Phase II Trial of Eribulin for Locally Advanced Refractory or Metastatic Salivary Gland Cancers
Phase: PHASE2
Conditions: Recurrent Salivary Gland Cancer, Stage IVA Salivary Gland Cancer, Stage IVB Salivary Gland Cancer, Stage IVC Salivary Gland Cancer
Sponsor: University of Washington

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Phase II Trial of Eribulin for Locally Advanced Refractory or Metastatic 
Salivary Gland Cancers 
 
Current Version Date: 12/18/2012 
 
 
 
Principal Investigator: Renato Martins, MD 
 
Co-Investigators:     Christina Baik, MD 
Laura Chow, MD 
 
 
          
 
Bernardo Goulart, MD 
 
 
 
 
 
Ted Gooley, PhD 
                 
 
 
 
Sarah G. Wallace 
 
 
 
 
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 TABLE OF CONTENTS  
1. Background  
 
 
 
 
 
 
 
 
 
 
4 
 
1.1 Salivary Gland Carcinoma 
 
 
 
 
 
 
 
 
 
1.2 Systemic therapy for advanced refractory and metastatic SGC   
 
 
 
 
1.3 Eribulin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Rationale  
 
 
 
 
 
 
 
 
 
 
5 
 
3. Trial Objectives  
 
 
 
 
 
 
 
 
 
5 
 
4. Trial Design 
 
 
 
 
 
 
 
 
 
 
5 
 
5. Subject Selection 
 
 
 
 
 
 
 
 
 
5 
 
5.1 Inclusion Criteria 
 
 
 
 
 
 
 
 
 
 
5.2 Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
6. Trial Treatments  
 
 
 
 
 
 
 
 
 
7 
 
6.1  Drug Supplies  
 
 
 
 
 
 
 
 
 
 
6.1.1 Formulation and Packaging  
 
 
 
 
 
 
 
 
6.1.2 Preparation and Dispensing  
 
 
 
 
 
 
 
 
6.2 Treating the Patient 
 
 
6.2.1 Conditions prior to administering treatment 
 
 
6.2.2 Eribulin administration 
 
 
6.2.3 Dose Modifications  
 
 
 
 
 
 
 
 
 
6.3 Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
7. Trial Procedures  
 
 
 
 
 
 
 
 
 
9 
 
7.1 Screening Visit  
 
 
 
 
 
 
 
 
 
7.2 Day 1 of each Cycle 
 
 
 
 
 
 
 
 
 
 
 
7.3 End of Treatment Visit  
 
 
 
 
 
 
 
 
7.4 Thirty Day Post Treatment Visit 
7.5 Subject Withdrawal 
 
 
 
 
 
 
 
 
 
8. Assessments 
 
 
 
 
 
 
 
 
 
 
10 
 
8.1 Efficacy Assessments  
 
 
 
 
 
 
 
 
 
8.1.1 Definition of Measurable Disease  
 
 
 
 
 
 
 
 
8.1.2 Baseline Documentation of Tumor Burden 
 
 
 
 
 
 
 
8.1.3 Response Criteria 
 
 
 
 
 
 
 
 
 
8.2 Time to Event Measures 
 
 
 
 
 
           
9. Adverse Event Reporting 
 
 
 
 
 
 
 
 
12 
 
9.1 Adverse Events  
 
 
 
 
 
 
 
 
 
9.2 Definition of an Adverse Event 
 
 
 
 
 
 
 
9.3 Serious Adverse Events 
 
 
 
 
 
 
 
 
9.4 Adverse Event Reporting Requirements 
 
 
 
 
 
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10. Data analysis/Statistical Methods 
 
 
 
 
 
 
 
13 
 
10.1 Sample Size Determination  
 
 
 
 
 
 
    
10.2 Efficacy Analysis 
 
 
 
 
 
 
 
 
                 
10.3 Analysis of Other Endpoints  
 
 
 
 
 
 
 
 
APPENDIX 1 Schedule of Assessments  
 
 
 
 
 
 
14 
 
 
 
 
 
           
 
 
 
 
 
 
 
 
 
 
 
 
 
