A Randomized Phase III Trial of Eribulin Compared to Standard Weekly Paclitaxel as First- or Second-Line Therapy for Locally Recurrent or Metastatic Breast Cancer
Phase: PHASE3
Conditions: Breast Adenocarcinoma, HER2/Neu Negative, Invasive Breast Carcinoma, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7
Sponsor: Academic and Community Cancer Research United

  
RU011201I 
 
Academic and Community Cancer Research United (ACCRU) 
 
A Randomized Phase III Trial of Eribulin Compared to Standard Weekly Paclitaxel as First- or 
Second-Line Therapy for Locally Recurrent or Metastatic Breast Cancer 
 
ACCRU protocol # RU011201I 
 
For any communications regarding this protocol, please contact the protocol resource person on the 
following page. 
 
 
ACCRU Study Chair: Minetta C. Liu, M.D 
 
 
 
 
 
 
 
 
Statisticians: 
David Hillman, M.S. √ 
 
 
 
Drug Availability 
Commercial Agents: Paclitaxel 
Drug Company Supplied: Eribulin mesylate (IND #126070) 
√ Study contributor(s) not responsible for patient care. 
 
Study Participants 
Date Activated 
ACCRU Membership 
January 17, 2014 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
 
 
 
 
Document History 
(effective date) 
Pre-activation ACCRU 
 December 20, 2013 
Activation ACCRU 
January 17, 2014 
Addendum 1 
May 26, 2015 
Addendum 2 
Addendum 3 
Addendum 4 
November 13, 2015 
June 22, 2018 
April 28, 2021  
 
This trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s). 
 (ICH E6 section 6.2.5) 
 
 

 
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Index 
 
Schema 
 1.0 
Background  
 2.0 
Objectives 
 3.0 
Patient Eligibility 
 4.0 
Test Schedule 
 5.0  
Stratification Factors 
 6.0 
Registration/Randomization Procedures 
 7.0 
Protocol Treatment 
 8.0 
Dosage Modifications Based on Adverse Events during Protocol Directed Therapy 
 9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring 
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
 
  
 
 
 
 
 
 
 
 
 
 

 
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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment will continue until disease progression, unacceptable toxicity, or patient withdrawal. 
 
If a patient is deemed ineligible or a cancel, please refer to Section 16.0 for follow-up information. 
 
1See Section 7.0 for dose and administration. 
2Cycle length for Arm A = 21 days 
3Cycle length for Arm B = 28 days 
 
 
Generic name:   Eribulin mesylate 
Brand name(s): Halaven 
ACCRU Abbreviation: E7389   
Availability: Eisai Co, Ltd 
Generic name:   Paclitaxel 
Brand name(s): Taxol 
ACCRU Abbreviation: TAXOL  
Availability: Commercially available  
 
Event Monitoring 
(see Sections 13 and 18) 
 
Arm A: 
Eribulin1 on Days 1 and 8 of 
 each cycle2 
1:1 Randomization 
Arm B: 
Paclitaxel1 on Days 1, 8, and 15 of 
each cycle3 
Disease progression, 
Unacceptable adverse events, 
Or patient refusal 
Pre-registration 
 
Follow-up/Observation 

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1.0 
Background 
1.1 
Rationale for selected approach and trial design. 
Metastatic breast cancer is generally incurable with few patients achieving long-term 
survival with standard chemotherapy.1 Despite a marked increase in the choice of active 
agents for the treatment of metastatic disease, overall survival has changed little during 
the last half century. Most recently, the introduction of new cytotoxic agents, new 
formulations of existing drugs and modifications of dose and/or schedule have resulted in 
improvements in outcome with generally well tolerated toxicity profiles. These advances 
have not only resulted in improved treatment options for patients with metastatic disease, 
but also in clinical trials investigating the most promising treatment approaches in the 
adjuvant setting. 
Paclitaxel is a taxane derivative and is among the most active agents in the treatment of 
breast cancer. A major limitation of paclitaxel is poor water solubility, requiring 
Cremophor® EL as a water soluble solvent. Cremophor® EL requires specialized 
intravenous tubing and has been associated with significant toxicities, including the risk 
of anaphylaxis (for which premedication with corticosteroids and antihistamines is 
required); bone marrow suppression; and peripheral neurotoxicity. Its poor solubility also 
requires paclitaxel to be dissolved in a relatively large volume of fluid administered over 
a longer period of time than many other chemotherapy agents. Given these toxicities and 
inconvenience, there has been interest in new microtubule stabilizing agents that modify 
the toxicity profile with the potential for similar or even superior efficacy. Two of the 
more effective agents currently in use are nanoparticle albumin bound paclitaxel (nab-
paclitaxel) and ixabepilone. 
In October 2008, the CALGB/Alliance Breast Committee activated Protocol 40502, a 
phase III clinical trial comparing the current standard of weekly paclitaxel at 90 mg/m2 to 
weekly nab-paclitaxel at 150 mg/m2 and weekly ixabepilone at 16 mg/m2 as first-line 
therapy in patients with taxane naïve metastatic breast cancer. Planned interim analyses 
of the primary endpoint of PFS were performed by the Alliance Data and Safety 
Monitoring Board on June 24, 2011 and then again on November 18, 2011. The first 
review led to the conclusion that it is very unlikely that ixabepilone (with or without 
bevacizumab) will be better than standard weekly paclitaxel (with or without 
bevacizumab). The second review led to the conclusion that it is very unlikely that nab-
paclitaxel (with or without bevacizumab) will be better than standard weekly paclitaxel 
(with or without bevacizumab). Both ixabepilone and nab-paclitaxel were shown to have 
a higher toxicity profile than paclitaxel as well. Therefore, accrual to the ixabepilone arm 
closed on July 8, 2011, and accrual to the nab-paclitaxel arm (and thus the trial as whole) 
closed on November 30, 2011 with 799 of 900 planned subjects.2 
Eribulin is a novel, non-taxane, tubulin-targeted agent whose activity in patients with 
heavily pretreated advanced breast cancer was established in three phase II clinical 
trials.3,4 The established dose and schedule of administration for eribulin mesylate is 1.4 
mg/m2 on days 1 and 8 of each 21-day cycle, with a break on day 15. Results from a 
randomized, open-label, phase III clinical trial (EMBRACE) demonstrated a statistically 
significant OS improvement with eribulin versus the treatment physician’s choice (TPC) 
of standard single agent therapy in patients who had received 2-5 prior chemotherapy 
regimens for metastatic breast cancer and had prior exposure to an anthracycline and 
taxane.5 97% of subjects on the control arm received single agent chemotherapy, and the 
remaining 3% received single agent endocrine therapy; no patients received best 

 
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RU011201I 
 
 
supportive care alone, although that was included as an option. Reported toxicities were 
acceptable and not unexpected. 
 
Demonstration of an OS benefit with single agent chemotherapy and a manageable 
toxicity profile in a heavily pretreated breast cancer population led eribulin to receive 
approval by the US Food and Drug Administration in November 2010. The approved 
indication is for the treatment of metastatic breast cancer patients with prior exposure to 
an anthracycline and taxane and who have received at least two chemotherapeutic 
regimens for metastatic disease. The next logical investigation is to compare eribulin to 
other microtubule stabilizing agents earlier in the treatment of advanced disease. The 
proposed phase III clinical trial is designed as the successor to CALGB 40502 and will 
compare eribulin mesylate (1.4 mg/m2 on days 1 and 8 of each 21-day cycle) to paclitaxel 
(90 mg/m2 on days 1, 8, and 15 of each 28-day cycle) as first- or second-line 
chemotherapy in patients with locally recurrent or metastatic breast cancer.  
 
1.2 
Primary translational objectives 
 
The format of this clinical trial provides the framework for a number important 
correlative studies focused on toxicity and efficacy related to the microtubule stabilizing 
agents. The primary aim of these translational efforts is to develop tools that will allow 
physicians to promptly and accurately identify patients with the highest likelihood of 
treatment benefit and the lowest probability of toxicity. Specifically, this trial will 
investigate the following relative to eribulin and standard weekly paclitaxel: 
 
1.2.1 
Use of the Patient-Reported Outcomes Version of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE) to collect relevant patient-reported 
symptom toxicity information. 
 
The PRO-CTCAE is an item bank consisting of individual questions to assess 
symptom toxicity events from the patient perspective (e.g., nausea, fatigue). The 
PRO-CTCAE was developed to complement the CTCAE, under an ongoing 
contract with the NCI (PI: Dr. Ethan Basch). To date, 78 symptoms in the 
CTCAE have been developed for patient self-reporting via the PRO-CTCAE, 
have undergone cognitive testing in patients, and are undergoing validation in a 
separate national study.6 In this study, the feasibility of assessing administration 
of 11 PRO-CTCAE symptoms (fatigue, nausea, vomiting, diarrhea, constipation, 
insomnia, sensory neuropathy, mucositis, pain, anorexia, alopecia) to patients on 
a weekly basis via an automated telephone system (i.e., interactive voice 
response system [IVRS]) will be assessed. The PRO-CTCAE system is hosted 
and maintained on servers at the NCI and has undergone rigorous security and 
privacy assessment per NCI requirements. 
 
1.2.2 
The rs7349683 polymorphism in EPHA5 as a predictor of peripheral neuropathy. 
 
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. These 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.7 Variability in 
hepatic metabolism and membrane transport was the focus of many initial studies 
addressing the sources of interindividual differences in CIPN.8-13 More recently, 
genome-wide approaches have been used to identify single nucleotide 
polymorphisms (SNPs) and genes important in this dose-limiting toxicity.14-17 

 
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The Kroetz laboratory performed the first genome-wide association study 
(GWAS) of paclitaxel-induced peripheral neuropathy using samples from 
CALGB 40101 (“Cyclophosphamide and doxorubicin [CA x 4 cycles] versus 
paclitaxel [4 cycles] as adjuvant therapy for breast cancer in women with 0-3 
positive axillary lymph nodes: A phase III randomized study”).14 A single 
nucleotide polymorphism in FGD4 was associated with the onset of sensory 
peripheral neuropathy in the discovery cohort of 858 genetic Europeans 
(rs10771973; HR, 1.57; 95% CI, 1.30-1.91; P = 2.6 x 10-6) and in a European 
(HR, 1.72; 95% CI, 1.06-2.80; P = 0.013) and African American (HR, 1.93; 95% 
CI, 1.13-3.28; P = 6.7 x 10-3) replication cohort. 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.18 The more common FGD4 polymorphism identified in CALGB 
40101 may be associated with Schwann and nerve cell communication in 
peripheral nerves following paclitaxel treatment. There was also evidence that 
markers in EPHA5 (rs7349683; p=9.6 x 10-7; HR=1.63) and FZD3 (rs10771973; 
p=3.1 x 10-9; OR=0.57) were associated with the onset or severity of paclitaxel-
induced sensory peripheral neuropathy.14 Similar analyses in other taxane-treated 
cohorts have led to the discovery of additional SNPs and genes. To date, 
members of the ephrin receptor gene family have been most consistently 
implicated in CIPN. rs7349683 in EPHA5, reported in CALGB 40101,14 has been 
replicated in a smaller paclitaxel-treated breast cancer population19 and variants 
in related ephrin receptor genes (rs301927 in EPHA6 and rs209709 in EPHA8) 
have also been associated with CIPN.19,20 EPHA5 encodes an ephrin receptor 
involved in axon guidance. In mice, EPHA5 is important for neuronal 
regeneration following injury.21 We hypothesize that patients carrying a reduced 
function EPHA5 allele may have an attenuated repair response following 
paclitaxel-induced injury. The current study provides a unique population to test 
the general relevance of this EPHA5 SNP for the prediction of CIPN associated 
with treatment with microtubule targeting agents. 
 
1.3 
Secondary translational objectives 
 
The format of this clinical trial provides the framework for a number important 
correlative studies focused on toxicity and efficacy related to the microtubule stabilizing 
agents. The primary aim of these translational efforts is to develop tools that will allow 
physicians to promptly and accurately identify patients with the highest likelihood of 
treatment benefit and the lowest probability of toxicity. Specifically, this trial will 
investigate the following relative to eribulin and standard weekly paclitaxel: 
 
1.3.1 
Common single nucleotide polymorphisms in FGD4, FZD3, and VAC14 as 
predictors of peripheral neuropathy. 
 
1.3.2 
Circulating markers of cell death as predictors of clinical benefit. 
 
1.3.3 
Tubulin isotype expression, mutations, and signaling pathway modifications as 
predictors of clinical benefit. 
 
Detailed information related to these secondary translational objectives is 
provided in Sections 14.0 and 17.0. 
 
 

 
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1.4 
Importance of the trial 
 
The primary goal for the treatment of metastatic breast cancer is to palliate symptoms and 
control disease progression in the setting of maintaining quality of life. Despite the 
known efficacy of the standard taxanes, there are a number of toxicities and 
inconveniences that impact negatively on patient quality of life and the ability to deliver 
more effective therapy.22 For paclitaxel, which is among the most active agents in the 
treatment of breast cancer, these toxicities and inconveniences are compounded by the 
Cremophor® EL solvent required for solubility and include the risk of hypersensitivity 
reactions, bone marrow suppression, peripheral neuropathy, the need for steroid 
premedications (with the potential for added toxicity), prolonged infusion times, and the 
need for specialized intravenous tubing. 
 
Although two combination chemotherapy regimens, namely gemcitabine/paclitaxel23 and 
capecitabine/docetaxel,24 have been associated with improved survival over taxane 
monotherapy for the treatment of anthracycline exposed advanced disease, evaluation of 
the data is difficult given the fact that subjects received limited additional therapy 
following participation in these clinical trials; it is likely that at least similar survival 
benefits would be seen with sequential single agent therapy (i.e., paclitaxel followed by 
gemcitabine versus gemcitabine/paclitaxel; docetaxel followed by capecitabine versus 
capecitabine/docetaxel). Combination regimens are also complicated by increased 
toxicity over sequential single agent therapy, limiting the value of symptom control on 
the quality of life endpoints. Sequential single agent chemotherapy therefore remains an 
important treatment approach in metastatic breast cancer, and optimizing the agent, 
formulation, dose, and schedule is necessary to our efforts to maximize treatment benefit 
and significantly improve clinical outcomes. 
 
Eribulin is a new chemotherapeutic agent with OS benefits in heavily pretreated patients 
with advanced breast cancer. Direct comparison of this agent to standard weekly 
paclitaxel will provide clinicians with important information on the relative clinical 
benefits and toxicity profiles associated with each of these potentially effective 
microtubule stabilizing agents. It also provides an important opportunity to investigate 
putative biomarkers that may function either as surrogate measures for the selection of 
those patients who are most likely to respond to specific therapies, or as early 
determinates of response or resistance during therapy. Data from the proposed clinical 
trial will be critical in making future decisions regarding systemic therapy in patients 
with metastatic disease, and in designing the next generation of adjuvant trials. 
 
1.5 
Use of control and experimental arms 
 
1.5.1 
Paclitaxel 
 
Paclitaxel is among the most active agents in the treatment of breast cancer. The 
mechanism of action is related to disruption of microtubule disassembly due to 
the binding of paclitaxel to dimeric tubulin; this results the cessation of mitosis 
and eventual cell death. Response rates in taxane naïve metastatic breast cancer 
have ranged from 20-60% with activity noted in anthracycline pretreated disease. 
Randomized phase III trials of paclitaxel have highlighted the significance of 
dose and schedule on efficacy and tolerability. Studies evaluating a dose 
relationship for paclitaxel documented improved response rates at 175 mg/m2 
compared to 135 mg/m2,25 and doses above 175 mg/m2 yielded more toxicity in 
the absence of further improvements in response rates or survival 26. Duration of 
exposure of cycling cells to paclitaxel may be an important determinant of anti-

 
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tumor efficacy;27,28 however, long duration infusions have been associated with 
increased hematologic toxicity with an increase in efficacy at 24 but not 96 
hours.29 
 
Weekly dosing of paclitaxel in patients with metastatic breast cancer was initially 
evaluated on the basis of mathematical models that predicted superiority for more 
frequent dosing.30 In a phase II trial, thirty patients with metastatic breast cancer 
received weekly paclitaxel therapy at an initial dose of 100 mg/m2 until disease 
progression.31 The overall response rate (ORR) was 53% (95% confidence 
interval [CI], 34% to 72%), with a median response duration of 7.5 months. 
Grade 3/4 neutropenia occurred in four patients; febrile neutropenia was not 
observed. Peripheral neuropathy prohibited dose escalation above 100 mg/m2, 
and grade 3 neuropathy was observed in two of 21 patients at <100 mg/m2. 
CALGB 9840 subsequently randomized 577 women with taxane naïve metastatic 
breast cancer to receive weekly paclitaxel at 100 or 80 mg/m2 versus standard 
three-weekly paclitaxel at 175 mg/m2 as first or second-line therapy.32 Weekly 
paclitaxel was superior to standard three-weekly paclitaxel with respect to 
response rates (42 versus 29%, odds ratio [OR] 1.75, p=0.0004) and time to 
progression (TTP; 9 versus 5 months, hazard ratio [HR] 1.43, p<0.001). Toxicity 
was also different; weekly paclitaxel caused less grade 3/4 granulocytopenia (9 
versus 15%, p=0.017) but more grade 3/4 sensory neuropathy despite a mid-trial 
dose reduction from 100 to 80 mg/m2 per week (24 versus 12%, p=0.0003).  
 
