
months, 24 months, and/or study termination. Questionnaires may be mailed, emailed, or faxed in 
advance to patients and/or completed during visits. Questionnaires must be completed by the patient 
and can be completed up to 7 days prior to drug administration. Translation services may be used for 
completion of questionnaires. Results will be compiled by research staff. 
 
 
Neuropathy measurements 
1. 10-point modified neuropathy score (mTNS), found in Appendix D, will be performed by research 
staff at the start of each cycle and at study termination. Results will be compiled by research staff. 
 
2. FACT/GOG-NTX questionnaire, found in Appendix E, will be self-administered to each patient on 
the following schedule: at the start of each cycle and at study termination. Questionnaires may be 
mailed, emailed, or faxed in advance to patients and/or completed during visits. Questionnaires must 
be completed by the patient and can be completed up to 7 days prior to drug administration. 
Translation services may be used for completion of questionnaires. Results will be compiled by 
research staff. 
 
 
 

ICF_001.pdf: 
Consent Form 06-27--2016
Page 1 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
CC#11996: Study Title: A Phase Ib/II study of eribulin in combination with 
cyclophosphamide in patients with solid tumor malignancies
This is a clinical trial, a type of research study.  Your study doctor, Dr. Hope Rugo and her 
associates from the UCSF Department of Medicine, will explain the clinical trial to you.
Clinical trials include only people who choose to take part.  Please take your time to make your 
decision about participating.  You may discuss your decision with your family and friends and 
with your health care team.  If you have any questions, you may ask your study doctor.
You are being asked to take part in this study because you have cancer that has spread to other 
parts of your body and your doctor has recommended treatment with chemotherapy.
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to test the safety of eribulin (Halaven™) and cyclophosphamide 
(Cytoxan®) given together at different doses.  We want to find out what effects, good and/or bad, 
these drugs have on you and your cancer.
Eribulin is a drug that has been approved by the U.S. Food and Drug Administration (FDA) for 
breast cancer that has spread to other parts of the body.  Cyclophosphamide has been approved 
for different types of cancers (including breast cancer).  However, the combination of eribulin 
and cyclophosphamide is considered experimental; that means this combination has not been 
approved by the FDA.
The funding for this study is provided by Eisai Inc., the maker of eribulin.  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Up to 18 patients will participate in this study in the first portion of this study (Phase Ib).  
Approximately 40 patients will participate in the phase II portion. A combined total of 58 
subjects will be enrolled at UCSF in both phases of the study.
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY?
Each study visit may last between 3 to 6 hours depending on the particular procedures. The first 
day of the study drug dose will last over 8 hours due to the pharmacokinetics (PK) blood 
samplings.
Before you begin the main part of the study...
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020
NCT# 01554371


Consent Form 06-27--2016
Page 2 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
You will need to have the following exams, tests or procedures to find out if you can be in the 
main part of the study. These exams, tests or procedures are part of regular cancer care and may 
be done even if you do not join the study. If you have had some of them recently, they may not 
need to be repeated. This will be up to your study doctor.
 
Medical history and physical exam

Review of any medications you are currently taking or have taken within the last 30 days

Radiographic studies which may include a CT scan (to monitor the cancer in your
organs), PET scan, or bone scan (if your cancer has spread to your bones)

Other radiology tests may need to be done depending on your type of cancer

Electrocardiogram (EKG): Done to monitor how your heart is working

Laboratory/blood tests: Routine tests done to see if your kidney, liver, and other organs
are working well

Pregnancy test (if you are a female of childbearing age)

Research blood tests
During the main part of the study...
If the exams, tests and procedures show that you can be in the main part of the study, and you 
choose to take part, then you will need to have the tests and procedures described below.
Study drug administration:
You will receive treatment with eribulin and cyclophosphamide as described below. The 
same treatment will be repeated every 3 weeks (21-days).  This 3-week period is called a 
treatment cycle.
Cyclophosphamide is injected into a vein on the first day (Day 1) of each cycle. The injection 
will take approximately 60-120 minutes. The exact dose of cyclophosphamide you receive 
will also be calculated based on your weight and height.
You will also receive eribulin.  Eribulin is injected into a vein on Day 1 and Day 8 of each 
cycle.  The injection will take approximately 2-5 minutes.  The exact dose of eribulin you 
receive will also be calculated based on your weight and height.
At the beginning of the study (the Phase Ib portion), the first group of patients will be treated 
with a lower dose of study drug.  If this low dose causes no or minimal side effects, new 
patients enrolled in the study will be given a slightly higher dose.  Additional patients will be 
given higher doses until we have determined the highest dose that can be given without 
severe side effects; patients in the second part of the study (Phase II portion) will receive this 
highest dose.
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 3 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
Neither you nor your doctor can choose the group you will be in.  You can ask your doctor 
what group you will be in and what dose of study drug you will be receiving.
Procedures that are part of regular cancer care:

