Clinical trial NCT01596751
Conditions: Metastatic Breast Cancer
Keywords: metastatic breast cancer triple negative PLX Eribulin
Sponsor: Hope Rugo, MD
Start date: 2012-07-12; Completion date: 2019-07-05
Enrollment: 67 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of the Phase 1b portion of the study is to determine the best dose of PLX3397 when given in combination with standard dose eribulin (Halaven™). The purpose of the Phase 2 portion of the study is to find out what effects, good and/or bad, these drugs have on patients and their metastatic breast cancer.

Detailed description:
This is a nonrandomized, open label phase Ib/II study evaluating the safety and efficacy of eribulin in combination with PLX3397, a novel CSF1 inhibitor, in patients with metastatic breast cancer. The phase II portion of this trial will be limited to patients with triple negative disease.

The phase I portion of this trial is a dose escalation of PLX3397 to determine the maximum tolerated dose (MTD) of PLX3397 when given in combination with standard dose eribulin. Patients will be enrolled in cohorts of three, using the dose levels and plan outlined in the statistical section, with 6 patients enrolled at the MTD. All patients with accessible tumor will be required to have a tumor biopsy at study start before starting therapy. Pharmacokinetics of PLX3397 and eribulin, and blood levels of CSF1 will be obtained as outlined in section 14. To allow rapid accrual to phase Ib, and an earlier start to the phase II trial, patients will be enrolled in phase I with both hormone receptor positive and negative disease, and at any line of therapy assuming eligibility criteria are otherwise met.

Dose limiting toxicity (DLT) will be defined as any treatment-related toxicity meeting the criteria below and occurring within the first 21 days of combination therapy. Patients must receive at least 14 days of PLX3397 and 2 doses of eribulin during the first cycle in order to be considered evaluable for DLT (unless the missed doses are due to a DLT).

Patients in each cohort will be followed for at least 3 weeks (one full cycle) before opening accrual to the next dose level. If one patient in any cohort develops a DLT, an additional 3 patients will be enrolled at that level. If no additional toxicities occur in the six patients, then this particular dose would be used for the phase II trial, and the next higher dose would be considered the MTD. A minimum of 12 and maximum of 24 patients will be enrolled in the phase I study. The phase II trial will not open until the last patient in the phase I study has been followed for at least 3 weeks.

The phase II portion of this trial will evaluate progression free survival (PFS) in patients with Triple negative breast cancer (TNBC) treated with PLX3397 and eribulin, using the dose of PLX3397 determined in the phase Ib study in a two-step design. Please see the statistical section for details regarding enrollment and statistical design. Treatment is preceded by a 5 to 7 day lead-in phase, in which patients will take PLX3397 alone daily. Patients with accessible tumor will undergo a core biopsy of tumor before the start of PLX3397 treatment, and then a fine needle aspiration or core biopsy will be performed on the day of or the day before the start of eribulin (day -1 to day 0).

Arms: arm 1: Treatments are given in 21 day cycles. For each cycle, treatment includes:

* PLX3397 at a dose of 600 mg/day taken by mouth in the form of 100-200 mg gelcaps
* Eribulin at dose of 1.4 mg/m2 given intravenously on days 1 and 8. arm 2: Treatments are given in 21 day cycles. For each cycle, treatment includes:

* PLX3397 at a dose of 800 mg/day taken by mouth in the form of 100-200 mg gelcaps
* Eribulin at dose of 1.4 mg/m2 given intravenously on days 1 and 8 arm 3: Treatments are given in 21 day cycles. For each cycle, treatment includes:

* PLX3397 at a dose of 1000 mg/day taken by mouth in the form of 100-200 mg gelcaps
* Eribulin at dose of 1.4 mg/m2 given intravenously on days 1 and 8 arm 4: Treatment begins with a 7 day Lead-in phase of PLX3397 alone, followed by 21 day cycles of PLX3397 in combination with eribulin.

Lead-in phase treatment:

* PLX3397 at a dose of 800 mg/day given by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest.

Treatment given in each 21 day cycle:

* PLX3397 at a dose of 800 mg/day given by mouth in the form of 100-200 mg gelcaps for 5 days followed by 2 days of rest, repeated weekly
* Eribulin at dose of 1.4 mg/m2 given intravenously on days 1 and 8
Interventions: intervention 1: PLX3397 intervention 2: Eribulin
Intervention descriptions: intervention 1: Dosage Form: 100 mg or 200 mg capsules, Dosage: 400 - 1000 mg, oral administration intervention 2: Dosage Form: 1 mg per 2 mL (0.5 mg per mL); Solution (clear, colorless, sterile, packaged in glass vial) Dosage: 1.4 mg/m2, 2-5 min IV, Day 1, 8 q21 days

Protocol documents:
Prot_SAP_000.pdf: 
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Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like Breast Cancer by 
Targeting Macrophages:  A Multicenter Phase Ib/II study of PLX 3397 and Eribulin in 
Patients with Metastatic Breast Cancer
UCSF Protocol No.:  12751
Version Number: 10.0
Version Date: 03/03/2016
Study Drug: PLX3397 
IND:  114838
Principal Investigator
Hope Rugo, M.D.
Protocol Project Manager  
Lead Clinical Research Coordinator
Statistician
Lead Patient Advocate
Clinical Research Coordinator
Collaborating Institution Principal Investigators
Ingrid Mayer, M.D.
Vanderbilt-Ingram Cancer Center
Kimberly Blackwell, M.D.
Duke University Cancer Center
Collaborating Project Investigators
Lisa Coussens, M.D.
Shelley Hwang, M.D.
NCT#: 01596751


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Revision History
Version 10.0
Version 9.0
03-03-2016
09-18-2015
Version 8.0
03-10-2015
Version 7.0
01-06-2014
Version 6.0
02-07-2013
Version 5.0
09-20-2012
Version 4.0
06-25-2012
Version 3.0
05-29-2012
Version 2.0
03-26-2012
Version 1.0
12-14-2011
SCHEMA
First Cohort = 600 mg/day 
3-6 patients
Second Cohort = 800 mg/day 
3-6 patients
Third Cohort = 1000 mg/day
3-6 patients
Phase II
Lead in period of 7 d with PLX3397 at 800 mg PO 
5 days on, 2 days off, repeated weekly
Given as 400 mg q am and 400 mg q pm 
Starting Day 1:
Phase Ib Study
PLX3397 200 mg gelcaps, PO Daily
Eribulin 1.4 mg/m2 IV day 1 and 8
Each cycle of treatment lasts 21 days
 