11. References 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
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1.  Background 
 
1.1 
Salivary Gland Carcinoma 
 
Salivary gland cancers (SGC) are rare neoplasms, constituting approximately 5% of head 
and neck cancers, with an overall incidence of 1-3 per 100,000 persons.  There are 
multiple histological subtypes including adenoid cystic carcinoma, mucoepidermoid 
carcinoma, and adenocarcinoma.  The biologic behavior of these cancers is quite variable 
[Laurie].  Initial therapy for patients who present with localized disease consists of 
surgery and/or radiation therapy.  Neutron beam radiotherapy has been demonstrated to 
have superior efficacy to conventional radiotherapy for the treatment of localized 
disease [Griffin].  As the University of Washington is one of only a few neutron facilities 
operating worldwide, it has become a referral center for the treatment of this rare 
neoplasm.  Despite optimal treatment, many patients progress either locally or with 
distant metastatic disease.  Due to the rare nature of this disease, conducting clinical 
trials is difficult; therefore there is limited clinical trial data to guide systemic 
therapeutic treatments.   
 
1.2  
Systemic therapy for advanced refractory and metastatic SGC 
 
There is no current standard of care for palliative chemotherapy in patients with 
advanced SGC.   A recent review cited 12 small trials reporting the use of chemotherapy 
for salivary gland carcinomas [Laurie].   In general, objective responses to any cytotoxic 
agent or regimen are infrequent and stabilization of disease is more commonly observed. 
Agents with activity include cisplatin, mitoxantrone, vinorelbine, epirubicin, and 
paclitaxel.   Combination chemotherapy also appears to be effective. The only 
randomized clinical trial done in this cancer demonstrated a higher response rate with 
cisplatin and vinorelbine compared to vinorelbine alone [Airoldi].  Data is insufficient to 
conclude that combination chemotherapy is superior to single agent therapy and 
combination therapy certainly has more toxicity.  Despite scientific rationale for the use 
of molecular targeted agents such as imatinib (c-kit) [Hotte], gefitinib (EGFR), and 
trastuzumab (HER2) [Agulnik], the results of these agents in phase II clinical trials have 
been disappointing. 
 
1.3  
Eribulin 

Eribulin mesylate is a non-taxane microtubule dynamics inhibitor. Eribulin mesylate is a 
synthetic analogue of halichondrin B, a product isolated from the marine sponge 
Halichondria okadai.  
 
Eribulin inhibits the growth phase of microtubules without affecting the shortening phase 
and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a 
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tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of 
mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. 
 
In 2010, the Food and Drug Administration approved eribulin mesylate under the trade 
name HALAVEN for the treatment of patients with metastatic breast cancer who have 
previously received at least two chemotherapeutic regimens for the treatment of 
metastatic disease. Prior therapy should have included an anthracycline and a taxane in 
either the adjuvant or metastatic setting. 
2.  Rationale 
Patients with locally advanced refractory or metastatic salivary gland cancers have 
limited treatment options.  
This trial has the potential to benefit patients with salivary gland cancers by improving 
treatment options.  Due to the relative rarity of this disease, this has been an 
underserved population and is difficult to conduct adequately powered clinical trials. 
Additionally, pharmaceutical companies have not pursued drug development in this 
disease since it is not considered commercially viable.  
3.  Trial Objectives 
 
 
Primary:  
x Evaluate the response rate of eribulin per RECIST criteria in patients with locally 
advanced refractory or metastatic SGC. 
 
Secondary: 
x Determine the safety and toxicity of eribulin in patients with locally advanced 
refractory or metastatic SGC.  
x Evaluate the duration of response and time-to-progression. 
 
Exploratory:  
x Evaluate overall survival. 
 
4.  Trial Design 
 
This is an open-label, single-center, phase II study of eribulin for patients with locally 
advanced refractory or metastatic SGC. 
 
Patients will receive eribulin 1.4 mg/m2 administered intravenously (IV push) over 2 to 5 
minutes on Days 1 and 8 of a 21-day cycle. Treatment will be continued until disease 
progression, unacceptable toxicity or withdrawal of patient consent. 
 
