Conditions: Estrogen Receptor Negative HER2/Neu Negative Progesterone Receptor-negative Stage IV Breast Cancer Triple-negative Breast Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
This phase I/IB trial studies the side effects and best dose of eribulin mesylate and everolimus in treating patients with breast cancer that does not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 protein (triple-negative) and has spread to other places in the body (metastatic). Eribulin mesylate and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of everolimus and eribulin (eribulin mesylate), and determine the recommended Phase IB dose (RP2D) of the drug combination in patients with resistant metastatic triple negative breast cancer (TNBC). (Phase I) II. To evaluate the event-free survival (EFS) rate for patients with resistant metastatic TNBC at the RP2D of everolimus and eribulin to determine if the drug combination is worthy of further study. (Phase IB)

SECONDARY OBJECTIVES:

I. To determine response rate in patients with resistant metastatic TNBC. (Phase IB) II. To determine overall survival (OS) in patients with resistant metastatic TNBC. (Phase IB) III. To determine toxicity in patients with resistant metastatic TNBC. (Phase IB) IV. To determine pharmacokinetics (PK) for everolimus and eribulin in patients with resistant metastatic TNBC. (Phase IB) V. To collect blood, skin punch biopsies, and tumor biopsies before and after treatment from all patients and perform proteomic analysis to determine the level of inhibition of the phosphatidylinositol 3 kinase (PI3K) pathway in tumor cells versus non-therapeutic targets. (Phase IB)

OUTLINE: This is a dose-escalation study of everolimus.

Patients receive everolimus orally (PO) once daily (QD) on days 1-21 and eribulin mesylate intravenously (IV) on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 21 days and then periodically.

Arms:
arm 1: Patients receive everolimus PO QD on days 1-21 and eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: everolimus intervention 2: eribulin mesylate intervention 3: pharmacological study intervention 4: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Correlative studies intervention 4: Optional correlative studies

Protocol document:
Prot_SAP_000.pdf: 
IRB #14036 
10/08/2019 
Version: 15
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTIC RESERCH 
TITLE:   
PHASE I/IB TRIAL OF ERIBULIN AND EVEROLIMUS IN PATIENTS WITH 
TRIPLE NEGATIVE METASTATIC BREAST CANCER 
CITY OF HOPE PROTOCOL NUMBER: 
14036 
VERSION: 15 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
Initial Approval 
Protocol Dated 07/08/14 
Version 00 
Amendment 01 
Protocol Dated 07/17/14 
Version 01 
Amendment 02 
Protocol Dated 07/30/14 
Version 02 
Amendment 03 
Title Page Change Dated 10/14/14 
Version 03 
Amendment 04 
Protocol Dated 10/30/14 
Version 04 
Amendment 05 
Protocol dated 01/26/15 
Version 05 
Amendment 06 
Protocol dated 04/27/15 
Version 06 
Amendment 07 
Protocol dated 05/27/15 
Version 07 
Amendment 08 
Protocol dated 7/15/15 
Version 08 
Amendment 09 
Protocol dated 12/10/15 
Version 09 
Amendment 10 
Protocol dated 04/29/16 
Version 10 
Amendment 11 
Protocol dated 09/23/16 
Version 11 
Amendment 12 
Protocol dated 01/13/2017 
Version 12 
Amendment 13 
Protocol dated 02/01/2017 
Version 13 
Amendment 14 
Title Page Change Dated 10/31/2017 
Version 14 
Amendment 15 at Continuation     Title Page Dated 10/08/2019 
Version 15 
SPONSOR/IND NUMBER: IND Exempt 
DISEASE SITE:  
 
BREAST 
STAGE (if applicable):  
IV
MODALITY: 
 
CHEMOTHERAPY
PHASE/TYPE: 
 
PHASE IB 
PRINCIPAL INVESTIGATOR:
Yuan Yuan, M.D.
COLLABORATING INVESTIGATOR(S):
John Yim, M.D.
Tim Synold, M.D.
PARTICIPATING CLINICIANS:
Warren Chow, M.D., Daneng Li, M.D., 
Dean Lim, M.D., Joanne Mortimer, M.D., 
Jana Portnow, M.D., Lucine Tumyan, 
M.D., M.D., James Waisman, M.D., Mina 
Sedrak, M.D., Niki Patel, M.D., Christina 
Yeon, M.D., Daphne Stewart, M.D.,
Stephen Koehler, M.D., Samuel Chung, 
M.D., James Shen, M.D., Behnam 
Ebrahimi, M.D, Swapnil Rajurkar, M.D., 
Naveen Gupta, M.D. Mehdi Kebria, M.D. 


STUDY STATISTICIAN:
Suzette Blanchard
PARTICIPATING SITES:
City of Hope, Duarte CA
City of Hope, South Pasadena CA
STUDY SPONSOR AND MONITOR:
City of Hope, Rancho Cucamonga CA


 
 
 
 
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Study Synopsis and Design 
Study Rationale  
Patients with metastatic breast cancer (MBC) have a median overall survival (OS) of 
approximately 27 months. While OS has improved due to the introduction of new therapeutic 
agents, drug resistance is an ongoing challenge in the treatment of patients with MBC. Most 
patients with MBC become resistant to standard chemotherapeutic agents such as anthracyclines 
and taxanes or platinums; and while the development of hormonal therapies and anti-HER2 
therapies have revolutionized treatment for patients with hormone receptor-positive and HER2-
positive breast cancer, patients with hormone receptor-negative/HER2-negative cancer (triple 
negative breast cancer, TNBC) are in need of more efficacious therapies.  
Mutations in the PI3K pathway are the second most common mutations in breast cancer, and are 
the most common activating mutations, found in as many as 26%-45% of breast cancers. Triple 
negative breast cancers demonstrate higher levels of AKT activation, with consequent activation 
of the mammalian target of rapamycin (mTOR) pathway downstream of AKT. Everolimus 
inhibits cytokine and growth-factor-dependent cell proliferation by inhibiting the mTOR 
pathway. Everolimus has shown significant anti-tumor activity, but since the PI3K-mTOR 
pathway is downstream of numerous other effectors known to play a role in cancer cell 
proliferation and/or survival, there is an increasing focus on the drug’s possibilities when 
combined with other anti-tumor therapies. Increased efficacy has been observed when 
everolimus is combined with many other drugs. Eribulin mesylate is a synthetic analog of 
halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. It acts as 
a cancer therapeutic via a tubulin-based anti-mitotic mechanism, which leads to G2/M cell cycle 
arrest, disruption of mitotic spindles, and ultimately apoptotic cell death. It inhibits cell growth in 
a wide range of cancer cell lines and in patients with advanced solid tumors and MBC.  
Based on our preclinical findings, we hypothesize that the combination of everolimus and 
eribulin will have a synergistic effect and will increase clinical activity in patients with 
metastatic TNBC. Previous studies of each of these drugs in MBC show acceptable toxicity, and 
we hypothesize that this drug combination could offer a novel approach to treat patients with 
metastatic TNBC who are resistant to anthracyclines and taxanes or platinums. 
Objectives 
The overall objective of this study is to conduct a phase I/Ib trial of everolimus plus eribulin in 
metastatic TNBC patients who progressed after anthracyclines and/or taxanes or platinums. The 
trial will consist of a Phase I trial and with an extension to Phase Ib.  
Primary Objective for Phase I Study 
The primary objective of the Phase I portion of the study is to determine the safety and 
tolerability of everolimus and eribulin, and determine the recommended PhaseII dose (RP2D) of 


 
 
 
 
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the drug combination in patients with resistant metastatic TNBC. 
Primary Objective for Phase Ib Study 
The primary objective of the Phase Ib portion of the study is to evaluate the event-free survival 
(EFS) rate for patients with resistant metastatic TNBC at the RP2D of everolimus and eribulin to 
determine if the drug combination is worthy of further study. 
Secondary Objectives for Phase Ib Study 
The secondary objectives of the Phase Ib portion of the study are to determine response rate, OS, 
toxicity, and pharmacokinetics (PK) for everolimus and eribulin in patients with resistant 
metastatic TNBC. 
A further secondary objective is to collect blood, skin punch biopsies, and tumor biopsies before 
and after treatment from all patients, and perform proteomic analysis to determine the level of 
inhibition of the PI3K pathway in tumor cells versus non-therapeutic targets.  
Study Design 
This is a Phase I/Ib trial of everolimus plus eribulin in metastatic TNBC patients who are 
resistant to anthracyclines and taxanes or platinums.
Phase I Study 
The Phase I portion of the trial will use the toxicity equivalence range (TEQR) design. Based on 
this design, the target equivalence range for dose-limiting toxicities (DLTs) is 0.20-0.35. 
Toxicity levels of ≥0.51 will be considered too toxic, and doses which achieve this level will be 
stopped. Patients will enter the protocol in cohorts of three. This phase will be considered 
complete when 12 patients are studied at a single dose level with a toxicity level <0.51. The 
RP2D will be the dose closest to the target of 0.25 below 0.51 based on isotonic regression. 
Based on these requirements, the TEQR design will use a minimum of 6 patients and a 
maximum of 24 patients (median of 18) to determine the RP2D.
The PMT team for protocol 14036 reviewed the data: dose level 2 was closed after 2 of 3 
evaluable participants experienced DLTs at an observed rate of 67%; for dose level 1, we saw 4 
DLTs in 8 evaluable participants giving an observed DLT rate of 50% on this dose.  Our 
equivalence range for DLT rate for this trial is 20-35%, our observed rate  of 50% is above 35% 
so we plan to de-escalate. Two participants experienced grade 4 neutrophil count decrease and 
2 experienced mucositis (1 grade 3 DLT, 1 participant received 71% of Everolimus due to grade 
2 which is a DLT). Thus, the team decided to amend the protocol to allow for two new dose 
levels at a lower dose of Eribulin, and start the next cohort of patients at dose level B1. 


 
 
 
 
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Dosing Schedule: cycle length is 21 days 
Dose level A
Everolimus (oral)
Eribulin (intravenous)
A-1
2.5mg daily (day 1 to 21)
1.4mg/m2 on days 1, 8
A1
5mg daily (day 1 to 21)
1.4mg/m2 on days 1,8
A2
7.5mg daily (day 1 to 21)
1.4mg/m2 on days 1,8
A3
10mg daily (day 1 to 21)
1.4mg/m2 on days 1, 8
Dose level B
Everolimus (oral)
Eribulin (intravenous)
B1
5mg daily (day 1 to 21)
1.1mg/m2 on days 1,8
B-1
2.5mg daily (day 1 to 21)
1.1mg/m2 on days 1,8
Phase Ib Study 
In the Phase Ib portion of the trial, a Simon’s Optimal two-stage design will be used to determine 
if the combination of everolimus and eribulin results in a greater rate of patients who are event-
free at 4 months than with eribulin alone. Based on data from the EMBRACE trial, we set the 4-
month EFS rate for eribulin at 45%. We want to determine if the drug combination has a 4-
month EFS rate of ≥70% (25% improvement). Setting both the type I and type II errors to 0.1 
after 12 patients (from the RP2D at the end of the phase I trial), if ≤5 patients are event-free at 4 
months, the study will stop accrual. If ≥6 patients are event-free at 4 months we will enroll 15 
more patients for a total of 27 patients at the RP2D. If ≥16 patients out of the 27 are event-free at 
4 months we will consider the combination worthy of further study. 
The rationale for calling this a Phase Ib trial is that this trial is a large combination Phase I trial 
that will indicate if there is some activity of the drug combination, but it will not provide the 
activity information that a randomized Phase II trial would provide. Nonetheless, it still will 
provide information about whether the drug combination should be studied further. 
Study Endpoints 
Primary Endpoint 
The primary endpoints of the study are:  
x
Phase I: DLT. 
x
Phase IB: EFS at 4 months. 
Secondary Endpoints 


 
 
 
 
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The secondary endpoints are: 
x
Phase Ib: Response rate, PFS, OS, toxicity profile and PK parameters 
Sample Size and Accrual Rate 
The expected combined sample size for the Phase I/Ib trial will be 33. We anticipate 18 study 
participants for Phase I portion, and 15 additional at the RP2D to finish out the Phase II portion 
of the trial (minimum sample size=6 and maximum =45 (Phase I: 24 + Phase II: 15 + 6 for 
unevaluable/ineligible patients over the whole trial)).   
At the time of adding schedule B, 14 participants had been treated of which 12 are evaluable for 
dose escalation.  With the addition of 2 more doses we expect to treat 12 to 15 more patients  for 
a total of ~29 on the phase I portion of the trial, thus we expect the trial sample size to stay 
within the above planned limit of 45.  
Our accrual is just over 1 participant a month so the phase I portion should be completed after 2 
years from start of the trial. We will need to follow the last patient for 4 months to get EFS at 4 
months on the 12 patients studied at the RP2D, and expect to do the initial assessment of activity 
at approximately 2 1/2 years. If 6 or more of the patients studied at the RP2D are event free we 
will add on 15 additional patients. Based on the same accrual rate we should complete the 
accrual of the Phase Ib portion within approximately 12 months or at  42 months after start of the 
study. 
Inclusion CriteriaPatients with histologically confirmed stage IV TNBC (patients who had 
metastatic disease within 6 months of lumpectomy or mastectomy for treatment of TNBC may 
be excused from repeat biopsy) with measurable disease; 
Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly –
obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 
1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety 
concern) may submit an archived specimen only upon agreement from the study PI.
Chemotherapy for metastatic disease (patients with 0-3 lines of chemotherapy for MBC)
Prior radiation therapy allowed;  
Patients who previously received anthracyclines and/or taxanes or platinums ; 
age ≥18 years; 
Life expectancy ≥3 months;  
Eastern Cooperative Oncology Group performance score (ECOG PS) 0- 2;  
Adequate bone marrow, liver and renal function; 
Be willing to use dexamethasone mouth wash as directed.


 
 
 
 
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Exclusion Criteria
Patients may not be receiving any other investigational agents; patients received chemotherapy 
and/radiation therapy within 2 weeks from study entry; patients with symptomatic brain 
metastases; uncontrolled current illness including, but not limited to, ongoing or active infection 
(>Grade 2), symptomatic congestive heart failure, unstable angina pectoris, myocardial 
infarction within the past 6 months, cardiac ventricular arrhythmias requiring anti-arrhythmic 
therapy, or psychiatric illness/social situations that would limit compliance with study 
requirements; pregnant women; prior eribulin use; patients with known history of HIV; chronic 
hepatitis B; or chronic hepatitis C ; Concomitant use with strong or moderate CPY3A4/PgP 
inhibitors and CPY3A4/PgP inducers is not permitted; patient who is noncompliant with oral 
medication and mouth wash regimen. 
Clinical Observations and Tests to be Performed 
Pre-study assessments should be performed within 28 days prior to initiating therapy. 
We will assess tumor response using response evaluation criteria in solid tumors (RECIST)
Version 1.1 criteria based on radiologic imaging every 2 cycles of treatment (6 weeks). 
Toxicity will be evaluated based on the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v4.0.
Patients enrolled in the expanded phase Ib cohort at the RP2D will also be asked to undergo 
serial blood sampling to evaluate the PK of everolimus and eribulin. Although it is unlikely that 
these two agents will interact negatively, both drugs are substrates for the membrane transporter 
P-glycoprotein. Therefore, PK studies will be performed in the expanded cohort treated at the 
RP2D to evaluate the PK of the drug combination. 
For correlative studies, blood will be collected from patients who consented at the prior time 
points: prior to the first dose of everolimus and eribulin, at 4 and 8 hours after the first dose of 
everolimus and eribulin on day 1, and at two post-dose time points on days 4 and 8 of the first 
cycle for patients enrolled on the expanded cohort of RP2D.
Two sets of optional punch biopsies (two biopsies per set for a total of four biopsies) will be 
performed on patients who consented as follows:  
x
First set 
o
Biopsy 1 (3mm diameter) will be performed one week prior to any dosing.  
o
Biopsy 2 (3mm diameter) will be performed on the same site as Biopsy 1 on the 
day of the first dose of eribulin and everolimus; cycle 1 (prior to any dosing).  
x
Second set 


 
 
 
 
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o
Biopsy 3 (3mm diameter) will be performed on a new site on the day of the first 
dose of eribulin and everolimus; cycle 1 (prior to any dosing). 
o
Biopsy 4 (3mm diameter) will be performed on the same site as Biopsy 3, one 
week later on the day that the second dose of eribulin is given (prior to dosing). 
Patient will be asked to provide a fresh tumor tissue from a newly obtained core or excisional 
biopsy of a tumor lesion. Newly –obtained is defined as a specimen obtained up to 6 weeks (42 
days) prior to initiation of treatment on day 1. Subjects for whom newly-obtained samples cannot 
be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only 
upon agreement from the study PI. 
For patient who consented for optional tumor biopsy upon disease progression, a sample of 
tumor tissue will also be collected in patients who provided additional consent .
Serum, peripheral blood mononuclear cells (PBMC), skin biopsy tissue and tumor tissue will be 
processed and stored according to established laboratory protocols and stored at -80°C until 
proteomic analysis. Analysis will be performed by Luminex and mass spectrometry, and western 
blotting for pAKT (Ser473), and AKT, p4E-BP1 (ser65/Thr70) and 4E-BP1, pS6K1 (Thr389) 
and S6K1, and pS6 (Ser235/236) and S6. 
Statistical Considerations
Tables will be created to summarize all toxicities and side effects by dose, course, organ, and 
severity. Rates and associated 95% confidence limits will be estimated for DLTs at the RP2D, 
EFS at 4 months and response. Kaplan Meier methods will be used to estimate the median and 
95% confidence limits for EFS and OS. Descriptive statistics will be provided for the research 
participant demographics and PK parameters. 
Sponsors 
City of Hope is the sponsor and Novartis and Eisai will supply the drug.  