Add eribulin 1.4 mg/m2 IV day 1 and 8
Continue PLX3397 at 800mg PO 5 days on, 2 days off, 
repeated weekly 
(400 mg q am and 400mg q pm)


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Table of Contents
1.0
Background and Rationale....................................................................................................7
1.1
Background .......................................................................................................................7
1.2 
Clinical Studies ...............................................................................................................18
1.3
Rationale .........................................................................................................................23
2.0
Objectives ...........................................................................................................................23
2.1
Primary Objective ...........................................................................................................23
2.1.2
Phase II ....................................................................................................................23
2.2
Secondary Objectives......................................................................................................23
2.2.1
Phase Ib....................................................................................................................23
2.2.2
Phase II ....................................................................................................................24
3.0
Study Design and Eligibility Criteria .................................................................................24
3.1
Study Design...................................................................................................................24
3.1.1
Phase Ib....................................................................................................................24
3.1.2
Phase II ....................................................................................................................25
3.2
Inclusion Criteria.............................................................................................................25
3.3
Exclusion Criteria ...........................................................................................................27
4.0
Patient Registration.............................................................................................................27
4.1
Stratification....................................................................................................................27
4.2
Randomization and Blinding ..........................................................................................27
4.3
Registration .....................................................................................................................27
4.3.1
UCSF Helen Diller Family Comprehensive Cancer Center....................................27
4.3.2
Participating sites.....................................................................................................27
5.0
Investigational Treatment Plan...........................................................................................28
5.1
Dose and Schedule..........................................................................................................28
6.0
General Concomitant Medication and Supportive Care Guidelines...................................29
6.1
Use of Myeloid Growth Factors......................................................................................30
7.0
Toxicity Management & Dose Modifications ....................................................................30
7.1
PLX3397 .........................................................................................................................30
7.2
Eribulin............................................................................................................................32
8.0 
Schedule of Assessments....................................................................................................35
8.1
Screening Assessments (same for both the Phase Ib and Phase II study).......................38
8.2
Assessments During Treatment ......................................................................................38
8.3
Follow-Up Assessments..................................................................................................39
9.0
Criteria for Evaluation ........................................................................................................40
9.1
Response Definitions ......................................................................................................40
9.2
Toxicity Definitions ........................................................................................................45
10.0
Criteria for Termination......................................................................................................45
10.1
Conditions for Terminating the Study.........................................................................45
10.2
Conditions for Individual Patient Termination ...........................................................45
11.0
Drug Information................................................................................................................45
11.1
Eribulin mesylate (E7389)...........................................................................................46
11.1.3
Mode of Action........................................................................................................46
11.1.4
Storage and Stability................................................................................................47
11.1.5
Metabolism ..............................................................................................................47
11.1.6
Preparation & Administration..................................................................................47


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11.1.7
Side Effects..............................................................................................................47
11.1.8
Nursing Implications ...............................................................................................48
11.2
PLX3397 .....................................................................................................................48
11.2.1
PLX3397 Administration.........................................................................................48
11.2.2
PLX3397 Packaging and Labeling ..........................................................................48
11.2.3
PLX3397 Storage and Stability ...............................................................................49
11.2.4
PLX3397 Accountability, Reconciliation, and Return............................................49
11.2.5
PLX3397 Compliance .............................................................................................49
11.2.6
PLX3397 Toxicity ...................................................................................................49
12.0
Statistical Considerations....................................................................................................51
12.1
Endpoint Definitions ...................................................................................................51
12.2
Analysis Plan...............................................................................................................52
12.3
Accrual Objectives ......................................................................................................54
12.4
Estimated Duration of Study .......................................................................................54
12.5
Data Safety Monitoring...............................................................................................54
12.6
Replacement Policy.....................................................................................................54
12.7
Pharmacokinetic studies..............................................................................................54
12.7
Correlative studies.......................................................................................................54
13.0
Data Collection and Management ......................................................................................55
14.0
Correlative studies ..............................................................................................................56
14.1
Tumor biopsies............................................................................................................56
14.2
CSF1 levels..................................................................................................................56
14.3
Blood for leukocyte subtyping ....................................................................................56
14.4
Pharmacokinetic sampling ..........................................................................................56
14.5.
Archival tumor samples...............................................................................................57
14.6.2
Evaluation of dynamic tissue and blood biomarkers most likely to show early 
biologic changes that predict clinical response .....................................................................58
14.6.3 Determine magnitude of change in serum CSF1........................................................58
15.0
Reporting Adverse Drug Reactions....................................................................................58
15.1
Adverse Event Definitions ..........................................................................................58
15.2
Recording of an Adverse Event...................................................................................59
15.3
Follow-up of Adverse Events......................................................................................60
15.4
Adverse Events Monitoring.........................................................................................60
15.5
Expedited Reporting....................................................................................................61
15.6
Reporting DLTs...........................................................................................................63
16.0
Data Safety Monitoring Plan ..............................................................................................63
16.1
Oversight and Monitoring Plan ...................................................................................63
16.2
Monitoring and Reporting Guidelines.........................................................................63
16.3
Review and Oversight Requirements..........................................................................64
17.0
Study Management .............................................................................................................65
17.1
Pre-study Documentation............................................................................................65
17.2
Independent Ethics Committees/Institutional Review Board .....................................65
17.3
Informed Consent........................................................................................................65
17.4
Oversight and Monitoring Plan ...................................................................................65
17.5
Coordinating Center Processing and Documenting FDA Correspondence ................66
17.6
Record Keeping and Record Retention.......................................................................66
17.7
Regulatory Documentation..........................................................................................67