As a result of these trial results, weekly paclitaxel appears to be superior to 
standard three-weekly paclitaxel, and it is currently the preferred schedule of 
administration in the treatment of metastatic breast cancer. 
 
1.5.2 
Eribulin 
 
Halichondrin B is a large polyether macrolide isolated from the rare marine 
sponge Halichondrin okadai. It exhibits potent anticancer effects both in vitro 
and in vivo33-35 with a tubulin-based mechanism that appears to be distinct from 
all other antitubulin agents.33,36,37 E7389 (eribulin) is a structurally simplified, 
synthetic analog of this marine natural product that exhibits similar anticancer 
properties in preclinical models38 through a tubulin-based antimitotic mechanism 
similar to that of halichondrin B. It is a nontaxane microtubule dynamics 
inhibitor that suppresses microtubule growth and sequesters tubulin into 
nonfunctional aggregates, preventing mitotic spindle formation with subsequent 
G2-M arrest and apoptosis. It exhibited potent anticancer effects in preclinical 
models of various malignancies, including breast cancer.33,36,38-41 This mechanism 
of action is distinct from that of other antitubulins, such that it may be effective 
in patients with disease that is resistant to these agents. In fact, eribulin 
demonstrated antitumor activity in preclinical studies with cell lines that are 
paclitaxel resistant as a result of beta tubulin mutations.42 The in vivo animal 
model data also predicted that this agent would achieve greater efficacy than the 
taxanes and with fewer adverse effects. 
 
Three phase I clinical trials were conducted and demonstrated a manageable 
toxicity profile – two studies with a weekly schedule on days 1, 8, and 15 in 28-
day cycles43,44 and one study with a three-weekly schedule.45 Neutropenia was the 
DLT at a maximum tolerated dose of 1.4 mg/m2 as a bolus injection on days 1, 8, 
and 15 in 28-day cycles. This was selected as the initial dose and schedule for 
further development. 

 
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Subsequent phase II studies in patients with heavily pretreated advanced breast 
cancer demonstrated that eribulin is therapeutically active with a manageable 
toxicity profile that includes a low incidence of clinically significant peripheral 
neuropathy. The first study included 103 subjects who had received prior 
anthracyclines and taxanes with a median of four prior chemotherapy regimens.4 
The ORR was 11.5% by independent review with a clinic benefit rate of 17.2% 
(defined as responses in addition to stable disease of at least six months 
duration). Median PFS was 2.6 months, and median OS was 9.0 months. The 
most common grade 3/4 study drug-related adverse event was neutropenia (64%) 
with a low incidence of grade 3/4 fatigue (5%) and febrile neutropenia (4%). The 
incidence of peripheral neuropathy was also low (26% grade 1/2; 5% grade 3). 
Of note, the schedule was modified to days 1 and 8 in 21-day cycles for the last 
33 subjects because cycle 1 dose delays, reductions, or omissions were needed as 
a result of neutropenia in 44 of the initial 70 treated patients. 
 
The second related phase II study continued the 21-day schedule and treated 291 
subjects who had received prior anthracycline, taxane, and capecitabine therapy 
for locally advanced or metastatic breast cancer – again with a median of four 
prior chemotherapy regimens.3 The findings were very similar to the other study. 
The ORR was 9.3% by independent review and 14.1% by investigator 
assessment with a clinic benefit rate of 17.1% (defined as responses in addition to 
stable disease of at least six months duration). Median PFS was 2.6 months, and 
median OS was 10.4 months. The most common grade 3/4 study drug-related 
adverse event was neutropenia (54%) with a low incidence of grade 3/4 
asthenia/fatigue (10%) and febrile neutropenia (5.5%). Eribulin was associated 
with a 24.1% incidence of peripheral neuropathy overall (5.5% grade 3; 0% 
grade 4); of the 56 subjects who had pre-existing neuropathy, the majority (79%) 
did not experience worsening symptoms with the administration of eribulin. No 
grade 4 non-hematologic events were reported in either heavily pretreated patient 
population. 
 
EMBRACE (Study 305) was an open label, phase III clinical trial with a 2:1 
randomization to eribulin versus the physician’s choice of standard single agent 
therapy.5 Eligible subjects were patients with progressive, locally recurrent or 
metastatic breast cancer who had received 2-5 prior chemotherapy regimens, 
including exposure to an anthracycline and taxane (actual median of 4 prior 
regimens). Eribulin mesylate was administered as a 1.4 mg/m2 IV bolus injection 
over 2-5 minutes on days 1 and 8 in 21-day cycles. The physician’s choice of 
therapy included any monotherapy (chemotherapy, endocrine therapy, or biologic 
therapy) or supportive care alone. 97% of subjects on the control arm received 
single agent chemotherapy (26% vinorelbine, 18% gemcitabine, 18% 
capecitabine, 16% taxane, 9% anthracycline, 10% other), and the remaining 3% 
received single agent endocrine therapy; no patients received best supportive care 
alone. 762 patients were treated on protocol with improved median OS of 13.1 
months versus 10.6 months in favor of eribulin (HR 0.81, 95% CI 0.66-0.99, 
p=0.041). Median PFS was not statistically significant at 3.7 months versus 2.2 
months (HR 0.87, 95% CI 0.71-1.05, p=0.14), but ORR favored eribulin at 12.2 
versus 4.7% (p=0.002) by independent review. Grade 3 and grade 4 neutropenia 
occurred in 21% and 24% of subjects treated with eribulin, respectively, leading 
to the discontinuation of therapy in only <1% of patients. The rate of grade 3/4 
febrile neutropenia with eribulin was 4%. Grade 3 and grade 4 peripheral 
neuropathy occurred in 8% and 0.4% of subjects treated with eribulin, 
respectively, despite the history of prior taxane exposure. 

 
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In September 2009, accrual completed to an international, open-label, 
randomized, phase III clinical trial of eribulin versus capecitabine in patients with 
locally advanced or metastatic breast cancer previously treated with 
anthracyclines and taxanes.46 The study enrolled 1102 patients for first-line, 
second-line, or third-line chemotherapy with co-primary endpoints of OS and 
PFS. Eribulin mesylate was administered as a 1.4 mg/m2 IV bolus injection over 
2-5 minutes on days 1 and 8 in 21-day cycles. Capecitabine was administered 
orally as 2500 mg/ m2 in two divided doses on days 1-14 in 21-day cycles. 
Results of the final analysis were presented in December 2012 using the planned 
stratification factors of geographic region and HER2 status. An improvement in 
median OS was observed with 15.9 months versus 14.5 months in favor of 
eribulin, but this was not statistically significant for the entire study population 
(HR 0.879, 95% CI 0.770-1.003, p=0.056). Planned stratification by HER2 
status, however, revealed a nominally significant benefit in median OS for 
patients with HER2 negative disease (15.9 months versus 13.5 months for 
eribulin versus capecitabine; HR 0.84, p=0.0299). Median PFS for the overall 
population was similar between the eribulin and capecitabine treatment groups by 
independent review (4.1 months versus 4.2 months respectively, HR 1.079, 95% 
CI 0.932-1.250, p=0.305). The same observation was made for ORR on the 
independent reviewer assessment (11.0% versus 11.5% for eribulin versus 
capecitabine respectively). Eribulin was generally well tolerated and had a safety 
profile consistent with data from EMBRACE (Study 305) and the phase II 
studies. Febrile neutropenia was reported in 2% of patients in Study 301 versus 
4.6% of patients in EMBRACE (Study 305). No new safety signals were noted 
for eribulin. 
 
1.6 
Specific hypotheses of the current study 
 
 1.6.1 Treatment with eribulin will result in less neurotoxicity in comparison to 
treatment with standard weekly paclitaxel. 
 
1.6.2 
Patient-reported PRO-CTCAE data can be collected and used to detect 
differences in symptoms that result from exposure to eribulin and standard 
weekly paclitaxel. 
 
1.6.3 
Selected single nucleotide polymorphisms will predict for the risk of peripheral 
neuropathy associated with exposure to eribulin and standard weekly paclitaxel. 
 
1.6.4 
Serum based biologic correlates will predict for survival and/or response to 
therapy with eribulin specifically or the microtubule dynamics inhibitors in 
general. 
 
1.6.5 
Tumor based biologic correlates will predict for survival and/or response to 
therapy with eribulin specifically or the microtubule dynamics inhibitors in 
general. 
 
 

 
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2.0 
Objectives 
 
2.1 
Primary 
 
2.1.1 
To demonstrate that patient-reported PRO-CTCAE data will be able to detect 
differences in symptoms between participants treated with eribulin and standard 
weekly paclitaxel at 12 weeks. 
 
2.1.2 
To validate rs7349683 in EPHA5 as a predictor of peripheral neuropathy from 
treatment with a microtubule targeting agent (i.e., eribulin or paclitaxel). 
 
2.2 
Secondary 
 
2.2.1 
To compare overall survival, progression free survival (PFS), objective response 
rate (ORR), duration of response (DOR), and time to treatment failure (TTF) in 
patients receiving eribulin versus standard weekly paclitaxel. 
 
2.2.2 
To compare the 12 month rate of disease progression in patients receiving 
eribulin versus standard weekly paclitaxel. 
 
2.2.3 
To evaluate the clinical value and feasibility of collecting patient-reported 
symptom toxicity information via the Patient-Report Outcomes Version of the 
Common Terminology Criteria for Adverse Events (PRO-CTCAE); to further 
validate the PRO-CTCAE sensory neuropathy items; and to compare patient-
reported neurotoxicity between arms using the EORTC QLQ-CIPN20 
instrument. 
 
2.2.4 
To assess the toxicities in patients receiving eribulin versus standard weekly 
paclitaxel. 
 
2.3 
Exploratory 
 
2.3.1 
To compare new metastasis free survival in patients receiving eribulin versus 
standard weekly paclitaxel. 
 
2.4 
Correlative 
 
2.4.1 
To explore the relationship between common single nucleotide polymorphisms in 
FGD4, FZD3, and VAC14 as predictors of peripheral neuropathy from treatment 
with a microtubule targeting agent (i.e., eribulin or paclitaxel). 
 
2.4.2 
To evaluate circulating nucleosomes and the apoptosis associated M30 neo-
epitope as potential biomarkers associated with clinical benefit from treatment 
with eribulin specifically or the microtubule dynamics inhibitors in general. 
 
2.4.3 
To evaluate tubulin isotype expression, mutations, and signaling pathway 
modifications in tumor tissue as potential biomarkers associated with clinical 
benefit from treatment with eribulin specifically or the microtubule dynamics 
inhibitors in general. 
 
 

 
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3.0 
Patient Eligibility 
 
3.1 
Pre-registration – Inclusion criteria 
 
3.1.1 
Informed consent document signed and dated by patient. 
 
3.2 
Registration – Inclusion Criteria  
 
3.2.1 
Age ≥18 years. 
 
3.2.2 
Histologic confirmation of invasive adenocarcinoma originating in the breast. 
 
3.2.3 
Stage IV disease or Stage IIIC disease (using the 7th edition AJCC criteria) not 
amenable to local therapy. 
 
3.2.4 
Clinical or radiographic evidence of disease progression. 
 
3.2.5 
Documentation of HER2 negative breast cancer at the time of protocol 
registration. [Note: HER2 negativity is defined as 0 or 1+ by 
immunohistochemistry OR nonamplified or equivocal by FISH. Status may be 
defined on the basis of historic results on the breast primary or a metastatic site, 
whichever is most recent. Repeat biopsies are not required for participation in 
this protocol.] 
 
3.2.6 
Known hormone receptor status at the time of protocol registration. [Note: ER 
and/or PgR status are considered positive with a cut-off of ≥1% invasive tumor 
cells. Status may be defined on the basis of historic results on the breast primary 
or a metastatic site, whichever is most recent. Repeat biopsies are not required 
for participation in this protocol.] 
 
3.2.7 
Prior systemic therapy as per the following criteria: 
 
3.2.7.1 
Patients must demonstrate resolution of all toxicities related to prior 
chemotherapy, endocrine therapy, targeted therapy, or biologic therapy 
to grade ≤1, including peripheral neuropathy, with the exception of 
alopecia (any grade permissible). 
 
3.2.7.2 
No more than one prior chemotherapy regimen for advanced or 
metastatic breast cancer is allowed. Prior chemotherapy for metastatic 
disease must have been completed ≥14 days prior to randomization. 
 
• 
Any single agent therapy, and any combination of cytotoxic, 
endocrine, biological targeted agents, and/or humanized 
antibodies, scheduled to be administered as a preplanned treatment, 
given concomitantly, sequentially or both, is considered one 
regimen. 
 
• 
Planned neoadjuvant chemotherapy and postoperative adjuvant 
chemotherapy is considered one regimen. 
 
 
 

 
13  
RU011201I 
 
 
• 
If the dosing of one or more of the chemotherapy components of a 
regimen must be reduced for toxicity, the modified version of the 
original regimen is not considered a new regimen. 
 
• 
If one or more of the chemotherapy components of a regimen must 
be omitted for toxicity, the modified version of the original 
regimen is not considered a new regimen. 
 
• 
If one of the chemotherapy components of a regimen must be 
replaced with another similar drug of the same therapeutic class, 
the modified version of the original regimen is not considered a 
new regimen. However, if a new component, dissimilar to any of 
the original components, is added to the regimen, the modified 
version is considered a new regimen. 
 
• 
If chemotherapy is interrupted for surgery or radiotherapy and then 
continues with an unchanged schedule and components, treatment 
is considered as one regimen despite the interruption. 
 
3.2.7.3 
Prior treatment may include a taxane as per the following criteria: 
 
• 
Prior taxane (including paclitaxel) in the adjuvant or neoadjuvant 
setting is allowed, provided that the interval between the 
completion of (neo)adjuvant therapy and disease recurrence is >12 
months. 
 
• 
Prior taxane in the metastatic setting is allowed, provided that the 
agent administered in the metastatic setting was not standard 
paclitaxel. 
 
3.2.7.4 
Any number of prior endocrine therapies is allowed and must be 
discontinued prior to randomization. 
 
3.2.7.5 
Any number of biologic therapies (e.g., bevacizumab) or 
immunotherapies is allowed in the absence of co-administered 
chemotherapy and must have been completed ≥28 days prior to 
randomization. 
 
3.2.7.6 
Prior treatment with an investigational agent is allowed but must have 
been completed ≥28 days prior to randomization with resolution of all 
treatment-related toxicities to grade ≤1. 
 
3.2.8 
Prior local therapy as per the following criteria: 
 
3.2.8.1 
Minor surgical procedures must be completed ≥7 days prior to 
randomization with documentation of adequate recovery from 
associated complications to grade ≤1. These include (but are not 
limited to) laparoscopy, thoracoscopy, bronchoscopy, 
mediastinoscopy, endoscopic ultrasonography, skin biopsy, 
percutaneous needle biopsy, and routine dental procedures. As a 
precautionary measure, it is recommended, but not strictly required, 
that placement of a central venous access device, thoracentesis, or 

 
14  
RU011201I 
 
 
paracentesis be done 7 days before the initiation of protocol directed 
chemotherapy with documentation of adequate recovery from 
associated complications to grade ≤1. 
 
3.2.8.2 
Major surgical procedures and open biopsies must be completed ≥28 
days prior to randomization with documentation of adequate recovery 
from associated complications to grade ≤1. 
 
3.2.8.3 
Prior radiotherapy must be completed ≥14 days prior to randomization 
with documentation of adequate recovery from associated toxicities to 
grade ≤1. 
 
3.2.9 
Concurrent supportive therapy as per the following criteria: 
 
3.2.9.1 
Treatment with bisphosphonates or denosumab is allowed and 
recommended per the standard of care. 
 
3.2.9.2 
Therapeutic anticoagulation is allowed for patients on a stable dose of 
warfarin or low molecular weight heparin. 
 