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5.  Subject Selection 
 
5.1 
 Inclusion Criteria 
 
Patients are eligible to be included in the study only if they meet all of the following 
criteria: 
x Patients must have histologically or cytologically documented salivary gland 
cancers. Patients that do not have a salivary gland primary must have one of the 
following histologies - adenoid cystic carcinoma, mucoepidermoid carcinoma, 
acinic cell carcinoma).  
x Patients must have recurrent and/or metastatic disease that is progressive and not 
amenable to surgery or curative radiotherapy occurring within 6 months of study 
entry, as evidenced by: at least a 20% increase in radiographically or clinically 
measurable disease, appearance of any new lesions, or deterioration in clinical 
status. 
x Age > 18 years. 
x ECOG performance status of 0, 1, or 2. 
x Patients with measurable disease per RECIST 1.1 criteria [Eisenhauer].  
o At least one lesion of ≥ 1.5 cm in long-axis diameter for nonlymph nodes or 
≥ 1.5 cm in short-axis diameter for lymph nodes which is serially measurable 
according to RECIST 1.1 using either computerized tomography (CT) or 
magnetic resonance imaging (MRI).  
o Lesions that have had radiotherapy must show evidence of progressive 
disease (PD) based on RECIST 1.1 to be deemed a target lesion. 
x Patients must have normal organ and marrow function as defined below: 
o absolute neutrophil count >1,500/μL 
o platelets >100,000/μL 
o creatinine clearance ≥40 mL/min 
o bilirubin ≤1.5 ULN 
o Alkaline phosphatase ≤3 ULN. If total ALP is >3 x ULN (in the absence of 
liver metastasis) or >5 x ULN in subjects with liver metastasis AND the 
subject is known to have bone metastases, then liver ALP iso-enzyme should 
be used to assess liver function rather than total ALP. 
o AST and ALT ≤3 X ULN,  
x Women of child-bearing potential (WOCP) and men must agree to use adequate 
contraception (hormonal or barrier method of birth control or abstinence) prior to 
study entry and for the duration of study participation.  
x Life expectancy of > 12 weeks. 
x Signed and dated informed consent document indicating that the patient has been 
informed of all the pertinent aspects of the trial prior to enrollment.    
 
5.2  
Exclusion Criteria 
 
Subjects presenting with any of the following will not be included in the trial:  
x Patients with symptomatic CNS metastases must have stable disease after 
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treatment with surgery or radiation therapy. 
x Second primary malignancy that is clinically detectable or clinically significant at 
the time of consideration for study enrollment 
x Radiotherapy within 14 days of study treatment. 
x Major surgery within 21 days of study treatment.  Minor surgery within 2 weeks of 
study treatment.  Placement of vascular access device and biopsies allowed and is 
not considered major or minor surgery. 
x Treatment with any chemotherapy or investigational agents within 4 weeks of the 
start of study treatment. Subjects must have recovered from toxicities of prior 
therapy. 
x Patients with peripheral neuropathy > grade 2 
x Significant cardiovascular impairment: congestive heart failure >Class II according 
to the New York Heart Association (NYHA), unstable angina or myocardial 
infarction within 6 months of enrollment, or serious cardiac arrhythmia (> grade 
2). 
x Concomitant severe or uncontrolled medical disease. 
x Significant psychiatric or neurologic disorder which would compromise 
participation in the study 
x Pregnant or breast-feeding females. 
6.  Trial Treatments 
 
All patients enrolled will receive treatment with eribulin.   
6.1  
Drug Supplies  
6.1.1  Formulation and Packaging  
Eribulin mesylate will be supplied by Eisai in single-use vials at a concentration of 1 mg/2 
mL (0.5 mg/mL) solution in ethanol: water (5:95). Eribulin is a clear, colorless, sterile 
solution for intravenous administration.  
 
6.1.2  Preparation and Dispensing  
Aseptically withdraw the required amount of eribulin mesylate from the single-use vial 
and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. 
Do not dilute in or administer through an intravenous line containing solutions with 
dextrose. Do not administer in the same intravenous line concurrent with the other 
medicinal products. 
 