Physical exam (once per cycle)

Performance score: You will be asked questions about your daily activities to evaluate
your level of daily function.

Laboratory/blood tests (twice per cycle in the Phase Ib portion, and twice per cycle in
Cycle 1 and Cycle 2, then once per cycle in Cycle 3 and beyond in the Phase II portion)

CT, PET/CT, bone scan, and/or other radiology tests (every 6 weeks in the Phase Ib
portion, and every 9 weeks in the Phase II portion)
Procedures that are for research purposes only:

EKG (once; cycle 1)

Blood samples for Pharmacokinetic (PK) tests (Cycle 1): PK blood samples will be
collected over an 8-hour period at the following time points: before you receive the study 
drug infusion (pre-dose), at the end of your study drug infusion, and then 15 minutes, 30 
minutes, 1, 2, 3, 4, 6 and 8 hours following your infusion.

Blood sample for Pharmacogenomic tests (once; before your first treatment)

Blood samples for measuring circulating tumor cells (CTCs) (Cycle 1 and possibly Cycle
2, depending on the results from your Cycle 1 test)

Archival tumor tissue (this is optional – permission is given at the end of this form)

Neuropathy assessment (before your first treatment, then once per cycle beginning with
cycle 2)

Neuropathy questionnaire (before your first treatment, then once per cycle beginning with
cycle 2)

Quality of Life (QOL) questionnaire (before your first treatment, then at 6 weeks, 3 
months, 12 months, 18 months, 24 months, and/or at study termination )
When you are finished receiving eribulin and cyclophosphamide...
If you decide to discontinue your participation in the study or if your study doctor decides you 
should not continue in the study, the following procedures will be carried out within 30 days 
after you receive your last dose of study drug:

Physical exam

Performance test

Laboratory/blood tests

Blood sample for research tests

Neuropathy assessment
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 4 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD

Review of any medications you are taking

Review of any side effects you may be experiencing

Neuropathy questionnaire

Quality of Live (QOL) questionnaire

Radiographic studies which may include a CT scan (to monitor the cancer in your
organs), PET/CT scan or bone scan (if your cancer has spread to your bones)
Study location: Study procedures will be done at UCSF, Mt. Zion Campus, 
 