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17.8
Patient Enrollment.......................................................................................................67
17.9
Study Drug Supply and Accountability.......................................................................68
17.10
Coordinating Center Documentation of Distribution..................................................68
17.10.1
Approval of Protocol and Amendments...............................................................68
18.0
References...........................................................................................................................69
Appendix 1:  Strong CYP3A4 Inhibitors and Inducers.................................................................74
Appendix 2:  Drugs With A Risk Of Torsades De Pointes ...........................................................75
Appendix 3:  Drug Diaries.............................................................................................................77


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LIST OF ABBREVIATIONS
AE
Adverse event
ALT
Alanine transaminase
ANC
Absolute neutrophil count
AST
Aspartate transaminase
BUN
Blood urea nitrogen
CCC
Comprehensive Cancer Center (UCSF)
CEC
Circulating endothelial cell
CHR
Committee on Human Research (UCSF IRB)
CR
Complete response
CSF
Colony-stimulating factor
CT
Computerized tomography
CTX
Chemotherapy
CTC
Circulating tumor cell
CTMS
Clinical Trials Management System 
DLT
Dose limiting toxicity
DSMB
Data safety monitoring board
DSMC
Data safety monitoring committee (UCSF)
ECOG
Eastern Cooperative Oncology Group
EF
Ejection Fraction
FDA
Food and Drug Administration
FISH
Fluorescent in-situ hybridization
HER2
Human Epidermal Growth Factor Receptor 2
IHC
Immunohistochemistry
MCB
Metastatic breast cancer
MRI
Magnetic Resonance Imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
OS
Overall survival
PET
Positron emission tomography
PK
Pharmacokinetics
PFS
Progression-free survival
PR
Partial response
RFS
Relapse-free survival
RR
Response rate
SAE 
Serious adverse event
TAM
Tumor associated macrophage
TN
Triple negative
TNBC
Triple negative breast cancer
TTP
Time to progression
UCSF
University of California San Francisco
ULN
Upper limit of normal


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1.0
Background and Rationale
1.1
Background
TRIPLE NEGATIVE BREAST CANCER
The marked difference in breast cancer (BC) outcome between black women and white women 
in the United States has long been recognized as an important health care concern[1]. Although 
BC incidence is lower overall among black women, the mortality rate is consistently higher[2-4]. 
Recent data has demonstrated a cross-over in age adjusted incidence of BC, with a higher rate in 
black women under age 40 than white women (number of BCs per 100,000 woman-years 15.5 
versus 13.1), than with subsequent cross over with higher rates in white women than black 
women aged 40 or older (281.3 versus 239.5)[5]. Many of the determinants resulting in racial 
differences in BC outcome have been attributed to disparities in screening, diagnosis and 
treatment. However, studies of racial differences in BC treatment now indicate that factors apart 
from health care access contribute to disparities in BC outcome.
A significant finding to emerge has been the discovery that African American women have 
biologically more aggressive disease, independent of social factors[1]. In a SEER-based cancer 
registry of over 100,000 women, 57% of African American women had high-grade disease, 
compared to 41% in white women[6]. In both SEER and multi-center studies, estrogen receptor 
(ER)-negative, progesterone receptor (PR)-negative disease has been found to be more prevalent 
among African Americans. Carey et al evaluated 496 BCs in the Carolina Breast Cancer study, 
and found a significantly higher incidence of basal-like BCs in premenopausal compared to 
postmenopausal African American women (39 versus 14%) and non-African American women 
of any age (16%)[7]. In contrast, luminal A or low-grade, hormone receptor-positive BC, were 
found less commonly in younger black women. In the California Cancer Registry, women with 
ER, PR and HER2 negative BC (triple negative, TNBC) were more likely to be under age 40 and 
non-Hispanic black or Hispanic[8]. Non-Hispanic black women had the poorest survival, with a 
5-year survival for late-stage tumors of only 14%.
There is now evidence that biological features of BC affect response to specific therapies. 
Analysis of gene expression patterns has led to classification of BCs into a number of subsets 
correlated with biologic behavior, outcome, and therapeutic response[9]. Perou et al used 
specific gene expression patterns to classify BC into four groups: luminal type, which are often 
ER positive, basal-like type, which are often ER negative, a type which over-expresses HER-2, 
and the normal breast type[10]. These groupings have been extensively validated, including one 
series of over 1000 BCs[11]. Further sub-classifications have been defined.
TNBC refers to a heterogeneous group of tumors defined on the basis of negative ER, PR, and 
lack of HER-2 gene amplification associated with a poor prognosis, some of which exhibit 
abnormalities in the BRCA genes. Many of these tumors are highly proliferative with short 
duration of response to therapy with either primary or rapid development of resistance to 
standard therapy[12]. The basal-like classification is based on gene expression data, and most, 
but not all TNBC are categorized as basal-like[13, 14]. Basal-like or TNBC account for ~15% of 
BC diagnoses. Compared to other BCs, TNBC is commonly of higher grade, occurs more 
frequently in younger women and those of African American descent, and is associated with 