Store undiluted eribulin mesylate in the syringe for up to 4 hours at room temperature or 
for up to 24 hours under refrigeration (40°F or/ 4°C). Store diluted solutions of eribulin 
mesylate for up to 4 hours at room temperature or up to 24 hours under refrigeration. 
 
Discard unused portions of the vial. 
 
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6.2 Treating the Patient 
6.2.1 Conditions patients must meet prior to administering any treatment on 
Day 1 and 8 of each cycle  
Prior to receiving any study treatment on Day 1 or 8 of each cycle, the patient must have 
all of the following criteria met: 
x Neutrophils are > 1.0 X 109/L, 
x Platelets > 75 X 109/L, 
x No grade 3 or 4 non-hematological toxicities. 
 
The Day 8 dose may be delayed for a maximum of 1 week. 
x If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the 
dose. 
x If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer eribulin 
at a reduced dose and initiate the next cycle no sooner than 2 weeks later. 
 
Blood tests should be performed before starting any study treatment administration and 
if the above criteria are not met, treatment should be delayed until the criteria for start 
of treatment are met. If a delay of > 3 weeks (one cycle) is required, the patient should 
be removed from the study and continue to be treated in accordance with the 
Investigator’s standard clinical practice. 
 
6.2.2 Eribulin administration 
Patients will receive eribulin 1.4 mg/m2 administered intravenously (IV push) over 2 to 5 
minutes on Days 1 and 8 of a 21-day cycle. Treatment will be continued until disease 
progression, unacceptable toxicity or patient withdraws consent. 
 
Guidelines for dose modification and dose interruption of study drug are described in 
Table 6-1. 
 
6.2.3 Dose Modifications   
Any dose reduction or dose delay of study drug is based upon the severity of toxicity, as 
graded by NCI Clinical Toxicity Criteria (NCI-CTCAE, version 4.0). Once a dose has been 
reduced during a treatment cycle, re-escalation will not be permitted during any 
subsequent cycles. 
 
All toxicity-related causes for dose reductions or dose delays, must be recorded as an AE. 
Please refer to Table 6-1 for recommended study drug dose adjustments. Patients 
requiring a delay in study treatment > 3 weeks or > 2 dose reductions, will be 
discontinued from study treatment. 
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Event Description 
Recommended 
Dose 
Permanently reduce the dose for any of the following: 
x ANC <500/mm3 for >7 days 
x ANC <1,000 /mm3 with fever or infection 
x Platelets <25,000/mm3 
x Platelets <50,000/mm3 requiring transfusion 
x Non-hematologic Grade 3 or 4 toxicities 
x Omission or delay of Day 8 dose in previous cycle 
for toxicity 
x Creatinine clearance 30-50 mL/min 
x ECG > 480 hold drug until QTc value is within 
protocol specified range. 
1.1 mg/m2 
Occurrence of any event requiring permanent dose 
reduction while receiving 1.1 mg/m2 
0.7 mg/m2 
Occurrence of any event requiring permanent dose 
reduction while receiving 0.7 mg/m2 or a Creatinine 
clearance <30 mL/min 
Discontinue eribulin 
 
6.3  
 Concomitant Medications  
Concomitant therapies considered as supportive care are acceptable while participating 
in this study including granulocyte colony stimulating factors (GCSF), palliative radiation 
and bisphosphonates for bone metastasis. Patients that require palliative radiation should 
wait 7-14 days before resuming eribulin therapy.  
7.  Trial Procedures  
Prior to undergoing any study-specific procedure, patients must read and sign the 
current Institutional Review Board (IRB)-approved informed consent form.    
The schedule of assessments is presented in Table 1 (Visit Schedule) in the Protocol 
Summary.   
Assessments outlined in the visit schedule include the following components:  
7.1  
Screening Visit  
The screening visit will occur up to 30 days prior to initiating study treatment. 
x Medical History – SGC diagnosis, prior SGC treatment history, and demographics.  
x Physical examination – examination of major organ systems, ECOG performance 
status, body weight and vital signs (i.e., blood pressure, heart rate).   
x Laboratory Evaluations will be obtained up to 14 days prior the first dose of 
eribulin 
o Hematology (CBC with platelets and absolute neutrophil count) 
o Blood chemistry (sodium, potassium, chloride, carbon dioxide, creatinine, 
BUN, glucose, calcium, LDH, albumin, bilirubin, AST, ALT, total protein, 
alkaline phosphatase, magnesium) 
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o Pregnancy test – serum or urine pregnancy test performed for all women of 
childbearing potential 
x CT scan for known sites of involvement. 
x ECG If < 450, no further monitoring.  If > 450, needs ECG prior to second dose of 
eribulin. If > 480, eribulin needs to be held until QTc value is within protocol 
specified range. 
 