.
DESCRIPTION OF PROCEDURES
Blood drawing (venipuncture):
This involves inserting a needle into a vein in your arm.  Each blood sample will be 
approximately 2 teaspoons.
Bone Scan:
A bone scan is a test that makes detailed images of your bones and any tumors on them.  Before 
the bone scan a small amount of radioactive substance is injected into your vein.  About 3 hours 
later you will lay on a table under a machine which will make an image of your bones.  The test 
itself will take about 1 hour, but the whole process takes up to 4 hours.
CT or PET/CT scan:
You will have a computerized tomography (CT) scan or positron emission tomography/CT 
(PET/CT) scan to check the status of your tumor.  These scans use special x-ray equipment to 
make detailed pictures of body tissues and organs.
You may first be injected with contrast material (iodine dye and/or radioactive substance).  This 
contrast material makes your tissues and organs more visible in the pictures.  You will be asked 
to rest for about 30 minutes while the contrast material circulates throughout your body.
For the scan, you will need to lie still on a table inside a large doughnut-shaped machine.  The 
table will move and the machine will make clicking and whirring noises as the pictures are taken.  
Each scan will take between 15 minutes to an hour.
EKG (electrocardiogram):
An EKG records the natural electrical activity of your heart.  You will lie down, and wires or 
“leads” will be attached to your chest with an adhesive.  You will be asked to lie still while the 
machine prints out an electrical “picture” of your heart activity.  The EKG takes about 15 
minutes.
Neuropathy assessment:
Exam by the study doctor to check for any numbness or tingling in the toes and fingers
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 5 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
Questionnaires (Neuropathy and Quality of Life (QOL)):
Because the study drug eribulin may potentially cause nerve damage, the study doctors will 
assess you for any nervous system changes throughout your participation in the study.  This will 
be done by filling out these two questionnaires.  These are standard questionnaires that are 
commonly used by health care professionals.
Blood samples for research:
This includes Pharmacogenomic (PG), Pharmacokinetic (PK), and circulating tumor cell (CTC) 
tests.  These tests are done to look for the presence or absence of certain genetic material (DNA 
or RNA) and proteins in your blood.  This genetic material and protein are referred to as 
“biomarkers”.  These biomarkers may come from healthy cells or from cancer cells circulating in 
your blood.
Studying these biomarkers may help us understand why different people respond differently to 
the study drugs (for example how it is stored, broken down, and excreted from the body, or why 
some people respond favorably to the drugs and some don’t).
No more than 2 tablespoons will be taken at any one time.
Archival Tumor Tissue samples for research (optional):
This tissue will be taken from a biopsy or surgery that was performed to diagnose your cancer.  
You do not need to undergo any extra procedure to donate this sample.  Only extra tissue (tissue 
that is not needed to plan your care and which would normally be discarded) will be used to 
perform these research tests.
Research tests performed on this tissue will involve looking for biomarkers (similar as for the 
blood samples above)
Blood sample for future genetic research (optional):
You may be asked to donate a blood sample (1-2 tablespoons) before the start of the treatment 
for future genetic testing. This sample is optional and will be discussed in greater detail at the 
end of this consent.  
WHAT ARE MY RESPONSIBILITIES WHILE I AM IN THE STUDY?
It is important that you follow the instructions of the study doctor and study team. It is important 
that you come to all of your scheduled study visits.  It is also important that you follow the 
schedule when you take the study drug.
It is important that during the study, you tell the study doctor and/or the study team all changes 
in how you feel. You need to tell them even if you do not believe these changes are related to the 
study. This may include mental or emotional changes. You will be checked during the study for 
side effects. You will also be checked for other injuries or illnesses that may happen while you 
are in the study.
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 6 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
Before taking any medicines besides the study drug, you must first ask the study doctor. These 
medicines may be ones that are ordered by a doctor. They may also be drugs like allergy 
medicines, cough and cold medicines and pain relievers, or they may be vitamins, herbs and 
minerals.  The use of any investigational or antitumor therapies (other than eribulin and 
cyclophosphamide given as part of the study) is prohibited.
Only you, the study subject, can take the study drug.
HOW LONG WILL I BE IN THE STUDY?
You may continue participating in the study as long as the doctor feels you are benefitting from 
the treatment, or until you no longer wish to participate.
Your study doctor or the sponsor may also decide to end your participation at any time without 
your approval if: 

The study is stopped by the Sponsor or the FDA for any reason

You fail to follow instructions given by the study doctor

There is a change in your medical condition

The study doctor believes it is best for you to no longer be in the study
For your safety, you will be asked to return to this office for a follow-up visit if you leave the 
study. Your visit may include tests like physical exams and blood draws. Your visit may also 
include questions about your medical condition. It is important that you tell the study staff any 
problems or changes in the way you felt while you were in the study.
The researchers will continue to monitor your health for up to 10 years after you complete the 
final study visit. This will involve reviewing your medical record periodically to see how you are 
doing.
CAN I STOP BEING IN THE STUDY?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely.
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
study drugs can be evaluated by your doctor. Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped.
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY?
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 7 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don't know all the side effects that may happen.  
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. Many side effects go away soon after you stop taking the study drugs. In 
some cases, side effects can be serious, long lasting, or may never go away.  There is also a risk 
of death.
You should talk to your study doctor about any side effects you experience while taking part in 
the study.
Risks of eribulin:
Common side effects:

Decreased white blood cells (may increase chance of infection)

Decreased red blood cells (may cause weakness and tiredness)