3.2.10 Radiographically measurable or non-measurable disease as per RECIST 
guidelines (version 1.1, see Section 11.0): 
 
3.2.10.1 Measurable disease is defined as at least one lesion that can be 
accurately measured with the longest diameter as ≥1.0 cm by CT scan 
or ≥1.0 cm with calipers by clinical examination. The exceptions to 
these criteria are pathologic lymph nodes, which must be ≥1.5 cm in 
the short axis when assessed by CT scans with slice thickness ≤0.5 cm. 
 
3.2.10.2 Non-measurable lesions include the following: small lesions (longest 
diameter <1.0 cm for all lesions other than pathologic lymph nodes, 
which are ≥1.0 cm and <1.5 cm in the short axis), bone metastases, 
pleural effusions, pericardial effusions, ascites, inflammatory breast 
disease, leptomeningeal disease, lymphangitis pulmonis, lymphangitis 
cutis, and abdominal masses not followed by CT or MRI. 
 
3.2.11 ECOG performance status of 0, 1, or 2. 
 
3.2.12 Life expectancy of >12 weeks. 
 
3.2.13 History of brain metastases as per the following criteria: 
 
3.2.13.1 Patients with a history of resected brain metastases are eligible only if 
they are asymptomatic and have stable MRI scans for 3 consecutive 
months, including <28 days of study registration. 
 
3.2.13.2 Patients who receive stereotactic radiosurgery or whole brain radiation 
for brain metastases are eligible only if they are asymptomatic and 
have stable MRI scans for 3 consecutive months, including <28 days of 
study registration. 
 
 

 
15  
RU011201I 
 
 
3.2.14 Adequate organ function per blood work obtained <7 days prior to registration: 
 
3.2.14.1 Absolute neutrophil count ≥1500/µL. 
 
3.2.14.2 Platelet count ≥100,000/µL. 
 
3.2.14.3 Hemoglobin ≥9 g/dL. 
 
3.2.14.4 Total bilirubin ≤1.5 times the upper limit of normal (ULN) except for 
unconjugated hyperbilirubinemia of Gilbert’s syndrome. 
 
3.1.14.5 SGOT (AST) and SGPT (ALT) <3x ULN except in the case of liver 
metastases, where ≤5x ULN is allowed. 
 
3.2.14.6 Creatinine ≤2.0 mg/dL or creatinine clearance >50 mL/min. 
 
3.2.14.7 QTc interval ≤500 msec on the baseline electrocardiogram. 
 
3.2.15 Negative pregnancy test done ≤72 hours prior to registration for women of 
childbearing potential only. 
 
Note: All female subjects will be considered to be of child-bearing potential 
unless they are postmenopausal (at least 12 months consecutive amenorrhea, in 
the appropriate age group and without other known or suspected cause), or have 
been sterilized surgically (i.e., bilateral tubal ligation ≥1 menstrual cycle prior to 
randomization, or have undergone a hysterectomy and/or bilateral 
oophorectomy). 
 
Female subjects of child-bearing potential must agree to use highly effective 
contraception during the study treatment and for 3 months after the final dose of 
study treatment. Female subjects exempt from this requirement are subjects who 
practice total abstinence. If currently abstinent, the subject must agree to use a 
double barrier method of contraception (i.e., condom and occlusive cap 
[diaphragm or cervical/vault caps]) with spermicide or until they are established 
on highly effective contraception for at least one menstrual cycle if they become 
sexually active during the study treatment and for 3 months after the final dose of 
study treatment. 
 
Highly effective contraception includes: 
 
• 
Placement of intrauterine device or system 
• 
Barrier methods of contraception: condom or occlusive cap (diaphragm 
or cervical/vault cap) with spermicide 
• 
Vasectomized partner with confirmed azoospermia 
 
Male subjects and their female partner who are of child-bearing potential (as 
defined above), and are not practicing total abstinence, must agree to use highly 
effective contraception during study treatment and for 3 months after the final 
dose of study treatment. If currently abstinent, the subject must agree to use a 
double barrier method of contraception if they become sexually active, or until 
they are established on highly effective contraception as described above. 
 

 
16  
RU011201I 
 
 
3.2.16 Ability to complete questionnaire(s) independently or with assistance. 
 
3.2.17 Willingness to provide blood and tissue samples for correlative research purposes 
(see Sections 6.1.2, 14.0, and 17.0). [Note: These tissue samples are from 
archived tissue, if available; new biopsies are not required.] 
 
3.2.18 Ability to comprehend and respond to questions using a telephone keypad. 
 
3.3 
Exclusion criteria 
 
3.3.1 
Prior malignancy, other than carcinoma in situ of the cervix and non-melanoma 
skin cancers, unless the prior malignancy was diagnosed and definitively treated 
≥5 years previously, there is no subsequent evidence of recurrence, and the 
patient is considered by a physician to be at <30% risk of relapse. 
 
3.3.2 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic, and teratogenic effects on the developing fetus and 
newborn are unknown: 
 
• Pregnant women 
• Nursing women 
• Men or Women of childbearing potential who are unwilling to 
employ adequate contraception 
 
3.3.3 
Presence of a serious nonhealing wound, ulcer, or bone fracture. 
 
3.3.4 
History of CTCAE grade >3 hypersensitivity to paclitaxel or Cremophor® EL. 
 
3.3.5 
Pre-existing peripheral neuropathy grade ˃2 at registration. 
 
3.3.6 
Significant cardiovascular impairment (e.g., New York Heart Association 
congestive heart failure of grade II or above, unstable angina, myocardial 
infarction within the past 6 months, or serious cardiac arrhythmia). 
 
3.3.7 
Subjects with known positive HIV status. 
 
3.3.8 
History of stroke or transient ischemic attack <6 months prior to registration. 
 
3.3.9 
History of uncontrolled seizures. [Note: Patients are eligible for the study if the 
seizures are well controlled with standard medications.] 
 
3.3.10 Severe or uncontrolled intercurrent illness/infection. 
 
3.3.11 Concurrent administration of any other investigational agent considered to have 
potential efficacy in the treatment of breast cancer. 
 
3.3.12 Prior exposure to eribulin mesylate. 
 

17 
RU011201I 
 
 
4.0 
Test Schedule 
Tests and procedures 
Baseline/ Pre-treatment 
(<7 days prior to 
randomization unless 
noted otherwise) 
Active Monitoring/Treatment 
 
Follow-up/ 
Observation10 
(Every 12 
weeks until 
progression 
unless 
otherwise 
specified) 
Days 1, 8 for 
Arm A 
 
Days 1, 8, and 
15 for Arm B 
 
(unless 
otherwise 
specified) 
Prior to each 
new cycle, 
starting with 
cycle 2 
(≤7 days) 
Every 12 
weeks 
(+/- 7 days) 
At end of 
treatment 
 (PD, 
withdrawal, or 
removal)10 
History, physical examination (including measurements 
of clinically evident disease), weight, BSA 
X 
 
X 
 
X 
X11 
ECOG Performance Status (PS)  
X 
 
X 
 
X 
 
Height  
X 
 
 
 
 
 
Adverse event assessment13,14 
X 
 
X 
 
X 
X11 
Pregnancy test (serum or urine β-HCG)1 
X  
 
  
 
 
 
Hematology: CBC w/ diff and platelets  
X 
X 
  
 
X 
 
Chemistries: SGOT (AST), SGPT (ALT), alkaline 
phosphatase, total bilirubin, creatinine, calculated 
creatinine clearance16, Ca, glucose, Na, K 
X 
 
X 
 
X 
 
Contrast enhanced CT scans of chest/abdomen/pelvis 
(see Section 11.0)4 
X2 
 
 
X 
 
X 
Bone scan17  
X2 
 
 
X3 
 
X3,12 
Brain MRI with gadolinium5  
X 
 
 
X 
 
X 
Concomitant medications 
X 
 
X 
 
X 
 
Electrocardiogram  
X 
 
X18 
 
 
 
Mandatory blood samples (see Section 14.0)6,R  
X 
 
  
X 
X 
 
Mandatory archived tissue sample (see Section 17.0)7,R  
X 
 
 
 
 
 
EORTC QLQ-CIPN20 (see Appendix IV)8  
X 
 
X 
 
X 
 
PRO-CTCAE (see Appendix V, VI, & VII)  
X9 
X9 
 
 
X15 
X 
1. For women of childbearing potential only. Must be performed ≤72 hours prior to registration. 
2. Must be performed ≤28 days prior to registration. 
3. For patients with a history of bone metastases or for whom there is clinical suspicion of bone metastases at study entry. 
 

 
18  
RU011201I 
  
 
4. For patients with a documented allergy to iodine, shellfish, or CT contrast, noncontrast enhanced CT scans of the chest AND gadolinium enhanced MRI of 
the abdomen and pelvis may be performed. 
5. For patients with known brain metastases, or if clinically indicated. 
6. Use of study kits is required (see Section 14.0). May also be drawn on cycle 1 day 1 prior to the administration of chemotherapy. 
7. Must be submitted within 90 days of registration unless the site can provide documentation of their unsuccessful efforts to obtain the required tissue. 
8. The EORTC QLQ-CIPN20 questionnaire will be administered via paper form. 
9. Items from the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) will be administered prior to 
the initiation of study treatment and then weekly during study treatment via a telephone Interactive Voice Response System (IVRS). 
10. For patients who discontinue study treatment without disease progression (see Section 13.8.1). Follow-up can be discontinued after 2 years if the patient is 
no longer receiving study treatment.  If the patient remains on study treatment as of September 30, 2021, follow-up will be discontinued. 
11. Information may be obtained through phone calls to the patient or office notes from health care providers (see Section 13.6). 
12.  Every 24 weeks (sooner if clinically indicated). 
13. Patient PRO-CTCAE scores should be printed from the PRO-CTCAE web system and provided to the clinician at the time of clinical grading of adverse 
events during treatment and at the end of treatment (see Section 1.1in Appendix VI). 
14. All adverse events observed during study participation will be reported on the eCRF. All adverse events, regardless of relationship to the study drug, will be 
collected beginning from the time the subject signs the study ICF through the last visit and for 30 days after last dose. Serious adverse events will be 
collected for 30 days after the last dose, or any time if the investigator considers it related to study drug. After the 30 days, only those adverse events related 
to peripheral neuropathy need to be collected. 
15. There will be a 12 week follow-up survey administered one time via booklet (see appendix VII). 
16. Cockcroft-Gault GFR = (140-age) * (wt. in kg) * (0.85 if female) / (72 * Cr) 
17. F-18 (sodium fluoride) PET imaging or Tc99 radionuclide bone scans, per physician discretion. 
18. Prior to cycle 2 only. 
R. Research funded (see Section 19.0). 
 

 
19  
RU011201I 
 
 
 
5.0 
Stratification Factors (documented at the time of registration) 
 
5.1 
Prior taxane exposure: Yes versus no. 
 
5.2 
ER/PR status: ER or PR positive versus ER and PR negative. 
 
5.3 
Planned line of chemotherapy on study: First-line versus second-line. 
 
 
6.0 
Registration/Randomization Procedures 
 
6.1 
Pre-registration procedures (Step 1) 
 
6.1.1 
Documentation of IRB approval and ongoing IRB approval (no less than 
annually) must be on file at the Registration Office 
 before a 
site investigator may pre-register any patients. Approvals should be uploaded 
using the online ACCRU Regulatory Management System (ARMS). Sites must 
also have approval of regulatory documents and have completed required 
training. Please refer to the Study Completion Guidelines (access the ACCRU 
web page and click on Regulatory) for a complete list of requirements. If the 
necessary documentation is not submitted in advance of attempting patient 
registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. [Note: When the study has 
been permanently closed to patient enrollment, submission of annual IRB 
approvals to the Registration Office is no longer necessary.] 
 
6.1.2 
To pre-register a patient, fax 
 a completed pre-registration 
eligibility checklist to the Registration Office between 8:00 AM and 4:30 PM 
Central Time Monday through Friday. 
 
Confirmation of pre-registration will be received via email at the time pre-
registration is complete. If this email is not received, you can contact the 
Registration Office at 
to confirm pre-registration. 
 
6.1.3 
All patients who sign and date an informed consent document must be pre-
registered, regardless of whether they proceed to Registration (Step 2). 
 
6.1.3.1 If the patient does not go on to registration, the completed screening 
disposition form must be faxed to the Registration Office 
 If the patient did not meet the eligibility criteria, then the 
Inclusion/Exclusion Criteria Form must also be faxed to the Registration 
Office. 
 
6.2 
Registration procedures (Step 2) 
 
6.2.1 
Upon confirmation of patient pre-registration, the site will register the patient as 
follows: 
 
Fax 
 a completed eligibility checklist and the screening 
disposition form to the Registration Office between 8:00 AM and 4:30 PM 
Central Time Monday through Friday. 
Confirmation of registration will be received via fax at the time registration is 

 
20  
RU011201I 
 
 
 
complete. If this fax is not received, you can contact the Registration Office at 
to confirm registration. 
 
Prior to the initiation of protocol study intervention, this process must be 
completed in its entirety and an ACCRU subject ID number must be available as 
noted in the instructions. It is the responsibility of the individual and institution 
registering the patient to confirm the process has been successfully completed 
prior to release of the study agent. 
 
6.2.2 
At the time of registration, the following must be recorded: 
 
• Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn about, prevent, or treat cancer. 
 
• Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn, prevent, or treat other health problems (e.g., 
diabetes, Alzheimer’s disease, or heart disease). 
 
• Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn about, prevent, or treat cancer. 
 
• Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn, prevent, or treat other health problems (e.g., 
diabetes, Alzheimer’s disease, or heart disease). 
 
6.2.3 
Correlative research 
 
Mandatory correlative research components are part of this study. The patient 
will be automatically registered onto this component (see Sections 3.2.17, 14.0, 
and 17.0). 
 
6.2.4 
Prior to accepting the registration/randomization, the registration/randomization 
application will verify the following: 
 
• Patient eligibility 
 
• Existence of a signed and dated consent form 
 
• Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.3 
Other requirements for registration 
 
6.3.1 
Study drugs must be available on site at the time of registration. 
 
6.3.2 
Blood draw kits must be available on site at the time of registration. 
 
6.3.3 
Patient questionnaire booklets must be available on site at the time of 
registration. Copies are not acceptable for this submission. 
 
 

 
21  
RU011201I 
 
 
 
6.3.4 
PRO-CTCAE Site Credentialing: At least one staff member from the site is 
required to obtain credentialing to perform PRO-CTCAE patient training. The 
staff member should send an e-mail request to the PRO-CTCAE Coordinator at 
 to schedule a date and time for live interactive training 
using the telephone; no instructional videos will be available. 
 
Training will require about 45 minutes and is required only once per site.  
 
Training will include the following: (1) how to register a patient to PRO-CTCAE 
telephone reporting using the interactive voice response system (IVRS); (2) how 
to explain and demonstrate the PRO-CTCAE telephone system to patients; (3) 
how to monitor patients’ PRO-CTCAE reporting. The PRO-CTCAE Coordinator 
will provide e-mail certification of successful credentialing to the site and to the 
ACCRU Regulatory Office. This office will update their regulatory records to 
indicate that training has been completed. Sites may check for updates on their 
status by contacting 
 
 
For any questions or concerns, please send an e-mail to
 
 
6.3.5 
PRO-CTCAE Patient Training: Each patient must be trained to use the telephone 
symptom reporting system. 
 
Note: Site study staff must clearly convey to the patient that the information 
regarding symptoms collected by the PRO-CTCAE self-report are for research 
purposes only and are not monitored by a physician. Study staff must advise 
patients to directly contact their doctor for any concerning symptoms. 
 
All patients enrolled at U.S. and Canadian sites who can read and speak English 
or Spanish will be required to participate in PRO-CTCAE reporting by telephone 
using the PRO-CTCAE interactive voice response system (IVRS). Site study 
staff will train the patient how to use the IVRS; this training will require about 10 
to 20 minutes per patient. 
 
Because patients will self-report PRO-CTCAE symptoms from home, patients 
will not require access to a telephone during regularly scheduled clinic visits. 
However, in order for site personnel to train patients, access to a telephone will 
be required. If this is not possible, the site study staff may provide this training 
over the telephone by calling the patient after s/he leaves the clinic. Patients 
reporting by telephone will call telephone number 
, enter their 
user ID and PIN, then answer the verbal questions concerning symptoms and 
health concerns. This will require about 5 minutes. 
 
A reference card for the telephone IVRS system will be provided to the patient as 
shown in Appendix VII. This reference card, available in English and Spanish, is 
available through ACCRU. Both a help line and e-mail address are listed on the 
 
 or call telephone number 
. 
 
 

 
22  
RU011201I 
 
 
 
6.4 
Other requirements for the initiation of protocol directed therapy 
 
6.4.1 
Protocol directed therapy cannot begin prior to registration and must begin <21 
days after registration. 
 
6.4.2 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.4.3 
All required baseline symptoms (see Section 10.3) must be documented and 
graded. 
 