 
 
 
 
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SECTION 
 
 
 
 
 
 
 
 
 
PAGE
1.0 
Background and Study Rationale.......................................................................... 13 
1.1 
Metastatic Breast Cancer .......................................................................... 13 
1.1.1 Triple Negative Breast Cancer ...................................................... 13 
1.2 
Eribulin and Everolimus ........................................................................... 13 
1.2.1 Eribulin mesylate (E7389) ............................................................ 13 
1.2.2 Everolimus (RAD001, Afinitor) ................................................... 14 
1.3 
Rationale for the Combination of Eribulin and Everolimus in TNBC ..... 15 
1.4 
Rationale for Current Study ...................................................................... 16 
2.0 
Specific Objectives ............................................................................................... 17 
2.1 
Primary Objective for Phase I Study ........................................................ 17 
2.2 
Primary Objective for Phase IB Study ...................................................... 17 
2.3 
Secondary Objectives for Phase IB Study ................................................ 17 
3.0 
Study Endpoints .................................................................................................... 17 
3.1 
Primary Endpoint ...................................................................................... 17 
3.2 
Secondary Endpoints ................................................................................ 17 
4.0 
Study Design ......................................................................................................... 17 
4.1 
Phase I Study............................................................................................. 18 
4.2 
Phase IB Study .......................................................................................... 18 
5.0 
Patient Eligibility .................................................................................................. 19 
5.1 
Inclusion Criteria ...................................................................................... 19 
5.2 
Exclusion Criteria ..................................................................................... 20 
5.3 
Informed Consent...................................................................................... 21 
5.4 
Inclusion of Women and Minorities ......................................................... 21 
6.0 
Screening, Registration, and Follow-up Studies ................................................... 21 
6.1 
Subject Identification and Recruitment .................................................... 21 
6.2 
Informed Consent Process ........................................................................ 21 
6.3 
Dose Level Assignment ............................................................................ 22 
6.4 
Study Calendar .......................................................................................... 23 
6.5 
Registration Guidelines ............................................................................. 25 
7.0 
Study Treatment Protocol ..................................................................................... 26 


 
 
 
 
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7.1 
Eribulin mesylate (E7389) ........................................................................ 26 
7.1.1 Nomenclature ................................................................................ 26 
7.1.2 Chemical and structural formula ................................................... 26 
7.1.3 Physical and chemical characteristics ........................................... 26 
7.1.4 Description .................................................................................... 27 
7.1.5 Storage .......................................................................................... 27 
7.1.6 Dosage........................................................................................... 27 
7.2 
Everolimus ................................................................................................ 27 
7.2.1 Nomenclature ................................................................................ 27
 
Chemical and structural formula ................................................... 27
 
Physical and chemical characteristics ........................................... 27 
7.2.4 Description .................................................................................... 27 
7.2.5 Storage .......................................................................................... 27 
7.2.6 Dosage........................................................................................... 28 
7.3 
Treatment Overview ................................................................................. 28 
7.4 
Planned Duration of Therapy .................................................................... 28 
7.5 
Subject Follow-Up .................................................................................... 28 
7.6 
Supportive Care, Other Concomitant Therapy, Prohibited Medications .. 28 
7.6.1 Concomitant medications.............................................................. 28 
7.6.2 Vaccinations .................................................................................. 30 
8.0 
Dose Delays/Modifications ................................................................................... 31 
8.1 
Everolimus ................................................................................................ 31 
8.1.1 Dose Limiting Toxicities .............................................................. 31
8.1.2 Stomatitis........................................................................................32 
8.1.3 Rash............................................................................................... 33 
8.1.4 Non-infectious pneumonitis .......................................................... 34 
8.1.5 Dosing guidelines for everolimus-related non-hematologic toxicities
 
........................................................................................................34 
8.1.6 Dosing guidelines for Everolimus-related hematologic toxicities 35 
8.1.7 Management of infections............................................................. 36 
8.1.8 Management of diarrhea ............................................................... 37
8.1.9 Management of hyperglycemia..................................................... 37


 
 
 
 
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8.2 
Eribulin ..................................................................................................... 37 
8.2.1 Dose delays during therapy ........................................................... 37 
8.2.2 Dose adjustment during therapy ................................................... 37 
9.0 
Discontinuation of Study Treatment ..................................................................... 38 
9.1 
Patient-initiated Discontinuation of Study Treatment .............................. 38 
9.2 
Investigator-initiated Discontinuation of Study Treatment ...................... 38 
10.0 
Data Safety Monitoring......................................................................................... 38 
10.1 
Definition of Risk Level ........................................................................... 38 
10.2 
Monitoring and Personnel Responsible for Monitoring ........................... 39 
10.3 
Definitions................................................................................................. 39 
10.4 
Reporting of Unanticipated Problems and Adverse Events ...................... 40 
10.5 
Additional Reporting ................................................................................ 42 
10.5.1 Eisai............................................................................................... 42 
10.5.2 Novartis ......................................................................................... 42 
10.6 
Adverse Event Documentation ................................................................. 42 
10.7 
Comprehensive AEs and Potential Risks .................................................. 42 
10.7.1 Eribulin ......................................................................................... 43 
10.7.2 Everolimus .................................................................................... 44 
10.8 
Other AE Factors to Consider ................................................................... 45 
11.0 
Statistical Considerations ...................................................................................... 45 
11.1 
Design ....................................................................................................... 45 
11.1.1 Phase I portion .............................................................................. 46 
11.1.2 Phase IB portion ............................................................................ 49
 
11.2 
Sample Size and Accrual Rate...................................................................50
 
11.3 
Statistical Analysis Plan.............................................................................50
 
11.4 
Definitions..................................................................................................50
 
 
11.4.1 Response and Progression...............................................................50
 
 
11.4.2 Guidelines for Evaluation of Measurable Disease..........................51 
 
 
11.4.3 Response Criteria............................................................................52
12.0 
Correlative Translational Studies .......................................................................... 54 
12.1 
Pharmacokinetics ...................................................................................... 54 


 
 
 
 
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12.1.1 Everolimus PK sampling (whole blood) ....................................... 55 
12.1.2 Eribulin PK sampling (plasma) ..................................................... 55 
12.1.3 Sampling Schedule........................................................................ 55 
12.1.4 Analytical methods ....................................................................... 56 
12.1.5 Pharmacokinetic data analysis ...................................................... 56 
12.1.6 Specimen collection/documentation ............................................. 57 
12.2 
Molecular Studies ..................................................................................... 57 
12.2.1 Blood collection ............................................................................ 57 
12.2.2 Skin punch biopsy ......................................................................... 58 
12.2.3 Skin biopsies will be analyzed for several biomarkers in epidermal and 
vascular tissue (see Section 12.2.4). Tumor biopsy ................................. 58 
12.2.4 Proteomic Analysis ....................................................................... 60 
13.0 
Data Reporting and Protocol Deviations .............................................................. 61 
13.1 
Data Reporting .......................................................................................... 61 
13.1.1 Confidentiality of records ............................................................. 61 
13.1.2 Subject consent form..................................................................... 61 
13.2 
Protocol Deviations ................................................................................... 62 
13.2.1 Deviation policy ............................................................................ 62 
13.2.2 Reporting of unplanned deviations ............................................... 62 
13.2.3 Resolving disputes ........................................................................ 63 
14.0 
Human Subject Issues ........................................................................................... 63 
14.1 
Potential Risks to the Research Subjects .................................................. 63 
14.2 
Potential Benefits to Research Subjects and Society ................................ 63 
14.3 
Alternatives ............................................................................................... 63 
14.4 
Institutional Review Board ....................................................................... 63 
14.5 
Recruitment of Subjects ............................................................................ 63 
14.6 
Advertisements ......................................................................................... 63 
14.7 
Study Location and Performance Sites ..................................................... 64 
14.8 
Confidentiality .......................................................................................... 64 
14.9 
Financial Obligations and Compensation ................................................. 64 
15.0 
References ............................................................................................................. 64


 
 
 
 
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Appendix A  Performance Status Criteria..........................................................................68
Appendix B  Patient Diary for Everolimus.........................................................................69
Appendix C  Registration Procedures................................................................................71


 
 
 
 
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Abbreviations 
AE 
 
Adverse event  
AKT  
Protein kinase B  
AUC0-τ 
Area under the plasma concentration-time curve from time zero to the last 
measurable concentration 
BHT  
Butylated hydroxytoluene  
CBR  
Clinical benefit rate  
CI 
 
Combination indices 
COH  
City of Hope  
CRA  
Clinical research associate  
CRF 
 
Clinical report form 
CTU  
Clinical trials unit  
DLT 
 
Dose-limiting toxicity  
ECOG PS 
Eastern cooperative oncology group performance score  
EDC  
Electronic data capture  
EFS 
 
Event-free survival  
ER 
 
Estrogen receptor  
HIPAA 
Health Insurance Portability and Accountability Act  
IC50  
Half maximal inhibitory concentration  
INR 
 
International normalized ratio  
LD 
 
Longest diameter  
MBC  
Metastatic breast cancer  
MTD  
Maximum tolerated dose  
mTOR  
Mammalian target of rapamycin  
NCI CTCAE National cancer institute common terminology criteria for adverse events 
OS 
 
Overall survival  
PARP  
Poly ADP ribose polymerase 
PBMC  
Peripheral blood mononuclear cells  
PD  
 
Progressive Disease  
PFS 
 
Progression-free-survival  


 
 
 
 
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PI3K  
Phosphatidylinositide 3-kinase 
PK 
 
Pharmacokinetics 
PMT  
Protocol management team  
PR 
 
Partial response  
RECIST 
Response evaluation criteria in solid tumors  
RP2D  
Recommended Phase IB dose  
SAE 
 
Serious adverse event 
SD 
 
Stable disease  
TEQR  
Toxicity equivalence range  
TNBC  
Triple negative breast cancer  
TSC1/TSC2 Tuberous sclerosis complex  
UP 
 
Unanticipated problem  


 
 
 
 
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1.0 Background and Study Rationale 
1.1
Metastatic Breast Cancer 
Patients with metastatic breast cancer (MBC) have a median overall survival (OS) of 
approximately 27 months;1 and median OS is even lower in previously treated patients.2 While 
OS has improved due to the introduction of new therapeutic agents, drug resistance is an ongoing 
challenge in the treatment of patients with MBC. Most patients with MBC become resistant to 
standard chemotherapeutic agents such as anthracycline and/or taxanes or platinums; and while 
the development of hormonal therapies and anti-HER2 therapies have revolutionized treatment 
for patients with hormone receptor-positive and HER2-positive breast cancer,3 patients with 
hormone receptor-negative/HER2-negative cancer (triple negative breast cancer, TNBC) are in 
need of more efficacious therapies to improve clinical outcomes.  
1.1.1
Triple Negative Breast Cancer 
Metastatic TNBC is an aggressive disease with a poor prognosis reflected by low rates of 
relapse-free survival and OS.4 Many patients with TNBC receive anthracyclines and/or taxanes; 
and many develop resistant or refractory disease in the metastatic setting. Even when drug 
resistance is not noted, patients with TNBC have a suboptimal response to chemotherapy.5 Since 
TNBC shares many features with BRCA1-associated breast cancer, which is particularly 
susceptible to DNA-damaging agents, platinum combination therapy, including cisplatin and 
carboplatin, is commonly used to treat patients with TNBC. However, studies have shown that 
platinum combination therapy does not result in a significant improvement in outcome when 
compared with other regimens. The use of poly ADP ribose polymerase (PARP) inhibitors was 
suggested to be a promising novel approach to the treatment of TNBC, however, the highly 
anticipated results of the BSI-201trial of carboplatin, gemcitabine, and olaparib in patients with 
TNBC showed disappointing results. New effective therapeutic approaches to treat patients with 
metastatic TNBC are therefore needed. 
1.2
Eribulin and Everolimus 
1.2.1
Eribulin mesylate (E7389) 
Eribulin mesylate is a synthetic analog of halichondrin B, a natural product isolated from the 
marine sponge Halichondria okadai.6 It acts as a cancer therapeutic via a tubulin-based anti-
mitotic mechanism, which leads to G2/M cell cycle arrest, disruption of mitotic spindles, and 
ultimately apoptotic cell death. It inhibits cell growth in a wide range of cancer cell lines 
including: breast; colon; prostate; ovarian; small cell lung cancer; non-small cell lung cancer; 
histiocytic lymphoma; promyelocytic leukemia; pharyngeal squamous cell carcinoma; 
melanoma; and uterine sarcoma.7  
Studies have assessed eribulin in advanced solid tumors defining the safety, pharmacokinetics 
(PK), maximum tolerated dose (MTD), and tumor response.8 Eribulin has also been studied in 
patients with MBC.9 The E7389-A001-201 study enrolled 103 MBC patients after anthracycline 
and taxane failure. Patients received eribulin monotherapy in two different schedules; days 1, 8, 
and 15 of a 28-day cycle; and days 1 and 8 of a 21-day cycle. The most common drug-related 
adverse events (AEs) were Grade 3-4 neutropenia (60.4%, 28-day cycle and 65.7%, 21-day 


 
 
 
 
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cycle) and fatigue (52.4%). The clinical benefit rate (CBR) was 17.2%. Six of the 59 (10.2%) 
evaluable patients on the 28-day cycle and 4/28 (14.3%) patients on the 21-day cycle had a 
partial response (PR).8 The EMBRACE trial was a phase 3 open-label randomized study of 
eribulin monotherapy versus treatment of physician’s choice in 762 MBC patients who had 
previously received 2-5 chemotherapy regimens for MBC (84% of patients had previous 
hormonal therapy). Eribulin (1.4mg/m2) given intravenously on days 1 and 8 of a 21-day cycle 
showed a clinically meaningful OS improvement from 10.6 to 13.1 months (p=0.041). The CBR 
was 23% in the eribulin group versus 17% in the treatment of physician’s choice. The most 
common toxicities included asthenia (54%), neutropenia (52%), peripheral neuropathy (34.6%), 
nausea (28.3%), and constipation (21%). Neutropenia was the most common Grade 4 AE in 
patients receiving eribulin (24.1%).9
1.2.2
Everolimus (RAD001, Afinitor) 
Everolimus inhibits cytokine and growth-factor-dependent cell proliferation by inhibiting the 
mammalian target of rapamycin (mTOR).10 mTOR functions as a sensor of mitogens, growth 
factors, energy, and nutrient levels; and it facilitates cell-cycle progression through the G1 to S-
phase. The regulation of mTOR signaling is complex and involves positive regulators such as 
protein kinase B (AKT) that phosphorylate and inactivate negative regulators including the 
tuberous sclerosis complex (TSC1/TSC2). The phosphatidylinositide 3-kinase (PI3K)-mTOR 
pathway is frequently activated in many human cancers; and oncogenic transformation may 
sensitize tumor cells to mTOR inhibitors.11, 12 Everolimus has shown significant anti-tumor 
activity,13-20 but since the PI3K-mTOR pathway is downstream of numerous other effectors 
known to play a role in cancer cell proliferation and/or survival, there is an increasing focus on 
the drug’s possibilities when combined with other anti-tumor therapies. Increased efficacy has 
been observed with all combination partners tested.21-27
Everolimus has been evaluated in a number of clinical trials including in patients with solid 
tumors and MBC.28-30 In patients with advanced solid tumors, oral everolimus is rapidly 
absorbed with a median time to peak concentration of 1-2 hours post-dose. The steady-state 
AUC0-τ (area under the plasma concentration-time curve from time zero to the last measurable 
concentration) is dose-proportional over the dose range of 5-70mg in a weekly regimen and 5-
10mg in a daily regimen. In a randomized, double-blind, multicenter phase III study of 
everolimus and exemestane versus placebo and exemestane for estrogen receptor (ER)-positive 
MBC, 724 patients were randomized in a 2:1 ratio to receive either 10mg daily everolimus 
(N=485) or matching placebo (N=239) in addition to open-label 25mg daily exemestane. The 
study demonstrated a statistically significant clinical benefit of the everolimus and exemestane 
over placebo and exemestane by a 2.4-fold increase in median progression-free-survival (PFS) 
(6.93 months versus 2.83 months), resulting in a 57% risk-reduction of progression or death. 
Objective response was observed in 9.5% of patients in the everolimus and exemestane arm 
versus 0.4% in the placebo and exemestane arm (p<0.0001). Furthermore, the CBR for patients 
receiving everolimus and exemestane was 33.4% versus 18% in patients receiving placebo and 
exemestane (p<0.0001.) The most common grade 3-4 AEs in the everolimus and exemestane 
group versus the placebo and exemestane group were stomatitis (8% versus 1%), anemia (6% 


 
 
 
 
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versus <1%), dyspnea (4% versus 1%), hyperglycemia (4% versus <1%), fatigue (4% versus 
1%), and pneumonitis (3% versus 0%).30
Approximately 35,982 cancer patients have been treated with everolimus as of  31-Mar-2014:
x
19,668 patients in Novartis-sponsored clinical trials
x
2,394 patients in the individual patient supply program
x
More than 13,930 patients in investigator-sponsored studies.
1.3
Rationale for the Combination of Eribulin and 
Everolimus 
in TNBC 
Mutations in the PI3K pathway are the second most 
common 
mutation in breast cancer, and are the most common 
activating 
mutations, found in 26%-45% of breast cancers. Patients 
with TNBC 
demonstrate higher levels of AKT activation compared to other patients with breast cancers, with 
consequent activation of the mTOR pathway downstream of AKT. There is a well known 
feedback response with mTOR inhibition that seems to activate AKT. We performed preclinical 
evaluation of the effect of eribulin treatment on the PI3K pathway in TNBC and HER2-
expressing breast cancers, both alone and in combination with everolimus.  
We first evaluated the effect of eribulin on the growth of 
multiple breast 
cancer cell lines including TNBC cell lines. The half 
maximal 
inhibitory concentration (IC50) for eribulin ranged from 
0.1nM-0.3nM in 
TNBC cells to ~0.06nM in the HER2-overexpressing cell 
line, SKBR3, to 
0.5nM-0.8nM in hormone receptor-positive breast cancer 
cells. 
Importantly, eribulin clearly inhibited the 
phosphorylation of AKT in TNBC cells with inhibition 
of the Ser473 pAKT beginning between 1nM and 
10nM and nearing complete inhibition at 50nM, with no effect on total AKT (Figure 1). In the 
HER2-expressing cell line, SKBR3, eribulin began to have its effect on pAKT at 10pM (Figure 
2). This effect appeared to begin at 2-4 hours.  
In TNBC cells, everolimus has effects at very low doses, but increasing doses beyond a certain 
concentration did not show a linear incremental improvement in cell inhibition such that in some 
lines an IC50 was not achieved even at 10,000nM. We then evaluated everolimus using log 
dilutions in combination with standard dilutions of eribulin and found synergistic growth 
inhibition in TNBC cell lines using the MTT assay, except for at the highest doses (Figure 3).
Figure 1: MDA468 
cells were treated with
Figure 2: SKBR3 cells 
underwent same


 
 
 
 
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0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
MDA468 Halaven RAD001 72h
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
BT549 Halaven RAD001 72h
Figure 3 Two TNBC cell lines, MDA468 and BT549 are shown. Left panels: MTT assay of MDA468 and BT549 in the presence of eribulin in 
standard serial dilution, and everolimus in log dilution, either alone, or in combination. Right panels: combination indices (CI’s) for different 
combinations. With the exception of eribulin at 1.6nM with everolimus at 10,000nM in MDA468 cells (H1.6+R10), all CI’s are <1 (horizontal 
line), indicative of synergy.
We then performed western blots for pAKT and the mTOR target, pS6K1, and found that the 
combination of eribulin and everolimus suppressed both pAKT and pS6K1 at 24 hours; AKT 
was suppressed by eribulin in a dose-related fashion. A well known phenomenon associated with 
mTOR inhibition is the enhancement of pAKT when mTOR is inhibited, and this was seen at 24 
hours with everolimus alone. However, in combination with eribulin, both the increased pAKT 
and pS6K1 were suppressed (Figure 4; lanes 7 and 9 versus lane 5). 
                               1    2    3   4    5    6    7    8   9  10  11 12  13 
P-S6K1    
P70-S6K        
                             1    2    3   4    5    6    7    8    9  10  11 12  13 
P-AKT   
 