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increased visceral and central nervous system metastasis as well as inferior survival[15, 16]. 
Despite initial high responses to combination neoadjuvant chemotherapy (CTX), relapses are 
seen early following diagnosis among women with TNBC[17].
CHEMOTHERAPY FOR ADVANCED STAGE BREAST CANCER
Approximately 30% of women diagnosed with early stage BC will develop systemic recurrence 
and 5% will present with de novo metastatic disease, with only a few patients achieving long-
term survival with standard CTX. A disproportionate percent of patients with metastatic BC 
(MBC) will have TNBC.  CTX is a critical component of treatment for metastatic BC (MBC), 
particularly for hormone resistant disease, resulting in improved cancer related symptoms and 
prolonged survival. Many combination CTX regimens have been studied in an effort to improve 
outcome. Although these have demonstrated improved response rates compared to single agents, 
this has been at the expense of increased toxicity without improved survival[18]. International 
guidelines recommend use of sequential single agent CTX except in the case of visceral crisis or 
rapidly progressing disease[19]. Microtubule inhibitors are one of the most effective classes of 
agents available for treating early and late stage BC, and are considered a standard of care for 
MBC treatment. Microtubule function is vital to cell survival and plays an important role in 
proliferation and motility, maintenance of cell shape and protein trafficking. Several agents 
affecting microtubule dynamics are active anti-tumor agents and induce polymerization, or cause 
non-functional tubulin aggregates blocking cell division by interfering with mitotic spindle 
function, consequently resulting in cell cycle arrest and cell death[20].  
Paclitaxel (PTX) is one of the most widely used agents in this class, although its Cremaphor 
solvent causes bone marrow and peripheral nerve toxicity, and requires steroid premedication to 
prevent anaphylaxis. In advanced disease, weekly dosing is superior to an every 3 wk 
schedule[21]. 
Nab-paclitaxel 
(nab-PTX) 
is 
albumin-bound 
PTX 
delivered 
without 
premedication, and is associated with less toxicity than Cremaphor-based PTX. Weekly therapy 
is effective in PTX- and docetaxel-resistant disease[22]. Treatment with the novel halichondrin 
analogue, eribulin, improved survival (OS) compared to treatment of physician’s choice (TPC) in 
patients with heavily pre-treated and taxane plus anthracycline-resistant MBC (eribulin:13.1 mo 
vs. TPC: 10.7 mos, HR 0.81, p=0.041)[23], and has been recently approved by the FDA for 
treatment of advanced breast cancer (see specific data below). Response rates were higher in the 
eribulin arm (12.2 vs. 4.7%, p=0.002), and although PFS was longer by investigator assessment, 
by central review PFS was not significantly different (3.7 versus 2.2 months, HR 0.87, p=0.14). 
Subset analysis suggested benefit from eribulin across risk groups. In the overall study, grade 3-4 
toxicities included higher rates of neutropenia (21% versus 14%) and febrile neutropenia (3% 
versus 0.8%); anemia, asthenia/fatigue, nausea, mucositis and hand-foot syndrome were more 
prevalent in the TPC arm. Within patients with TNBC, current data indicates no difference in 
response to therapy based on race, although this remains controversial[24, 25]. Nonetheless, 
median time to progression (TTP) remains short for patients with this aggressive subtype of 
BC[12]; in the recent phase III eribulin trial, 144 patients were identified with TNBC, and in this 
group the PFS for eribulin was 2.23 mos, compared to 1.9 mos for TPC. Clearly, additional 
treatment approaches for patients with chemotherapy-resistant TNBC are critical. 
MYELOID CELLS, MAMMARY GLAND DEVELOPMENT AND BREAST CANCER
Leukocytes are normal cellular components of all tissues, are critical for regulating normal tissue 
homeostasis, and are significant paracrine regulators of all physiologic and pathologic tissue 


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repair processes. In mammary glands, every stage of development is accompanied by changes in 
the surrounding stroma that is populated by immune cells particularly those of the innate lineage. 
Mechanisms whereby innate immune cells are recruited to developing mammary epithelial 
structures have not been fully elucidated, although the process is clearly triggered by 
estrogen[26]. Studies of mice in which CSF-1 is absent owing to a Csf1 homozygous null 
mutation (Csf1op/op) have shown that many tissues, including mammary glands, are severely 
depleted of macrophages (Ms), indicating an essential requirement for CSF-1for 
Mmaturation and function[27, 28]. Csf1op/op mice have inhibited mammary development 
characterized by fewer numbers of terminal end buds, reduced branching and diminished ductal 
length compared to wild type mice[26]. Thus, in M-deficient glands, although a ductal tree 
eventually develops that fills the fat pad, the resulting gland is atrophic[28]. A similar defect was 
reported in CSF-1 receptor (CSF1R)-null mutant mice[29].
While BC has not historically been linked to underlying inflammation or infection, it exhibits 
tumor-associated inflammation characterized by infiltration of leukocytes into developing tumors 
where increases in T cells and myeloid cells in neoplastic stroma parallels progression[30-32]. In 
BCs, Ms are the most abundant innate immune cell type present where they regulate 
angiogenic processes via production of pro-angiogenic factors including vascular endothelial 
growth factor (VEGF) and proteases[33]. In a transgenic mouse model of mammary 
adenocarcinoma development, e.g., MMTV-PyMT mice[34], increased M infiltration in 
premalignant tissue occurs immediately before activation of angiogenesis and onset of 
malignancy[35, 36]. CSF-1 is broadly expressed by mammary tumor cells, and its expression 
correlates with extent of M infiltration[37]. MMTV-PyMT mice carrying the Csf1op/op 
mutation exhibit 95% decreased infiltration of Ms in tumors, inhibited angiogenesis, 
significantly delayed tumor progression and diminished pulmonary metastasis[35].
Another myeloid population implicated in BC development are the so-called immature myeloid 
suppressor cells (IMCs)[38, 39] that express low to undetectable levels of major 
histocompatibility complex (MHC)-II and costimulatory molecules, thus they cannot induce anti-
tumor responses similar to Ms activated by type 1 cytokines (M1-Ms). Rather, IMCs 
promote tumor development by exerting inhibitory activity on both tumor-specific and non-
specific T cells and by providing factors for tumor growth and neovascularization[40, 41]. 
In BC, like in mammary gland development, Ms are reregulated in part by CSF1, mediated by 
the CSF1R[42]. A second CSF1R ligand, interleukin (IL)-34, possesses similar binding affinities 
and also regulates M recruitment to tissues, but exhibits distinct tissue distribution[43-45]. 
Paracrine interactions between Ms and MECs form positive feed-forward loops involving M-
expressed EGF, and CSF1 expressed by neoplastic cells, that together regulate carcinoma cell 
chemotaxis along collagen fibers towards blood vessels directed by perivascular Ms[46, 47]. 
Based on these findings, it seems reasonable to postulate that blockade of cellular and/or 
molecular programs enhancing M recruitment in BC may represent tractable targets for anti-
cancer therapy. Indeed, blockade of CSF1 or CSF1R results in decreased M presence in tissues 
and in experimental tumors, correlates with diminished angiogenesis, reduced tumor growth and 
metastasis in some models[35, 48-52]. 