6.4.4 
Protocol directed chemotherapy must be administered at an ACCRU institution 
under the supervision of a medical oncologist. 
 
6.5 
Randomization procedures 
 
6.5.1 
When combined, the stratification factors defined in Section 5.0 create 8 strata 
groups. 
 
6.5.2 
After the patient is registered into the study, the values of the stratification factors 
will be recorded, and the patient will be assigned to one of the following 
treatment groups using Medidata Rave Balance, which is based on the Pocock 
and Simon47 dynamic allocation procedure. The goal of this procedure is to 
maintain arm balance within each of the 8 strata, with the target arm ratio being 
1:1. 
 
• 
Eribulin mesylate 
 
• 
Paclitaxel 
 
 
7.0 
Protocol Treatment 
 
7.1 
Treatment doses and schedule 
 
7.1.1 
Pretreatment medications for paclitaxel (required) 
 
Agent 
Dose 
Route 
Comments 
Dexamethasone 
10-20 mg 
IV 
Administer 30-60 minutes 
prior to paclitaxel 
Diphenhydramine 
50 mg 
IV or PO 
Famotidine (or 
equivalent) 
20 mg 
IV  
 
 
 
 

 
23  
RU011201I 
 
 
7.1.2 
Chemotherapy  
 
Arm 
Agent 
Dose 
Route 
Day(s) 
Cycles 
A 
Eribulin 
mesylate 
1.4 mg/m2 
IV over 2-5 
minutes 
1 and 8 
q21 days 
B 
Paclitaxel 
90 mg/m2 
IV over 1 
hour 
1, 8, and 15 
q28 days 
 
7.2 
The BSA formula of Dubois or of Gehan and George will be used for all chemotherapy 
dose calculations. Use actual weight. 
 
7.3 
The patient must return to the consenting ACCRU institution for chemotherapy 
administration and clinical evaluation per protocol. 
 
 
8.0 
Dosage Modifications Based on Adverse Events during Protocol Directed Therapy 
 
ALERT: ADR reporting may be required for some adverse events (See Section 10.0) 
 
8.1 
Dose levels (Based on Adverse Events outlined below). 
 
Dose Level 
Eribulin mesylate 
(mg/m2) 
Paclitaxel (mg/m2) 
0* 
1.4 
90 
-1 
1.1 
75 
-2 
0.7 
60 
* Dose level 0 refers to the starting dose. 
 
8.2 
Dose modifications for eribulin mesylate 
 
8.2.1 
Guidelines for hematologic toxicity on day 1 
 
(CTCAE v4.0 System/Organ/Class [SOC] is INVESTIGATIONS) 
 
8.2.1.1 
Delay eribulin mesylate administration for ANC <1000/mm3 or 
platelets <75K/mm3. 
 
8.2.1.2 
Discontinue protocol directed treatment if chemotherapy is delayed for 
>4 weeks due to hematologic toxicity. 
 
8.2.1.3 
If the ANC recovers to >1000/mm3 within 4 weeks, resume treatment 
as follows: 
 
• 
If the ANC was <500/mm3 for >7 days, decrease eribulin 
mesylate by one dose level and maintain for all subsequent 
doses. 
 
• 
If the ANC was <1000/mm3 with fever or infection, decrease 
eribulin mesylate by one dose level and maintain for all 
subsequent doses. 
 

 
24  
RU011201I 
 
 
 
8.2.1.4 
If the platelets recover to >75K within 4 weeks, resume treatment as 
follows: 
 
• 
If the platelets were <25K/mm3, decrease eribulin mesylate by 
one dose level and maintain for all subsequent doses. 
 
• 
If the platelets were <50K/mm3 and required platelet 
transfusion (per physician discretion), decrease eribulin 
mesylate by one dose level and maintain for all subsequent 
doses. 
 
8.2.2 
Guidelines for hematologic toxicity on day 8 
 
8.2.2.1 
Delay eribulin mesylate administration for ANC <1000/mm3 or 
platelets <75K/mm3 until recovery to these values. 
 
8.2.2.2 
If recovery occurs before day 15, eribulin mesylate is administered, 
and that day of treatment will be considered the new day 8. Decrease 
eribulin mesylate by one dose level and maintain for all subsequent 
doses. 
 
8.2.2.3 
If recovery does not occur before day 15, the eribulin mesylate dose is 
omitted, and treatment will resume as scheduled on day 1 of the next 
cycle. Decrease eribulin mesylate by one dose level and maintain for 
all subsequent doses. 
 
8.2.3 
Guidelines for other grade 3 or 4 non-hematologic toxicity 
 
(CTCAE v4.0 System/Organ/Class [SOC] is OTHER UNSPECIFIED 
ADVERSE EVENTS) 
 
8.2.3.1 
For other grade 3 non-hematologic toxicity attributed to chemotherapy, 
delay chemotherapy administration. 
 
8.2.3.2 
If the delay for grade 3 non-hematologic toxicity occurs on day 1 and 
the toxicity improves to grade 2 or better within 7 days (with or 
without maximal supportive care), resume treatment with one dose 
level reduction. 
 
8.2.3.3 
If the delay for grade 3 non-hematologic toxicity occurs on day 8 and 
the toxicity improves to grade 2 or better before day 15, eribulin 
mesylate is administered, and that day of treatment will be considered 
the new day 8. Decrease eribulin mesylate by one dose level and 
maintain for all subsequent doses. Initiate the next cycle no sooner than 
2 weeks later. 
 
8.2.3.4 
If the delay for grade 3 non-hematologic toxicity occurs on day 8 and 
the toxicity does not improve to grade 2 or better before day 15, the 
eribulin mesylate dose is omitted, and treatment will resume as 
scheduled on day 1 of the next cycle. Decrease eribulin mesylate by 
one dose level and maintain for all subsequent doses. 
 

 
25  
RU011201I 
 
 
 
8.2.3.5 
For other grade 4 non-hematologic toxicity attributed to chemotherapy, 
protocol participation must be permanently discontinued. 
 
8.2.3.6 
If chemotherapy is delayed or skipped for >4 weeks, protocol 
participation must be permanently discontinued. 
 
8.3 
Dose modifications for paclitaxel 
 
8.3.1 
Guidelines for hematologic toxicity on day 1 
 
(CTCAE v4.0 System/Organ/Class [SOC] is INVESTIGATIONS) 
 
8.3.1.1 
Delay paclitaxel administration for ANC <1000/mm3 or platelets 
<75K/mm3. 
 
8.3.1.2 
Discontinue protocol directed treatment if chemotherapy is delayed for 
>4 weeks due to hematologic toxicity. 
 
8.3.1.3 
If treatment is delayed for ANC <1000/mm3 or platelets <75K/mm3 
and the counts recover within 4 weeks, decrease paclitaxel by one dose 
level and maintain for all subsequent doses. 
 
8.3.1.4 
For platelets 75-99K/mm3, do not delay treatment, decrease paclitaxel 
by one dose level, and maintain for all subsequent doses. 
 
8.3.2 
Guidelines for hematologic toxicity on day 8 or 15 
 
8.3.2.1 
Skip the day 8 or 15 administration of paclitaxel for ANC <1000/mm3 
or platelets <75K/mm3. These doses are not made up. 
 
8.3.2.2 
If treatment is skipped for ANC <1000/mm3 or platelets <75K/mm3, 
decrease paclitaxel by one dose level and maintain for all subsequent 
doses. 
 
8.3.2.3 
For platelets 75-99K/mm3, do not delay treatment, decrease paclitaxel 
by one dose level, and maintain for all subsequent doses. 
 
8.3.3 
Guidelines for hepatic dysfunction 
 
(CTCAE v4.0 System/Organ/Class [SOC] is INVESTIGATIONS) 
 
Transaminase level 
 
Bilirubin level 
Dose modification 
AST or ALT < 2.5  
and 
T. bilirubin > 1.5 x ULN, but < 3 x ULN 
Reduce one dose level♦ 
AST or ALT > 2.5, but < 10 x ULN  
and 
T. bilirubin < 1.5 x ULN  
Reduce one dose level♦ 
AST or ALT > 2.5 but < 10 x ULN  
and 
T. bilirubin > 1.5 x ULN, but < 3 x ULN 
Reduce two dose levels*♦ 
AST or ALT > 10 x ULN  
or 
T. bilirubin > 3 x ULN 
Discontinue protocol therapy 
 * 
No reductions below dose level -2. 
♦ Dose reductions stay at the same level unless hepatic function worsens (i.e., for abnormal LFTs that remain at the same 
level, another dose reduction should not be made). 

 
26  
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8.3.4 
Guidelines for other grade 3 or 4 non-hematologic toxicity 
 
(CTCAE v4.0 System/Organ/Class [SOC] is OTHER UNSPECIFIED 
ADVERSE EVENTS) 
 
8.3.4.1 
For other grade 3 non-hematologic toxicity attributed to chemotherapy, 
delay (day 1) or skip (day 8 or 15) chemotherapy administration until 
the toxicity improves to grade 2 or better and then resume treatment 
with one dose level reduction. 
 
8.3.4.2 
For other grade 4 non-hematologic toxicity attributed to chemotherapy, 
protocol participation must be permanently discontinued. 
 
8.3.4.3 
If chemotherapy is delayed or skipped for >4 weeks, protocol 
participation must be permanently discontinued. 
 
8.4. 
Dose modifications for peripheral neuropathy secondary to chemotherapy (eribulin 
mesylate or paclitaxel) 
 
8.4.1 
For intolerable grade 2 peripheral neuropathy, decrease chemotherapy by one 
dose level and maintain for all subsequent doses. 
 
8.4.2 
Skip chemotherapy administration for grade 3 peripheral neuropathy. When the 
symptoms improve to grade 2 or better, treatment may resume with one dose 
level reduction for all subsequent doses. (The time to resolution to grade 2 or 
better should be the adverse event duration used for adverse event reporting.) 
 
8.4.3 
Discontinue protocol directed treatment if grade 4 peripheral neuropathy 
develops. 
 
8.5 
General guidelines 
 
8.5.1 
Chemotherapy drug dose reductions are permanent. Once reduced, the dose 
may not be dose escalated. 
 
8.5.2 
If chemotherapy must be reduced below dose level -2 for toxicity, protocol 
participation must be permanently discontinued. 
 
8.5.3 
If chemotherapy is delayed or skipped for >4 weeks, protocol participation must 
be permanently discontinued. 
 
8.5.4 
For grade >3 hypersensitivity reactions, protocol participation must be 
permanently discontinued. 
 
 

 
27  
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9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics, antidiarrheals, analgesics, and all other supportive medications may be used 
at the discretion of the treating physician and in keeping with good clinical practice. All 
concomitant medications received from the first day of study treatment administration 
until 30 days after the final dose must be recorded in the medical records. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and in 
accordance with institutional policies and recommendations. 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse events and other events of interest 
 
10.1.1 Adverse event characteristics 
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for AE reporting. Each CTCAE term in the current version is a unique 
representation of a specific event used for medical documentation and scientific 
analysis and is a single MedDRA Lowest Level Term (LLT). 
 
All appropriate treatment areas should have access to the CTCAE version 4.0 
document, which can be downloaded from the CTEP web site: 
  
 
Site investigators will report CTCAE grades for all AEs (for both increasing and 
decreasing severity). 
 
10.2 
Expected versus unexpected events 
 
10.2.1 The determination of whether an AE is expected or unexpected is based on 
agent-specific information provided in the Investigator Brochure and/or Section 
15.0 of the protocol. 
 
10.2.2 Unexpected AEs are those not listed in the agent-specific information provided in 
the Investigator Brochure and/or Section 15.0 of the protocol. 
 
10.2.3 An “unexpected adverse experience” refers to any adverse experience that is 
neither identified in nature, severity, or frequency of risk in the information 
provided for IRB review, nor mentioned in the consent form. 
 
10.3 
Assessment of attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 

 
28  
RU011201I 
 
 
 
Events determined to be possibly or probably attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between 
the drug and the adverse event. 
 
10.4 
Routine reporting 
 
Routine AE reporting for Phase 3 clinical studies using an investigational agent/intervention 
and a commercial agent on separate arms must be reported as defined by the general 
guidelines. 
 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical 
investigation subject administered an investigational product. An AE does not necessarily 
have a causal relationship with the medicinal product. For this study, the study drug(s) 
are eribulin mesylate and paclitaxel. 
 
The criteria for identifying AEs are as follows: 
 
● 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product. 
 
● 
Any new disease or exacerbation of an existing disease. However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE. 
 
● 
Any deterioration in nonprotocol-required measurements of a laboratory value or 
other clinical test (e.g., ECG or x-ray) that results in symptoms, a change in 
treatment, or discontinuation of study drug. 
 
● 
Recurrence of an intermittent medical condition (e.g., headache) not present 
pretreatment (at baseline). 
 
● 
An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, whether prescribed in the 
protocol or not. A laboratory result should be considered by the site investigator to be 
an AE if it: 
 
o 
Results in the withdrawal of study drug 
 
o 
Results in withholding of study drug pending some investigational outcome 
 
o 
Results in an intervention, based on medical evaluation (e.g., potassium 
supplement for hypokalemia) 
 
o 
Results in any out of range laboratory value that in the site investigator’s 
judgment fulfills the definitions of an AE with regard to the subject’s medical 
profile 
 
All AEs observed during the study will be reported on the CRF (found in the Forms 
Packet). All AEs, regardless of relationship to study drug or procedure, should be 
collected beginning from the time the subject signs the study informed consent form 
through the last visit and for 30 days after last dose. Serious AEs will be collected for 30 

 
29  
RU011201I 
 
 
 
days after the last dose, or any time if the investigator considers it related to study drug. 
After the 30 days, only peripheral neuropathy AEs need to be collected. 
 
Abnormal laboratory values should not be listed as separate AEs if they are considered to 
be part of the clinical syndrome that is being reported as an AE. Any laboratory 
abnormality considered to constitute an AE should be reported on the Adverse Event 
CRF. 
 
It is the responsibility of the site investigator to review all laboratory findings in all 
subjects and determine if they constitute an AE. Medical and scientific judgment should 
be exercised in deciding whether an isolated laboratory abnormality should be classified 
as an AE. 
 
Every effort must be made by the site investigator to categorize each AE according 
to its severity and its relationship to the study treatment. 
 
10.5 
Serious adverse events and other events of interest 
 
To determine if an adverse event is a serious adverse event, the following criteria must be 
used. In addition, all adverse events reported using CTCAE classification and graded as 4 
or 5 are to be considered serious. 
 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 
● 
Results in death 
 
● 
Is life-threatening (i.e., the subject was at immediate risk of death from the adverse 
event as it occurred; this does not include an event that, had it occurred in a more 
severe form or was allowed to continue, might have caused death) 
 
● 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
● 
Results in persistent or significant disability/incapacity or substantially disrupts the 
ability to conduct normal life functions 
 
● 
Results in a congenital anomaly/birth defect (in the child of a subject who was 
exposed to the study drug) 
 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may 
jeopardize the subject or may require intervention to prevent one of the outcomes in the 
definition of SAE listed above should also be considered SAEs. Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in 
such situations. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
In addition to the above, other events of interest include pregnancy or exposure to study 
drug through breastfeeding; and AEs associated with study drug overdose, misuse, abuse, 
or medication error. These events of interest are to be captured using the SAE procedures 
but are to be considered as SAEs only if they meet one of the above criteria. All AEs 
associated with events of interest are to be reported on the CRF whether or not they meet 
the criteria for SAEs. 
 

 
30  
RU011201I 
 
 
 
The following hospitalizations are not considered to be SAEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with the 
hospitalization: 
 
● 
Hospitalizations for respite care 
 
● 
Planned hospitalizations required by the protocol 
 
● 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
 
● 
Hospitalization for administration of study drug or insertion of access for 
administration of study drug 
 
● 
Hospitalization for routine maintenance of a device (e.g., battery replacement) that 
was in place before study entry 
 
● 
Death, hospitalization, or other serious outcomes for signs and symptoms of 
progression of the cancer. [Note: Disease progression is a study endpoint and should 
not be captured in the CRF as per the guidelines for disease progression.] 
 
The criteria for assessing severity are different than those used for seriousness (see 
Serious Adverse Events and Other Events of Interest for the definition of an SAE). 
Serious AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in 
the detail indicated on the Serious Adverse Event Form. The definitions are as follows: 
 
Mild - Discomfort noticed, but no disruption of normal daily activity 
Moderate 
- Discomfort sufficient to reduce or affect normal daily activity 
Severe - Incapacitating, with inability to work or to perform normal daily activity 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly or probably attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between 
the drug and the adverse event. 
 