AKT                
 
1.
DMSO 
2.
Eribulin 10nM 
3.
Eribulin 50nM 
4.
BKM 0.5uM 
5.
RAD 0. 1uM 
6.
Eribulin 10Nm+ BKM 0.5uM 
7.
Eribulin 10nM+ RAD 0. 1uM 
8.
Eribulin 50nM+ BKM 0.5uM 
9.
Eribulin 50nM+ RAD 0. 1uM 
10. BKM 0.5uM + RAD 0. 1uM 
11. Eribulin 10nM + BKM 0.5uM + RAD 0. 1uM 
12. Eribulin 50nM + BKM 0.5uM + RAD 0. 1uM 
13. MDA468 
1.4
Rationale for Current Study 
Based on our preclinical findings, we hypothesize that the combination of everolimus and 
eribulin will have a synergistic effect with a dual inhibition of both AKT and mTOR and will 
increase clinical activity in patients with metastatic TNBC. Previous studies of each of these 
drugs in MBC show acceptable toxicity, and we hypothesize that this drug combination could 
Figure 4:
MDA468 cells were 
treated with BKM


 
 
 
 
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offer a novel approach to treat patients with metastatic TNBC who are resistant to anthracyclines 
and taxanes or platinums. 
2.0 Specific Objectives 
The overall objective of this study is to conduct a phase I/Ib trial of everolimus plus eribulin in 
metastatic TNBC patients who are resistant to anthracyclines and/or taxanes or platinums. The 
trial will consist of a Phase I portion and a Phase Ib portion.  
2.1
Primary Objective for Phase I Study 
The primary objective of the Phase I portion of the study is to determine the safety and 
tolerability of everolimus and eribulin, and determine the recommended Phase Ib dose (RP2D) of 
the drug combination in patients with resistant metastatic TNBC.  
2.2
Primary Objective for Phase Ib Study 
The primary objective of the Phase IB portion of the study is to evaluate the event-free survival 
(EFS) rate for patients with resistant metastatic TNBC at the RP2D of everolimus and eribulin to 
determine if the drug combination is worthy of further study. 
2.3
Secondary Objectives for Phase Ib Study 
The secondary objectives of the Phase Ib portion of the study are to determine response rate, OS, 
toxicity, and PK for everolimus and eribulin in patients with resistant metastatic TNBC. 
A further secondary objective is to collect blood, skin punch biopsies, and tumor biopsies before 
and after treatment from all patients and perform proteomic analysis to determine the level of 
inhibition of the PI3K pathway in tumor cells versus non-therapeutic targets.  
3.0 Study Endpoints 
3.1
Primary Endpoint 
The primary endpoints of the study are:  
x
Phase I: DLT (see Section 11 for statistical considerations). 
x
Phase IB: EFS at 4 months (see Section 11 for statistical considerations). 
3.2
Secondary Endpoints  
The secondary endpoints are: 
x
Phase Ib: Response rate, PFS, OS, toxicity profile and PK parameters. 
4.0 Study Design 
This is a Phase I/Ib trial of everolimus plus eribulin in metastatic TNBC patients who are 
resistant to anthracyclines and/or taxanes or platinum.


 
 
 
 
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4.1
Phase I Study 
The Phase I portion of the trial will use the toxicity equivalence range (TEQR) design. Based on 
this design, the target equivalence range of dose-limiting toxicities (DLTs) is 0.20-0.35. Toxicity 
levels of ≥0.51 will be considered too toxic, and doses which achieve this level will be stopped. 
Patients will enter the protocol in cohorts of three. This phase will be considered complete when 
12 patients are studied at a single dose level with a toxicity level <0.51. The RP2D will be the 
dose closest to the target of 0.25 below 0.51 based on isotonic regression. Based on these 
requirements, the TEQR design will use a minimum of 6 patients and a maximum of 24 patients 
(median of 18) to determine the MTD. (see Section 11).  
The PMT team for protocol 14036 reviewed the data: dose level 2 was closed after 2 of 3 
evaluable participants experienced DLTs an observed rate of 67%;  dose level 1, we saw 4 DLTs 
in 8 evaluable participants giving an observed DLT rate of 50% on this dose.  Our equivalence 
range for DLT rate for this trial is 20-35%, our observed rate of 50% is above 35%  so we plan 
to de-escalate. Two participants experienced grade 4 neutrophil count decrease and 2
experienced mucositis (1 grade 3 DLT, 1 participant received 71% of Everolimus due to grade 2 
which is a DLT). Thus, the team decided to amend the protocol to allow for two new dose 
levels at a lower dose of Eribulin, and start the next cohort of patients at dose level B1. 
Dosing Schedule: cycle length is 21 days 
Dose level A
Everolimus (oral)
Eribulin (intravenous)
A-1
2.5mg daily (day 1 to 21)
1.4mg/m2 on days 1, 8
A1
5mg daily (day 1 to 21)
1.4mg/m2 on days 1,8
A2
7.5mg daily (day 1 to 21)
1.4mg/m2 on days 1,8
A3
10mg daily (day 1 to 21)
1.4mg/m2 on days 1, 8
Dose level B
Everolimus (oral)
Eribulin (intravenous)
B1
5mg daily (day 1 to 21)
1.1mg/m2 on days 1,8
B-1
2.5mg daily (day 1 to 21)
1.1mg/m2 on days 1,8
4.2
Phase Ib Study 
In the Phase Ib portion of the trial, a Simon’s Optimal two-stage design will be used to determine 
if the combination of everolimus and eribulin results in a greater rate of patients who are event-
free at 4 months than with eribulin alone. Based on data from the EMBRACE trial, we set the 4-
month EFS rate for eribulin at 45%. We want to determine if the drug combination has a 4-
month EFS rate of ≥70% (25% improvement). Setting both the type I and type II errors to 0.1 
after 12 patients (from the MTD at the end of the phase I trial), if ≤5 patients are event-free at 4 
months, the study will stop for further accrual. If ≥6 patients are event-free at 4 months we will 
enroll 15 more patients for a total of 27 patients at the RP2D. If ≥16 patients out of the 27 are 


 
 
 
 
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event-free at 4 months we will consider the combination worthy of further study (see Section 
11).
Patient will be asked to provide a fresh tumor tissue from a newly obtained core or excisional 
biopsy of a tumor lesion. Newly –obtained is defined as a specimen obtained up to 6 weeks (42 
days) prior to initiation of treatment on day 1. Subjects for whom newly-obtained samples cannot 
be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only 
upon agreement from the study PI. 
For patients who consented for optional tumor biopsy upon disease progression, a sample of 
tumor tissue that may be biopsied or resected will also be collected (see Section 12.2).
To reduce dose-limiting oral mucositis, a mandatory dexamethasone mouth wash (alcohol-
free 0.5 mg/5 mL dexamethasone solution) will be used for primary prophylaxis of oral 
mucositis (Section 8.1.2).
We will assess tumor response using response evaluation criteria in solid tumors (RECIST) 
Version 1.1 criteria based on radiologic imaging every 2 cycles of treatment (6 weeks). 
Toxicity will be evaluated based on the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v4.0. 
Patients enrolled in the expanded cohort at the RP2D will also be asked to undergo serial blood 
sampling to evaluate the PK of everolimus and eribulin. Although it is unlikely that these two 
agents will interact negatively, both drugs are substrates for the membrane transporter P-
glycoprotein. Therefore, PK studies will be performed in the expanded cohort treated at the 
RP2D to evaluate the PK of the drug combination (see Section 12.1).
For correlative studies, blood will be collected from patients prior to the first dose of everolimus 
and eribulin, at 4 and 8 hours after the first dose of everolimus and eribulin on day 1, and at two 
post-dose time points on days 4 and 8 of the first cycle for patients enrolled on the expanded 
cohort of RP2D and consented for additional research blood collection.  
Two sets of optional skin punch biopsies (2 biopsies per set for a total of 4 biopsies) will be 
performed for patients who consented for skin biopsy for the expanded cohort level. 
x
First set 
o
Biopsy 1 (3mm diameter) will be performed one week prior to any dosing.  


 
 
 
 
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o
Biopsy 2 (3mm diameter) will be performed on the same site as Biopsy 1 on the 
day of the first dose of eribulin and everolimus; cycle 1 (prior to any dosing).  
x
Second set 
o
Biopsy 3 (3mm diameter) will be performed on a new site on the day of the first 
dose of eribulin and everolimus; cycle 1 (prior to any dosing). 
o
Biopsy 4 (3mm diameter) will be performed on the same site as Biopsy 3, one 
week later on the day that the second dose of eribulin is given (prior to dosing). 
Patient will be asked to provide a fresh tumor tissue from a newly obtained core or excisional 
biopsy of a tumor lesion prior to study entry. Newly –obtained is defined as a specimen obtained 
up to 6 weeks (42 days) prior to initiation of treatment on day 1. Subjects for whom newly-
obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an 
archived specimen only upon agreement from the study PI. 
For patients who consented for optional tumor biopsy upon progression, a sample of tumor tissue 
that may be biopsied or resected and will also be collected (see Section 12.2).
Serum, peripheral blood mononuclear cells (PBMC), skin biopsy tissue and tumor tissue will be 
processed and stored according to established laboratory protocols and stored at -80°C until 
proteomic analysis. Analysis will be performed by Luminex and mass spectrometry, and western 
blotting for pAKT (Ser473), and AKT, p4E-BP1 (ser65/Thr70) and 4E-BP1, pS6K1 (Thr389) 
and S6K1, and pS6 (Ser235/236) and S6 (see Section 12.2).
5.0 Patient Eligibility 
5.1
Inclusion Criteria 
x
Patients must have histologically confirmed stage IV TNBC (patients who had metastatic 
disease within 6 months of lumpectomy or mastectomy for treatment of TNBC may be 
excused from repeat biopsy). 
x
Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. 
Newly –obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of 
treatment on day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. 
inaccessible or subject safety concern) may submit an archived specimen only upon agreement 
from the study PI.
x
Patients must have had prior treatment with antracyclines and/or taxanes (resistant) or 
platinum including adjuvant or neoadjuvant therapy. 
x Both measurable as well as non-measurable disease by RECIST 1.1 will be allowed.  
x Patients with chemotherapy for metastatic disease (patients with 0-3 prior lines of 
chemotherapy for MBC).  
x
Age ≥18 years. 
x
Life expectancy of ≥ 3 months. 


 
 
 
 
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x
Performance status: ECOG PS 0-2.
x
Adequate bone marrow, liver and renal function as assessed by the following: 
Hemoglobin ≥9.0g/dl, absolute neutrophil count (ANC) ≥1,500/mm3, Platelet count 
≥100,000/mm3, Creatinine ≤1.5 times the ULN Liver Function Tests:  Total bilirubin less 
≤ to 1 times ULN,  ALT and AST ≤ to 2.5 times the ULN if no liver metastases.  For 
patients with known liver metastases, AST and ALT must be ≤ to 5 times the ULN.
x
Women of child-bearing potential must agree to use adequate contraception (hormonal or 
barrier method of birth control or abstinence) prior to study entry and for up to 8 weeks 
after ending treatment. Should a woman become pregnant or suspect that she is pregnant 
while participating on the trial, she should inform her treating physician immediately (see 
Section 5.2).
x
Ability to understand and the willingness to sign a written informed consent document. 
x
Be willing to use dexamethasone mouth wash as directed. 
5.2
Exclusion Criteria
x
Patients who have had chemotherapy or radiotherapy within 2-weeks prior to entering the 
study or those who have not recovered from AEs due to agents administered >3 weeks 
prior to entering the study. 
x
Patients may not be receiving any other investigational agents. 
x
Patients with symptomatic brain metastases are excluded from this clinical trial. 
x
Uncontrolled current illness including, but not limited to, ongoing or active infection 
(>Grade 2 based on the NCI CTCAE v4.0, symptomatic congestive heart failure, unstable 
angina pectoris, myocardial infarction within the past 6 months, cardiac ventricular 
arrhythmias requiring anti-arrhythmic therapy, or psychiatric illness/social situations that 
would limit compliance with study requirements.  
x
Pregnant women. 
x
Prior eribulin use. 
x
Patients with HIV, chronic hepatitis B, or chronic hepatitis C (known from the existing 
medical record).  
x
Concomitant use with strong or moderate CPY3A4/PgP inhibitors and CPY3A4/PgP 
inducers. 
x
Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, must use highly effective methods of contraception during 
the study and 8 weeks after ending treatment. Highly effective contraception  methods 
include combination of any two of the following: 
o
Use of oral, injected or implanted hormonal methods of contraception or; 
o
Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
o
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; 
o
Total abstinence; 
o
Male/female sterilization. 


 
 
 
 
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Women are considered post-menopausal and not of child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to 
randomization. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child-bearing potential. 
x
Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate 
contraception, during the study and for 8 weeks after the end of treatment. 
x
Noncomplaint with oral medication and/or dexamethasone mouth wash 
5.3
Informed Consent  
All subjects must have the ability to sign a written informed consent (see Section 6.2 for 
informed consent process). 
5.4
Inclusion of Women and Minorities  
The study is open to patients of all races and ethnicities. However, given the cancer under study, 
only women will be recruited to the study. 
6.0 Screening, Registration, and Follow-up Studies  
6.1
Subject Identification and Recruitment 
Patients with histologically-confirmed stage IV resistant metastatic TNBC will be identified and 
asked to participate in the study by the clinician. All patients will be recruited from patients 
undergoing treatment at City of Hope (COH). 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will 
be performed only after obtaining written informed consent (see Section 6.2). Studies or 
procedures performed for clinical indications (not exclusively to determine study eligibility) may 
be used for baseline values, even if the studies were done before informed consent was obtained 
(see Study Calendar for further details of study-related tests; Section 6.4).
6.2
Informed Consent Process 
Patients will be given copies of the consent form and the patient bill of rights to review and sign 
if they consent to participate in the study. The Principal Investigator or Co-Investigators will 
explain the nature, duration, purpose of the study, potential risks, alternatives, and potential 
benefits, and all other information contained in the informed consent document. In addition, they 
will review the experimental subject’s bill of rights and the Health Insurance Portability and 
Accountability Act (HIPAA) research authorization form. Research subjects will be informed 
that they may withdraw from the study at any time and for any reason without prejudice, 
including as applicable, their current or future care or employment at COH or any relationship 
they have with COH. General questions will be answered by the Principal Investigator and Co-
Investigators, and more complex questions requiring a medical opinion will be answered by the 
Principal Investigator and Co-Investigator physicians.  


 
 
 
 
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Should sufficient doubt be raised regarding the adequacy of comprehension, further clarifications 
will be made and the questionnaire repeated until a satisfactory result is obtained. Prospective 
research subjects who cannot adequately comprehend the fundamental aspects of the research 
study with a reasonable amount of discussion, education, and proctoring will be ineligible for 
enrollment. 
6.3
Dose Level Assignment 
Dose level will be assigned as described in Section 11.


 
 
 
 
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6.4
Study Calendar 
ERIBULIN/EVEROLIMUS SCHEDULE Q21 DAYS
Pre-Studyi
Cycle 1
Cycle 2 +
Off Studyi
Day1+/-
3days
Day 2
Day 3
Day 4
Day 6
Day 7
Day 8+/-
3days
Day 9
Day 12
Day 15i
Day 16
Day 21
Day 1+/-
3days
Day 2i
Day 3
Day 4
Day 6
Day 7
Day 8+/-
3days
Day 11
Day 12
Day 15
Day 16
Day 21j
Everolimus
Å………. Continuous Day 1 through 21……….Æ
Å ……….Continuous Day 1 through 21……….Æ
Eribulina
X
X
X
X
Informed consent
X
Demographics
X
Medical history
X
Height
X
EKG b
X
B-HCG c
X
Con-Meds
X
X----------------------------------------------------------------------------------------------------------------------------------------------------X
X
Everolimus dose 
diary 
X----------------------------------------------------------------------------------------------------------------------------------------------------X
X
Physical exam
X
X
X
X
Vital signs
X
X
X
X
Weight
X
X
X
X
Performance status
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
Serum chemistry d
X
X
X
X
Tumor Biopsy i
X
X
Skin Punch Biopsy e
X
X
X
Blood/Correlative h
X
X
X
X
Pharmacokineticsf
X
X
X
X
X
X
X
Adverse events 
X----------------------------------------------------------------------------------------------------------------------------------------------------X
X
Tumor measurements
X
Tumor measurements are repeated every 2 cycles (~6 weeks). Documentation (radiologic) must be provided for patients removed 
from study for progressive disease.
X
Radiologic 
X
Radiologic measurements are repeated every 2 cycles (~6 weeks).
X


 
 
 
 
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evaluationg
a: Actual body weight will be used for BSA and Eribulin dose calculation. b: Pre-study and every two cycles. c: Serum pregnancy test (women of childbearing potential). d: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, magnesium, total protein, SGOT [AST], 
SGPT [ALT], sodium.  e: Two sets of punch biopsies (two biopsies per set for a total of four biopsies – Optional for patients who consented at RP2D level) will be performed as 
follows: First set - Biopsy 1 will be performed one week prior to any dosing (pre-study). Biopsy 2 will be performed on the same site as Biopsy 1 on the day of the first dose of 
eribulin and everolimus; cycle 1 (prior to any dosing). Second set: Biopsy 3 will be performed on a new site on the day of the first dose of eribulin and everolimus; cycle 1 (prior to 
any dosing). Biopsy 4 will be performed on the same site as Biopsy 3, one week later on the day that the second dose of eribulin is given (prior to dosing). f: To be performed in a 
subset of patients enrolled on the Phase Ib portion of the study (see section 12.0). g: Staging images (CT scans, bone scan) must be performed within 28 days prior to study entry.
h: Blood correlative studies will be collected pre-study, before the first dose of everolimus and eribulin, at 4 and 8 hours after the first dose of everolimus and eribulin on day 1, 
and at two post-dose time points on days 4 and 8 of the first cycle for patients on the expanded cohort of RP2D.  i. Mandatory tumor biopsy specimen (fresh frozen and/or paraffin-
embeded) will be obtained prior to study entry. An optional tumor tissue biopsy will be obtained upon disease progression. j: Pre-study assessments should be performed within 28 
days prior to initiating therapy, unless otherwise noted. For the on-study treatment, there is a +/- 3 days of window allowed. 
 Items e, f, h:  ONLY for patients enrolled to the expanded cohort, i.e. RP2D. 