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T CELLS REGULATE PROTUMOR MACROPHAGE/MONOCYTE ACTIVITY
Experimental studies have revealed that B and T cells exert pro-tumor activity indirectly by 
regulating myeloid cell bioactivity, including Ms, IMCs and mast cells, resulting in resistance 
to endocrine therapies and enhanced development of metastasis[32, 53-55]. We reported that 
interleukin (IL)-4-expressing TH2 CD4+ T cells promote invasion and metastasis of mammary 
adenocarcinomas by regulating protumor M and IMC activity, i.e., increased expression of 
EGF, transforming growth factor (TGF), reactive oxygen species (ROS), inducible nitrogen 
oxygen synthase (iNOS)[32, 56], and repression of cytotoxic CD8+ T lymphocytes (CTL)[32]. 
Using the MMTV-PyMT mouse model of mammary carcinogenesis[34], we revealed that 
PyMT/CD4+ T cell-deficient mice (CD4-/-) exhibited a significantly attenuated metastatic 
phenotype[32] similar to that of CSF1op/op/PyMT mice[35]. IMCs and Ms in tumors of CD4-
deficient/PyMT mice expressed elevated levels of type 1 cytokines, e.g., tumor necrosis factor 
(TNF), IL-6, IL-12p40, IL-1, and Nos2 mRNA, indicative of a prevalent TH1 immune 
microenvironment and M1-M phenotype[32], whereas IMCs and Ms from CD4-
proficient/PyMT mice were instead indicative of alternatively activated M2-Ms that expressed 
higher levels of arginase-1 (Arg-1) and Tgf, thus characterizing a protumor TH2 
microenvironment[32]. PyMT/IL4R-deficient and PyMT mice treated with neutralizing 
antibodies to IL-4, phenocopied PyMT/CD4-/- mice with diminished metastasis and presence of 
M1-IMCs and M1-Ms in carcinomas[32]. Together this data indicates that TH2-CD4+ T cells 
promote metastasis by enhancing pro-tumor bioactivities of Ms and IMCs, and that depletion 
of Ms and/or IMCs, or blockade of their IL-4-regulated pathways, may provide a survival 
advantage by limiting progression and metastasis.
RATIONALE FOR MACROPHAGE TARGETING IN TNBC
Patients with metastatic TNBC represent a significant challenge as many have CTX-resistant 
disease at relapse, and others develop resistance quickly after initial response. Despite promising 
advances with agents inhibiting DNA repair, (PARP inhibitors), all patients with advanced TN 
disease will eventually die from their disease[57, 58]. Recently, Martin and colleagues reported 
that BCs in African Americans displayed different expression profiles correlating with the TN 
phenotype[59]. Importantly however, differences in the tumor microenvironment were also 
identified. Specifically, tumor-associated Ms were independently increased in tumors of 
African American women. Supporting this finding, a response signature for colony stimulating 
factor (CSF)1, a primary regulator of tissue M maturation and infiltration, was identified in 17-
25% of BCs associated with decreased expression of ER and PR[60]. Campbell and colleagues 
studied tissue M infiltration in two independent cohorts and found a significant correlation 
between intratumoral Ms and specific tumor features, including high grade, hormone receptor-
negativity, basal-like subtype, and the number of Ms was associated with increased risk of 
death from cancer[61]. Studies in transgenic mouse models of mammary carcinogenesis have 
revealed that Ms promote carcinogenesis and enhance metastasis by high-level expression of 
epidermal growth factor (EGF) and activation of EGF-regulated signaling cascades in mammary 
epithelial cells (MECs)[62]. These data, along with others, indicate that M infiltration may be a 
prognostic indicator, and could serve as a potential target for novel therapies.  Since high-grade, 
TN tumors characterized by increased M infiltration are disproportionately represented among 
women of African American ancestry, identifying an alternate treatment approach to this 
biologic group of tumors has potential to close the outcome disparity observed among African 


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Americans diagnosed with breast cancer.[33, 63]
PRELIMINARY STUDIES
LEUKOCYTE PROFILING IN BC
Based on our previous studies demonstrating that CD4+ T cells and M2-Ms enhance 
development of pulmonary metastasis in MMTV-PyMT mice[32, 56], we postulated that the 
density of CD4, CD8 and CD68-positive immune cells in human BC would provide prognostic 
information. To evaluate this, we established a classification and regression tree algorithm to 
define a “signature” in a screening cohort of BC tissues (n=179, cohort I). High and low 
thresholds for each marker were established through a decision tree analysis with 10-fold cross-
validation of each tree model. All BC samples were categorized as having either a 
CD68high/CD4high/CD8low or a CD68low/CD4low/CD8high immune signature, and the same 
thresholds were then applied to a validation BC cohort (cohort II, n=498). Kaplan Meyer analysis 
in the two cohorts (677 pts) demonstrated significantly reduced relapse-free survival (RFS) for 
pts bearing the CD68high/CD4high/CD8low signature (Fig 1A-B). Multivariate Cox regression 
analysis revealed that the CD68high/CD4high/CD8low signature was an independent predictor of 
decreased OS and RFS after controlling for grade, nodal status, tumor size, ER, PR and HER2 
status in both cohorts (p<0.05 and p=0.001, respectively). Kaplan-Meier analysis of Cohort II 
also demonstrated significantly reduced RFS in node-positive pts (Fig 1C). Analysis of the 
prognostic value of the immune signature within individual tumor subtypes revealed that the 
CD68high/CD4high/CD8low phenotype was associated with reduced OS and RFS in TNBCs (Fig 
1D). This correlation in TN disease is particularly important given the aggressive nature of 
TNBCs that often becomes refractory to CTX. These results indicate that infiltration by Ms 
and T cells may influence BC recurrence in lymph node-positive pts. 
NEOADJUVANT CTX CORRELATES WITH MYELOID INFILTRATION
To identify biomarkers or parameters of immune cell presence in BCs in a prospective manner, 
and to identify pts most likely to benefit from M-targeted therapy, we have started to evaluate 
freshly isolated, unfixed human BC tissue, resected from women undergoing surgery at UCSF, to 
reveal leukocyte complexity by fluorescent-activated cell sorting (FACS). Thus far, we have 
evaluated 4 invasive ductal carcinomas (IDC) and one ductal carcinoma in situ (DCIS), with 
adjacent normal breast tissue also available from 3 of the IDCs (Fig 1D). With regards to 
variances in immune complexity in these tumors, the most obvious variance identified thus far is 
that the samples from women who had received neoadjuvant CTX contained ~6-fold higher % of 
Ms (CD14+CD11b+), as compared to BC tissue from women who had not received 
neoadjuvant CTX (Fig 1E-F). Since immunosuppressive monocytes (IMCs) regulate cancer 
development in murine models, and since these would not be efficiently depleted by therapeutic 
strategies targeting CSF1 or CSF1R, we evaluated samples for lineage markers that would 
identify accumulation of this population and thus far, have not found evidence of their 
accumulation within BC or adjacent normal tissue (Fig 1E,G).
CYTOTOXICS INDUCE EXPRESSION OF M/MONOCYTE CHEMOATTRACTANTS
To reveal the molecular mediators involved in CTX-associated M recruitment, we evaluated 
MECs from murine mammary and human breast tumors in vitro for mRNA expression of 
monocyte/M cytokines/chemokines following exposure to PTX, cisplatin or radiation therapy, 
and found increased expression of important M/IMC chemoattractant mRNAs, including