10.6 
SAE reporting requirements for the IND agent (eribulin mesylate) 
 
Note: Treatment related SAEs for paclitaxel must be reported by submitting form 
MedWatch 3500A to the FDA.  
 
 
 
 
 
 

 
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The Serious Adverse Event reports must be submitted within 24 hours using the Eisai 
Clinical Study Report Form for Serious Adverse Events & Events of Special Interest 
(found in the Forms Packet) by following the instructions outlined. 
 
An AE that occurs on a treatment arm using an investigational agent or intervention under an 
IND must be assessed in accordance with the guidelines for investigational agents. Where 
indicated, a report must be submitted. 
 
All SAEs occurring <30 days after the final dose of study treatment, regardless of 
causality assessment, must be reported on a completed SAE form by fax as soon as 
possible, but no later than 24 hours after awareness. Fax the form to the ACCRU 
SAE Coordinator at 
 All SAEs must be followed to resolution, or if 
resolution is unlikely, to stabilization. 
 
Any SAE occurring >30 days after the final dose of study treatment and judged by the 
site investigator to be related to the study treatment must be reported to ACCRU 
regardless of the length of time that has passed since study completion. Deaths and life-
threatening events should be reported within 24 hours by faxing the completed SAE 
form. The detailed contact information for reporting of SAEs is provided in the 
Investigator File. 
 
10.6.1 Reporting guidelines 
 
10.6.1.1 For urgent safety issues, please ensure all appropriate medical care is 
administered to the subject and contact the appropriate study team 
member listed in the Investigator File. 
 
10.6.1.2 It is very important that the SAE report form be filled out as 
completely as possible at the time of the initial report. This includes the 
site investigator’s assessment of causality. 
 
10.6.1.3 SAEs need to be reported at each occurrence. 
 
10.6.1.4 Any follow-up information received on SAEs should be forwarded 
within 24 hoursof its receipt. If the follow-up information changes the 
site investigator’s assessment of causality, this should also be noted on 
the follow-up SAE form. 
 
10.6.1.5 Preliminary SAE reports should be followed as soon as possible by 
detailed descriptions including copies of hospital case reports, autopsy 
reports, and any supplementary documents requested by ACCRU. 
 
10.6.1.6 The site investigator should notify his/her IRB/IEC of the occurrence 
of the SAE, in writing, in accordance with local requirements. A copy 
of this communication must be forwarded to ACCRU. 
 
 

 
32  
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10.6.2 Death 
 
10.6.2.1 Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND, requires SAE 
reporting within 24 hours. 
10.6.2.2 Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an IND 
requires SAE reporting within 24 hours. 
 
10.6.2.3 Reportable categories of death including the following: 
 
• 
Death attributable to a CTCAE term. 
 
• 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
 
• 
Sudden death NOS: A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of 
life that cannot be attributed to a CTCAE term associated with 
Grade 5. 
 
10.6.2.4 Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts 
and polyps) – Other (Progressive Disease)” under the system 
organ class (SOC) of the same name. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
10.6.3 
Secondary malignancy 
 
10.6.3.1 A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm. 
 
10.6.3.2 All secondary malignancies that occur following treatment with an 
agent under an IND/IDE are to be reported. Three options are available 
to describe the event: 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelogenous Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
10.6.3.3 Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 

 
33  
RU011201I 
 
 
 
10.6.4 Second malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require only 
routine reporting. 
 
10.6.5 Reporting of pregnancy 
 
10.6.5.1 Any pregnancy where the estimated date of conception occurs either 
prior to the study termination visit or within 90 days of the last study 
treatment must be reported. If an adverse outcome of a pregnancy is 
suspected to be related to study drug exposure, this should be reported 
regardless of the length of time that has passed since the exposure to 
study treatment. An induced abortion or a spontaneous abortion is 
considered to be an SAE and should be reported in the same time 
frame and in the same format as all other SAEs (see Reporting of 
SAEs). 
 
10.6.5.2 Pregnancies must be reported as soon as possible but no later than 24 
hours by fax or email. The contact information for the reporting of 
pregnancies is provided in the Investigator File. The Pregnancy Report 
Form (see Forms Packet) must be used for reporting. All pregnancies 
must be followed to outcome. The outcome of the pregnancy must be 
reported as soon as possible but not later than 1 business day. 
 
10.6.5.3 A subject who becomes pregnant must be withdrawn from the study. 
 
10.6.6 Reporting of Other Events of Interest: Overdose 
 
10.6.6.1 Study drug overdose >10% is the accidental or intentional use of the 
drug in the amount higher than the starting dose being studied. 
 
10.6.6.2 Any study drug overdose during the study should be noted on the CRF 
(AE Log found in the Forms Packet). 
 
10.6.6.3 All AEs associated with an overdose should both be entered on the 
Adverse Event CRF and reported using the procedures detailed in 
Reporting of SAEs, even if the events do not meet serious criteria. If 
the AE associated with an overdose does not meet serious criteria, it 
must still be reported using the SAE form and in an expedited manner 
but should be noted as non-serious on the SAE form and the Adverse 
Event CRF. 
 
10.6.7 Additional instructions 
 
10.6.7.1 Any event that results in persistent or significant disability/incapacity, 
congenital anomaly, or birth defect must be reported via expedited 
mechanisms if the event occurs following treatment on a trial under an 
IND. 
 
10.6.7.2 Use the ACCRU protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 

 
34  
RU011201I 
 
 
 
10.6.7.3 Mayo Clinic Cancer Center (MCCC) Institutions: Provide copies, 
along with the UPIRTSO cover sheet, by fax 
to the 
ACCRU Regulatory Affairs Unit (RAU) Risk Information Specialist 
who will determine and complete IRB reporting. The RAU will submit 
to the ACCRU SAE Coordinator for submission to Eisai Inc.  
 
10.6.7.4 Non-Mayo ACCRU sites: Once the ACCRU SAE Coordinator 
receives the report via fax, the ACCRU SAE Coordinator will forward a 
copy of the above expedited reports to Eisai Inc. at 
 The ACCRU SAE Coordinator will forward to 
as appropriate. The ACCRU IND 
Coordinator will assist the investigator in notifying the FDA if required. 
 
10.7 
Other Required Reporting for routine CRFs 
 
10.7.1 Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per the CTCAE v4.0 grading 
unless otherwise stated in the table below: 
 
System Organ 
Class (SOC) 
Adverse Event/Symptoms 
Baseline 
Each 
evaluation 
Investigations 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
Aspartate aminotransferase 
increased 
X 
X 
Alanine aminotransferase 
increased 
X 
X 
Blood bilirubin increased 
X 
X 
General disorders 
and administration 
site conditions 
Fatigue 
X 
X 
Gastrointestinal 
disorders 
Nausea 
X 
X 
Vomiting 
X 
X 
Constipation 
X 
X 
Skin and 
subcutaneous tissue 
disorders 
Alopecia 
X 
X 
Nervous systems 
disorders 
Peripheral sensory 
neuropathy 
X 
X 
Blood and 
lymphatic system 
disorders 
Anemia 
X 
X 
Immune system 
disorders 
Allergic reaction 
X 
X 
Psychiatric 
disorders 
Depression 
X 
X 
Insomnia 
X 
X 
Note: For this trial ALL adverse events (not just AEs listed in the table) will be collected by date of 
occurrence regardless of greatest grade or nadir event. A reasonable effort should be made to collect a 
resolution date for those patients that discontinue treatment with peripheral neuropathy as an AE. 
 
 
 

 
35  
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10.7.2 Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
10.8 
PRO-CTCAE administration and data collection 
 
Participants will be registered into the PRO-CTCAE IVRS system and trained to self-
report by local study personnel, and will complete a baseline PRO-CTCAE self-report. 
Subsequently, throughout trial enrollment, weekly, on a day/time selected by the each 
patient, the patient will be asked to call in to the PRO-CTCAE telephone system and self-
report 11 selected symptoms (fatigue, nausea, vomiting, diarrhea, constipation, insomnia, 
sensory neuropathy, mucositis, pain, anorexia, alopecia) assessed using 20 items (shown 
in APPENDIX V). The PRO-CTCAE system is hosted and maintained on servers at the 
NCI and has undergone rigorous security and privacy assessment per NCI requirements. 
The average length of this call is <5 minutes. Patients who do not call in will receive an 
automated reminder call. If there is no response to the reminder call, an automatic email 
notification will be sent to a central PRO-CTCAE Coordinator at MSKCC, who will then 
attempt to reach the patient (directly or through the local site depending on site 
preferences or requirements) to conduct the questionnaire and assess reasons for non-
compliance. 
 
When patients report severe symptoms, an automated email notification will be sent to 
local study personnel and local clinical staff. 
 
At each visit requiring clinical AE grading for a given patient, the site will print a 
customized “shared” patient-clinician AE reporting form, from the PRO-CTCAE system. 
The form will automatically include that patient’s previously self-reported PRO-CTCAE 
responses. Clinicians will then record on this customized AE form the clinical CTCAE 
grades. Additional questions on this form will ask whether the AE form was used at each 
assessment, whether the patient’s PRO-CTCAE responses were seen and/or used by the 
individual providing the clinical grades, and whether the patient’s PRO-CTCAE 
responses impacted the clinical grading of AEs (if they were seen and/or used by the 
individual providing the grades). All of these questions from the form will then be 
entered by site staff into Medidata Rave (along with all other case report forms; standard 
source documentation at sites will be required for all case report forms including the AE 
form). 
 
After 12 weeks, each participating patient will be given a paper-based questionnaire at a 
study visit in clinic to assess satisfaction and the usability of the PRO-CTCAE system. A 
questionnaire will also be administered to site staff and clinicians to assess satisfaction 
and usability of the PRO-CTCAE system. 
 
As noted above, at the time of the initiation of this trial, the PRO-CTCAE will be 
available via the NCI-hosted IVRS in English and Spanish. Other languages will not yet 
be supported, and therefore patients without verbal fluency in one of these languages will 
not be eligible for this correlative study. We will track the number of patients who are 
ineligible to participate in this correlative study due to language. We will also track the 
number of patients who refuse to participate in this correlative study, and the reasons for 
refusal. 
 
All participating patients will also be asked to complete the EORTC QLQ-CIPN20 

 
36  
RU011201I 
 
 
 
questionnaire (paper form; shown in APPENDIX IV) prior to initiating study treatment, 
once per cycle (on day 1 of cycle 2 and beyond), and at the discontinuation of treatment. 
These data will be used to provide further validation of the PRO-CTCAE sensory 
neuropathy items and to compare patient-reported neurotoxicity between treatment arms. 
The EORTC QLQ-CIPN20 is a validated questionnaire (2, 3) assessing peripheral 
neuropathic side-effects of chemotherapy over the past week using 20 items each rated by 
the patient on a 1 (not at all) to 4 (very much) integer scale. The scoring algorithm 
provided by the scale developers will be used three scales: sensory scale, motor scale, and 
autonomic scale. 
 
 
11.0 
Treatment Evaluation Using RECIST Guidelines48 
 
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) guidelines 
(version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the short axis measurements in the case of lymph nodes are used in the RECIST guideline. 
[Note: See the footnote for the table regarding measureable disease in Section 11.4.4, as it 
pertains to data collection and analysis.] 
 
11.1 
Schedule of evaluations: for the purposes of this study, patients must be reevaluated 
every 12 weeks (+/-7 days). 
 
11.2 
Definitions of measurable and non-measurable disease 
 
11.2.1 Measurable Disease 
 
11.2.1.1 A non-nodal lesion is considered measurable if its longest diameter can 
be accurately measured as ≥1.0 cm with CT scan, CT component of a 
PET/CT, or MRI. 
 
11.2.1.2 A superficial non-nodal lesion is measurable if its longest diameter is 
≥1.0 cm in diameter as assessed using calipers (e.g., skin nodules) or 
imaging. In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
11.2.1.3 A malignant lymph node is considered measurable if its short axis is 
>1.5 cm when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 0.5 cm). 
 
11.2.1.4 Tumor lesions in a previously irradiated area are not considered 
measurable disease unless there is radiographic evidence of progression 
after irradiation. 
 
11.2.2 Non-Measurable Disease 
 
11.2.2.1 All other lesions (or sites of disease) are considered non-measurable 
lesions and include the following: small lesions (longest diameter <1.0 
cm for all lesions other than pathologic lymph nodes, which are >1.0 cm 
and <1.5 cm in the short axis), bone metastases, pleural effusions, 
pericardial effusions, ascites, inflammatory breast disease, 

 
37  
RU011201I 
 
 
 
leptomeningeal disease, lymphangitis pulmonis, lymphangitis cutis, and 
abdominal masses not followed by CT or MRI. 
[Note: “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. In addition, lymph nodes that have a short axis <1.0 cm are 
considered non-pathological (i.e., normal) and should not be recorded or 
followed.] 
 
11.2.3 Special considerations for bone metastases 
 
11.2.3.1 Lytic bone lesions or mixed lytic-blastic bone lesions with an 
identifiable soft tissue component that is evaluable by cross sectional 
imaging (i.e., CT or MRI) may be considered measurable disease if the 
soft tissue component meets the definition of measurability as 
described above. 
 
11.2.3.2 Blastic bone lesions are considered non-measurable disease. 
 
11.3 
Guidelines for the evaluation of measurable disease 
 
11.3.1 Measurement methods 
 
11.3.1.1 All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
 
11.3.1.2 The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. For patients having only lesions measuring at least 1 cm to 
less than 2 cm must use CT imaging for both pre- and post-treatment 
tumor assessments. 
 
11.3.1.3 Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used at the same evaluation 
to assess the antitumor effect of a treatment. 
 
11.3.2 Acceptable modalities for measurable disease: 
 
11.3.2.1 CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 0.5 cm or less. 
If CT scans have slice thickness greater than 0.5 cm, the minimum size 
for a measurable lesion should be twice the slice thickness. 
 
11.3.2.2 MRI: 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. The lesions should be measured on the 
same pulse sequence. 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. 
 

 
38  
RU011201I 
 
 
 
11.3.2.3 PET-CT: If the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time. 
 
11.3.2.4 Chest X-ray: Lesions on chest x-ray are acceptable for the 
documentation of new lesions, but not for the monitoring of measurable 
disease. 
 
11.3.2.5 Physical Examination: For superficial non-nodal lesions, physical 
examination is acceptable, but imaging is preferable, if both can be done. 
In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 
11.3.2.6 FDG-PET: FDG-PET scanning is allowed to complement CT scanning 
in assessment of progressive disease [PD] and particularly possible 
“new” disease. A “positive” FDG-PET scanned lesion is defined as one 
which is FDG avid with an update greater than twice that of the 
surrounding tissue on the attenuation corrected image; otherwise, an 
FDG-PET scanned lesion is considered “negative.” New lesions on the 
basis of FDG-PET imaging can be identified according to the following 
algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
 
i. 
If the positive FDG-PET at follow-up corresponds to a new site 
of disease confirmed by CT, this is PD. 
 
ii. If the positive FDG-PET at follow-up is not confirmed as a new 
site of disease on CT at the same evaluation, additional follow-
up CT scans (i.e., additional follow-up scans at least 4 weeks 
later) are needed to determine if there is truly progression 
occurring at that site. In this situation, the date of PD will be the 
date of the initial abnormal PDG-PET scan. 
 
iii. 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, it is not classified as PD. 
 
11.3.3 Measurement at follow-up evaluation: 
 
11.3.3.1 In the case of stable disease (SD), follow-up measurements must have 
met the SD criteria at least once after study entry at a minimum interval 
of 12 weeks (+/- 7 days) (see Section 11.4.4). 
 
11.3.3.2 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 

 
39  
RU011201I 
 
 
 
differentiate between response or stable disease (an effusion may be a 
side effect of the treatment) and progressive disease. 
 
11.3.3.3 Cytologic and histologic techniques can be used to differentiate between 
PR and CR in rare cases (e.g., residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain.) 
 
11.4 
Measurement of effect 
 
11.4.1 Target lesions and target lymph nodes 
 
11.4.1.1 Measurable lesions (as defined in Section 11.2.1) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as 
“Target Lesions” and recorded and measured at baseline. These lesions 
can be non-nodal or nodal (as defined in 11.2.1), where no more than 2 
lesions are from the same organ and no more than 2 malignant nodal 
lesions are selected. 
 
[Note: If fewer than 5 target lesions and target lymph nodes are 
identified (as there often will be), there is no reason to perform 
additional studies beyond those specified in the protocol to discover 
new lesions.] 
 
11.4.1.2 Target lesions and target lymph nodes should be selected on the basis of 
their size, be representative of all involved sites of disease, but in 
addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion 
(or malignant lymph node) does not lend itself to reproducible 
measurements in which circumstance the next largest lesion (or 
malignant lymph node), which can be measured reproducibly should be 
selected. 
 