 
 
 
 
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6.5
Registration Guidelines 
General Guidelines 
Eligible patients will be registered on the study centrally at the Data 
Coordinating Center (DCC) at the City of Hope.  Staff (including physicians, 
protocol  nurses and/or CRAs) should call the DCC at (626) 256-4673, ext. 
64267 to verify dose level and slot availability, and to reserve a slot for a 
specific prospective subject.  Slots can only be held for a limited time as 
specified in Appendix C. 
 
 
 
Eligible patients must be registered within 2 weeks prior to start of protocol 
                  therapy.     
Issues that would cause treatment delays should be discussed with the 
Principal Investigator. If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study may be canceled. The Data 
Coordinating Center should be notified of cancellations as soon as possible. 
Registration Process 
Once a slot at a dose level has been reserved, the signed informed consent has 
been obtained, all pretreatment evaluations have been performed, and 
patient’s eligibility has been confirmed by the Data Coordinating Center, a 
patient will be registered on study. 
To register a patient, the treating physician should contact the protocol nurse 
or the responsible Clinical Research Associate (CRA) in Clinical Trial Office 
(CTO) to complete the eligibility/registration form. The protocol nurse or 
CRA will contact the Data Coordinating Center at the City of Hope (626-256-
4673, ext. 64267 or e-mail dcc@coh.org), EMAIL a copy of the completed 
eligibility checklist, required pre-study tests (per protocol – and may include 
laboratory, CT and pathology reports), signed Informed Consent, signed 
Patients' Bill of Rights and HIPAA authorization form to dcc@coh.org. See 
Appendix C (“Registration Procedures”).
The protocol nurse or CRA will then call the Data Coordinating Center (626-


 
 
 
 
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256-4673 ext. 64267) to confirm receipt of all registration documents. To 
complete the registration process, the Data Coordinating Center will: 
x
Verify and confirm the patient’s eligibility.
x
Assign a patient accession number (for example, COH-001, COH-002, 
etc.). 
x
Register the patient on study centrally (the City of Hope CRA assigned 
to the trial will still be responsible for accessioning via MIDAS).  If 
multi-site study, COH DCC staff will be responsible for registering the 
participating site patients at City of Hope. 
x
Assign the patient to a dose level (as applicable).  
x
Complete and email a Confirmation of Registration form within 24 
hours to include the COH patient study number and dose level (as 
applicable) to the study team, which will include the Principal 
Investigator, treating physician, protocol nurse, CRA and COH IDS 
Pharmacy. 
x
Call the protocol nurse and/or CRA to verbally confirm registration. 
x
A patient failing to meet all protocol requirements will not be 
registered. 
7.0 Study Treatment Protocol 
7.1
Eribulin mesylate (E7389) 
7.1.1
Nomenclature  
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). 
7.1.2
Chemical and structural formula 
Molecular formula: C41H63NO14S (C40H59NO11࣭CH4O3S). 
Molecular weight: 826.00. 
7.1.3
Physical and chemical characteristics  
Appearance: White powder.  
Hygroscopicity: Eribulin is hygroscopic.  


 
 
 
 
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7.1.4
Description 
Eribulin currently used in clinical studies contains 1.0mg drug substance in 2.0mL of 
solution. Eribulin rug product is a clear, colorless, and sterile solution packaged in a glass 
vial.
7.1.5
Storage 
The long-term storage condition for commercial Eribulin is 25°C (do not freeze). 
Investigational labeled Eribulin is stored in the refrigerator at 2-8 °C.  .  
7.1.6
Dosage 
The drug product will provided by Eisai for this trial. It will be administered per Eisai’s 
directions without dilution or diluted in up to 100mL 0.9% sodium chloride (for 
injection). Do not dilute in or administer through an intravenous line containing solutions 
with dextrose.  
7.2
Everolimus 
7.2.1
Nomenclature  
Chemical name: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R) -
1,18-dihydroxy-12-[1]-19,30-dimethoxy15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-
azatricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20pentaone 
7.2.2
Chemical and structural formula 
Molecular formula: C53H83NO14. 
Molecular weight: 958.2. 
7.2.3
Physical and chemical characteristics  
Appearance: White to faintly yellow powder.  
7.2.4
Description 
Everolimus stabilized with butylated hydroxytoluene (BHT) is amorphous, and contains 
0.2% BHT as an antioxidant. The drug substance, everolimus, contains 15 asymmetric 
carbon atoms and 4 substituted double bonds. The configuration of the asymmetric 
carbon atoms and the double bonds are guaranteed by the microbial origin of rapamycin, 
the starting material of the synthesis, and by the X-ray analysis performed on crystalline 
everolimus. The configuration at carbon 40 is not changed by the chemical derivatization 
that converts rapamycin into everolimus. 
7.2.5
Storage  
Stability: Shelf-life of 36 months when stored at <30°C. Protect from light and moisture. 


 
 
 
 
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7.2.6
Dosage 
2.5mg and 5mg tablets will be provided by Novartis for this trial. Everolimus should be 
administered orally, once daily at the same time every day either consistently with food 
or consistently without food. Tablets should be swallowed whole with a glass of water. 
The tablets must not be chewed or crushed. For patients unable to swallow tablets, 
everolimus tablet(s) should be dispersed completely in a glass of water (containing 
approximately 30mL) by gently stirring, immediately prior to drinking. The glass should 
be rinsed with the same volume of water and the rinse should be completely swallowed to 
ensure that the entire dose is administered. 
7.3
Treatment Overview 
For a tabular view of the treatment, monitoring, and follow-up schedule, see study 
calendar in Section 6.4. For dose levels see the study design (Section 4.0).
7.4
Planned Duration of Therapy 
Treatment cycle length is 21 days with response evaluation every 2 cycles. 
7.5
Subject Follow-Up
Patients will be followed after removal from study until death. Patients removed from 
study for AEs will be followed until resolution or stabilization of the AE (See Section 10
for further AE information). 
7.6
Supportive Care, Other Concomitant Therapy, Prohibited Medications 
Ondansetron will be used as pre-medication for prophylaxis of eribulin induced nausea.  
If needed, prior to each treatment with eribulin, patients may be pre-medicated with 
dexamethasone 10mg to prevent a hypersensitivity reaction.  Ondansetron 8mg oral tablet 
will be used as needed at home for treatment related nausea and/or vomiting. 
7.6.1
Dexamethasone Mouth Wash
To reduce dose-limiting oral mucositis, a mandatory dexamethasone mouth wash 
(alcohol-free 0.5 mg/5 mL dexamethasone solution) will be used for primary 
prophylaxis of oral mucositis. Patients will start the prophylactic oral care regimen on 
the same day they start treatment with everolimus + eribuline. The mouthwash should be 
taken as directed in section 8.1.2. Treating physician or other health provider of the 
treatment team will write the prescription of the steroid-based mouthwash. Usage of the 
mouth wash should be documented by patient and followed up during clinic visit.After 
first two cycles of treatment, patient can use the steroid mouth wash 4 times a day as 
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7.6.2
Concomitant medications 
Patients must be instructed not to take any medications (over-the-counter or other 
products) during the protocol treatment period without prior consultation with the 
investigator. The investigator should instruct the patient to notify the study site about any 
new medications he/she takes after the start of study drug. All medications (other than 
study drug) and significant non-drug therapies (including physical therapy and blood 
transfusions) taken within 28 days of starting study treatment through the 30-day safety 
follow up visit should be reported on the CRF. 
7.6.2.1
Angioedema with concomitant use of angiotensin-converting enzyme (ACE) 
inhibitors 
Patients taking concomitant ACE inhibitor therapy may be at increased risk for 
angioedema (e.g. swelling of the airways or tongue, with or without respiratory 
impairment). 
7.6.2.2
Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates 
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal 
wall.  Inhibitors of CYP3A4 or PgP may cause increased everolimus concentrations. 
Inducers of CYP3A4 or PgP may cause decreased everolimus concentrations. 
Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of the 
multidrug efflux pump, PgP (PgP, MDR1, and ABCB1).  The extent of absorption and 
subsequent elimination of systemically absorbed everolimus may be influenced by 
products that are substrates, inhibitors, or inducers of CYP3A4 and/or PgP.  In vitro 
studies showed that everolimus is a competitive inhibitor of CYP3A4 and of CYP2D6, 
potentially increasing the concentrations of products eliminated by these enzymes. 
Therefore,  
x
Co-administration with strong inhibitors of CYP3A4 or with a P-glycoprotein (PgP) 
inhibitor is not permitted. 
x
Coadministration with PgP substrates should be with caution as everolimus can affect 
their drug concentrations. 
x
Co-administration with moderate CYP3A4 inhibitors is not permitted.   If a patient 
requires co-administration of moderate CYP3A4 inhibitors, everolimus therapy must 
be interrupted. Once the inhibitor is discontinued, everolimus can be resumed only 
after discussion with the PI and a after a minimum washout period of 2 days (or 
longer depending on agent’s half life).   
x
Grapefruit, Seville oranges, and starfruit affect P450 and PgP activity. Concomitant 
use is not permitted. 


 
 
 
 
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x
Coadministration of a CYP3A4 inducer is not permitted except topical steroid. Oral 
dexamethasone mouth wash is allowed.
x
Coadministration with CYP3A4 and CYP2D6 substrates should be done with caution. 
For a current table of Substrates, Inhibitors and Inducers please access the following 
website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm.
Please refer to the tables below listing relevant inducers and inhibitors of CYP3A and for 
a list of relevant substrates, inducers, and inhibitors of PgP. 
Clinically relevant drug interactions: inducers, and inhibitors of isoenzyme CYP3A 
Inducers
mitotane, genistein, thioridazine, bexarotene, clobazam, danshen, Echinacea, garlic (allium sativum), ginkgo 
(ginkgo biloba), glycyrrhizin, methylprednisolone, primidone, raltegravir, sorafenib, telaprevir, terbinafine, 
carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, 
rifampin, St. John’s wort, troglitazone, efavirenz, nevirapine, topiramate, avasimibe, bosentan, etravirine, 
nafcillin, ritonavir, talviraline (not available in US market), tipranavir, amprenavir, aprepitant, armodafinil (R-
modafinil), dexamethasone*, nevirapine, prednisone, pleconaril (not available in US market), rufinamide
Inhibitors
Strong inhibitors:
Boceprevir, cobicistat, telaprevir,clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, voriconazole, tipranavir, 
elvitegravir, posaconazole. 
Moderate inhibitors:
Aprenavir, cyclosporine, schisandra sphenanthera, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, 
darunavir, diltiazem, erythromycin, fluconazole, grapefruit juice (citrus parasidi fruit juice), imatinib, tofisopam, 
verapamil, amprenavir, fosamprenavir, dronedarone.
*Topical steroid such as oral dexamethasone mouth wash is allowed.  
Clinically relevant drug interactions: substrates, inducers, inhibitors of PgP and 
PgP/CYP3A dual inhibitors 
Substrates
Talinolol, everolimus, digoxin, fexofenadine, indinavir, vincristine, colchicine, topotecan, paclitaxel
Inducers
rifampin, St John’s wort


 
 
 
 
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PgP Inhibitors and PgP/CYP3A Dual Inhibitors
Azithromycin, fluvoxamine, nelfinavir, paroxetine, amiodarone, captopril, carvedilol, clarithromycin, 
conivaptan, diltiazem, dronedarone, elacridar, erythromycin, felodipine, fexofenadine, ginkgo (ginkgo biloba), 
indinavir, itraconazole, , lopinavir, mibefradil, milk thistle (silybum marianum), nifedipine, nitrendipine, 
quercetin, quinidine, ranolazine, ritonavir, saquinavir, schisandra chinensis, St John’s wort (hypericum 
perforatum), talinolol, telmisartan, tipranavir, valspodar, verapamil.
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011, which 
summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug Interaction 
Studies”, the University of Washington’s Drug Interaction Database, and Indiana University School of 
Medicine's Drug Interaction Table.
7.6.3
Vaccinations 
Immunosuppressants may affect the response to vaccination and vaccination during 
treatment with everolimus may therefore be less effective. The use of live vaccines 
should be avoided during treatment with everolimus.  Examples of live vaccines are: 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, 
and TY21a typhoid vaccines. 
8.0 Dose Delays/Modifications 
8.1
Everolimus 
The most common AEs reported for everolimus that may require dose modifications are 
stomatitis, rash, and non-infectious pneumonitis.30
8.1.1
Dose Limiting Toxicities 
Definition of dose limiting toxicities (DLTs) based on CTCAE 4.0. All toxicities will be 
attributed to study drug (everolimus) except hematological toxicities.  Hematological 
DLTs will be defined for the combination of eribulin and everolimus.  If a hematological 
DLT occurs, dose reduction or delay will be conducted according to rules defined in 8.1.6 
and 8.2.2. 
DLT is defined as an AE or abnormal laboratory value as at least possibly related to the 
study medication and meets any of the criteria per CTCAE 4.0 . The following table is 
recommended for the most anticipated toxicities.  
Decisions to escalate, de-escalate, or expand a dose level will be based on the first course 
of treatment. To be evaluable for toxicity, a patient must receive at least 1 complete 
course of treatment (at least 75% of planned dose of both drugs without toxicity) and be 
followed for at least 21 days (more if there is a dose delay) or have experienced a DLT as 
defined above. All patients enrolled are to be fully followed for toxicity; any patients who 


 
 
 
 
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are not evaluable for toxicity will be replaced. Intra-patient dose escalation is not 
allowed.
Table 8.1.1a Criteria for defining dose-limiting toxicities. 
Toxicity
DLT criteria
Hematology
CTCAE grade ≥3 neuropenia lasting more than  7 consecutive days
CTCAE grade 4 thrombocytopenia
CTCAE grade 4 neutropenia
CTCAE Grade 3 neutropenia with fever (temperature ≥38.5C)
Non-
hematology
Any CTCAE grade ≥3 AEs with the following exceptions
Exceptions to 
DLT criteria
Grade 3 alopecia
Controllable  grade 3 nausea and vomiting
<5 days of CTCAE grade 3 fatigue
Triglycerides < 1,500mg/dl, which recover within 1  week
Grade 3 laboratory abnormalities that are correctable to grade 2 or less 
within 24 hours
Grade 3 hyperglycemia that is controlled to Grade 2 and under should 
not be considered DLT. For management of hyperglycemia, please refer
to section 8.1.9.
Treatment 
delays
>2 weeks as a result of unresolved toxicity during the first cycle of 
therapy (failure of ANC to recover to ≥1,000/μL or platelets to recover to 
≥50,000/μL within 14 days of the last treatment)
Others
Failure to complete at least 75% of planned dose of either one of the
drugs during cycle 1, due to toxicity, will also be considered a DLT.
  
Follow-up for toxicities. 
Patients whose treatment is interrupted or permanently discontinued due to an AE or 
clinically significant laboratory value, must be followed up weekly  (or more frequently if 
clinically indicated) for 4 weeks, and subsequently at approximately 4 week intervals, 
until resolution or stabilization of the event, whichever comes first. Appropriate clinical 
experts such as cardiologist, pulmonologists etc should be consulted as deemed 
necessary. All patients must be followed up for 21 days when taken off study . 
  
8.1.2
Stomatitis 
Inflammation of the mucous membranes in the mouth may occur. Ulcerated areas in the 
oral cavity, inner surface of the lips, or tongue, closely resembling aphthous stomatitis 
may occur. Onset typically occurs early (≤1 month after treatment initiation) and is 


 
 
 
 
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transient. 44%-70% of everolimus-treated patients develop mouth ulcers, stomatitis, or 
oral mucositis, which are mostly Grade 1 or 2.
To reduce dose-limiting oral mucositis, a mandatory dexamethasone mouth wash 
(alcohol-free 0.5 mg/5 mL dexamethasone solution) will be used for primary 
prophylaxis of oral mucositis. Steroid based mouth wash was studied in a randomized 
phase II study evaluating miracle mouth wash plus hydrocortisone versus prednisolone
mouth rinses as prophylaxis for everolimus- associated stomatitis[37]. This study 
provided evidence of a reduced incidence of mTOR-associated stomatitis with 
prophylactic use of a steroid mouth rinse. The 25% incidence of all-grade and 8%/0% 
incidence of G2/3 stomatitis compare favorably with the 67% and 24%/8% incidence of 
all-grade and G2/3 stomatitis, respectively, in BOLERO-2. These preliminary data also 
demonstrated the safety and tolerability of these 2 steroid mouth rinses. 
Currently, there is an ongoing phase II trial examining the effect of dexamethasone based 
mouth wash[38]. We would like to utilize this dexamethasone based mouth wash for the 
current study. The mouth care regimen consists of a steroid-based mouthwash (alcohol-
free 0.5 mg/5 mL dexamethasone solution) . Patients will start the prophylactic oral care 
regimen on the same day they start treatment with everolimus + eribuline. The 
mouthwash should be taken as follow: 
-
Swish and spit 10ml of mouthwash 4 times each day 
-
Hold mouthwash in mouth for a minimum of 2 minutes 
-
Swish it around in the mouth, so it comes in contact with every surface of the 
mouth 
-
Spit it out  (do not swallow) 
-
Abstain from eating or drinking for a leat 1 hour after performing mouthwash 
regimen 
-
Continue with assigned oral care regimen for the first 2 months (56 days) of 
everolimus + eribuline therapy, after with mouthwash will be stopped. 
Treating physician or other health provider of the treatment team will write the 
prescription of the steroid-based mouthwash. Usage of the mouth wash should be 
documented by patient and followed up during clinic visit.After first two cycles of 
treatment, patient can use the steroid mouth wash 4 times a day as needed .
Upon diagnosis of ≥ grade 1 stomatitis, a normal saline (0.9% sodium chloride) mouth 
rinse will be added while patient is continuing the dexamethasone mouthwash. The 
normal saline is administered as a 10mL swish and spit (QID) (must be done prior to the 
steroid mouthwash QID).  Patients administered normal saline (0.9% sodium chloride)
mouth rinse (swish and spit), then waited for 10-15 mins, and then administered 
dexamethasone mouth wash. No dose adjustment is required for grade I stomatitis.