Fatigue

Hair loss

Peripheral neuropathy (a form of damage to the nerves supplying the hands and feet,
which leads to numbness or the feeling of “pins and needles” and/or impairment of 
muscle strength in the hands and feet)

Nausea

Constipation
Less common side effects:

Eyes watering

Upset Stomach/abdominal pain

Inflammation or ulcers in the mouth (stomatitis)

Dry mouth

Fluid retention

Upper respiratory tract infection

Low potassium in the blood (can cause constipation, weakness, and abnormal heart
rhythms)

Muscle spasms, muscular weakness

Change in taste

Dizziness
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 8 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD

Insomnia

Depression

Rash

Liver function test changes
Risks of Cyclophosphamide:

Decrease in bone marrow function (resulting in lower level of blood cells)

Low levels of all blood cells (white blood cells, red blood cells, platelets)

Liver function test changes

Inability to have children

Rash

Skin pigmentation changes

Nail changes

Stevens-Johnson syndrome (severe reaction that includes a painful rash that spreads and
blisters, causing the top layer of skin to die and shed)

Congestive heart failure

Infusion-related symptoms such as fever, chills, rigors, headache

Abdominal pain

Nausea

Vomiting

Diarrhea

Inflammation or ulcers in the mouth and digestive tract (mucositis)

Hair loss

Anorexia

Pain

Irritation of the bladder, which causes pain and can result in blood in the urine

Scarring of the bladder

Inflammation and pain in the urinary tract

Kidney damage

Stomach flu

Inflammation and scarring of the lungs
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 9 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD

Jaundice

Infections

Secondary cancer

Anaphylaxis (a severe, whole-body allergic reaction, which may require immediate
medical attention)

SIADH (Excessive water retention that may cause electrolytes in your blood to fall to low
levels)

General feeling of being sick (Malaise)

Lack of energy or strength
Additional information on cyclophosphamide (Cytoxan®) may be found in the approved 
package insert.
OTHER RISKS
Medications:
Before taking any over the counter medicines, herbal products, vitamins, food supplements, or 
any other types of special products while participating in this study, please discuss this with the 
study doctor who will tell you whether it is appropriate to start or continue taking these 
medicines.  You should also talk to the study doctor before taking any medicines other doctors 
may have prescribed for you.  This is to ensure that there are no harmful interactions between the 
study drug and any other medicines you are taking.  Your study doctor may need to change or 
discontinue these for the duration of the study.
Blood drawing (venipuncture) risks:
Drawing blood may cause temporary discomfort from the needle stick, bruising, and infection.
Radiation (x-ray) risks:
The amount of radiation you will be exposed to is relatively small.  Such doses of radiation may 
be potentially harmful, but the risks are so small that they are difficult to measure.  If you have 
already had many x-rays, you should discuss this with the researchers before agreeing to be in 
the study.
CT and PET/CT scan risks:
CT scans involve the risks of radiation (see above).  In addition, if contrast material is used, there 
is a slight risk of developing an allergic reaction, from mild (itching, rash) to severe (difficulty 
breathing, shock, or rarely, death).  The contrast material may also cause kidney problems, 
especially if you are dehydrated or have poor kidney function.  The study doctors will ask you 
about any allergies or related conditions before the procedure.  If you have any of these 
problems, you may not be allowed to have a CT scan.
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 10 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
Having a CT scan may mean some added discomfort for you.  In particular, you may be bothered 
by feelings of claustrophobia when placed inside the CT scanner, or by lying in one position for 
a long time.  If contrast material is used, you may feel discomfort when it is injected.  You may 
feel warm and flushed and get a metallic taste in your mouth. Rarely, the contrast material may 
cause nausea, vomiting or a headache.
Bone scan risks:
Risks include radiation exposure as well as possible bruising from the injection of contrast.  
Some subjects may be uncomfortable lying flat.
Pregnancy risks:
The effects of the study drugs (eribulin and cyclophosphamide) on an unborn child are currently 
unknown.  Therefore it is important that you take measures to avoid becoming pregnant while 
participating in the study.  If you are pregnant, breast-feeding, or if you are not planning to take 
precautions against pregnancy, you are not allowed to take part in this study.
If you are a woman who is not menopausal, a pregnancy test will be performed prior to study 
start.  You should discuss any pregnancy plans with your study doctor before you are registered 
in this study.  Additionally you must agree to use medically acceptable contraception as 
suggested by your study doctor for the time you are receiving the study drugs.
If it is possible for you to become pregnant, you must agree to use two highly effective forms of 
birth control - one of which must be a barrier method (for example, use of a spermicide, an 
intrauterine device (IUD) or oral contraceptive, plus a barrier method such as a condom, 
diaphragm or cervical cap).  Oral contraception must not be used alone.
You and your partner must use adequate birth control from at least the first day of your last 
normal menstrual period before you take a study drug, and should continue until 30 days after 
the last dose of study drug.
The only subjects who will be exempt from the birth control requirement are those who are 
unable to become pregnant:

Women who had hysterectomy (uterus removed), bilateral oophorectomy (both ovaries
removed), bilateral tubal ligation and documentation of the procedure.

Postmenopausal women in the appropriate age group who had their last period more than
1 year before start of the study treatment.

If your partner had a vasectomy more than 3 months ago and a follow-up check showed
zero sperm count, then you do not need other birth control.
If you are abstinent (no sexual intercourse), you must agree to use an acceptable method of birth 
control if you become sexually active during the study.
If you become pregnant during the study or think that you might be pregnant, you must notify the 
study doctor immediately.
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 11 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
Unknown Risks:
The experimental treatments may have side effects that no one knows about yet.  The researchers 
will let you know if they learn anything that might make you change your mind about 
participating in the study.
For more information about risks and side effects, ask your study doctor.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
Taking part in this study may or may not make your health better.  While doctors hope eribulin 
combined with cyclophosphamide will be more useful against cancer compared to the usual 
treatment, there is no proof of this.  We do know that the information from this study will help 
doctors learn more about eribulin as a treatment for cancer.  This information could help future 
cancer patients.
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY?
If you choose not to participate in this research study, other procedures or treatments for your 
cancer could include:

Surgery to remove tumors

Radiation to shrink tumors

Other anticancer therapy (either experimental or not experimental), which may include
cyclophosphamide or other chemotherapy.

Getting no treatment

Getting comfort care.  This type of care could help reduce pain, tiredness, appetite
problems and other problems caused by the cancer. It does not treat the cancer directly, 
but instead tries to improve how you feel. Comfort care tries to keep you as active and 
comfortable as possible.
Depending on your type of cancer, its location and your general condition, all, some, or none of 
these alternatives may be appropriate.
Another choice available to you is simply to receive supportive care to help manage only the 
symptoms and pain produced by your cancer.  Your study doctor will discuss the other 
treatments available to you for your cancer.
Please talk to your doctor about your choices before deciding if you will take part in this study.
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE?
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 12 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
We will do our best to make sure that the personal information in your medical record is kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be given 
out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include:

The sponsor (Eisai, Inc.), it’s affiliated Eisai companies, and it’s consultants who are
helping to conduct this study

Government agencies such as the National Cancer Institute (NCI) and the Food and Drug
Administration (FDA), involved in keeping research safe for people.