11.4.1.3 Baseline Sum of Dimensions (BSD): A sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target lymph 
nodes will be calculated and reported as the baseline sum of dimensions 
(BSD). The BSD will be used as reference to further characterize any 
objective tumor response in the measurable dimension of the disease. 
 
11.4.1.4 Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the 
target lymph nodes will be calculated and reported as the post-baseline 
sum of dimensions (PBSD). If the radiologist is able to provide an 
actual measure for the target lesion (or target lymph node), that should 
be recorded, even if it is below 0.5 cm. If the target lesion (or target 
lymph node) is believed to be present and is faintly seen but too small to 
measure, a default value of 0.5 cm should be assigned. If it is the 
opinion of the radiologist that the target lesion or target lymph node has 
likely disappeared, the measurement should be recorded as 0 cm. 
 
11.4.1.5 The minimum sum of the dimensions (MSD) is the minimum of the 
BSD and the PBSD. 
 

 
40  
RU011201I 
 
 
 
11.4.2 Non-target lesions and non-target lymph nodes 
 
11.4.2.1 Non-measurable sites of disease (Section 11.2.2) are classified as non- 
target lesions or non-target lymph nodes and should also be recorded at 
baseline. These lesions and lymph nodes should be followed in accord 
with 11.4.3.3. 
 
11.4.3 Response criteria 
 
11.4.3.1 All target lesions and target lymph nodes followed by CT/MRI/PET-
CT/physical examination must be measured on re-evaluation at 
evaluation times specified in Section 11.1. Specifically, a change in 
objective status to either a PR or CR cannot be done without 
remeasuring target lesions and target lymph nodes. 
 
[Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment.] 
 
11.4.3.2 Evaluation of target lesions 
 
a. Complete Response (CR): All of the following must be true: 
 
i. 
Disappearance of all target lesions. 
 
ii. Each target lymph node must have a reduction in the short axis 
to <1.0 cm. 
 
b. Partial Response (PR): At least a 30% decrease in PBSD (sum of 
the longest diameter for all target lesions plus the sum of the short 
axis of all the target lymph nodes at current evaluation) taking as 
reference the BSD (see Section 11.4.1). 
 
c. 
Progression (PD): At least one of the following must be true: 
 
i. 
At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (<1.0 cm short axis) 
and increased to ≥1.0 cm short axis during follow-up. 
 
ii. At least a 20% increase in PBSD (sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the 
target lymph nodes at current evaluation) taking as reference 
the MSD (Section 11.4.1). In addition, the PBSD must also 
demonstrate an absolute increase of at least 0.5 cm from the 
MSD. 
 
iii. See Section 11.3.2 for details in regards to the requirements 
for PD via FDG-PET imaging. 
 
d. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, 
nor sufficient increase to qualify for PD taking as reference the 
MSD. 
 

 
41  
RU011201I 
 
 
 
11.4.3.3 Evaluation of non-target lesions including non-target lymph nodes 
 
a. Complete Response (CR): All of the following must be true: 
 
i. 
Disappearance of all non-target lesions. 
 
ii. Each non-target lymph node must have a reduction in short axis 
to <1.0 cm. 
 
b. Non-CR/Non-PD: Persistence of one or more non-target lesions or 
non-target lymph nodes. 
 
c. Progression (PD): At least one of the following must be true: 
 
i. 
At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (<1.0 cm short axis) 
and increased to ≥1.0 cm short axis during follow-up. 
 
ii. Unequivocal progression of existing non-target lesions and non-
target lymph nodes. [Note: Unequivocal progression should not 
normally trump target lesion and target lymph node status. It 
must be representative of overall disease status change.] 
  
iii. See Section 11.3.2 for details in regards to the requirements for 
PD via FDG-PET imaging. 
 
11.4.4 Overall objective status 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-
target lymph nodes, and new disease. 
 
Criteria for patients with measurable disease +/- non-measurable disease: 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 

 
42  
RU011201I 
 
 
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.4.3.1 
** NOTE: This study uses the protocol RECIST v1.1 template dated 2/16/2011. For data collection and analysis 
purposes the objective status changed from SD to PR in the ACCRU protocol RECIST v1.1 template as of 
2/16/2011 and to match RECIST v1.1 requirements. 
 
Criteria for patients with non-measurable disease only: 
Non-Target Lesions & 
Non-Target Lymph Nodes 
New 
Sites of Disease 
Overall 
Objective Status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated (NE) 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*See Section 11.4.3.1 
 
 
12.0 
Descriptive Factors – Not applicable 
 
 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
 
13.1 
Patients who achieve a CR, PR, or SD will continue treatment per protocol. 
 
13.2 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
 
13.3 
A patient is deemed ineligible if after registration it is determined that the patient did not 
satisfy all eligibility criteria for study entry at the time of registration. The patient will go 
directly to the event-monitoring phase of the study. 
 
13.4 
If the patient received treatment, all data up until the point of confirmation of ineligibility 
must be submitted. Event monitoring will be required per Section 18.0 of the protocol. 
 
13.5 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol. 
 
13.6 
A major violation occurs if protocol requirements regarding treatment in cycle 1 of the 
initial therapy are severely violated such that evaluability for primary end point is 
questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 18.0 of the protocol. 
 

 
43  
RU011201I 
 
 
 
13.7 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the Off Treatment Form must be 
submitted. The patient will go directly to the event-monitoring phase of the study, and 
event monitoring will be required per Section 18.0 of the protocol. 
 
13.8 
Follow-up procedures 
 
13.8.1 Survival data will be collected every 12 weeks after the Off-treatment Visit. This 
data may be collected through a clinic visit, phone call, or written 
communication. In addition to survival follow-up, the following assessments will 
be conducted during the Follow-Up Period: 
 
13.8.1.1 Record all the subsequent anti-cancer therapies in the CRF. 
 
13.8.1.2 Subjects with new onset of peripheral neuropathy during the study, or 
deterioration of pre-existing peripheral neuropathy on study, will be 
followed until resolution to baseline, the start of a new anti-cancer 
treatment, or death. 
 
13.8.1.3 For subjects who have discontinued study treatment without disease 
progression, tumor assessments will be performed at the same 
frequency as during the Treatment Cycles (i.e., every 12 weeks from the 
date of randomization) or sooner, if clinically indicated, until disease 
progression, or before another anti-cancer therapy is initiated. 
Assessments will utilize the same methodology and acquisition 
techniques as were used for the Screening Period assessments. Bone 
scans will be performed every 24 weeks in all subjects, or sooner, if 
clinically indicated. 
 
13.8.2 The site and date of first new metastasis will be captured for all subjects. 
 
13.8.2.1 For subjects who discontinue protocol directed therapy due to 
progression with a new site of metastasis, the information will be 
collected at the time of disease progression on eribulin or paclitaxel. 
 
13.8.2.2 For subjects who discontinue protocol directed therapy due to 
progression without a new site of metastasis (i.e., disease progression 
documented by an increase in the size of known lesions), the 
information will be collected in conjunction with monitoring for overall 
survival. 
 
13.8.2.3 For subjects who discontinue protocol directed therapy without disease 
progression and eventually develop a new metastasis, the information 
will be collected as appropriate during the Follow-Up period. 
 
13.8.3 If a subject fails to attend a scheduled assessment, the PI or designee will make 
every attempt to contact the subject to determine their status. All contact attempts 
will be recorded in the subject’s medical notes. 
 
13.8.4 Subjects will only be judged as lost to follow-up if documentation is provided of 
the following: 
 

 
44  
RU011201I 
 
 
 
13.8.4.1 Three unsuccessful attempted telephone contacts, at least 1 month 
apart for a period of at least 4 months, with the subject, the subject’s 
family, or the primary care (family) doctor [Note: The last contact 
attempt must be at least 4 months after the subject failed to attend a 
scheduled assessment.] 
 
13.8.4.2 Documented search of 
 
 
13.8.5 If all attempts fail to confirm the subject’s status, the subject will be considered 
as “lost to follow-up”, and this will be recorded in the CRF. 
 
 
14.0 
Body Fluid Biospecimens 
 
14.1 
Summary table of research blood and blood products to be collected 
 
Biospecimen  
Mandatory 
or optional 
Timing 
Correlative science 
justification 
Information on 
submission 
EDTA  
(whole blood) 
Mandatory 
Serial 
draws 
Pharmacogenetic 
studies and optional 
banking 
(Appendix VI) 
Section 14.2 
SST 
(serum) 
Mandatory 
Serial 
draws  
Circulating marker 
analyses 
and optional banking 
(Appendix VI) 
Section 14.2 
CellSave  
(whole blood) 
Mandatory 
Serial 
draws 
Circulating marker 
analyses 
and optional banking 
(Appendix VI) 
Section 14.2 
 
14.2 
Blood/Blood Products Handling 
 
14.2.1 Kits are required for this study. 
 
(Mayo Clinic Rochester may use Study Refer cards.) 
 
14.2.1.1 The kit contains supplies and instructions for collecting, processing, 
and shipping specimens. 
 
14.2.1.2 Participating institutions obtain kits by submitting a completed Supply 
Order Form (found in the Forms Packet) via fax. A small, but 
sufficient, supply of the specimen collection kits should be ordered 
prior to patient entry. Additional kits will be supplied on request. 
Unused kits should not be sent back to Biospecimen Accessioning and 
Processing (BAP) Receiving or the BAP Shared Resource. 
 
14.2.1.3 Kits will be sent via FedEx® Ground at no additional cost to the 
participating institutions. Allow at least two weeks to receive the kits. 
Kits will arrive inside the shipping boxes. 

 
45  
RU011201I 
 
 
 
14.2.1.4 Kits will not be sent via rush delivery service unless the participating 
institution provides its own FedEx® account or alternate billing 
number. ACCRU will not cover the cost for rush delivery of kits. 
 
14.2.2 Samples should be collected Monday – Thursday. However, if the subject can 
only be seen on Fridays, please contact the Biospecimen Resource Manager for 
additional instructions (see protocol resource pages for contact information). 
 
14.2.3 Specimen tube(s) must be labeled with the protocol number, ACCRU patient ID 
number, time and date of the blood draw. 
 
14.2.4 Blood/blood products must be collected and shipped according to specific 
instructions provided in the kit and the table below. 
 
Collection 
tube 
Volume 
to collect 
per tube 
(number 
of tubes 
to collect) 
Blood 
product 
being 
processed 
and 
submitted 
Timepoints 
Additional 
processing 
required 
at site 
Storage and 
shipping 
conditions1 
Baseline 
Every 
12 
weeks 
End of 
treatment 
EDTA tube 
(purple top) 
10 mL (1) 
Whole blood 
for WBC, 
plasma 
X 
X 
X 
Yes 
Frozen on 
dry ice 
SST tube 
(marble top) 
8.5 mL (2) 
Serum 
X 
X 
X 
Yes 
Frozen on 
dry ice 
CellSave tube 
(yellow/purple) 
10 mL (2) 
Whole blood 
for circulating 
tumor cells 
X 
X 
X 
None 
Ambient 
temperature 
1.  See Section 14.2.5 for detailed shipping instructions. 
 
14.2.5 Shipping 
 
14.2.5.1 Verify that ALL sections of the Blood Specimen Submission Form 
(see Forms Packet), BAP Requisition Form (provided in kit), and 
specimen collection labels are completed and filled in correctly. Enter 
information from the Blood Specimen Submission Form into the 
remote data entry system within 7 days after specimen collection (see 
Forms Packet). 
 
14.2.5.2 Specimens collected in the CellSave tubes should be shipped at 
ambient temperature on the same day they are drawn. 
 
14.2.5.3 Specimens collected in the EDTA and SST tubes should be processed 
as directed in the kit instructions, stored at -20ºC for 24 hours, and then 
shipped frozen with plenty of dry ice. The kit instructions include 
information on places to obtain dry ice if not available on site. 
 
14.2.5.4 Samples should be shipped to BAP Freezer Mondays – Thursdays 
according to kit instructions. Samples should not be sent on weekends 
or just prior to federal holidays. (If samples can only be shipped on 
Fridays, please contact the Biospecimen Resource Manager for 
additional instructions.) 

 
46  
RU011201I 
 
 
 
14.2.5.5 The BAP kits include a smart shipper label (3x5 white barcoded label) 
affixed to the shipping boxes. The smart shipper label is a pre-
addressed return label, which replaces the need for an airbill. Shipping 
costs will be covered by ACCRU if the shipping box provided with the 
BAP kit is used for shipping the specimens to BAP Receiving. 
 
14.2.5.6 BAP Freezer will receive the samples and immediately forward 
specimens to the 
 
 
 
14.2.6 BAP Shared Resource will process the specimens. 
 
14.2.6.1 DNA will be extracted from white blood cells, divided into aliquots, 
and stored at -70ºC by BAP, according to patient consent information. 
One aliquot of DNA will be provided to 
 
to validate 
polymorphisms in FGD4, EPHA5, and FZD3 as predictors of 
peripheral neuropathy. 
 
14.2.6.2 Serum will be divided into aliquots and stored at -80ºC by BAP, 
according to patient consent information. Two aliquots will be 
provided to Dr. Minetta Liu’s laboratory at the Mayo Clinic to quantify 
nucleosomes and the M30 neo-epitope as predictors of treatment 
benefit. 
 
14.2.6.3 As part of ongoing ACCRU research, we will collect whole blood, 
white blood cells, DNA, serum, and plasma for future research studies, 
according to patient consent information. Samples will be stored by 
BAP until specific analyses are identified and may be used for 
exploratory biomarker analyses, validation studies, or potential 
diagnostic development. As protocols are developed, they will be 
presented through ACCRU for IRB review and approval. 
 
14.2.6.4 Whole blood collected in the CellSave tubes will be provided directly 
to Dr. Minetta Liu’s laboratory at the Mayo Clinic to enumerate and 
phenotype circulating tumor cells. Any CTCs collected for 
enumeration will be stored at -20ºC by Dr. Liu’s laboratory, according 
to patient consent information. As protocols are developed, they will 
be presented for ACCRU and IRB review and approval. 
 
14.3 
Return of genetic testing research results 
 
The results generated by the proposed genetic analyses are not currently anticipated to 
have clinical relevance to the patients or their family members. Therefore, the genetic 
results will not be disclosed to the patients or their physicians. 
 
If at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought to determine the most appropriate manner of disclosure and 
to determine whether or not validation in a CLIA-certified setting will be required. 
Sharing of research data with individual patients should only occur when data have been 
validated by multiple studies and testing has been done in CLIA-approved laboratories. 
 

 
47  
RU011201I 
 
 
 
 
15.0 
Drug Information 
 
IND number 126070 
 
Investigator brochure 
 
• 
The IB will be available on the ACCRU web site. 
 
15.1 
Eribulin mesylate 
 
15.1.1 Eisai Inc. will package eribulin mesylate as open-label supplies. Eribulin 
mesylate will be supplied to the sites in glass vials containing 1.0 mg eribulin 
mesylate in 2.0 mL of solution. Eribulin mesylate is a clear, colorless, and sterile 
solution packaged in a glass vial. 
 
Excipients of the eribulin mesylate formulation are ethanol, hydrochloric acid, 
sodium hydroxide, and water for injection. 
 
Chemical Name, Structural Formula of Eribulin mesylate 
 
• 
Test drug code: E7389 
 
• 
Generic name (INN): eribulin / (USAN): eribulin mesylate 
 
• 
Chemical name (USAN/INN):  
 
(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)
-2-[(2S)-3-Amino-2-hydroxypropyl]-3-methoxy-26-methyl-20,27-
dimethylidenehexacosahydro-11,15:18,21:24,28-triepoxy-7,9-ethano-12,15-
methano-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-
b][1,4]dioxacyclopentacosin-5(4H)-one methanesulfonate (salt) 
 
 

 
48  
RU011201I 
 
 
 
Chemical Structure: 
 
 
 
• 
Molecular formula: C41H63NO14S (C40H59NO11・CH4O3S) 
 
• 
Molecular weight: 826.00 
 
15.1.2 Labeling for Eribulin mesylate 
 
Eribulin mesylate will be labeled in accordance with regulatory compliance of 
the participating countries and translated into the required language(s) for each 
country. 
 
The following information will be provided: 
 
• 
For clinical trial use only 
 
• 
Name and address of Eisai Inc. 
 
• 
Chemical name/drug identifier 
 
• 
Lot number/batch number 
 
• 
Storage conditions, expiration date if necessary 
 
15.1.3 Storage Conditions 
 
Eribulin mesylate will be stored in accordance with the labeled storage 
conditions. Temperature monitoring is required at the storage location to ensure 
that the study drug is maintained within an established temperature range. The 
site investigator or designee is responsible for ensuring that the temperature is 
monitored throughout the total duration of the study and that records are 
maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such 
as a calibrated chart recorder, or by manual means, such that minimum and 
maximum thermometric values over a specific time period can be recorded and 
retrieved as required. 
 