 
7.2  
Day 1 of each Cycle 
Day 1 will occur every 21 days (+/- 4 days) 
x Physical examination – examination of major organ systems, ECOG performance 
status, body weight and vital signs (i.e., blood pressure, heart rate).   
x Laboratory Evaluations 
o Hematology (CBC with platelets and absolute neutrophil count) 
o Blood chemistry (sodium, potassium, chloride, carbon dioxide, creatinine, 
BUN, glucose, calcium, LDH, albumin, bilirubin, AST, ALT, total protein, 
alkaline phosphatase, magnesium) 
x Adverse Event Assessment 
x CT scan for known sites of involvement after every 2 cycles (i.e. after cycle 2, 4, 
6, etc. Once patients have completed 4 cycles of therapy, they can have CT scans 
after every 3 cycles.) 
 
7.3  
End of Treatment Visit 
Patients will undergo the following assessments when all study treatment is discontinued: 
x Physical examination – examination of major organ systems, ECOG performance 
status, body weight and vital signs (i.e., blood pressure, heart rate).   
x Laboratory Evaluations 
o Hematology (CBC with platelets and absolute neutrophil count) 
o Blood chemistry (sodium, potassium, chloride, carbon dioxide, creatinine, 
BUN, glucose, calcium, LDH, albumin, bilirubin, AST, ALT, total protein, 
alkaline phosphatase, magnesium) 
x Adverse Event Assessment 
 
7.4  
Thirty Day Post Treatment Visit 
Patients will undergo evaluation for toxicity 30 days (+/- 6 days) after the last dose of 
study treatment. Patients will undergo the following assessments: 
x Physical examination – examination of major organ systems, ECOG performance 
status, body weight and vital signs (i.e., blood pressure, heart rate).   
x Laboratory Evaluations 
o Hematology (CBC with platelets and absolute neutrophil count) 
o Blood chemistry (sodium, potassium, chloride, carbon dioxide, creatinine, 
BUN, glucose, calcium, LDH, albumin, bilirubin, AST, ALT, total protein, 
alkaline phosphatase, magnesium) 
x Adverse Event Assessment 
 
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7.5  
Subject Withdrawal  
Patients will be removed from study if they present with disease progression, as 
defined by radiological RECIST 1.1 criteria. Subjects will also be removed from study if 
they require more than two dose level reductions. Subjects will also be removed from 
study if they require more than 3 weeks to recover from adverse events. Patients may 
withdraw consent at any time.   
8.  Assessments  
The schedule of assessments is presented in Appendix 1. The description of assessments 
is provided in Section 7.  
8.1  
Efficacy Assessments  
Patients will have their tumors assessed for response by conventional imaging methods 
(typically CT scans), which will be performed at baseline (at least 30 days prior to the 
first study drug dose) and than at least every 2 cycles (~ every 6 weeks) after initial dose. 
Once patients have completed 4 cycles of therapy, they can have CT scans after every 3 
cycles.  
8.1.1  Definition of Measurable Disease 
 
Measurable disease: the presence of at least one lesion that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥10 mm with spiral CT 
scan for non-lymph nodes or ≥ 1.5 cm in short-axis diameter for lymph nodes 
 
Non-measurable disease: all other lesions, including small lesions (longest diameter <10 
mm with spiral CT scan).  
 