The University of California
Participation in research may involve a loss of privacy, but information about you will be 
handled as confidentially as possible.  A medical record will be created because of your 
participation in this study.  Your consent form and some of your research test results will be 
included in this record.  Therefore, your other doctors may become aware of your participation.  
Hospital regulations require that all health care providers treat information in medical records 
confidentially.
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for taking part in 
studies.  Check with your health plan/insurance company to find out what they will pay for.  
Taking part in this study may or may not cost you or your insurance company more than the cost 
of getting regular cancer treatment.
The study drug eribulin will be provided by the sponsor (Eisai, Inc.) at no cost to you.  
Cyclophosphamide will be billed to you or your insurance.
Procedures that are done specifically for this study (which are not part of your regular care) will 
be paid for by the study sponsor.  Other procedures, which are also done in this study but are part 
of your normal care, will be paid for by your or your insurance.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You can 
print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
WILL I BE PAID FOR TAKING PART IN THIS STUDY?
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 13 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
You will not be paid for taking part in this study.
You may be eligible to be reimbursed for reasonable travel expenses of up to a maximum of $25 
related to each study visit.  The study doctor or staff can explain the procedures and requirements 
(such as receipts) for such reimbursement.  You will not receive any other money or payments.
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY?
It is important that you tell your study doctor, Hope Rugo, M.D., if you feel that you have been 
injured because of taking part in this study. You can tell the doctor in person or call him/her  
Treatment and Compensation for Injury:  If you are injured as a result of being in this 
study, the University of California will provide necessary medical treatment. The costs of 
the treatment may be billed to you or your insurer just like any other medical costs, or 
covered by the University of California, depending on a number of factors. The 
University does not normally provide any other form of compensation for injury. For 
further information about this, you may call the office of the Committee on Human 
Research at 415-476-1814.
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution.
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY?
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study.  Contact your study doctor Hope Rugo, M.D., 
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the Office of the Committee on Human Research at 415-476-1814.
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 14 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This Web 
site will not include information that can identify you. At most, the Web site will include a 
summary of study results.  You can search this Web site at any time. 
************************************************************
Please note: This section of the informed consent form is about additional research studies that 
are being done with people who are taking part in the main study. You may take part in these 
additional studies if you want to. You can still be a part of the main study even if you say "no" to 
taking part in any of these additional studies.
You can say "yes" or "no" to each of the following studies. Please mark your choice for each 
study.
1. About Using Archival Tumor Tissue Specimens for Research
As part of this study, research tests will be done on your tumor tissue specimens from the prior 
biopsy or surgery that was performed to diagnose your cancer. (if you give permission, below).
If there are any leftover tumor tissue specimens after these research tests are done, we would like 
to keep these specimens for future research. If you agree, these specimens will be kept and may 
be used in research to learn more about cancer and other diseases.  The research that may be 
done with your specimens is not designed specifically to help you. It might help people who 
have cancer and other diseases in the future.
A small amount of genetic material (DNA) may be obtained from your specimens to understand 
what mutations (changes) have developed in the DNA to cause the cancer, as well as help 
scientists understand why your tumor may or may not respond to the study drugs.
Reports about research done with your tissue will not be given to you or your doctor. These 
reports will not be put in your health record. The research will not have an effect on your care.
Things to Think About
The choice to let us keep the left over specimens for future research is up to you. No matter what 
you decide to do, it will not affect your care.
If you decide now that your specimens can be kept for research, you can change your mind at 
any time. Just contact us and let us know that you do not want us to use your tissue. Then any 
tissue that remains will no longer be used for research.  To do this, please contact your study 
doctor at the address below:
Hope Rugo, M.D.
University of California San Francisco, 
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 15 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
In the future, people who do research may need to know more about your health. While the study 
doctors may give them reports about your health, they will not give them your name, address, 
phone number, or any other information that will let the researchers know who you are.
Sometimes tissue is used for genetic research (about diseases that are passed on in families). 
Even if your tissue is used for this kind of research, the results will not be put in your health 
records.
Your tissue will be used only for research and will not be sold. The research done with your 
tissue may help to develop new products in the future.
Benefits
The benefits of research using tissue include learning more about what causes cancer and other 
diseases, how to prevent them, and how to treat them.
Risks
The greatest risk to you is the release of information from your health records. We will do our 
best to make sure that your personal information will be kept private. The chance that this 
information will be given to someone else is very small.
Making Your Choice
Please read the sentence below and choose “yes” or “no”.  No matter what you decide to do, it 
will not affect your care.
I agree to donate a leftover tumor tissue specimen that was previously collected as part of my 
clinical care for research tests related to this study.
YES 
NO
2. About Using Blood Sample for Future Research
As the main part of the study, you are going to have blood samplings before the start of the 
treatment. We would like to draw extra blood (1-2 tablespoons) for future genetic study when 
drawing the study blood samplings. The research that may be done with your blood is not 
designed specifically to help you.  It might help people who have cancer and other diseases in the 
future. 
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 16 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
A small amount of genetic material (DNA) may be obtained from your blood and a genome scan 
(a method to detect anomalies in the sequence of individual people’s DNA) will be performed to 
understand what mutations (changes) have developed in the DNA to cause the cancer, as well as 
help scientists understand why your tumor may or may not respond to the study drugs.
Reports about research done with your blood will not be given to you or your doctor. These 
reports will not be put in your health record. The research will not have an effect on your care.
Things to Think About
The choice to let us collect and use your blood for future genetic research is up to you. No matter 
what you decide to do, it will not affect your care.
If you decide now that your blood sample can be collected and used for research, you can change 
your mind at any time. Just contact us and let us know that you do not want us to use your blood 
sample. Then any sample that remains will no longer be used for research.  To do this, please 
contact your study doctor at the address below:
Hope Rugo, M.D.
University of California San Francisco
In the future, people who do research may need to know more about your health. While the study 
doctors may give them reports about your health, they will not give them your name, address, 
phone number, or any other information that will let the researchers know who you are.
This blood sample will be used for genetic research and the results will not be put in your health 
records.
Your blood sample will be used only for research and will not be sold. The research done with 
your blood sample may help to develop new products in the future. 
Benefits
The benefits of research using blood sample include learning more about what causes cancer and 
other diseases, how to prevent them, and how to treat them.
Risks
The greatest risk to you is the release of information from your health records. We will do our 
best to make sure that your personal information will be kept private. The chance that this 
information will be given to someone else is very small.
Genetic information that results from this study does not have medical or treatment importance at 
this time.  However, there is a risk that information about taking part in a genetic study may 
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 17 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
influence insurance companies and/or employers regarding your health. To further safeguard 
your privacy, genetic information obtained in this study will not be placed in your medical 
record.
Taking part in a genetic study may also have a negative impact or unintended consequences on 
family or other relationships.  If you do not share information about taking part in this study, you 
will reduce this risk.  Although your name will not be with the sample, it will have other facts 
about you such as age, sex, ethnicity and treatment.  These facts are important because they will 
help us learn if the factors that cause cancers to occur or get worse are the same or different 
based on these facts.  Thus it is possible that study finding could one day help people of the same 
race, ethnicity, or sex as you.  However, it is also possible through these kinds of studies that 
genetic traits might come to be associated with your group.  
Making Your Choice
Please read the sentence below and think about your choice. After reading the sentence, put your 
initials in the "Yes" or "No" box.  If you have any questions, please talk to your doctor or nurse, 
or call our research review board at IRB's phone number.
I agree to allow my blood sample to be used for future genetic research to learn about, prevent, 
or treat cancer or other diseases.
YES 
NO
************************************************************
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 18 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to 
keep.
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of 
health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled.
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Date
Signature of the Person Obtaining Consent
Date
Witness – Only required if the participant is a non-English speaker
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