 
 
 
 
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Dose adjustments for stomatitis
Grade
Symptom
Management
Everolimus Dose Adjustment
2
Symptomatic but can 
eat and swallow a 
modified diet.
x Manage with topical analgesic mouth 
treatment (e.g. benzocaine, butyl 
aminobenzoate, tetracaine 
hydrochloride, menthol or phenol) 
with or without topical 
corticosteroids (i.e. triamcinolone 
oral paste).
x Avoid agents containing alcohol, 
hydrogen peroxide, iodine and thyme 
derivatives.
x Interrupt everolimus 
administration until 
resolution to ≤grade 1 or 
baseline grade / value.
x If resolution occurs within 
≤7 days, everolimus should 
be re-started at the dose 
level prior to interruption.
x If resolution takes >7 days, 
or if event recurs within 28 
days, hold everolimus until 
recovery to ≤ grade 1 or 
baseline grade / value and 
reintroduce everolimus at 
one dose level lower, if 
available.
x Patients will be withdrawn 
from the study if they fail to 
recover to d grade 1 or 
baseline grade / value 
within 28 days.
3
Symptomatic and 
unable to adequately 
eat or hydrate orally.
Same as above.
x Temporary dose 
interruptions until recovery 
to Grade ≤1. Re-initiate 
everolimus at a lower dose.
4
Severe (symptoms are 
life threatening).
x Discontinue everolimus and 
treat with appropriate 
medical therapy.
8.13    Rash 
Rash is reported in 29%-59% of patients treated with everolimus. It may be erythematous 
maculopapular, acneiform, and eczematoid. Research participants should receive the 
following education about rashes: 
x
Inform research participant of the possibility of developing rash. 
x
Inform research participant to promptly report any signs or symptoms of rash to 
initiate treatment early. 
x
Educate research participants to employ good skin care including: 
o
Moisturize frequently. Use a thick, alcohol-free emollient cream. 
o
Take short lukewarm showers, using mild, moisturizing (fragrance-free) 
soap.


 
 
 
 
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o
Bathe in lukewarm water plus 1-2 cups of baking soda. 
o
Use a sunscreen of SPF 15 or higher, preferably containing zinc oxide or 
titanium dioxide (minimize sun exposure). 
Dose adjustments for rash 
Grade
Symptoms
Management
Everolimus Dose 
Modification
2
Moderate
x
Consider treatment with topical 
steroids, topical antibiotics and/or oral 
antihistamines
x Temporary dose 
interruptions until 
recovery to Grade ≤1.
x Re-initiate everolimus 
at the same dose.
x If rash recurs at 
Grade 2, interrupt 
dose until recover to 
Grade ≤1. Re-initiate 
everolimus at a lower 
dose.
3 (or 
intolerable 
grade 2 
papulopustular)
Severe
x
Consider oral antibiotics
x Temporary dose 
interruptions until 
recovery to Grade ≤1. 
Re-initiate everolimus 
at a lower dose.
4
Life-Threatening
x Discontinue 
everolimus and treat 
with appropriate 
medical therapy.
8.14    Non-infectious pneumonitis 
Non-infectious pneumonitis is reported in 14%-19% of patients treated with everolimus. 
Incidence of Grade 3 and 4 non-infectious pneumonitis has been reported up to 4% and 
up to 0.2%, of patients respectively. Fatal outcomes have been observed.
Dose adjustments for non-infectious pneumonitis 
Grade
Symptom
Management
Everolimus Dose Modification
2
Symptomatic, not 
interfering with ADL.
x Rule out infection.
x Consider treatment with 
corticosteroids.
x Consider interruption of 
therapy until symptoms 
improve to Grade ≤1.
x Re-initiate everolimus at a 
lower dose.
x Discontinue treatment if 
failure to recover within 4 
weeks.


 
 
 
 
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3
Symptomatic, 
interfering with ADL, 02
required.
x Rule out infection.
x Consider treatment with 
corticosteroids.
x Consider interruption of 
therapy until symptoms 
improve to Grade ≤1.
x Re-initiate everolimus at a 
lower dose. If toxicity recurs 
a Grade 3, consider 
discontinuation.
4
Life threatening, 
ventilator support 
indicated.
x Rule out infection.
x Consider treatment with 
corticosteroids.
x Discontinue everolimus.
8.15
Dosing guidelines for everolimus-related non-hematologic toxicities 
Toxicity
Action
Non-Infectious Pneumonitis
Please refer to table above.
AST or ALT elevation
Grade 1 (> ULN - 3.0 x ULN)
Grade 2 (> 3.0 - 5.0 x ULN)
Maintain current dose level
AST or ALT elevation
Grade 3 (>5.0 - 20.0 ULN)*
Interrupt everolimus administration until resolution to ≤grade 1 (or 
≤grade 2 if baseline values were within the range of grade 2). If 
resolution occurs ≤7 days, everolimus should be re-started at the dose 
level prior to interruption.
If resolution takes >7 days, or if event recurs within 28 days, hold 
everolimus until recovery to ≤grade 1 or baseline grade / value and 
reintroduce Everolimus at one dose level lower, if available.
AST or ALT elevation
Grade 4 (>20 x ULN)
Recurrence of grade 4 AST or ALT 
elevation after dose reduction or toxicity 
requiring Everolimus interruption for > 
28 days
Interrupt everolimus administration until resolution to ≤grade 1 (or ≤ 
grade 2 if baseline values were within the range of grade 2). If 
resolution occurs ≤7 days, everolimus should be re-started at one dose 
level lower. If resolution takes >7 days, discontinue everolimus.
Discontinue everolimus.
Intolerable grade 2 mucositis, or grade 3 
AE, except hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia 
Interrupt everolimus administration until resolution to ≤grade 1 or 
baseline grade / value.
If resolution occurs within ≤7 days, everolimus should be re-started at 
the dose level prior to interruption.
If resolution takes >7 days, or if event recurs within 28 days, hold 
everolimus until recovery to ≤ grade 1 or baseline grade / value and 
reintroduce everolimus at one dose level lower, if available.
Patients will be withdrawn from the study if they fail to recover to d
grade 1 or baseline grade / value within 28 days.


 
 
 
 
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Toxicity
Action
Any other grade 4
Hold everolimus until recovery to grade d1 or baseline value.
Reintroduce Everolimus at one dose level lower, if available.
Grade 3 or 4 clinical liver failure 
(asterixis or encephalopathy/coma)
Discontinue everolimus.
Recurrence of intolerable grade 2 
mucositis or grade 3 event after dose 
reduction
Reduce dose to the next lower dose level, if available. The lowest 
possible dose level of everolimus is 2.5mg daily. Below this level, 
everolimus must be discontinued. If toxicity recurs at Grade 3, consider 
discontinuation.
Recurrence of grade 4 after dose 
reduction
Discontinue everolimus.
Any non-hematologic toxicity requiring 
Everolimus interruption for > 28 days
Discontinue everolimus.
8.1.6
Dosing guidelines for Everolimus related hematologic toxicities 
Toxicity
Action
Grade 2 thrombocytopenia (platelets 
<75, ≥ 50x109/L)
No action
Grade 3 thrombocytopenia (platelets 
<50, ≥25 x 109/L)
Interrupt everolimus until resolution to grade d1
If resolution occurs ≤7 days, reintroduce everolimus at the dose 
level prior to interruption.
If resolution occurs >7 days, or event occurs within 28 days, 
reintroduce everolimus at one dose level lower, if available.
Grade 4 thrombocytopenia (platelets <25 
x 109/L)
Interrupt everolimus until recovery to grade d1. Then reintroduce 
everolimus at one dose level lower, if available.
Grade 3 neutropenia or anemia 
(neutrophil <1, ≥0.5 x 109/L)
Interrupt everolimus until resolution to grade ≤1 or baseline value
If AE resolution occurs ≤7 days, reintroduce everolimus at the same 
dose level.
If AE resolution occurs >7 days, or event occurs within 28 days, 
reintroduce everolimus at one dose level lower, if available.
Grade 4 neutropenia or anemia
Interrupt everolimus until recovery to grade d1 or baseline value. 
Reintroduce everolimus at one dose level lower, if available.*
Febrile neutropenia
Interrupt everolimus until resolution to grade d1 (or baseline value) 
and no fever. Reintroduce everolimus at one dose level lower, if 
available.*


 
 
 
 
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Recurrence of grade 3 toxicity after dose 
reduction
Reduce dose to the next lower dose level, if available. The lowest 
possible dose level of everolimus is 5mg every other day (2.5 mg 
daily). Below this level, everolimus must be discontinued.
* Recurrence of grade 4 toxicity 
(including febrile neutropenia) after dose 
reduction
Discontinue everolimus
* Any hematologic toxicity requiring 
Everolimus interruption for > 28 days
Discontinue everolimus
8.1.7    Management of infections 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoal infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, 
invasive fungal infections, such as aspergillosis or candidiasis and viral infections 
including reactivation of hepatitis B virus, have been described in patients taking 
everolimus Some of these infections have been severe (e.g. leading to sepsis, respiratory 
or hepatic failure) and occasionally have had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with 
everolimus. Treat pre-existing infections prior to starting treatment with everolimus. 
While taking everolimus, be vigilant for symptoms and signs of infection; if a diagnosis 
of infection is made, institute appropriate treatment promptly and consider interruption or 
discontinuation of everolimus. 
If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus and 
treat with appropriate antifungal therapy. 
Cases of pneumocystis jirovecii pneumonia (PJP), some with a fatal outcome, have been 
reported in patients who received everolimus. PJP may be associated with concomitant 
use of corticosteroids or other immunosuppressive agents.  Prophylaxis for PJP should be 
considered when concomitant use of corticosteroids or other immunosuppressive agents 
are required. 
8.1.8    Management of diarrhea 
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with 
supportive care such as loperamide, initiated at the earliest onset (for example 4 mg 
orally followed by 2mg orally every 2 hours until resolution of diarrhea). 
8.1.9 Management of hyperglycemia 
Grade 3 hyperglycemia has been observed in patients receiving everolimus therapy. The 
fasting state of patients should be verified when interpreting results. It is suggested that 
optimal glucose control should be achieved before starting a patient on everolimus and 


 
 
 
 
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should be monitored during everolimus therapy. Should hyperglycemia develop during 
protocol therapy, standard glucose control interventions should be implemented. If 
hyperglycemia was well-controlled and improved to less or equal then grade II, this will 
not count toward a DLT. 
8.2
Eribulin 
8.2.1
Dose delays during therapy 
Do not administer eribulin mesylate on Day 1 or Day 8 for any of the following:  
x
ANC <1×109/L  
x
PLT <75×109/L  
x
Grade 3 or 4 non-hematological toxicities attributed by eribulin. 
8.2.2
Dose adjustment during therapy  
Subjects should be clinically evaluated during treatment by physical examination and 
laboratory testing including complete blood counts as indicated per protocol (see Section 
6.4). If Grade 3 and 4 toxicities are present, treatment should be delayed to allow 
recovery. Subjects should only be retreated when ANC is ≥1×109/L and PLT are 
≥75×109/L and all other toxicity from a previous cycle has recovered to ≤Grade 2. 
Recommended dose reductions as indicated in the US Package Insert are as follows: 
Permanently reduce the 1.4mg/m2 eribulin mesylate dose to 1.1mg/m2 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 graded according to NCI CTCAE v4.0. 
x
Omission or delay of Day 8 dose in previous cycle for toxicity. 
Furthermore: 
x
If any event requires permanent dose reduction while receiving 1.1mg/m2, reduce 
the dose to 0.7mg/m2.
x
If any event requires permanent dose reduction while receiving 0.7mg/m2,
discontinue eribulin. 
There will be no dose reductions outside of the scheduled physical examination and 
laboratory testing including complete blood counts indicated per protocol (see 
Section 6.4). 


 
 
 
 
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9.0 Discontinuation of Study Treatment 
9.1
Patient-initiated Discontinuation of Study Treatment 
Even after a patient agrees to take part in the study, she may stop therapy or withdraw 
from the study at any time. If the study participant stops treatment but still allows the 
study physician to submit follow-up information, she will continue to be followed 
clinically according to the study schedule. Alternatively, she may choose to have no 
further interaction regarding the study in which case the Principle Investigator or Co-
Investigators must obtain written documentation as to the patient’s decision to withdraw 
fully from the study. 
9.2
Investigator-initiated Discontinuation of Study Treatment 
The investigator may require a study subject to discontinue study treatment in the event 
of one of the following: 
x
The patient develops a serious AE (SAE) that she cannot tolerate or that cannot be 
controlled with other medication (see Section 10).
x
The patient has disease progression. 
x
The patient has concurrent illness that prevents further administration of treatment 
If study therapy is stopped but the study subject allows the physician to submit follow-up 
information, she will continue to be followed clinically according to the study schedule. 
A Withdrawal/Discontinuation Form will be completed by the Principal Investigator, 
which will allow determination of which study subjects are receiving off-protocol 
therapy. 
10.0
Data Safety Monitoring 
10.1 Definition of Risk Level 
This is a Risk Level 3 study, as defined in the “Guidance, Policy and Procedures for Data 
and Safety Monitoring for In-House Trials at City of Hope”.
http://www.infosci.coh.org/prot_office/forms/Guidance.doc. Risks are at least balanced 
by the potential benefits to subjects and the importance of the knowledge that may result. 
Adverse events are expected and a formal plan for monitoring and reporting these AEs is 
required (outlined below). 
10.2 Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) consisting of the Principle Investigator, 
Collaborating Investigators, Co-Investigators, CRA, protocol nurse, and statistician is 
responsible for monitoring the data and safety of this study, including implementation of 
any stopping rules for safety and efficacy.  


 
 
 
 
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This study will utilize the Phase I tracking log to monitor data and safety for dose 
escalation, recording doses administered, and resultant AEs. The tracking log will contain 
dose levels administered, DLT-defining AEs, and documentation that the data from a 
dose level is complete before dose escalation. Those data and safety elements will be 
reported to the COH DSMC as applicable within the PMT report, which will be 
submitted quarterly or semi-annually from the anniversary date of activation, as noted in 
Table 1. Protocol-specific data collection will include the following items: patient 
demographics, toxicities summarized by dose, course, organ and severity and best overall 
response. 
Table 1: City of Hope PMT Reporting Timelines for the DSMC 
Risk Level
Phase
Standard Reporting Requirement
RL 1, RL2, and 
Compassionate Use Studies
No reports required
3
I
Every 3 months from activation date, as 
indicated in MIDAS
3
Pilot, Feasibility, 
II-IV
Every 6 months from activation date, as 
indicated in MIDAS
4
Pilot, Feasibility, 
I-IV
Every 3 months from activation date, as 
indicated in MIDAS
10.3 Definitions 
Adverse event (AE) An AE is any untoward medical experience or change of an existing 
condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention.  
Unexpected Adverse Event [21 CFR 312.32 (a) An AE is unexpected if it is not listed 
in the investigator’s brochure and/or package insert; is not listed at the specificity or 
severity that has been observed; is not consistent with the risk information described in 
the protocol and/or consent; is not an expected natural progression of any underlying 
disease, disorder, condition, or predisposed risk factor of the research participant 
experiencing the AE. 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected 
event OR is an expected natural progression of any underlying disease, disorder, 
condition, or predisposed risk factor of the research participant experiencing the adverse 
event 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or 
unexpected adverse event that results in any of the following outcomes:
x
Death 
x
Is life-threatening experience (places the subject at immediate risk of death from 
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x
Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of 
existing hospitalization 
x
A persistent or significant disability/incapacity 
x
A congenital anomaly/birth defect 
x
Secondary Malignancy 
x
Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the outcomes listed above (examples of such events include 
allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasisas of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse).
Unanticipated problem (UP) Any incident, experience, or outcome that meets all three
of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) 
the research procedures described in the protocol-related documents such as 
the IRB approved research protocol, informed consent document or 
Investigator Brochure (IB); and b) the characteristics of the subject 
population being studied; AND
2. Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or 
outcomes may have been caused by the drugs, devices or procedures 
involved in the research); AND
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than 
previously known or recognized. 
10.4  Reporting of Unanticipated Problems and Adverse Events 
Unanticipated Problems: Most unanticipated problems must be reported to the COH 
DSMC and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx. Any unanticipated problem that 
occurs during the study conduct will be reported to the DSMC and IRB by submitting 
electronically in iRIS (http://iris.coh.org). 
Serious Adverse Events - All SAEs occurring during this study, whether observed by 
the physician, nurse, or reported by the patient, will be reported according to definitions 
and guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and Table 2. Those 
SAEs that require expedited reporting will be submitted electronically in iRIS 
(http://iris.coh.org/).
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that do 
not meet the criteria of serious OR are not unanticipated problems will be reported only 
in the protocol continuation reports and PMT report (see Table 2).


 
 
 
 
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An event determined by the IRB of record to be an Unanticipated Problem (UP) will be
communicated to the Investigator and COH DSMC through the COH IRB Operations 
Director. The DSMC will review the case and make a determination as to whether the 
study will be suspended, terminated, amended, or allowed to continue without 
amendment. 
Table 2: City of Hope Adverse Event and Unanticipated Problem Reporting 
Timelines for the DSMC and IRB 
Required Reporting Timelines to DSMC for AE/SAEs
Externally Sponsored Studies
Required Reporting Timeframe to DSMC
Attribution
UNEXPECTED1
EXPECTED
Death while on active treatment or within 30 days of last day 
of treatment
Possibly, Probably, Definitely
No DSMC reporting required - IRB reporting may be necessary
Unlikely, Unrelated
Death after 30 days of last active treatment/therapy
Possibly, Probably, Definitely
No DSMC reporting required - IRB reporting may be necessary
Unlikely, Unrelated
Grades 3 and 4 AND meeting the definition of "serious"
Possibly, Probably, Definitely
No DSMC reporting required - IRB reporting may be necessary
Unlikely, Unrelated
Grades 1 and 2
Possibly, Probably, Definitely
No DSMC reporting required - IRB reporting may be necessary
Required Reporting Timeframe to IRB of Record
Attribution
UNEXPECTED
EXPECTED
Death 
Possibly, Probably, Definitely
5 calendar days
Annual
Unlikely, Unrelated
Annual
Annual
Grades 3 and 4 AND meeting the definition of a UP
Possibly, Probably, Definitely
5 calendar days
Annual
Unlikely, Unrelated
Annual 
Annual
Grade 1 and 2 AND meeting the definition of a UP
Possibly, Probably, Definitely
5 calendar days
Annual
Unlikely, Unrelated
Annual
Annual
10.5  Additional Reporting 
10.5.1 Eisai


 
 
 
 
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We will provide Eisai with copies of all SAEs within 7 working days of occurrence of the 
SAE. We will report any pregnancy occurring in association with use of an Eisai Product 
to Eisai.  
10.5.2
Novartis 
We will provide Novartis with copies of all SAEs within 24 hours of occurrence of the 
SAE. SAEs will be reported on the MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/MedWatch/MedWatch forms should be sent to the 
FDA online at the above internet address or at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD  20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
Collection of complete information concerning SAEs is extremely important. Full 
descriptions of each event will be followed by Novartis. Thus, follow-up information 
which becomes available as the SAE evolves, as well as supporting documentation (e.g., 
hospital discharge summaries and autopsy reports), should be collected subsequently, if 
not available at the time of the initial report, and immediately sent using the same 
procedure as the initial SAE report.  
An overdose is defined as the accidental or intentional ingestion of any dose of a product 
that is considered both excessive and medically important. For reporting purposes, 
Novartis considers an overdose, regardless of adverse outcome, as an important medical 
event. 
The principal investigator has the obligation to report all serious adverse events to the 
FDA, IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department 
(DS&E). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form). 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
• after the patient has provided informed consent and until at least 30 days after the
patient has stopped study treatment/participation 
• after protocol-specified procedures begin (e.g., placebo run-in, washout period, 
double-blind treatment, etc.) and 30 days after the patient has stopped study treatment 
• after the start of any period in which the study protocol interferes with the standard
medical treatment given to a patient (e.g., treatment withdrawal during washout period, 
change in treatment to a fixed dose of concomitant medication) and until 30 days after the 
patient has stopped study treatment must be reported to Novartis within 24 hours of 
learning of its occurrence (fax: 877-778-9739). This includes serious, related, labeled 
(expected) and serious, related, unlabeled (unexpected) adverse experiences. All deaths 


 
 
 
 
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during treatment or within 30 days following completion of active protocol therapy must 
be reported within 5 working days. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if 
the investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information.  
A SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event. The 
end date of the first event must be provided. 
The original copy of the SAE Report and the fax confirmation sheet must be kept within 
the Trial Master File at the study site. 
Follow-up information is sent to the same fax number as the original SAE Report Form 
was sent, using a new fax cover sheet, stating that this is a follow-up to the previously 
reported SAE, and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to 
that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind 
was broken or not (if applicable), and whether the patient continued or withdrew from 
study participation. 
If the SAE is not previously documented in the Everolimus Investigator Brochure or 
Package Insert (new occurrence) and is thought to be related to the Novartis study drug, a 
DS&E associate may urgently require further information from the investigator for
Health Authority reporting. Novartis may need to issue an Investigator Notification (IN), 
to inform all investigators involved in any study with the same drug that this SAE has 
been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating 
countries. 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious 
adverse experiences will be forwarded to the comapartor drug company by the 
investigator. 