8.1.2 Baseline Documentation of Tumor Burden 
 
x Target lesions: All measurable lesions should be identified and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size 
(those with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest 
diameter for all target lesions will be calculated and reported as the baseline sum 
longest diameter (SLD). The baseline SLD will be used as the reference by which to 
characterize the objective tumor response. 
 
x Non-target lesions: All other lesions (or sites of disease) should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of these 
lesions are not required, but the presence or absence of each should be noted 
throughout follow-up. 
 
8.1.3  Response Criteria  
 
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Radiological response will be defined as per the RECIST criteria. Treatment outcomes will 
be defined as: 
x Complete response (CR): complete resolution of all tumor lesions. 
x Partial response (PR): at least a 30% decrease in the sum of the longest diameter 
of the target lesions (primary tumor and lymph nodes).  
x Stable disease (SD): patients with changes that would not qualify as partial 
responses or progressive diseases.    
x Progressive disease (PD): at least a 20% increase in the sum of the longest 
diameter of the target lesions. 
 
8.2  
Time-to-Event Measures 
 
The following definitions for time-to-event measures will apply: 
 
x Duration of Tumor Response is measured from the date of the first objective 
assessment of PR or CR to the first date of disease relapse or death from any 
cause.  
x Time to Progression is measured from the date of enrollment to the first date of 
radiographic progression of disease per RECIST 1.1 criteria. 
 
9. 
 Adverse Event Reporting 
9.1  
Adverse Events  
Investigators are responsible for monitoring the safety of patients who have entered this 
study and for alerting the Cancer Consortium IRB to any event that seems unusual in 
accordance with IRB policy. The investigator is responsible for the appropriate medical 
care of patients during the study. The investigator remains responsible to follow, through 
an appropriate health care option, adverse events that are serious or that caused the 
patient to discontinue before completing the study. The patient should be followed until 
the event resolves or stabilizes. Frequency of follow-up is left to the discretion of the 
investigator. 
 
Safety measurements that will be used in the study include physical examinations and 
clinical laboratory tests (hematology and blood chemistries). The adverse event will be 
graded for toxicity using the NCI CTC version 4.0. Toxicity assessment will occur at each 
monthly treatment visit, see Schedule of Events, Appendix 1. Any adverse events leading 
to a treatment interruption or dose reduction along with all adverse events that are 
grade 3 and higher will be recorded in the CRF. 
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9.2  
Definition of an Adverse Event  
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The definitions of adverse events (AEs) and serious adverse events (SAEs) are given 
below.   
 
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An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), or signs (e.g., 
tachycardia, enlarged liver).   
 
9.3  
Serious Adverse Events  
An event that fulfills at least one of the following criteria will be designated a serious 
adverse event (SAE). SAEs will be reported to the Cancer Consortium IRB per Cancer 
Consortium policy/procedure.  
x Results in death 
x Requires initial inpatient hospitalization or prolongation of existing hospitalization 
x Is immediately life-threatening  
x Results in severe or permanent disability or incapacity 
x Is a congenital abnormality or birth defect 
x Any other important medical event that may jeopardize the subject or requires 
medical intervention to prevent one of the outcomes listed above. 
 
Any events that are unequivocally due to progression of disease should not be 
reported as a serious adverse event. 
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9.4
Adverse Event Reporting Requirements 
 
Adverse events will be collected after the patient has taken the first dose of study drug. 
After discontinuation from treatment, patients must be followed for all existing AEs for 
30 calendar days after the last dose of study drug or until another anti-cancer therapy is 
initiated.  
 
Prior to beginning study treatment, study site personnel will note the occurrence and 
nature of each patient’s medical condition(s). During the study, site personnel will again 
note any change in the condition(s) and/or the occurrence and nature of any adverse 
events. Toxicities are to be graded according to the NCI CTC version 4.0.  
 
A description of the event, including its date of onset and resolution, any action taken 
should be provided along with the investigator’s assessment of causality. An event that is 
due to unequivocal progression of disease should not be reported as an AE. Any adverse 
events leading to a treatment interruption or dose reduction along with all grades 3 and 
higher adverse events must be recorded on a case report form (CRF).  
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after 
the patient has initiated study therapy and until 30 days after the patient has stopped 
study treatment must be reported to Eisai within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30-day period should only be reported to Eisai if the 
investigator suspects a causal relationship to the study drug.   
 