 
49  
RU011201I 
 
 
 
Beginning in Fall 2018, a new formula of eribulin will be available which will 
allow for room temperature storage.  Monitor closely when drug is received on 
site to verify which formulation is received and follow storage recommendations 
as described within the shipment. 
 
Eisai # 
Dosage/Form 
Storage 
Conditions 
Total Allowable 
Excursions 
E7389 
(eribulin 
mesylate) 
E7389 
(eribulin mesylate, 
1 mg/vial) 
(Refrigerated 
formula) 
2°C - 8°C 
Not less than 2°C or 
greater than 25°C for a 
cumulative period of up to 
14 days. 
Temperature excursion 
down to 0°C for no more 
than 24 hours. 
E7389 
(eribulin 
mesylate) 
E7389 
(eribulin 
mesylate,1 
mg/vial) 
(Ambient 
formula) 
25°C 
Excursions permitted from 
15°C to 30°C (59°F to 
86°F). Do not freeze or 
refrigerate. 
 
15.1.4 Preparation 
 
Eribulin mesylate should not be mixed with other drugs or dextrose 
containing solutions. 
 
15.1.5 Administration 
 
Eribulin mesylate is administered as an IV infusion over 2-5 minutes on 
days 1 and 8 of each 21 day cycle of therapy. 
 
15.1.6 Potential Drug Interactions 
 
No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 
inducers, or P-glycoprotein (P-gp) inhibitors. Clinically meaningful 
differences in exposure (AUC) were not observed when eribulin mesylate 
was administered with or without ketoconazole and with or without 
rifampin. 
 
Eribulin mesylate does not inhibit CYP1A2, CYP2C9, CYP2C19, 
CYP2D6, CYP2E1, or CYP3A4 enzymes, or induce CYP1A2, CYP2C9, 
CYP2C19, or CYP3A4 enzymes at relevant clinical concentrations. 
Eribulin mesylate is not expected to alter the plasma concentrations of 
drugs that are substrates of these enzymes. 
 
15.1.7 Toxicities (Nursing Guidelines) 
 
15.1.7.1 Cytopenias are common with neutropenia and anemia being most 
common. Monitor blood counts prior to each dose. 
 
15.1.7.2 Peripheral neuropathy is common. 
 

 
50  
RU011201I 
 
 
 
15.1.7.3 Warn patients of probable alopecia. 
 
15.1.7.4 Monitor hepatic panel. 
 
15.1.7.5 Gastrointestinal side effects seen include but are not limited to nausea, 
constipation, dyspepsia, abdominal pain, stomatitis, dry mouth, 
dysgeusia, diarrhea and mucositis. 
 
15.1.7.6 Monitor renal function. 
 
15.1.8 Drug procurement 
 
Eisai Inc. will supply eribulin to McKesson Specialty Pharmacy. Each 
participating ACCRU treating location will order eribulin from McKesson 
Specialty Pharmacy by faxing the Drug Order Request Form (found in the Forms 
Folder on the ACCRU web site) to: 
 
 
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of eribulin and will use the Drug Order Request Form to order 
additional supplies as needed. 
 
All used, unused, and expired eribulin must be destroyed by incineration only, 
and cannot be destroyed until after reconciliation/accountability has been 
performed. 
 
15.2 
Paclitaxel 
 
15.2.1 Please refer to the FDA-approved package insert for paclitaxel for product 
information, extensive preparation instructions, and a comprehensive list of 
adverse events. 
 
15.2.2 Availability 
 
Paclitaxel is commercially available in a concentration of 6 mg/ml in 5 mL, 16.7 
mL, 25 mL and 50 mL multidose vials. Each mL of solution also contains 527 
mg of polyoxyethylated castor oil and dehydrated alcohol, USP. Please refer to 
the FDA approved package insert for complete product information. 
 
15.2.3 Preparation 
 
Paclitaxel must be diluted prior to administration with 0.9% sodium chloride 
Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium 
Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final 
concentration of 0.3 to1.2 mg/mL. Paclitaxel should be prepared and stored in 
glass, polypropylene, or polyolefin containers due to leaching of DEHP [di-
(2ethylhexyl) phthalate] plasticizer from polyvinyl chloride (PVC) containers. 
Non-PVC containing tubing and connectors should also be used. Paclitaxel 
should be administered through an in-line < 0.22 micron filter. 

 
51  
RU011201I 
 
 
 
 
15.2.4 Storage and Stability 
 
Intact vials should be stored at controlled room temperature (20°-25°C; 68°-
77°F) in the original package to protect from light, and remain stable until the 
expiration date on the label. Refrigeration does not adversely affect stability. 
Upon refrigeration components in the paclitaxel vial may precipitate, but will re-
dissolve upon reaching room temperature with little or no agitation. Diluted 0.3-
1.2 mg/mL solutions are stable for up to 27 hours at room temperature under 
normal room lighting. Although solutions may be chemically stable for longer 
periods in some situations, precipitation may occur unpredictably. The 
mechanism of this precipitation has not been determined. 
 
15.2.5 Administration 
 
Paclitaxel, 90 mg/m2 administered as an IV infusion over 1 hour, on days1, 8, 
and 15 of each 28 day cycle of therapy. Please see Section 7.1.1 for 
premedication regimen. 
 
15.2.6 Toxicities (Nursing Guidelines) 
 
15.2.6.1 Hypersensitivity reactions are common. They are thought to be due, at 
least in part, to the Cremophor EL® vehicle. Reactions generally occur 
within the first hour of administration. The most common symptoms 
observed in severe reactions include dyspnea, flushing, chest pain and 
tachycardia. Patients should be pretreated to prevent hypersensitivity 
reactions. 
 
15.2.6.2 Cardiovascular events observed with paclitaxel include hypotension 
and bradycardia; typically neither discontinuation of paclitaxel nor 
specific therapy for the event is required. 
 
15.2.6.3 The frequency and severity of neurologic events are dose-dependent. 
Peripheral neuropathy is rarely severe and may be the cause of 
paclitaxel discontinuation in 1% of patients. Sensory symptoms usually 
improve or resolve within several months of completion of treatment. 
Serious neurologic events such as grand mal seizures, syncope, ataxia 
and neuroencephalopathy are rare. Pre-existing neuropathies are not a 
contraindication to treatment with paclitaxel. 
 
15.2.6.4 The most common gastrointestinal toxicities, which include nausea, 
vomiting, diarrhea and mucositis, are typically mild or moderate in 
severity. Mucositis occurs more frequently with a 24 hour infusion 
than with shorter infusion schedules. 
 
15.2.6.5 Although 60% of all patients experience arthralgia and myalgia, there 
is no consistent relationship between the dose or schedule of paclitaxel 
and the frequency of these events. The symptoms, which usually begin 
2 or 3 days after paclitaxel treatment, are generally transient. Infusion 
site reactions are more common with 24 hour infusions. They are 
typically mild, consisting of erythema, tenderness, skin discoloration or 
swelling at the infusion site. Paclitaxel is generally considered to be an 

 
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irritant, but isolated cases of more severe tissue damage following 
extravasation have been reported. 
 
15.2.6.6 Almost all patients receiving paclitaxel experience alopecia. Nail 
changes are uncommon. Occasionally edema is seen, usually of mild 
severity. 
 
15.2.7 Drug procurement: 
 
Sites will obtain the paclitaxel commercially. 
 
 
16.0 
Statistical Considerations and Methodology 
 
16.1 
Overview of the statistical design 
 
This is a two arm Phase III trial in first- and second-line HER2 negative patients with 
locally recurrent or metastatic breast cancer. Patients will be randomized between the 
experimental and control arm with equal allocation (1:1) within strata defined by prior 
adjuvant taxanes (yes/no), hormone receptor status (ER or PgR positive/ER and PgR 
negative), and line of therapy (1st/2nd). Subjects will continue protocol directed therapy 
until documentation of disease progression, development of unacceptable toxicity, or 
withdrawal of consent. Those who discontinue study treatment without radiological 
progression will be followed with repeat imaging studies every 12 weeks. All subjects 
will be followed until death, withdrawal of consent, or study termination. 
 
The primary endpoint at the time of initial study design was overall survival (OS) with a 
target accrual of 910 patients to test for the superiority of eribulin mesylate (experimental 
arm) over standard weekly paclitaxel (control arm). 
 
Subsequent changes in standard practice patterns have had a significant impact on accrual 
(e.g., the FDA approval of palbociclib in combination with first and second line 
endocrine therapy) and the availability of first and second line clinical trials for advanced 
breast cancer (e.g., studies with checkpoint inhibitors for patients with hormone receptor 
negative, HER2 negative breast cancer). The decision was therefore made to reconfigure 
objectives with a focus on toxicity as related to PRO-CTCAE and rs7349683 in EPHA5, 
leading to an adjusted target accrual of 200 patients.  
 
16.2 
Endpoints 
 
The primary endpoints are (i) to demonstrate that patient-reported PRO-CTCAE data will 
be able to detect differences in symptoms between participants treated with eribulin and 
standard weekly paclitaxel at 12 weeks; and (ii) to validate rs7349683 in EPHA5 as a 
predictor of peripheral neuropathy from treatment with a microtubule targeting agent 
(i.e., eribulin or paclitaxel). The secondary endpoints include the following: overall 
survival (OS); progressive free survival (PFS; defined as the time from randomization to 
progression under RECIST 1.1 criteria, or death due to any cause, whichever occurs 
first); objective tumor response as defined by RECIST 1.1; duration of tumor response; 
time to treatment failure; treatment-related toxicity; the clinical value and feasibility of 
collecting patient-reported symptom toxicity information via PRO-CTCAE in patients 
receiving eribulin versus standard weekly paclitaxel. In addition, the PRO-CTCAE 
sensory neuropathy items will be validated specifically and compared to patient-reported 

 
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neurotoxicity between arms using the EORTC QLQ-CIPN20 instrument. 
 
16.3 
Sample size and power calculations 
 
16.3.1 PRO-CTCAE 
 
For the primary endpoint, the patient-reported maximum score (post baseline) across 
PRO-CTCAE items for each patient will be computed over the first 12 weeks and 
compared between arms using a two-sample independent samples t-test. Assuming 85% 
participation rate and a total accrual of 200 patients, the detectable effect size with 80% 
and 90% power is 0.43 and 0.50 standard deviation units using a two-sided α=0.05. This 
study will be able to detect a small (0.2 standard deviations) to moderate (0.5 standard 
deviations) effect size difference between arms.49 Subsequent analysis will compare the 
maximum score for each individual item between arms. P-values adjusted using 
Hochberg’s step-up method will additionally be computed to aid in interpretation across 
the 20 individual items. 
 
16.3.2  rs7349683 in EPHA5 
 
The primary statistical objective for the pharmacogenetic companion of this study is to 
validate a germline EPHA5 polymorphism (rs7349683) implicated in drug induced 
peripheral neuropathy.14,19,20 The primary statistical endpoint will be the cumulative dose 
level triggering a grade 2 or higher neuropathy event. Power calculations assume a 
modest accrual goal of 175-300 patients, evaluable samples from 90% of these patients, 
and an expected proportion of the population that is self-reported Caucasian as 0.81. 
Under these assumptions, the expected number of patients available for the 
pharmacogenomic questions will therefore be 128-219 (64-110 for each arm). To 
illustrate the power, we will focus on neuropathy triggered within the first six cycles. The 
patients who do not experience an event will be censored at the cumulative dose level 
received during the six cycles. The Cox score test will be used to test the association 
between the cumulative dose level triggering toxicity and the genotype. The goal is to 
validate the EPHA5 rs7349683 SNP. The relative minor allele frequency (MAF) for 
rs7349683 is estimated as 0.36 and the proportion of patients developing CIPN within six 
cycles is expected to range from 40-50%. The analyses are powered for an additive risk 
model. The hypothesis will be tested at the one-sided 0.05/3 level. The minimum effect 
size detectable with a power of 0.8 at this level is shown for sample sizes of 175-300 
patients. These effect sizes are similar to the values reported earlier by us and 
others.14,19,20 
 
 

 
54  
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Sample Size 
HR 
40% Incidence 
50% Incidence 
175 
200 
225 
250 
275 
300 
1.63 
1.60 
1.55 
1.50 
1.45 
1.43 
1.80 
1.70 
1.63 
1.60 
1.58 
1.55 
 
The analysis will be more complicated as treatment continues until progression. 
Therefore, the number of cycles received is subject to an informative censoring 
mechanism. The pharmacogenetics investigator team is deeply involved in the 
development of the requisite methodology in the context of CALGB 40502 and will 
apply the finalized approach to data generated from this study. The analyses will be 
stratified by regimen (eribulin or paclitaxel). 
 
 16.4 
Stopping rules 
 
The stopping rule specified below is based on safety profiles reported in related clinical 
trials: EMBRACE (eribulin versus treatment of the physician’s choice in patients with >2 
previous regimens for advanced/metastatic breast cancer), BOLD 301 (eribulin versus 
capecitabine as first, second, or third line treatment for advanced/metastatic breast cancer, 
and CALBG 40502 (paclitaxel versus nab-paclitaxel versus ixabepilone, each +/- 
bevacizumab, as first line therapy for locally recurrent / metastatic breast cancer). Since 
the hematologic safety profiles differ greatly between the eribulin and paclitaxel, the 
adverse event stopping rule is split into two parts for hematologic adverse events. The 
stopping rule was determined by taking the observed adverse event rates in these trials 
and calculating the 95% upper bound. The 95% upper bound was used as the cut point in 
the stopping rule. 
 
We note that the adverse event stopping rule may be adjusted at any time during the 
conduct of the trial and in consideration of newly acquired information regarding the 
adverse event profile of the treatment(s) under investigation. The study team may also 
choose to suspend accrual because of unexpected adverse events that have not crossed the 
specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe events 
considered at least possibly related to study treatment (i.e., an adverse event with 
attribution specified as “possible”, “probable”, or “definite”) and that satisfy the 
following: 
 
Hematologic events: 
 
• 
If more than 50% of the treated patients on the eribulin arm experience a grade 3 or 
higher neutropenia adverse event. 
 
• 
If more than 23% of the treated patients on the paclitaxel arm experience a grade 3 or 
higher neutropenia adverse event. 
 
 
 

 
55  
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Non-hematologic events: 
 
• 
If more than 7% of the treated patients in either the eribulin or paclitaxel arm 
experience a grade 4 or higher non-hematologic adverse event. 
 
In addition, we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related adverse event. 
 
16.5 
Study monitoring 
 
The efficacy and toxicity data for this study will be reviewed at least semiannually by the 
Mayo Clinic Data Safety Monitoring Board (DSMB). Early termination of accrual will be 
considered if there is evidence of unacceptable toxicity. 
 
16.6 
Statistical analysis of secondary and correlative objectives 
 
Analyses of all efficacy endpoints will be intention-to-treat, such that patients will be 
included in the arm to which they were randomized irrespective of treatment received. 
Further, patients who withdraw for toxicity, who withdraw consent for continued 
treatment, or who start off-protocol therapy will continue to be followed for overall 
survival, progression free survival, and time to new metastasis. Patients who withdraw 
consent to be followed will be censored. Analysis of objective response will be in 
evaluable patients with measurable disease. Analyses of toxicity will be conducted in the 
subset of patients to receive eribulin and standard weekly paclitaxel, respectively. 
 
For the time related secondary endpoints (OS, PFS, TTF, and DOR) and exploratory 
endpoint (new metastasis free survival), survival functions will be summarized using the 
Kaplan-Meier method according to treatment group. The primary analysis will use the 
stratified log-rank tests, as described for overall survival. As a secondary analysis we will 
use a multivariable Cox proportional hazard model to estimate adjusted hazard ratios for 
eribulin mesylate over standard weekly paclitaxel, study stratification factors, and 
covariates for known prognostic factors, including disease free interval and visceral 
versus non-visceral metastases. 
 
For the secondary endpoints of objective response and treatment-related toxicity, the 
primary analysis will use the Cochran-Mantel-Haenszel chi-squared test with study 
stratification factors. Secondary analyses will use logistic regression to test differences in 
proportions while controlling for the covariates listed above. 
 
All tests of secondary objectives will use a two-sided Type I alpha of 0.05, and point 
estimates will be reported with 95% confidence intervals. Analyses of correlative 
objectives will be performed as described in Appendix VI. 
 