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 CSF1, CCL8/MCP2 and IL34 (Fig 2A shows analysis of PyMT-derived carcinoma cells treated 
with PTX in vitro). Analysis of CSF1 mRNA expression in vivo revealed that mammary tumors 
of MMTV-PyMT mice had a 2-fold higher expression of CSF1 mRNA following PTX exposure 
(Fig 2B) that correlated with increased density of Ms in tumor stroma (Fig 2C).  
PLX3397: 
A 
POTENT 
ANTAGONIST 
OF 
THE 
CSF1R 
TYROSINE KINASE
PLX3397 
is 
a 
competitive 
ATP 
inhibitor 
with 
potent 
(nM) 
specificity 
for 
CSF1 and cKIT 
receptor 
tyrosine 
kinases, with 10-
100 
fold 
selectivity 
for 
these 
target 
kinases as opposed 
to 
other 
related 
kinases 
(e.g. 
KDR)[64].  
Specifically 
PLX3397 
is 
a 
selective inhibitor 
of Fms (CSF1R, 
the receptor for 
colony stimulating
factor [CSF-1, also 
known 
as 
macrophage-
colony stimulating 
factor, M-CSF], as 
well
as 
the 
ligand 
interleukin 34 [IL-
34]), 
Kit 
(the 
receptor for stem 
cell factor, SCF), 
and
 oncogenic 
Flt3 
(the receptor for 
Flt3 
ligand) 
activity 
intended 
Fig 1: Immune signature in human BC predicts RFS in Cohorts I and II (A, 
B; log rank (Mantel-Cox) p-values are denoted) and (C) Kaplan-Meier 
estimates of RFS for lymph node-positive patients extracted from Cohort II 
with log-rank (Mantel-Cox) p value denoted. (D) Kaplan-Meier estimates of 
RFS in TNBC wit.h log-rank (Mantel-Cox) p value denoted (E) FACS 
evaluation of 5 human breast tumors (T, tumor; IDC, invasive ductal 
carcinoma), 3 of which were evaluated along with adjacent normal breast 
tissue (Adj N) from the same patient. Details on tumor grade, ER, PR, HER2 
status and lymph node involvement are shown. (F) Increased percentage of 
M∅s (CD14+CD11b+) revealed by FACS in BC tissue from women treated 
with neoadjuvant CTX, versus untreated women (n=3 each). (G) FACS 
analysis of macrophages in ER+PR-HER2- BC (left) vs ER-PR-HER2- 
TNBC (right) evaluated for CD206, HLA-DR and CD80 expression showing 
no segregation of subpopulations. ER, estrogen receptor; PR progesterone 
receptor; LN, lymph node positivity, 


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for oral administration. When screened against a broad panel of kinases, IC50 values were > 1.0 
μM for all, with the majority > 10 μM. Ligand-dependent proliferation of M-NFS-60 and 
BAC1.2F5 cells is inhibited by PLX3397 with IC50s of 0.33, 0.23 and 0.31 μM, respectively. In 
THP-1 cells, CSF1R autophos-phorylation induced by M-CSF is inhibited by 7.0 nM PLX3397. 
Human osteoclast precursor cells were induced to differentiate into mature osteoclasts by 
RANK-L and M-CSF, and inhibited by PLX3397 with an IC50 of 33 nM. By contrast, in RS4:11 
cells, Flt3 auto-phosphorylation was induced by Flt3 ligand with autophosphorylation requiring 
high levels of PLX3397 (1500 nM) for inhibition.  PLX3397 is currently in a phase 1 trial 
(ClinicalTrials.gov Identifier: NCT01004861) under Protocol PLX108-01 entitled, “A Phase 1 
Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX3397 in Pts with 
Advanced, Incurable, Solid Tumors in which the Target Kinases Are Linked to Disease 
Pathophysiology.” The PLX3397 clinical formulation has demonstrated appreciable 
bioavailability and dose-dependent exposures to date, and is supplied as gel caps of 100 mg each.  
The plasma half-life of PLX3397 appears to be greater than 10 hours, and the trial has achieved 
exposures that are within the efficacious range predicted by preclinical studies. Nineteen pts have 
been enrolled to date, and the current dose level is 600 mg by mouth given once daily on an 
empty stomach. A maximum tolerated dose (MTD) has not yet been defined, and dose escalation 
is ongoing without consistent clinically significant toxicity. One younger pts experienced a 
reversible change in hair color to white, attributed to inhibition of KIT. The majority of the 
biomarker studies are ongoing; flow studies have demonstrated a reduction in monocytes that 
appear sensitive to CSF1 stimulation in pts treated with PLX3397.
MACROPHAGE-DEPLETION IMPROVES CHEMOSENSITIVITY
The combined implication of our preclinical data is that high levels of Ms such as observed in 
high grade TNBC, may limit response to CTX. Thus, we treated late-stage MMTV-PyMT mice 
with PTX, and agents blocking M and/or IMC infiltration. MMTV-PyMT mice were treated 
with PLX3397 starting at d80 followed with one cycle of PTX (10 mg/kg, Q5Dx3, i.v.) and 
monitored to endpoint (2.0 cm primary tumors or day 100). While PTX increased the Ms 
(CD45+CD11b+Ly6C-Ly6G-F4/80+) in tumor stroma, combined treatment with PLX3397 
significantly reduced PTX-induced M infiltration (Fig 3A) accompanied by reduced primary 
tumor growth (Fig 3B) and pulmonary metastasis (Fig 3C). Using a histopathological staging 
criteria[35, 65], PLX3397/PTX-treated mice developed fewer late-stage carcinomas containing 
large areas of necrosis and extensive cell death (p<0.05, cleaved caspase 3+ cells), decreased 
density of CD31+ vessels (p<0.05), with no accompanying change in epithelial proliferation (data 
not shown). PLX33897 treatment had no effect on infiltration of tumors by IMCs 
(CD45+CD11b+Ly6CHi) or DCs (CD45+CD11blo/-Ly6C-CD22-Ly6G-CD11cHiMHCIIHi) (data not 
shown).
Since PLX3397 inhibits both CSF1R and cKIT kinases, we treated mice bearing orthotopic 
mammary tumors (derived from carcinoma cells of MMTV-PyMT mice) with neutralizing 
monoclonal antibody (mAB) to CSF1 as monotherapy, and in combination with PTX. 
PLX3397/PTX and CSF1 mAB/PTX similarly depleted ~ 80% of M∅s with no diminution in 
the presence of IMCs (data not shown), and significantly reduced primary tumor growth (Fig 
4A), thus indicating that the cKIT inhibitory effects of PLX3397 were insignificant. Neither 
PLX3397 nor CSF1 mAB depletes IMCs within PyMT tumors; thus, we evaluated CD11b 
mAB/PTX to eradicate IMCs. CD11b is an integrin cell adhesion molecule expressed on 
granulocytes, M∅s, IMCs, DCs, and NK cells that in part, regulates transendothelial migration of 