Consent Form 06-27--2016
Page 19 of 19UCSF-CC# 11996
Protocol Version 5.0 (05-31-2013)Hope S. Rugo, MD
Medications and Foods to Avoid
The following is a list of medications to avoid while you are on this study, including medications 
which are prohibited and also those permitted if needed, but not recommended.
Before you begin treatment, the study doctor will review all medications you are taking. Make 
sure you talk with the study doctor before you start or stop taking any medications. This 
information will be reviewed at each study visit.
In addition to the listed medications you should also avoid eating or drinking juice from Seville 
oranges (also known as sour or bitter oranges), grapefruit, pomegranate, and starfruit. If you go 
to any other medical or dental visit, please take this list with you for the doctor’s reference.
Generic Name
Brand Names ®
Generic Name
Brand Names ®
Amprenavir
Agenerase
Nevirapine
Viramune
Atazanavir
Reyataz
Nicardipine
Astemizole
Opioid analgesics
Barbituates
Oxcarbazepine
Trileptal
Carbamazepine
Tegretol
Pentobarbital
Cisapride
Propulsid
Phenobarbital
Luminal
Conivaptan
Phenytoin
Dilantin
Delavirdine 
Rescriptor
Pimozide
Orap
Fosamprenavir
Lexiva
Posaconazole
Noxafil
Fosphenytoin
Cerebyx
Primidone
Imatinib
Quinidine
Cardioquin, Quinora
Indinavir
Crixivan
Rifabutin
Mycobutin
Isoniazid
Rifampin
Rifadin, Rimactane
Itraconazole
Sporanox
Rifapentine
Ketoconazole (oral)
Norvir
Nafcilin
Nefazodone
Nelfinavir
Viracept
Ketek
IRB NUMBER: 11-06948
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020