 
 
 
 
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10.4
Pregnancy 
Preclinical data regarding reproductive toxicity is described in the most recent 
Investigator Brochure. The potential reproductive risk for humans is unknown.  Women 
of childbearing potential should be advised to use highly effective contraception methods 
while they are receiving everolimus and up to 8 weeks after treatment has been stopped.   
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. The newborn will 
be followed for at least 12 months. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department 
(DS&E). Pregnancy follow-up should be recorded on the same form and should include 
an assessment of the possible relationship to the study treatment and any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. 
10.6  Adverse Event Documentation 
All AEs occurring after the subject has signed the informed consent must be fully 
recorded in the subject’s case report form.
Documentation must be supported by an entry in the subject’s file. A laboratory test 
abnormality considered clinically relevant, e.g., causing the subject to withdraw from the 
study, requiring treatment or causing apparent clinical manifestations, or judged relevant 
by the investigator, should be reported as an adverse event. Each event should be 
described in detail along with start and stop dates, severity, relationship to investigational 
product, action taken and outcome. 
10.7  Comprehensive AEs and Potential Risks 
The descriptions and grading scales found in the current version of the NCI CTCAE (v.4) 
will be utilized for AE reporting. A copy of the current CTCAE can be downloaded from 
the CTEP web site: http://ctep.cancer.gov/reporting/ctc.html. AEs will be collected 
according to the study calendar schedule in Section 6.4.
10.7.1
Eribulin 
The most common AEs reported in >1 of 10 subjects receiving eribulin are shown below 
based on 827 breast cancer subjects who received the recommended dose in Phase II and 
Phase III breast cancer studies. 


 
 
 
 
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AE
Adverse Reactions
(all grades)
Blood and Lymphatic System Disorders
Neutropenia  
54.5%
Leucopenia 
22.1%
Anemia  
20.3%
Nervous system disorders 
Peripheral neuropathy
32%
Headache
11%
Asthenia/Fatigue 
52.8%
Mucosal inflammation 
9.8%
Pyrexia 
16.6%
Gastrointestinal disorders
Constipation 
16.3%
Diarrhea 
15.0%
Nausea 
35.1%
Vomiting 
14.5%
Musculoskeletal and connective tissue disorders
Arthralgia/Myalgia 
12.7%
Back pain 
1.9%
Bone pain 
1.7%
Pain in extremity 
4.7%
Investigations
Weight decreased 
9.7%
Metabolism and nutrition disorders
Decreased Appetite 
18.5%
Respiratory, thoracic, and mediastinal disorders
Cough 
4.7%
Dyspnea 
5.6%
Skin and subcutaneous tissue disorders
Alopecia 
49.7%
Infections and Infestations
Urinary Tract Infection 
4.8%
10.7.2
Everolimus 
Adverse reactions reported in at least one phase III trial in at least 5% of patients and at a 
higher rate in the everolimus arm than in the placebo arm are shown below. 
System Organ Class
Very common
Common
Infections and infestations
Infections1
-
Metabolism and nutrition Disorders
decreased appetite2
diabetes mellitus
Vascular disorders
hypertension


 
 
 
 
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Nervous system disorders
dysgeusia, headache
-
Respiratory, thoracic and mediastinal disorders
cough, pneumonitis3 epistaxis, 
dyspnea
--
Gastrointestinal disorders
stomatitis4, diarrhea,
nausea, vomiting
dry mouth
Skin and subcutaneous tissue Disorders
rash, dry skin, pruritus
nail disorder
Acne
General disorders and
administration site conditions
fatigue, asthenia, mucosal
inflammation, edema
peripheral, pyrexia
-
Investigations
weight decreased
-
1 Includes all those reported for the system organ class and isolated cases of opportunistic infections, 
including reactivation of hepatitis B (<1%); 2 Reported as anorexia in C2240 according to MedDRA v11.0; 
3 Includes alveolitis, interstitial lung disease, lung infiltration, pneumonitis, pulmonary alveolar 
hemorrhage, and pulmonary toxicity; 4 Includes aphthous stomatitis and mouth and tongue ulceration 
Other notable adverse reactions, occurring in at least one pivotal trial more frequently 
with everolimus than with placebo, but with an incidence of <5% are listed below. All 
terms included are based on the highest percentage reported in a pivotal trial. 
x
Blood and lymphatic system disorders: Uncommon: Pure red cell aplasia (<1%).
x
Metabolism and nutrition disorders: Common: dehydration (2.5%), exacerbation 
of pre-existing diabetes mellitus (1.1%). Uncommon: new onset of diabetes 
(<1%).
x
Psychiatric disorders: Common: insomnia (3.3%).
x
Nervous system disorders: Uncommon: ageusia (<1%) 
x
Vascular disorders: Common: hemorrhage (4.7%, various locations); 
Uncommon: deep vein thrombosis (<1%). 
x
Cardiac disorders: Uncommon: congestive cardiac failure (<1%).
x
Respiratory, thoracic and mediastinal disorders: Common: pulmonary embolism 
(1.5%), hemoptysis (1.1%); Uncommon: acute respiratory distress syndrome 
(<1%). 
x
Gastrointestinal disorders: Common: oral pain (3.7%), abdominal pain (3.6%), 
dyspepsia (2.9%), dysphagia (2.6%). 
x
Skin and subcutaneous tissue disorders: Common: hand-foot syndrome (4.7%), 
erythema (3.7%). 
x
Musculoskeletal and connective tissue disorders: Common: arthralgia (2.8%). 
x
Renal and urinary disorders: Common: proteinuria (2.5%), renal failure (2.3%, 
including acute renal failure), increased day-time urination (1.8%). 
x
General disorders and administration site conditions: Common: chest pain 
(1.1%); Uncommon: impaired wound healing (<1%). 
In all phase III trials, the majority of observed key laboratory abnormalities were reported 
with an incidence of ≥10% (listed in decreasing frequency):


 
 
 
 
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x
Decreased hematology parameters include hemoglobin, lymphocytes, platelets, 
and neutrophils (or collectively as pancytopenia). 
x
Increased clinical chemistry parameters include cholesterol, triglycerides, glucose, 
aspartate transaminases, creatinine, alanine transaminases, and bilirubin. 
x
Decreased clinical chemistry parameters include phosphate and potassium.  
Most of observed abnormalities were mild (Grade 1) or moderate (Grade 2). Grade 4 
abnormalities include reductions in lymphocytes (2.2%), hemoglobin (2%), and 
potassium (2%), neutrophils, platelets, and phosphate (each <1%) and increases in 
creatinine (1%), cholesterol, AST, ALT, bilirubin, and glucose (each <1%). 
10.8 Other AE Factors to Consider 
Factors to be considered in assessing the relationship of the AE to study drugs include: 
x
The Temporal Sequence from Drug Administration: The event should occur after 
the drug is given. The length of time from drug exposure to event should be 
evaluated in the clinical context of the event.
x
Recovery on Discontinuation (de-challenge), Recurrence on Reintroduction (re-
challenge): Subject’s response after drug discontinuation (de-challenge) or 
subjects response after drug re-introduction (re-challenge) should be considered in 
the view of the usual clinical course of the event in question.
x
Underlying, Concomitant, Current Diseases: Each report should be evaluated in 
the context of the natural history and course of the disease being treated and any 
other disease the subject may have.
x
Concomitant Medication or Treatment: The other drugs the subject is taking or 
the treatment the subject receives should be examined to determine whether any 
of them may be suspected to cause the event in question.
x
The Pharmacology and Pharmacokinetics of the Test Drug: The pharmacokinetic 
properties (absorption, distribution, metabolism and excretion) of the test drug(s), 
coupled with the individual subject’s pharmacodynamics should be considered.
11.0
Statistical Considerations 
Primary Objective for Phase I Study 
The primary objective of the Phase I portion of the study is to determine the safety and 
tolerability of everolimus and eribulin, and determine the recommended Phase II dose 
(RP2D) of the drug combination in patients with resistant metastatic TNBC. 
Primary Objective for Phase Ib Study 
The primary objective of the Phase Ib portion of the study is to evaluate the event-free 
survival (EFS) rate for patients with resistant metastatic TNBC at the RP2D of 
everolimus and eribulin to determine if the drug combination is worthy of further study. 


 
 
 
 
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Secondary Objectives for Phase Ib Study 
The secondary objectives of the Phase Ib portion of the study are to determine response 
rate, OS, toxicity, and pharmacokinetics (PK) for everolimus and eribulin in patients with 
resistant metastatic TNBC. 
A further secondary objective is to collect blood, skin punch biopsies, and tumor biopsies 
before and after treatment from all patients, and perform proteomic analysis to determine 
the level of inhibition of the PI3K pathway in tumor cells versus non-therapeutic targets.  
11.1 Design 
11.1.1 Phase I portion 
The Phase I  portion of this study will use the toxicity equivalence range (TEQR) design 
of Blanchard and Longmate [35] to evaluate select dose levels of the everolimus in 
combination with eribulin and to determine the RP2D.  In this implementation of the 
TEQR design, we define the target equivalence range of the DLT rate as 0.20-0.35. DLT 
rate levels of 0.51 or higher will be considered too toxic and doses that achieve that level 
will not be revisited.  The dose escalation de-escalation rules will be the following. If the 
rate of participants that experience a DLT is below 0.20 we will escalate, if the rate is 
above 0.35 we will de-escalate and if it is between 0.20-0.35 we will stay at the current 
dose.  Participants will enter the protocol in cohorts of 3.  The starting dose will be dose 
level 1. This study will end when 12 research participants are studied at a single dose 
level with a toxicity level below 0.51.  Further we also implement the additional rules: 1) 
terminate the trial if dose level 1 is too toxic, and 2) if the current dose is safe but based  
on the data the next dose is deemed too toxic, stay at the current dose.  The RP2D will be 
the dose closest to target of 0.25 below 0.51 based on isotonic regression.The dose 
schedule is provided in Table 11.1 below.   
The PMT team for protocol 14036 reviewed the data: dose level 2 was closed after 2 of 3 
evaluable participants experienced DLTs an observed rate of 67%;  dose level 1, we saw 
4 DLTs in 8 evaluable participants giving an observed DLT rate of 50% on this dose. Our 
equivalence range for DLT rate for this trial is 20-35%, our observed rate  of 50% is 
above 35%  so we plan to de-escalate. Two participants experienced grade 4 neutrophil 
count decrease and 2 experienced mucositis (1 grade 3 DLT, 1 participant received 71% 
of Everolimus due to grade 2 which is a DLT). Thus, the team decided to amend the 
protocol to allow for two new dose levels at a lower dose of Eribulin, and start the next 
cohort of patients at dose level B1. 
Table  11.1 Dosing Schedule: cycle length is 21 days 


 
 
 
 
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Dose level A
Everolimus (oral)
Eribulin (intravenous)
A-1
2.5mg daily (day 1 to 21)
1.4mg/m2 on days 1, 8
A1
5mg daily (day 1 to 21)
1.4mg/m2 on days 1,8
A2
7.5mg daily (day 1 to 21)
1.4mg/m2 on days 1,8
A3
10mg daily (day 1 to 21)
1.4mg/m2 on days 1, 8
Dose level B
Everolimus (oral)
Eribulin (intravenous)
B1
5mg daily (day 1 to 21)
1.1mg/m2 on days 1,8
B-1
2.5mg daily (day 1 to 21)
1.1mg/m2 on days 1,8
Table 11.2 is a pictorial representation of  the dose escalation/de-escalation guidelines 
for a target toxicity of 25% and ε1=5% ε2= 10% giving an equivalence range of 20%-
35%. The numbers of research participants treated at the current dose is provided in the 
columns and the number of research participants experiencing a DLT in the rows.  Note 
that this design is similar to a 3+3 design for the first 3 patients seen at a dose as it 
escalates if 0 study participants experience DLTs, holds if 1 experiences a DLT (33%), 
and de-escalates if 2 experience a DLT, differing from a 3+3 at sample sizes. of 6 and 
above patients as it holds at 33% toxicity and de-escalates at 36% toxicity or above.
Based on the results of 1,000 simulated trials considering 4 toxicity probability schedules 
(Table 11.3) for the 4 doses in combination with the trial specifications listed above, the 
median sample size was 18 with 95% confidence limits of 12 and 24 and the sample size 
Table 11.2: Dose escalation/de-escalation guidelines
(E= escalate, D=de-escalate, S=stay, DU=de-escalate and do not return to this dose).
Number of research participants treated on the current dose level
(Standard sample size based on a cohort size =3 are  bolded.)
3
4
5
6
7
8
9
10
11
12
Number of  
Research 
Participants
Experiencing a 
DLT
0
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
2
DU
D
D
S
S
S
S
S
E
E
3
DU
DU
DU
D
D
D
S
S
S
S
4
DU
DU
D
D
D
D
S
5
DU
DU
D
D
D
6
DU
DU
D
7
DU


 
 
 
 
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at the MTD was  ≥ 12 in at least 91% of trials. Note Table 11.3 provides the rates at 
which each dose level for each schedule was chosen as the MTD (MTD rate) and the 
average number of research participants seen at each dose (Ave # Pts.). 
11.1.2  Phase Ib portion 
In the Phase Ib portion of the trial, a Simon’s Optimal two stage design [36] will be used 
to determine if the combination of everolimus and eribulin results in a greater rate of 
patients event free at 4 months than eribulin alone. Based on data from the Embrace trial 
we set the 4 month EFS rate for eribulin to be 45%. We want to determine if the 
combination has a 4 month EFS rate of 70% or higher, that is to show a 25% 
improvement.  Setting both the type I and type II errors to 0.1 after 12 patients (the 
number of patients at the RP2D dose at the end of the phase I trial), 
x
if ≤ 5 patients are event free at 4 months the study will stop.  
x
If 6 or more patients are event free at 4 months we will add on 15 more patients 
for a total of 27 at the RP2D.  
x
If 16 or more patients out of the 27 are event free we will determine the 
combination worthy of further study. 
Table 11.3:  Associated rates each dose level is identified as the MTD and average number of patients  studied for 4 
dose toxicity probability scenarios 
Toxicity Probability 
Scenarios
Dose levels
-1
1
2
3
No
MTD
Scenario 1
0.05
0.1
0.25
0.50
RP2D rate
0.03
0.29
0.56
0.12
0
Ave # Pts.
0.4
5.9
8.1
3.6
Scenario 2
0.025
0.05
0.20
0.40
RP2D rate
0.01
0.15
0.58
0.27
0
Ave # Pts
0.08
4.7
8.2
5.8
Scenario 3
0.025
0.05
0.1
0.25
RP2D rate
0.01
0.05
0.27
0.66
0
Ave # Pts
0.12
3.8
5.6
9.1
Scenario 4
0.1
0.25
0.4
0.5
RP2D rate
0.19
0.55
0.22
0.04
.01
Ave #Pts
2.5
8.27
4.7
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Primary Endpoints 
x Phase I: DLTs as defined in Section 5.7, Definition of Dose-Limiting Toxicity. 
x Phase Ib: Event free survival (EFS) 
Secondary EndpointsProgression Free Survival (PFS) 
x
Response rate 
x
Overall survival (OS) 
x
Toxicity profile 
x
PK parameters 
11.2
Sample Size and Accrual Rate 
The expected combined sample size for the Phase I/Ib trial will be 33. We anticipate 18 
study participants for Phase I portion, and 15 additional at the RP2D to finish out the 
Phase Ib portion of the trial (minimum sample size=6 and maximum =45 (Phase I: 24 + 
Phase Ib: 15 + 6 for unevaluable/ineligible patients over the whole trial)).   
At the time of adding schedule B, 14 participants had been treated of which 12 are 
evaluable for dose escalation.  With the addition of 2 more doses we expect to treat 12 to 
15 more patients  for a total of ~29 on the phase I portion of the trial, thus we expect the 
trial sample size to stay within the above planned limit of 45.  
Our accrual is just over 1 participant a month so the phase I portion should be completed 
after 2 years from start of the trial. We will need to follow the last patient for 4 months to 
get EFS at 4 months on the 12 patients studied at the RP2D, and expect to do the initial 
assessment of activity at approximately 2 1/2 years. If 6 or more of the patients studied at 
the RP2D are event free we will add on 15 additional patients. Based on the same accrual 
rate we should complete the accrual of the Phase Ib portion within approximately 12
months or  and 42 months after start of the study.   
11.3
Statistical Analysis Plan 
Tables will be created to summarize all toxicities and side effects by dose, course, organ 
and severity.  Rates and associated 95% confidence limits will be estimated for DLTs at 
the RP2D, EFS at 4 months and response. Kaplan Meier methods will be used to estimate 
the median and 95% confidence limits for PFS and OS. Descriptive statistics will be 
provided for the research participant demographics and PK parameters. 