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cells into tissue and tumor parenchyma. CD11b mAB treatment efficiently depletes both the 
M∅ and IMC population in tumors[66]. PyMT tumor-bearing mice treated with either CD11b 
mAB/PTX exhibited significant reduction in primary tumor growth similar to CSF1mAB/PTX 
or PLX3397/PTX (Fig 4B). Similar results were observed when tumor-bearing mice were treated 
with PLX3397/carboplatin and PLX3397/cisplatin (data not shown).
ANTI-TUMOR RESPONSE IN PLX3397/PTX-TREATED MICE
Tumors from PLX3397/PTX-treated MMTV-PyMT mice revealed increased % of CD4+, CD8+ 
T cells (Fig 5A) and DCs (data not shown) correlating with significantly (p<0.05) increased 
expression of cytotoxic effector molecules (interferon (IFN), granzyme A (GRZA), granzyme B 
(GRZB), perforin-1 (PRF1), and “Type-1” DC effectors molecules IL12p35 and interferon 
(IFN))[67], and decreased expression of immunosuppressive ARG1 (Fig 5B), thus indicating an 
overall reprogramming of the immune microenvironment where anti-tumor immune pathways 
had been bolstered. To evaluate the significance of this, we depleted MMTV-
PyMT/PLX3397/PTX-treated mice of CD8+ T cells with a neutralizing mAB to CD8a, and found 
that the improved outcome following PLX3397/PTX therapy was lost (Fig 5C) indicating 
enhanced chemosensitivity accompanying M-depletion also involved bolstering productive CD8+ 
T cell-dependent CTL responses. 
CD68 AND CD8 MRNA EXPRESSION PREDICTED RESPONSE TO CTX
To determine if stratification of BCs by CD68 and CD8 mRNA expression predicted response to 
CTX, we analyzed CD68 and CD8a mRNA expression in a cohort of 311 pts constructed from 2 
independent data sets[68, 69]. All pts provided fine needle aspirates (FNA) taken prior to 
neoadjuvant CTX and pathological response was assessed at the time of surgery. Using median 
expression as a threshold, examination of CD8 and CD68 mRNA in FNA samples demonstrated 
3 specific groups CD68>CD8, CD68<CD8 and CD68=CD8 (denoted CD68high/CD8low, 
CD68/CD8equal and CD68low/CD8high respectively). Analysis of the rate of pathological complete  
response (pCR) in these groups revealed that the CD68high/CD8low group had a significantly 
lower rate of pCR (7%) as compared to the other two groups, with the CD68low/CD8high 
exhibiting the highest rate of pCR at 27%, thus indicating that the balance between M and CD8 
infiltration can be used as a biomarker to predict response to neoadjuvant CTX. 
NONCLINICAL PHARMACOLOGY 


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PLX3397 is a selective  inhibitor of Fms (CSF1R, the receptor for colony stimulating factor 
[CSF-1, also known as macrophage-colony stimulating factor, M-CSF], as well as the ligand 
interleukin 34 [IL-34]), Kit (the receptor for stem cell factor, SCF), and oncogenic Flt3 (the 
receptor for Flt3 ligand) activity intended for oral administration. The effects of PLX3397 on 
multiple aspects of tumorigenesis have been characterized in cellular and in vivo assays. The 
proliferation of cell lines that depend on CSF-1, SCF, or endogenous Flt3-ITD (internal tandem 
duplications) is inhibited at inhibitory concentration of 50% (IC50) values below 1 µM. 
Furthermore, CSF-1-induced autophosphorylation of Fms and SCF-induced autophosphorylation 
of Kit are potently inhibited by PLX3397. Finally, the RANK-L- and CSF-1-dependent 
differentiation of osteoclast precursors is also potently inhibited by PLX3397. These in vitro 
results translate to PLX3397 effects in a variety of in vivo models for Fms-dependent 
proliferation, Fms-dependent osteoclast differentiation, Flt3-ITD dependent tumor growth, and 
Kit-dependent mast cell proliferation. While pharmacologic effects due to the inhibition of Fms 
and Kit are expected, the relative selectivity of PLX3397 against other kinases suggests that off-
target effects against other kinases should be reduced. The safety pharmacology of PLX3397 has 
been evaluated in 5 Good Laboratory Practice (GLP) studies (2 in vitro and 3 in vivo). Three of 
these studies addressed the potential adverse cardiovascular or cardiac electrophysiological 
effects of PLX3397. 
An inhibitory concentration of 50% (IC50) of 0.7 μM was obtained in the human ether-a-go-go 
(hERG) channel assay. However, no PLX3397-related prolongation of action  duration was 
observed in an isolated 
rabbit 
Purkinje 
fiber 
study. In an in vivo dog 
telemetry 
study, 
electrocardiographic 
parameters 
were 
unchanged by PLX3397 
treatment, 
but 
left 
ventricular 
contractility 
(LV 
dP/dtmax) 
and 
arterial pulse pressure 
were significantly lower 
compared to controls in 
dogs that received 300 
and 
1000 
mg/kg. 
Because PLX3397 binds 
to the hERG channel yet 
no QT prolongation has 
been 
identified 
nonclinically, 
an 
investigative 
safety 
pharmacology study was 
conducted in order to 
examine 
potential 
binding 
to 
hCav1.2 
whose 
inhibition 
has 
Fig 4: Combined treatment with CSF1 mAB or CD11b mAB and PTX 
reduces primary orthotopic PyMT-tumor growth (A,B). Higher percentage of 
IMCs in 4T1 tumors compared to PyMT tumors(C). PLX3397 plus PTX 
reduces 4T1 tumor growth (D). (*) p<0.05, (**) p <0.01. FVB/n: mammary 
i
f
i
i