Additional analyses will include the previously described analysis conducted over the 
first 24 weeks; a comparison of the incidence of patient-reported maximum score ≥3 (i.e., 
severity reported as “severe” or “very severe”; frequency reported as “frequently” or 
“almost constantly”; or interference reported as “quite a bit” or “very much”) between 
arms through 12 and 24 weeks using chi-squared testing for each item; and a comparison 
of the time to patient-reported score ≥3 between arms using Kaplan-Meier and log-rank 
analyses. Further, these three endpoints (maximum score/grade, incidence of score/grade 
≥3, and time to score/grade ≥3) will be compared between patient- and clinician-report 

 
56  
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overall and within arms using appropriate paired analyses. 
 
The PRO-CTCAE sensory neuropathy items will be further validated by computing 
Pearson correlations between each item and the EORTC QLQ-CIPN20 sensory scale 
score at baseline, 12 and 24 weeks. Note, additional secondary analysis on the EORTC 
QLQ-CIPN20 scale scores will be performed to further describe differences between 
arms using analysis of covariance to compare maximum score during treatment between 
arms while adjusting for baseline score; analysis of covariance to compare scores at 12 
and 24 weeks between arms while adjusting for baseline score; and pattern mixture 
models to compare neuropathy scale scores over time between arms while accounting for 
informative drop-out. 
 
For analyses related to the secondary hypotheses, descriptive statistics will be used to 
characterize the proportion of patients in the clinical trial who participate in the PRO-
CTCAE correlative study; the proportion of participating patients adhering to scheduled 
self reports at each time point during the trial; frequency of backup calls; success of 
backup calls for questionnaire completion; and reasons for missed reports. Patient 
participants will be asked to complete a satisfaction survey to assess their experiences 
using the PRO-CTCAE IVRS system. In addition, a CRF will be administered to all 
participating CRAs/research nurses and clinical investigators at sites regarding technical 
difficulties encountered and perceived value of the patient reports in clinician reporting 
and clinical management. In order to assess the feasibility of implementing the PRO-
CTCAE at sites, study personnel at 25 selected participating sites will be contacted and 
invited to participate in semi-structured interviews about their experiences with this new 
system. The purpose of these interviews will be to explore the barriers and challenges to 
widespread adoption of the PRO-CTCAE system for use in phase III clinical trials 
(including cost, technical issues, and administrative burden). These interviews will be 
conducted by staff members of the PRO-CTCAE project who are based at MSKCC, 
funded by the NCI PRO-CTCAE contract. Interviews will be conducted with 
CRAs/research nurses as well as with clinical investigators. 
 
 
17.0 
Pathology Considerations/Tissue Biospecimens 
 
17.1 
Summary table of tissue biospecimens to be collected 
 
Biospecimen  
Mandatory or 
optional 
Timing 
Correlative 
science 
justification 
Information on 
submission 
Formalin-fixed 
paraffin-embedded 
(FFPE) tissue1  
Mandatory2 
Within 90 
days of 
registration 
Tubulin related 
analyses 
(Appendix VI) 
Section 17.2 
1. 15 slides (five micron sections mounted on charged glass slides) may be sent instead if the local 
Pathology Department refuses to release the FFPE tissue block. 
2. If tissue is available, the site must send to ACCRU. If no tissue sample is available, please document on 
the CRF. 
 
17.2 
Paraffin Embedded Tissue Blocks/Slides 
 
17.2.1 One formalin fixed paraffin-embedded (FFPE) tumor tissue block must be sent 
from the original diagnosis or from the metastatic site with a corresponding H&E 
slide. 

 
57  
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17.2.2 The FFPE tissue block is preferred. However, those institutions whose 
Pathology Departments refuse to provide a tissue block should provide 15 
slides (five micron sections mounted on charged glass slides). Label the slides 
with the ACCRU patient ID number, accession number, and order of 
sections. Every 10th slide (i.e., slides labeled 1 and 10) should be stained with 
H&E for central review under the Research Base’s protocol for assessing tissue 
quality. The remaining unstained slides will be processed as described in 17.3. 
Do not bake or place cover slips on the slides. 
 
17.2.3 The following materials are mandatory (unless indicated otherwise) and required 
for shipment: 
 
• 
Paraffin embedded tissue blocks with a corresponding H&E slide (OR 15 
unstained slides with corresponding H&E slides) 
 
• 
Research Tissue Specimen Submission Form 
 
• 
Surgical Pathology Report 
 
• 
Operative Report (optional) 
 
Note: Please include the ACCRU patient ID number on all materials listed 
above. 
 
17.2.4 The block/slides must be appropriately packed to prevent damage (e.g., slides 
should be placed in an appropriate slide container) and placed in an individual 
plastic bag. The bag must be labeled with the protocol number, ACCRU patient 
ID number, and patient initials. 
 
17.2.5 Verify that the appropriate sections of the Tissue Specimen Submission Form are 
completed and filled in correctly. Enter information from the Tissue Specimen 
Submission Form into the remote data entry system on the same day the 
specimen is submitted (see Forms Packet). 
 
17.2.6 Ship all block/slide tissue specimens and accompanying materials to the ACCRU 
Research Base: 
 
 
 
 
 
17.2.7 If a corresponding H&E slide was not submitted with the block/slides, the 
ACCRU Operations Office will request that one be processed (i.e., cut from the 
tissue block and H&E stained as appropriate) and forwarded to the Study 
Pathologist or designee for review under the Research Base’s protocol for 
assessing tissue quality for the proposed correlative studies. If the tumor tissue is 
too small, assessment of tissue quality will occur at the time the translational 
studies are performed. 
 

 
58  
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17.3 
Study methodology and storage information 
 
17.3.1 BAP Shared Resource will process the specimens. 
 
17.3.1.1 Total RNA and DNA will be extracted, divided into aliquots, and 
stored at -80ºC by BAP, according to patient consent information. 
 
17.3.1.2 As part of ongoing ACCRU research, we will bank tumor tissue for 
future research studies, according to patient consent information. 
Samples will be stored in the ACCRU Central Operations Office (Attn: 
Pathology Coordinator) until specific analyses are identified and may 
be used for exploratory biomarker analyses, validation studies, or 
potential diagnostic development. As protocols are developed, they 
will be presented through ACCRU for IRB review and approval. 
 
17.3.2 The institutional pathologist will be notified by the ACCRU Operations Office 
(Pathology Coordinator) if the block may be depleted. 
 
17.3.3 Blocks requested to accommodate individual patient management will be 
returned promptly upon request. 
 
17.4 
Return of genetic testing research results 
 
The results generated by the proposed genetic analyses are not currently anticipated to 
have clinical relevance to the patients or their family members. Therefore, the genetic 
results will not be disclosed to the patients or their physicians. 
 
If at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought to determine the most appropriate manner of disclosure and 
to determine whether or not validation in a CLIA-certified setting will be required. 
Sharing of research data with individual patients should only occur when data have been 
validated by multiple studies and testing has been done in CLIA-approved laboratories. 
 
 
18.0 
Records and Data Collection Procedures 
 
The Data Management Plan (DMP) defines and documents the procedures necessary to ensure 
data quality. These activities must be followed to ensure data are properly entered, validated, 
coded, integrated, reconciled, and reviewed. 
 
18.1 
Submission timetable 
 
Access the RAVE system through the iMedidata portal at 
All data must be entered by Remote Date Entry (RDE) 
and completed by qualified and authorized personnel. All data on the CRF must 
reflect the corresponding source document. Please refer to the ACCRU website for 
instructions 
 
Pre-Registration Material(s) – 
Case Report Form (CRF) 
Active Monitoring / Treatment Phase 
(Compliance with Test Schedule Section 4.0) 
Screening Disposition 
Complete for all patients who sign an 
informed consent form 

 
59  
RU011201I 
 
 
 
Case Report Form (CRF) 
Active Monitoring / Treatment Phase 
(Compliance with Test Schedule Section 4.0) 
Institutional Contact  
[Note: update form as needed1] 
≤2 weeks after registration 
1. 
Update the CRF to report any changes, as needed. 
 
Initial Material(s) – 
CRF 
Active Monitoring / Treatment Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study 
≤2 weeks after registration 
On-Study: Prior Surgery2 
On-Study: Prior Radiation3 
On-Study: Prior Systemic Therapy4 
Adverse Events: Baseline 
RECIST Measurements: Baseline6 
Measurements (Non-Measurable 
Disease Only): Baseline6 
Electrocardiogram (ECG): Baseline 
Supporting Documentation: Baseline1  
Patient Status: Baseline 
Specimen Submission: Blood 
(Baseline) (see Section 14.0) 
Pregnancy Test 
Concomitant Medications 
Note: this is a cumulative log; 
complete at baseline and update as 
needed5 
Medical History and Current Medical 
Condition 
Note: this is a cumulative log; 
complete at baseline and update as 
needed5 
Scans and Photographs for Tumor 
Assessments (SCANS): Baseline 
OP and Path Reports (see Section 
17.0)1 
Off Treatment 
Submit ≤2 weeks after registration if 
withdrawal/refusal occurs prior to beginning 
protocol therapy 
Patient Questionnaire Booklet 
(EORTC QLQ-CIPN20) 
≤2 weeks after registration - Patient 
questionnaire booklet must be used; copies 
are not acceptable for this submission. 
Booklet Compliance– EORTC QLQ-
CIPN20 
≤2 weeks after registration - This form must 
be completed only if the booklet contains 
absolutely NO patient provided assessment 
information. 
Specimen Submission: Tissue (see 
Section 17.0) 
≤90 days after registration 
1. Attach an electronic copy in RAVE on the Supporting Documentation Form. This is in 
addition to the pathology material requirements for tissue submission (Section 17.0). 
2. Form will be required if the On Study form indicates patient had prior surgery. 

 
60  
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3. Form will be required if the On Study form indicates patient had prior radiation. 
4. Form will be required if the On Study form indicates patient had prior systemic therapy. 
5. Update the CRF to report any changes, as needed. 
6. Submit either the RECIST Form for measurable disease, or the Measurements Form for Non-
Measurable Disease Only, as applicable (do not submit both forms). 
 
Test Schedule Material(s) 
CRF 
Active Monitoring / Treatment Phase 
(Compliance with Test Schedule Section 4.0) 
At each 
evaluation 
during 
treatment 
Every 12 
weeks 
At end of 
treatment 
Follow-up/ 
Observation 
(every 12 
weeks until 
PD)13 
Treatment (Intervention) 
(Eribulin) 
X 
 
X 
 
Treatment (Intervention) 
(Paclitaxel) 
X 
 
X 
 
Treatment 
(Intervention): Dose 
Modifications, Omission 
and Delays (Eribulin) 
X 
 
  
 
Treatment 
(Intervention): Dose 
Modifications, Omission 
and Delays (Paclitaxel) 
X 
 
  
 
Adverse Event Log 
Note: this is a 
cumulative log5 
X4 
 
X4 
X 
RECIST Measurements 
 
X1 
  
X 
Measurements (Non-
Measurable Disease 
Only)  
 
X1 
 
 
Patient Status: 
Treatment (Intervention) 
X 
 
 
 
Patient Status: Clinical 
Follow-up / Observation 
 
 
 
X 
Supporting 
Documentation 
  
X1 
  
X1 
Laboratory Tests and 
Results 
X  
  
 
 
Laboratory Tests and 
Results End of 
Treatment 
 
 
X 
 
Hematology Test and 
Results 
X 
 
 
 
Specimen Submission: 
Blood 
 
X 
 
 
Specimen Submission: 
Blood End of Treatment 
 
 
X 
 
Concomitant 
X 
 
  
 

 
61  
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CRF 
Active Monitoring / Treatment Phase 
(Compliance with Test Schedule Section 4.0) 
At each 
evaluation 
during 
treatment 
Every 12 
weeks 
At end of 
treatment 
Follow-up/ 
Observation 
(every 12 
weeks until 
PD)13 
Medications 
Note: this is a 
cumulative log5 
Patient Questionnaire 
Booklet2 (EORTC QLQ-
CIPN20) 
X 
 
X 
 
Booklet Compliance3 
(EORTC QLQ-CIPN20) 
X 
 
X 
 
PRO-CTCAE Feedback 
Survey2 
 
X6 
 
 
Booklet Compliance3 
(PRO-CTCAE) 
 
X 
 
 
Patient Reported 
Adverse Events (PRO-
CTCAE) Status8 
X 
 
 
X 
Non-Protocol: Surgical 
Procedure9 
  
 
  
X 
Non-Protocol: 
Radiation10 
  
 
  
X 
Non-Protocol: Systemic 
Therapy11 
  
 
  
X 
Electrocardiogram 
(ECG) 
X12 
 
 
 
Off Treatment 
 
 
X 
 
Medical History and 
Current Medical 
Condition 
Note: this is a 
cumulative log5 
X  
 
X 
X  
Notice of New Primary7 
 
 
 
X 
Lost to Follow-Up7  
 
 
 
X 
Scans and Photographs 
for Tumor Assessments 
(SCANS) 
 
X 
 
X 
Consent Withdrawal 
(choose appropriate 
withdrawal form)7: 
• QOL Only 
• Specimen Only 
• Clin Follow-Up Only 
• All Follow-Up 
X 
 
 
X 
1. Submit either the RECIST Form for measurable disease, or the Measurements Form for Non-
Measurable Disease only, as applicable (do not submit both forms). Attach a copy of 
documentation of response or progression in RAVE on the Support Documentation Form. 

 
62  
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2. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
3. This form must be completed only if the patient questionnaire booklet contains absolutely NO 
patient provided assessment information. 
4. Patient PRO-CTCAE scores should be printed from the PRO-CTCAE web system and 
provided to the clinician at the time of clinical grading of adverse events during treatment and 
at end of treatment. See Section 1.6 in Appendix VI. 
5. Update the CRF to report any changes, as needed. 
6. There will be a 12 week follow-up survey administered one time via booklet. 
7. Submit only if applicable. 
8. This form will be completed by the Central PRO-CTCAE Project Coordinator, not by the 
CRA. 
9. Form will be required if Follow-Up Form indicates patient had non-protocol surgery not 
previously reported. 
10. Form will be required if Follow-Up Form indicates patient had non-protocol radiation not 
previously reported. 
11. Form will be required if Follow-Up Form indicates patient had non-protocol systemic therapy 
not previously reported. 
12. Form submitted one time only for testing done prior to cycle 2. 
13. Follow-up can be discontinued after 2 years if the patient is no longer receiving study 
treatment. If the patient remains on study treatment as of September 30, 2021, follow-up will 
be discontinued. 
 
Follow-up Material(s) 
CRF 
Survival 
Every 3 
months 
until PD 
At PD 
Every 3 
months 
after PD7 
Death 
At each 
event 
occurrence 
Supporting 
Documentation1 
 
 
 
 
X 
Patient Status: Survival 
and Disease Status 
Follow-Up / Event 
Monitoring 
X  
X  
X 
X 
 
Lost to Follow-Up3 
 
 
 
 
X 
Notice of New Primary3 
 
 
 
 
X 
Medical History and 
Current Medical 
Condition 
Note: this is a 
cumulative log2 
X 
X 
X 
X 
 
Non-Protocol: Surgical 
Procedure4 
 
 
 
 
X 
Non-Protocol: 
Radiation5 
 
 
 
 
X 
Non-Protocol: Systemic 
Therapy6 
 
 
 
 
X 
Consent Withdrawal 
(choose appropriate 
withdrawal form)3: 
•QOL Only 
• Specimen Only 
• Clinical Follow-Up 
 
 
 
 
X 

 
63  
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CRF 
Survival 
Every 3 
months 
until PD 
At PD 
Every 3 
months 
after PD7 
Death 
At each 
event 
occurrence 
Only 
• All Follow-Up 
1. Attach a copy of documentation of response or progression in RAVE on the Supporting 
Documentation Form. 
2. Update the CRF to report any changes, as needed. 
3. Submit only if applicable.  
4. Form will be required if Follow-Up Form indicates patient had non-protocol surgery not 
previously reported. 
5. Form will be required if Follow-Up Form indicates patient had non-protocol radiation not 
previously reported. 
6. Form will be required if Follow-Up Form indicates patient had non-protocol systemic therapy 
not previously reported. 
7. Follow-up can be discontinued after 2 years if patient is no longer taking study treatment. 
 
 
19.0 
Budget 
 
19.1 
Costs charged to the patient include routine clinical care, including paclitaxel and its 
administration costs. 
 
19.2 
Each site should review the test schedule (Section 4.0), taking into account local and 
regional coverage policies to determine which items are considered standard of care 
versus research at their site. Refer to the payment synopsis for funding provided per 
accrual to cover study costs, as well as any additional invoiceables that may be allowed. 
 
19.3 
Tests that are research funded include research blood kits/collection and tissue collection. 
 
19.4 
Eribulin mesylate will be provided free of charge by Eisai Inc.