 
 
 
 
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11.4 Definitions 
11.4.1 Response and progression 
Response and progression will be evaluated every 2 cycles in this study using RECIST 
Version 1.1. Changes in only the largest diameter (one-dimensional measurement) of the 
tumor lesions are used in the RECIST Version 1.1 criteria. Note: Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional 
meaning or accuracy. 
Measurable Disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm with 
conventional techniques (CT, MRI, x-ray) or as >10mm with spiral CT scan. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
Non-Measurable Disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <20mm with conventional techniques or <10mm using spiral CT scan), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all non-
measurable.
Target Lesions: All measurable lesions up to a maximum of five lesions per organ and 10 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). A sum of the longest 
diameter (LD) for all target lesions will be calculated and reported as the baseline sum 
LD. The baseline sum LD will be used as reference by which to characterize the objective 
tumor response.
Non-Target Lesions: All other lesions (or sites of disease) should be identified as non-
target lesions and should also be recorded at baseline. Non-target lesions include 
measurable lesions that exceed the maximum numbers per organ or total of all involved 
organs as well as non-measurable lesions. Measurements of these lesions are not required 
but the presence or absence of each should be noted throughout follow-up. 
11.4.2 Guidelines for evaluation of measurable disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the 


 
 
 
 
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conditions under which such lesions should be considered must be defined in the 
protocol.  
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment. 
Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended. 
Chest X-Ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.
Conventional CT and MRI: These techniques should be performed with cuts of ≤10mm in 
slice thickness contiguously. Spiral CT should be performed using a 5mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head 
and neck tumors and those of extremities usually require specific protocols.
Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions, and thyroid nodules. Ultrasound might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.
Endoscopy and Laparoscopy: The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated. Their uses in this specific context 
require sophisticated equipment and a high level of expertise that may only be available 
in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in reference centers. However, such 
techniques can be useful to confirm complete pathological response when biopsies are 
obtained.
Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. Specific additional criteria for standardized usage of CA-
125 response in support of clinical trials are being developed.
Cytology and Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 


 
 
 
 
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stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
11.4.3 Response criteria 
11.4.3.1 Evaluation of target lesions 
CR: Disappearance of all target lesions. 
PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, 
taking as reference the baseline sum LD. 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the treatment started. 
11.4.3.2 Evaluation of non-target lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. 
Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances the opinion of the treating physician should prevail, and the progression 
status should be confirmed at a later time. 
Note: If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
11.4.3.3 Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria. 
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Incomplete 
response/SD
No
PR
PR
Non-PD
No
PR


 
 
 
 
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SD
Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.” Every effort should be made to 
document the objective progression, even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
11.4.3.4 Confirmatory measurement/duration of response 
Confirmation: To be assigned a status of PR or CR, changes in tumor measurements must 
be confirmed by repeat assessments that should be performed no less than 4 weeks after 
the criteria for response are first met. In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 8 weeks.
Duration of Overall Response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started.  
11.4.3.5 Response review 
All responses will be reviewed by an expert(s) independent of the study at the study’s 
completion. This will include simultaneous review of the patients’ files and radiological 
images. 
.
12.0
Correlative Translational Studies 
12.1 Pharmacokinetics 
Patients enrolled in the expanded cohort at the MTD will be asked to undergo serial 
blood sampling to evaluate the PK of everolimus and eribulin. Although it is unlikely that 


 
 
 
 
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these two agents will interact negatively, both drugs are substrates for the membrane 
transporter P-glycoprotein. Therefore, PK studies will be performed in the expanded 
cohort treated at the MTD to evaluate the PK of the drug combination.32-34
All PK/Plasma Samples will be sent to: 
Dr. Tim Synold 
Analytical Pharmacology Core Facility (APCF) 
Shapiro Bldg., Room 1042 
Beckman Research Institute/City of Hope  
1500 E. Duarte Rd, Duarte, CA, 91010 
Phone (626) 256-4673
Fax – (626) 471-9376
Email – tsynold@coh.org  
12.1.1   Everolimus PK sampling (whole blood) 
At each of the time points below (Section 12.3.1), 5ml of anti-coagulated whole blood 
will be collected into a purple-top Vacutainer® tube containing EDTA for determination 
of everolimus. These tubes should be inverted several times to mix. Blood samples 
should be kept on ice until they can be transferred to the freezer. If you are using plastic 
Vacutainer ® tubes, the samples can be directly frozen at <-20ºC. If glass tubes are used 
for collection, whole blood must be transferred to polypropylene vials prior to being 
frozen at <-20qC. In either case, plasma should not be separated from whole blood. 
12.1.2 Eribulin PK sampling (plasma) 
At each of the time points below (Section 12.3.1), 5mL of anti-coagulated whole blood 
will be collected in green-top Vacutainer  tubes (sodium or lithium heparin) from a site 
distal to the site of drug administration at the times shown in the table below. Blood 
samples will be kept on ice until plasma is separated from whole blood by centrifugation 
at 1500 x g (within 1 hour). Plasma will be transferred to appropriately labeled 
polypropylene tubes and stored at <-70qC until analysis. A separate PK flow sheet will be 
used to record the actual times of blood draws, urine collections and other pertinent 
information. Each sample will be labeled with the patient’s name, medical record 
number, date of collection, scheduled sample collection time and actual sample collection 
time.  
12.1.3 Sampling Schedule 
Everolimus Sample Collection 
PK
Time Point
Sample
Type
Cycle
Day
Collection time
24-hour clock)
WB1
Whole Blood
1
D1 +/- 10 min
00:00
WB2
Whole Blood
1
D1 +/- 10 min
01:00
WB3
Whole Blood
1
D1 +/- 10 min
02:00


 
 
 
 
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WB4
Whole Blood
1
D1 +/- 10 min
04:00
WB5
Whole Blood
1
D1 +/- 10 min
06:00
WB6
Whole Blood
1
D2 +/- 2 hours
24:00
WB7
Whole Blood
2
D1 +/- 10 min
00:00
WB8
Whole Blood
2
D1 +/- 10 min
01:00
WB9
Whole Blood
2
D1 +/- 10 min
02:00
WB10
Whole Blood
2
D1 +/- 10 min
04:00
WB11
Whole Blood
2
D1 +/- 10 min
06:00
WB10
Whole Blood
2
D2 +/- 2 hours
24:00
Eribulin Sample Collection 
PK
Time Point
Sample
Type
Cycle
Day
Sample
Description
Collection time
24-hour clock)
P1
Plasma
2
D1
Pre
00:00
P2
Plasma
2
D1
End of infusion
00:05
P3
Plasma
2
D1
10 min
00:10
P4
Plasma
2
D1
15 min
00:15
P5
Plasma
2
D1
30 min
00:30
P6
Plasma
2
D1
1 hr +/- 10 min
01:00
P7
Plasma
2
D1
2 hr +/- 10 min
02:00
P8
Plasma
2
D1
4 hr +/- 10 min
04:00
P9
Plasma
2
D1
6 hr +/- 10 min
06:00
P10
Plasma
2
D2
24 hr +/- 2 hours
24:00
P11
Plasma
2
D3
48 hr +/- 3 hours
48:00
P12
Plasma
2
D4
72 hr +/- 3 hours
72:00
P13
Plasma
2
D8
167 hr +/- 3 hours
167:00
12.1.4 Analytical methods 
12.1.4.1 Everolimus blood concentrations 
Everolimus blood concentrations will determined in all samples in the Analytical 
Pharmacology Core Facility (APCF) at the City of Hope using a validated LC-MS/MS 
method. Briefly, following sample clean-up and LC separation from interfering 
substances in whole blood, a Micromass Quattro Ultima triple quadruple mass 
spectrometer operating in positive ion mode is used to detect everolimus according to the 
mass transition of m/z 975.5o908.5 with tacrolimus (m/z 821.5o768.5) as the internal 
standard. The limit of quantitation for everolimus in whole blood is 0.25ng/ml. 
12.1.4.2 Eribulin plasma levels 


 
 
 
 
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Eribulin plasma levels will be determined using a validated LC/MS/MS analytical assay 
also available in the Analytical Pharmacology Core Facility (APCF). Briefly, following 
reversed phase LC separation, eribulin and internal standard (ER-076349) will be 
monitored by tandem MS with electrospray positive ionization operating at a capillary 
voltage of 2.9 kV and a cone voltage of 58 V. The detector is set to monitor the 
parent/daughter transitions [MH+] for E (m/z 730 to m/z 712) and IS (m/z 732 to m/z 
681). The lower limit of quantitation of the assay is 0.1ng/ml from a 200 Pl aliquot of 
plasma. 
12.1.5 Pharmacokinetic data analysis 
Non-compartmental PK analyses of everolimus will be performed using statistical 
moment theory and according to the rule of linear trapezoids and statistical moment 
theory. Everolimus PK parameters (Cmax, Ctrough, AUC, CL/F, t1/2) will be determined 
for each individual and a two-stage approach will be used to describe the study 
population PK.  
Compartmental analyses will be performed for eribulin data using ADAPT II (USC 
Biomedical Simulations Resource, Los Angeles, CA). Secondary pharmacokinetic 
parameters (e.g. CLsys, Vd, t1/2’s, AUC0-∞) will be determined for each individual and a 
two-stage approach will be used to describe the study population pharmacokinetics. 
Population means and standard deviations will be compared to values obtained from 
patients treated on trials of single agent eribulin. 
12.1.6 Specimen collection/documentation 
Prior to drug administration on day 1 of cycle 1 of treatment, an indwelling heparin lock 
should be placed so that serial specimens can be collected. At each sampling time, 1mL 
of blood will be drawn and discarded to assure that the solution used to maintain catheter 
patency does not dilute the sample. Even if a patient has a central venous catheter, it is 
preferable for the day 8 PK samples to be drawn through a peripheral heparin lock. 
However, if the patient objects or has problems with peripheral venous access, the central 
venous catheter may be used for PK sampling. In the event that the central venous 
catheter is used, sufficient blood should be withdrawn before each PK sample to assure 
that the solution used to maintain catheter patency does not dilute the PK sample. It is 
important to document whether the sample was collected through a heparin lock or 
central venous catheter, especially for day 1 sampling. 
12.2 Molecular Studies 
12.2.1 Blood collection 
Blood collection will be performed from patients at the multiple time points for patients 
enrolled to expansion cohort (RP2D) and consented for additional blood collecton:
x
Prior to the first dose of everolimus and eribulin.  


 
 
 
 
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x
4 hours, 8 hours after dose of everolimus and eribulin, on day 1, day 4 and day 8 
of cycle 1.   
A serum specimen for proteomic analysis will consist of 7ml of blood in an uncoated 
tube (collected in the red top). This procedure is performed under standard sterile medical 
conditions. The red tube should be kept at cold on wet ice (do not invert) and delivered 
within 15-30 minutes. Serum will be collected and stored at -80°C for proteomic analysis 
in Dr John Yim’s Laboratory using Luminex and mass spectrometry, with confirming 
ELISA, such as for VEGF, since everolimus and eribulin are known to influence 
angiogenesis.  
A specimen for peripheral blood mononuclear cells (PBMC) and plasma collection will 
consist of 10ml of blood drawn into an ACD tube (yellow top). This tube will be kept at 
room temperature and inverted 5-10 times to prevent coagulation. The tube will be 
brought to a designated person/lab within 15-30 minutes. The processing and storage of 
these samples will follow the blood separation protocol established in Dr Yim’s 
laboratory for the purpose of biomarker analyses as above. Lysates will be stored in 
aliquots at -80°C until analysis. 
12.2.2 Skin punch biopsy 
Two sets of optional skin punch biopsies (two biopsies per set for a total of four biopsies) 
will be performed for patients who enrolled to dose expansion cohort (Phase Ib, RP2d) 
and consented as follows: 
x
First set 
o
Biopsy 1 (3mm diameter) will be performed one week prior to any dosing.  
o
Biopsy 2 (3mm diameter) will be performed on the same site as Biopsy 1 
on the day of the first dose of eribulin and everolimus; cycle 1 (prior to 
any dosing).  
x
Second set 
o
Biopsy 3 (3mm diameter) will be performed on a new site on the day of 
the first dose of eribulin and everolimus; cycle 1 (prior to any dosing). 
o
Biopsy 4 (3mm diameter) will be performed on the same site as Biopsy 3, 
one week later on the day that the second dose of eribulin is given (prior to 
dosing). 
Skin biopsy specimen will be placed in formalin containers and transported to Dr. John 
Yim’s lab for storage.  Specimen will be analyzed for several biomarkers in epidermal 
and vascular tissue (see Section 12.2.4). 


 
 
 
 
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12.2.3 Tumor biopsy 
Patient will be asked to provide a fresh tumor tissue from a newly obtained core or 
excisional biopsy of a tumor lesion upon study entry. Newly –obtained is defined as a 
specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1. 
Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or 
subject safety concern) may submit an archived specimen only upon agreement from the 
study PI. 
Tumors may be biopsied or resected at time of disease progression and will also be 
evaluated by proteomic analysis. Tumors for which frozen tissue can be obtained will be 
evaluated for breast cancer subtype using microarray analysis.  
The tumors will be placed in snap frozen in liquid nitrogen and sent to Dr John Yim’s 
laboratory (see Section 12.2.4).  
Protocol for Formaldehyde-Fixed, Paraffin Embedded Tissue Specimens That May Have 
Been or Biopsied or Resected Before, During, or After Treatment 
Paraffin embedded specimens will be processed in conjunction with the routine duties of 
the COH Anatomic Pathology Department. Additional collection or storage of research 
specimens outside of the storage per clinical standard of care (which will include 
additional tissue biopsy cores or parts of surgical tissue specimens, not required for 
standard pathological diagnosis) will be allowed and conducted under this protocol.  
Protocol Frozen Tissue Specimens That May Have Been or Biopsied or Resected Before, 
During, or After Treatment 
Tissue collection will be performed on patients undergoing clinically indicated biopsies 
or surgical resection while at COH. Once the tissue is biopsied or surgically removed, the 
specimen will be taken to the pathology laboratory where the pathologist will ensure that 
the tissue is adequate for routine pathology analyses (diagnosis, margin status 
assessment, and other indicated purposes). Then, and only then, if excess tissue remains, 
samples of that tissue will be harvested for archiving in the tissue bank. This archival 
tissue will be divided and placed into vials, labeled with the subject’s unique 
identification number (RPN) after all patient identifiers are removed, and flash-frozen in 
liquid nitrogen. It will then be placed into the City of Hope tissue bank freezer (located in 
the Department of Pathology/or if necessary due to storage space needs in the Pathology 
Core-tracked in the same data base/LIMS) at temperatures down to -80°C. This tissue 
will remain in the freezer for at least a one-month period of time, or longer if needed, to 
ensure that there is no additional diagnostic pathologic requirement for the frozen 
specimen. During this time, no analyses will be performed on the specimen. This period 
of time will be known as the “Fail-Safe” time period. The Fail-Safe time period is 
intended to allow the pathologists the opportunity to withdraw banked tissue for any 
additional diagnostic testing they determine is necessary to patient care.  After the 
pathologist determines with final certainty, by the publishing of the official final 


 
 
 
 
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pathologic report, that there is no diagnostic pathologic requirement for the frozen 
specimen, then the archived specimen on that patient will be released for research 
analyses, under appropriate research protocol approved by the IRB.  
Tissue collection for non-diagnostic/research purpose will preferably occur at the time of 
clinically indicated biopsies in the form of extra biopsy specimens. Alternatively, tissue 
collection for research purpose can occur under IRB-approved specific research protocols 
and after the patient signed the appropriate consent form. Patients, who are planning 
treatment with therapy prior to surgery, or have undergone definitive surgery, or are 
undergoing biopsy or removal of adjacent tissue or metastatic sites may be asked to 
consent to have an additional biopsy to collect pre-treatment or post-treatment tumor 
specimens for banking, or alternatively, allow for access tissue collection, such as lymph 
nodes, or other tissues (for example, brain metastasis). 
These procurements can never compromise the establishment of proper diagnosis and the 
final say in allowing for such biopsies will reside with the pathologist. 
In those patients who consent, the tissue collected at biopsy or in surgery, will be placed 
fresh frozen into the COH tissue bank freezer (located in the Department of Pathology/or 
if necessary due to storage space needs in the Pathology Core-tracked in the same data 
base/LIMS at temperatures down to -80°C. In addition, if samples are available, tissue 
will be also placed in a labeled plastic vial containing RNAlater™ (“RNAlater tissue 
protect tubes”, Ambien Inc. USA) and subjected to labeling, processing, and banking 
procedures as described above.  
Protocol for Formalin-Preserved Tissue Specimens That May Have Been or Biopsied or 
Resected Before, During, or After Treatment  
If any additional excess tissue remains, or procured during biopsy or surgery, samples of 
that tissue will be harvested for archiving in a formalin tumor bank in the department of 
Pathology.  This archival tissue will be divided and placed into vials, labeled with the 
subject’s unique identification number (RPN) after all patient identifiers are removed, 
and tissues will be released for research via IRB-approved protocols.  
12.2.4 Proteomic Analysis 
All specimens will be processed at Dr. John Yim’s lab located at: 
John Yim, M.D. Lab 
1710 Flower Street, Room 154 
Beckman Research Institute/City of Hope  
1500 E. Duarte Rd, Duarte, CA, 91010 
Analysis of PBMC will be performed by Western blotting for pAKT (Ser473), and AKT, 
p4E-BP1 (ser65/Thr70) and 4E-BP1, pS6K1 (Thr389) and S6K1, and pS6 (Ser235/236) 


 
 
 
 
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and S6. The use of PBMC’s for analysis in patients has been published.1 However, 
successful demonstration of inhibition in PBMC’s can be difficult. Nevertheless, we 
would prefer to attempt correlative studies in PBMC due to greater acceptance of patients 
to blood draws rather than skin punch biopsies. It is anticipated that compliance to skin 
punch biopsies will be lower than collection of PBMC. Furthermore, we are anticipating 
a synergistic inhibition of the PI3K-Akt-mTOR pathway that may result in more 
prominent correlative results with the combination of everolimus and eribulin which may 
improve the success rate in demonstrating inhibition. This should also apply to the skin 
punch biopsies.  
For patients in which pretreatment and post-treatment tumor biopsies were obtained in 
formalin immunohistochemistry analysis (IHC) will be performed for total AKT and 
pAKT at Ser473, total 4E-BP1, and p4E-BP1 at Thr70, total S6K1 and pS6K1 at Thr389, 
total S6, pS6 at Ser235/236 and Ki67. For patients in which fresh frozen tissue are 
available for both pretreatment and post treatment tumor biopsies, Western blot and IHC 
will be performed for total AKT and pAKT at Ser473, total 4E-BP1, and p4E-BP1 at 
Thr70, total S6K1 and pS6K1 at Thr389, total S6, pS6 at Ser235/236 and Ki67.  
For patients in which fresh frozen tissue are available for both pretreatment and post 
treatment tumor biopsies, we will also use the Zeiss PALM Microlaser system for laser 
capture microdissection of invasive ductal cancer cells only for RNA. The microdissected 
sample will be catapulted to an adhesive cap and loaded to collection tubes for which 
total RNA isolation and ultimate microarray analysis will be performed by the Integrated 
Genomics Core using the Affymetrix Human Genome U133 Plus 2.0 array. Patterns of 
gene expression will be compared to the established gene expression patterns correlating 
to 7 MBC subtypes displaying unique gene expression and ontologies. 
Skin IHC for pAKT (Ser473), and AKT, p4E-BP1 (ser65/Thr70) and 4E-BP1, pS6K1 
(Thr389) and S6K1, pS6 (Ser235/236) and S6 will be performed on 4-uM formalin-fixed 
paraffin-embedded sections using rabbit polyclonal antibodies (Cell-Signaling 
Technologies). Immunohistochemical analysis of total AKT and pAKT at Ser473, total 
4E-BP1, and p4E-BP1 at Thr70, total S6K1 and pS6K1 at Thr389, total S6, pS6 at 
Ser235/236 and Ki67 will be performed on 4-μm formalin-fixed paraffin-embedded 
sections. A histo-score (H-score) will be calculated by counting the percentage of 
keratinocytes from reparative epidermis or endothelial cells from vascular tissue that are 
positively stained with low, medium or high intensity. The final score ranging from 0 to 
300 and will be calculated by the formula: H-score = (low%) × 1 + (medium%) × 2 + 
(high%) × 3, where the constants 1, 2 and 3 will be weighting factors for low, medium 
and high intensity, respectively. Changes between pre and on-therapy expression in 
paired samples will be calculated as H-score ratio and data analyzed using an analysis of 
variance one-way test. 