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10. Data Analysis/Statistical Methods 
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10.1  Sample Size Determination 
This is an open-label single-arm phase II study.  We will utilize the optimal two-stage 
Simon design, which minimizes the expected number of patients enrolled under the null 
hypothesis and given various other assumptions [Simon].  The null hypothesis is that the 
true response rate is 5% and the alternative hypothesis is that the true response rate is 
20%.  If we additionally set the significance level to 0.05 (or less) and the power to be at 
least 80% (p0 = 0.05, p1 = 0.20, a = 0.05, b = 0.20), then Simon’s design dictates that 10 
subjects be treated in the first stage.  If there are no responses among these 10, the 
study will be terminated due to lack of efficacy (i.e., this will be considered reasonably 
strong evidence against the alternative hypothesis that the response rate is 20% or more). 
If at least one response is observed among these 10, an additional 19 subjects will be 
recruited for a total of 29 subjects.  If 3 or fewer responses are seen among the 29 (an 
observed response rate of 10.3% or less), the regimen will be deemed to be not 
sufficiently efficacious for further study.  Four or more responses among the 29 will be 
viewed as sufficient evidence to deem the regimen as potentially efficacious (i.e., 
reasonably strong evidence that the true response rate is greater than 5%).  The 
expected number of patients to be enrolled under the null hypothesis that the true 
response rate is 5% is 17.6, and the probability of terminating early in this scenario (after 
the first stage, i.e., if no responses are seen in the first 10 patients) is 0.60.   
 
10.2 Efficacy Analysis  
The primary endpoint will be overall response rate. As noted above, 4 or more observed 
responses among 29 patients would be considered potentially efficacious and would 
justify further study. Responses include both complete and partial responses, as defined 
by RECIST 1.1 criteria. Duration of response and time to progression will be reported as 
median values.  The disease control rate (DCR), defined as the stable disease + partial 
response rate will be calculated.  Toxicity rates will be described as the overall 
percentage of patients experiencing Grade 3 or higher toxicity. 
 
10.3 Analysis of Other Endpoints  
Demographic characteristics such as patient age, gender, tumor type, and ECOG 
performance status will be tabulated.  All continuous data will be summarized using 
descriptive statistics (mean, standard deviation, median, minimum and maximum 
values).  All categorical data will be summarized using frequencies and percentages.  
Study drug administration will be described in terms of the total number of months 
administered, the median (range) of months administered, dose intensity, dose 
modifications, and reasons for the deviations from planned therapy. 
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Appendix 1. Schedule of Assessments  
 
Screening 
Every 21 days 
 
 
Procedure 
within 30 
days 
within 7 
days 
Day 1 
Day 8 
End of 
tmt 
30 day 
post 5 
tmt 
Physical Exam 
X 
  
X 
X 
X 
X 
Medical History 
X 
  
  
  
  
  
Pregnancy Test 
  
X 
  
  
  
  
Hematology 1 
X 
  
X 
X 
X 
X 
Serum Chemistries 2 
X 
  
X 
X 
X 
X 
EGG 
X 
X4  
  
  
  
  
CT scans 3 
X 
  
X 
  
X 
  
Eribulin 
  
  
X 
X 
  
  
AE Assessment 
  
  
X 
X 
X 
X 
  
1 Serum chemistries include sodium, potassium, chloride, carbon dioxide, creatinine, BUN, glucose, calcium, 
LDH, albumin, bilirubin, AST, ALT, total protein, alkaline phosphatase, magnesium.  
2 CBC with platelets and absolute neutrophil count. 
 
3 CT scan for known sites of involvement after every 2 cycles of combined therapy. After 4 cycles of therapy 
scans may be repeated after every 3 cycles. 
4 If > 450, needs ECG prior to second dose of eribulin. 
5 30 day follow-ups can be done at patients’ local physician 
 
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Version date: Dec 18, 2012 
13. References 
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IRB Approved 
Document Release Date: 02/14/2018
Printed on 5/14/2018