 
 
 
 
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13.0
Data Reporting and Protocol Deviations 
13.1 Data Reporting 
13.1.1 Confidentiality of records 
The original data collection forms will be stored in a secure location. Clinical report 
forms (CRFs) will be stored in the electronic data capture (EDC) system. When results of 
this study are reported in medical journals or at meetings, identification of those taking 
part will not be disclosed. Medical records of subjects will be securely maintained in the 
strictest confidence, according to current legal requirements. They will be made available 
for review, as required by the FDA, or other authorized users such as the NCI, under the 
guidelines established by the Federal Privacy Act and rules for the protection of human 
subjects. 
13.1.2 Subject consent form 
At the time of registration, the original signed and dated Informed Consent form, HIPAA 
research authorization form, and the California Experimental Subject’s Bill of Rights (for 
the medical record) and two copies (for the subject and the research record) will be 
available. All Institutional, NCI, Federal, and State of California requirements will be 
fulfilled. 
Data Collection Forms and Submission Schedule  
1.0 All data will be collected using COH data collection forms via an electronic data 
capture system .   
2.0 ELIGIBILITY CHECKLIST:  The data manager at the registering site will 
have completed and faxed this form at the time of registration. 
3.0 ON-STUDY FORM (FORM OS):  Completed on-study forms due within two 
weeks of registration.  
4.0 TREATMENT FORM (FORM RX):  Completed treatment forms are due 
within four weeks of completion of a cycle.  
5.0 ADVERSE EVENT COLLECTION:  Completed adverse events collection 
form due within four weeks of completion of a cycle. 
6.0 FLOW SHEETS:  Protocol specific flow sheets are to be submitted along with 
each treatment form. 
7.0 RESPONSE/OFF-STUDY/FOLLOW-UP:  Form F/U is to be submitted each 
time a patient is evaluated for response and/or new follow-up information is 
obtained. 
8.0 SUPPLEMENTAL DATA FORM: 
The timeline for submission of the 


 
 
 
 
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supplemental data form will be protocol specific, if applicable.
.
Eligibility Checklist 
The Eligibility Checklist must be completed by a protocol nurse or clinical research 
associate and signed by an authorized investigator prior to registering the subject.  See 
Section 6.5 for the registration procedures. 
Prior Therapy Forms and On-Study Forms 
Within two weeks of registration, the clinical research associate will submit On Study 
forms. 
13.2 Protocol Deviations 
13.2.1 Deviation policy 
Brief interruptions and delays may occasionally be required due to travel delays, airport 
closure, inclement weather, family responsibilities, security alerts, government holidays, 
etc. This can also extend to complications of disease or unrelated medical illnesses not 
related to disease progression. These delays will not be considered protocol deviations. 
Planned deviations may be permitted in accordance with the COH policy on “Clinical 
Research Protocol Planned Deviations and Single Subject Exception.” These planned 
deviations, considered “Single Subject Exceptions”, are considered an Amendment to the 
Protocol. 
Additionally, 
x
Missed doses will not be made up. 
x
If growth factor is needed, it can be administered to patients after cycle 1, but 
growth factor is not allowed during cycle 1.  
13.2.2 Reporting of unplanned deviations 
All unplanned deviations will be reported to the COH IRB for review. 
13.2.3 Resolving disputes 
If there is a dispute among the persons involved in the provision of research treatment, in 
regard to whether a treatment deviates from the protocol, resolution will be resolved in 
accordance with the “Clinical Research Protocol Planned Deviations and Single Subject 
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14.0Human Subject Issues 
14.1 Potential Risks to the Research Subjects 
This is a Risk Level 3 study, as defined in the “Guidance, Policy and Procedures for Data 
and Safety Monitoring for In-House Trials at City of Hope”.
http://www.infosci.coh.org/prot_office/forms/Guidance.doc. Risks are at least balanced 
by the potential benefits to subjects and the importance of the knowledge that may result. 
AEs are expected and a formal plan for monitoring and reporting these AEs is required 
(outlined in Section 10).
14.2 Potential Benefits to Research Subjects and Society 
Based on our preclinical findings, we hypothesize that the combination of everolimus and 
eribulin will have a synergistic effect and will increase clinical activity in patients with 
TNBC. Previous studies of each of these drugs in MBC show acceptable toxicity, and we 
hypothesize that this drug combination could offer a novel approach to treat patients with 
TNBC MBC who are resistant to anthracyclines, taxanes or platinums. 
14.3 Alternatives 
The alternative is not to participate in the study. Not participating in the study will have 
no bearing on treatment or follow-up. 
14.4 Institutional Review Board 
In accordance with COH policies, an IRB that complies with the federal regulations at 45 
CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 17, must 
review and approve this protocol and the informed consent form prior to initiation of the 
study. All institutional, NCI, Federal, and State of California regulations must be 
fulfilled. 
14.5 Recruitment of Subjects 
All patients will be recruited from patients undergoing cancer treatment at COH.  
14.6 Advertisements  
Advertisements to include print, media (radio, television, or billboards), telephone 
scripts, etc., will be reviewed and approved by the IRB prior to their use to recruit 
potential study subjects.
14.7 Study Location and Performance Sites 
This study will be performed at COH. 


 
 
 
 
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14.8 Confidentiality 
This research will be conducted in compliance with federal and state of California 
requirements relating to protected health information (PHI). All the medical activity and 
research will follow HIPPA regulation. 
14.9 Financial Obligations and Compensation 
There will be no financial obligations incurred by the subject because of participating in 
this study. All translational studies will be performed solely for research purposes. 
If there is a serious medical complication as a result of the research, treatment will be 
available at COH, but there will be no compensation to the subject for this injury.  
15.0References 
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: a cancer journal 
for clinicians. 2013;63:11-30.
2. Andreopoulou E, Sparano JA. Chemotherapy in Patients with Anthracycline- and 
Taxane-Pretreated Metastatic Breast Cancer: An Overview. Curr Breast Cancer 
Rep 2013;5(1):42-50.
3. Chia SK, Speers CH, D'Yachkova Y, Kang A, Malfair-Taylor S, Barnett J, et al. 
The impact of new chemotherapeutic and hormone agents on survival in a 
population-based cohort of women with metastatic breast cancer. Cancer. 
2007;110:973-9.
4. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. 
Triple-negative breast cancer: clinical features and patterns of recurrence. Clinical 
cancer research : an official journal of the American Association for Cancer 
Research. 2007;13:4429-34.
5. Harris LN, Broadwater G, Lin NU, Miron A, Schnitt SJ, Cowan D, et al. 
Molecular subtypes of breast cancer in relation to paclitaxel response and 
outcomes in women with metastatic disease: results from CALGB 9342. Breast 
cancer research : BCR. 2006;8:R66. 
6. Hirata Y, Uemura, D. Halichondrins: Antitumor Polyether Macrolides from a 
Marine Sponge. Pure Appl Chem. 1986;58:701-10.
7. Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, et al. 
Induction of morphological and biochemical apoptosis following prolonged 
mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer 
research. 2004;64:5760-6.
8. Eisai Inc. Halaven Full Prescribing Information. Woodcliff Lake, NJ: Eisai Inc.; 
2012.


 
 
 
 
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9. Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. 
Eribulin monotherapy versus treatment of physician's choice in patients with 
metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. 
Lancet. 2011;377:914-23. 
10. Boulay A, Lane HA. The mammalian target of rapamycin kinase and tumor 
growth inhibition. Recent results in cancer research Fortschritte der 
Krebsforschung Progres dans les recherches sur le cancer. 2007;172:99-124. 
11. Francesc V CJ, Pouysségur J. p70 S6 Kinase-mediated protein synthesis is a
critical step for vascular endothelial cell proliferation. The Journal of biological 
chemistry. 1999;274:26776-82.
12. Yu Y SJ. MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate 
the mitogenic response of human endothelial cells to vascular endothelial growth 
factor. Journal of cellular physiology. 1999;178:235-46.
13. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, et al. 
Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: 
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14. Tsutsumi N YY, Shikada Y, et al. Essential role of PDGFRalpha-p70S6K
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vivo: role of PDGFRalpha during angiogenesis. Circulation research. 
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15. Mabuchi S AD, Connolly DC, et al. RAD001 (everolimus) delays tumor onset 
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16. Lane HA WJ, McSheehy PM, et al. mTOR inhibitor RAD001 (everolimus) has 
antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase 
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17. Lane HA, Wood JM, McSheehy PM, Allegrini PR, Boulay A, Brueggen J, et al. 
mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties 
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18. Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel 
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19. Zitzmann K, De Toni EN, Brand S, Goke B, Meinecke J, Spottl G, et al. The 
novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in 
human pancreatic neuroendocrine tumor cells. Neuroendocrinology. 2007;85:54-
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20. Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, et 
al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation 
in AML. Blood. 2007;109:3509-12.
21. Haritunians T, Mori A, O'Kelly J, Luong QT, Giles FJ, Koeffler HP. 
Antiproliferative activity of RAD001 (everolimus) as a single agent and combined 
with other agents in mantle cell lymphoma. Leukemia. 2007;21:333-9.
22. Ikezoe T, Nishioka C, Bandobashi K, Yang Y, Kuwayama Y, Adachi Y, et al. 
Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and 
rapamycin induces growth arrest of adult T-cell leukemia cells. Leukemia 
research. 2007;31:673-82. 
23. Wanner K, Hipp S, Oelsner M, Ringshausen I, Bogner C, Peschel C, et al. 
Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse 
large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. 
British journal of haematology. 2006;134:475-84.
24. Tuncyurek P, Mayer JM, Klug F, Dillmann S, Henne-Bruns D, Keller F, et al. 
Everolimus and mycophenolate mofetil sensitize human pancreatic cancer cells to 
gemcitabine in vitro: a novel adjunct to standard chemotherapy? European 
surgical research Europaische chirurgische Forschung Recherches chirurgicales 
europeennes. 2007;39:380-7.
25. Treeck O, Wackwitz B, Haus U, Ortmann O. Effects of a combined treatment 
with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of 
human cancer cells. Gynecologic oncology. 2006;102:292-9.
26. Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, et al. 
RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-
induced apoptosis, and prolongs survival in an ovarian cancer model. Clinical 
cancer research : an official journal of the American Association for Cancer 
Research. 2007;13:4261-70.
27. Sieghart W, Fuereder T, Schmid K, Cejka D, Werzowa J, Wrba F, et al. 
Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of 
patients undergoing liver transplantation. Transplantation. 2007;83:425-32.
28. O'Regan R ea. RAD001 (everolimus) in Combinations with Weekly Paclitaxel 
and Trastuzumab in Patients with HER-2-Overexpressing Metastatic Breast 
Cancer with Prior Resistance to Trastuzumab: A Multicenter Phase I Clinical 
Trial. Poster presented at SABCS 2008. 2008. 


 
 
 
 
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29. Fasolo A, et al. Multicenter Phase I Clinical Trial of Daily and Weekly 
everolimus (RAD001) in Combination with Vinorelbine and Trastuzumab in 
Patients with HER-2-Overexpressing in Metastatic Breast Cancer with Prior 
Resistance to Trastuzumab. Poster presented at SABCS. 2008. 
30. Beaver JA, Park, B. The BOLERO-2 trial: the addition of everolimus to 
exemestane in the treatment of postmenopausal hormone receptor-positive 
advanced breast cancer. Future Oncol. 2012 June; 8(6): 651–657.
31. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical 
trials. 1989;10:1-10.
32. O'Donnell A, Faivre S, Burris HA 3rd, et al.  Phase I pharmacokinetic and 
pharmacodynamic study of the oral mammalian target of rapamycin inhibitor 
everolimus in patients with advanced solid tumors.  J Clin Oncol. 
2008;26(10):1588-95.
33. Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of 
the mammalian target of rapamycin pathway with everolimus: a phase I tumor 
pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 
2008;26(10):1603-1610. 
34. Rojo F, Najera L, Lirola J, et al. 4E-binding protein 1, a cell signaling hallmark in 
breast cancer that correlates with pathologic grade and prognosis. Clin Cancer Res 
2007;13(1):81-89. 
35. Blanchard MS, Longmate JA. Toxicity equivalence range design (TEQR): A
practical Phase I design.  Contemporary Clinical Trials 32: 114-121 (2011). 
36.
Simon, R, (1989). Optimal Two stage designs for Phase II clinical trials. 
Controlled Clinical Trials, 10, 1-10.
1. 
Jones VL, J.L., McIntyre KJ, Oommen SP, Patt DA, Cortas TE, Harris RP, Wilks 
ST, Fox P, O'Shaughnessy, Evaluation of miracle mouthwash (MMW) plus 
hydrocortisone versus prednisolone mouth rinses as prophylaxis for everolimus-
associated stomatitis: Preliminary results of a randomized phase II study.
SABCS, 2015: p. P1-15-06.


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


 
 
 
 
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APPENDIX B 
IRB #14036 
Patient Diary for Everolimus 
Everolimus dose: Daily 
ASSIGNED DOSE LEVEL:    _________________________________
PATIENT INITIALS:              _________________________________
PATIENT STUDY ID #:         _________________________________
COURSE # :                             _________________________________
PATIENT DIARY 
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
Date:
Dose taken: 
Time taken:
NOTE:  Daily doses should be taken at the same time each day  


 
 
 
 
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____________________________________ 
       
__________________________ 
Signature of person filling out the diary 
 
Date completed/Returned to 
Study center


 
 
 
 
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APPENDIX C
City of Hope Data Coordinating Center 
Registration Procedures 
REGISTRATION PROCEDURES FOR PHASE I TRIALS 
I. REGISTRATION POLICIES 
A. Registrations for Phase I protocols will be done centrally through the City of 
Hope Data Coordinating Center (COH DCC) in the Division of Clinical 
Research Information Support  (CRIS) between the hours of 8:30 a.m. and 
4:30p.m., Monday through Friday (except holidays).    
B. Patients must begin protocol therapy within timeframe allowed per protocol in 
registration section.   
C. Pre-study laboratory tests, scans, and x-rays, must be completed prior to 
registration, within the time frame specified in the protocol (Staging image 
scans must be performed within 28 days prior to study entray). The eligibility 
checklist must be completed and signed by the treating physician. 
Additionally, patients must sign an informed consent and HIPAA authorization 
form prior to registration.   
A patient failing to meet all protocol requirements will not be registered.   
II. "HOLDING A SLOT" FOR A POTENTIAL PATIENT
x
 If a potential patient has been identified for a Phase I trial, the protocol nurse 
or CRA must contact the Data Coordinating Center (626-256-4673, ext. 
64267 or e-mail dcc@coh.org to verify that a dose-level is open. 
1. If the current dose-level is open, then the Data Coordinating Center will 
reserve the "slot" for that patient for 7 days to allow sufficient time to 
obtain the informed consent. After reserving a slot and consenting the 
patient, you will have 14 days to work up the patient. (Additional time may 
be allowed for scheduling of required tests and pending results, but the 
delay must be cleared by the DCC with the approval of the Protocol PI 


 
 
 
 
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before the 14 days expire).  Only one reserved slot will be allowed per 
physician at a new dose level.  If no patient is available in that time, the 
physician that has additional patients for the study will then be given 
another slot at that dose level.  If there are any issues with slot 
reservations, the matter will be discussed with the Phase I Program 
Director and the Data Coordinating Center. 
a. The protocol nurse or CRA must call back within 14 days days to 
complete the registration or cancel the patient. 
2. If no dose-level is open (based on the criteria for dose expansion or 
escalation - as described in the protocol), then the Data Coordinator 
Center can indicate the anticipated date of reopening and a slot may be 
reserved for that patient on the waiting list.  
3. No more than 3 patients may be held on the waiting list for a single 
protocol. 
a. If a patient on the waiting list becomes ineligible, then the protocol 
nurse or CRA must call to remove the patient from the list in a timely 
manner. 
4. No slot reservation at a given dose level will be made prior to escalation 
or expansion until the DCC is notified by the Protocol PI or designee of 
the dose escalation/expansion decision. 
II. REGISTRATION PROCEDURES 
x
Once a patient is eligible, all the pre-study requirements have been fulfilled, 
and informed consent obtained, then the protocol nurse or CRA must contact 
the Data Coordinating Center (626-256-4673, ext. 64267 or e-mail 
dcc@coh.org) and EMAIL a copy of the completed eligibility checklist, 
required pre-study tests (per protocol – and may include laboratory, CT and 
pathology reports), signed Informed Consent, signed Patients' Bill of Rights 
and HIPAA authorization form to dcc@coh.org. 
x
 
Upon receipt of the registration documents, the Data Coordinating 
Center will verify and confirm that the patient is eligible. 


 
 
 
 
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x
 
Assign a patient accession number (for example, COH-001, COH-
002, etc.). 
Register the patient on study centrally (the City of Hope CRA assigned to the                             
trialwill still be responsible for accessioning via MIDAS).  If multi-site study, COH DCC 
staff will be responsible for registering participating site patients at City of Hope. 
x
Assign the patient to a dose level (as applicable).  
Complete and email a Confirmation of Registration form within 24 hours to 
Include the COH patient study number and dose level (as applicable) to the study         
 
team, which will include the Principal Investigator, treating physician, protocol  
 
nurse, CRA and COH IDS Pharmacy. 
x
Call the protocol nurse and/or CRA to verbally confirm registration.