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been negatively correlated with risk for QT prolongation. IC50 for the inhibitory effect of 
PLX3397 on hCav1.2 calcium current was determined to be 0.2 μM. Central nervous system 
(CNS) and respiratory function were not affected in rats.
NONCLINICAL PHARMACOKINETICS 
PLX3397 binds extensively to albumin in 4 species (mouse, rat, dog and human). After 
intravenous (IV) administration in nonclinical studies, elimination terminal half-life (t1/2) values 
were 3.5 hours in mice, 5.1 hours in rats, 1.9 hours in dogs, and 3.7 hours in monkeys. PLX3397 
is metabolically stable and not susceptible to rapid metabolic degradation. CYP3A4 is the main 
CYP enzyme that metabolizes PLX3397. The results also suggest that CYP1A2 and 2C9 might 
also play a minor role in its metabolism. PLX3397 had no inhibitory effect on CYP1A2 and 3A4 
with an IC50 > 30uM. It had modest effects on the other major CYPs, (2C9, 2C19, and 2D6) 
with an IC50 ranging from 11.1 to 22.2 μMPLX3397, at 10 μM, did not significantly inhibit 
BCRP, BSEP, SMVT, OCT1, OCT2, OAT1,OAT3-mediated transport of probe substrate. 
Compared to vehicle control, PLX3397 inhibited the transport of probe substrates of uptake 
transporters OATP1B1, OATP1B3 and OATP2B1 with respective inhibition of 27.7%, 21.4% 
and 37.1%. PLX3397 also inhibited P-gp mediated transport of probe substrates with a small but 
statistically significant inhibition of 9.35% at 10 μM.
PLX3397 appears to penetrate into the CNS in rats.
NONCLINICAL TOXICOLOGY
Two high-dose GLP 4-week general toxicology studies were conducted with daily oral gavage 
administration of PLX3397 (once daily [QD] in rats and twice daily [BID] in dogs) at doses of 
20, 60, and 200 mg/kg/day in rats and 50, 100, and 300 mg/kg/day in dogs, with 16-day (rat) or 
14-day (dog) recoveries. Neither a noeffect-level (NOEL) nor a no-adverse-effect-level 
(NOAEL) of PLX3397 could be determined in either species due to toxicity. Significant adverse 
test article-related observations appear to be related to PLX3397-mediated inhibition of Fms and 
Kit kinases. PLX3397-related histopathologic observations included testicular spermatagonia 
reduction, bone marrow hypocellularity, thymic lymphoid reduction, bone hyperostosis and 
hypertrophy, ovarian follicular degeneration, and liver hepatocellular hypertrophy. All findings 
were partially or fully reversible. Two additional GLP toxicology studies at lower dose levels 
involved daily oral gavage administration of PLX3397 HCl for 4 weeks (QD in rats and dogs) at 
doses of 0.5, 2, and 10 mg/kg/day in rats and 1, 6, and 30 mg/kg/day in dogs, with 8-week 
recoveries. The NOAELs of PLX3397 were determined to be 10 mg/kg/day in rats and 6 
mg/kg/day in dogs in these additional studies. All adverse findings were fully reversible, 
including testicular spermatagonia reduction in dogs.
Two 13-week GLP toxicology studies involved daily oral gavage administration of PLX3397 
HCl for 13 weeks (QD in rats and dogs), with 8-week recoveries at doses of 0.5, 4 and 20 
mg/kg/day in rats and 1, 6, and 30 mg/kg/day in dogs. NOAELs were determined to be 4 
mg/kg/day in rats and 6 mg/kg/day in dogs. No new target organ toxicities were seen in either 
study In rats, anemia, and bone marrow depletion, and hepatocellular vacuolation associated with 
increased liver enzymes were seen. In dogs, findings of reproductive toxicity (spermatogonial 
reduction) and increased incidence of emesis were seen  at the t 30 mg/kg dose level, which were 
reversible.


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Potential effects of PLX3397 on embryofetal development in rats were assessed at 4, 10, and 40 
mg/kg/day. Based on changes in hematology parameters at 40 mg/kg/day in the dams, and fetal 
external and visceral malformations and skeletal developmental variations (findings primarily 
related to decreases in ossification) in the fetuses at 40 mg/kg/day, a dose level of 10 mg/kg/day 
was considered to be the NOAEL. PLX3397 was not mutagenic or clastogenic in the 
Ames,chromosomal aberration and micronucleus)  tests, andshowed no potential to cause 
phototoxicity in vitro in the NIH 3T3 fibroblast assay.
CONCLUSIONS FROM PRECLINICAL DATA
Results from these studies support a fundamental and functional interplay between M 
presence/bioactivity and CTX response and demonstrate that mouse modeling can guide 
development of clinical studies, aid in clinical trial design, and identify pts most likely to benefit 
from M-targeted therapy. PLX3397 is a novel oral highly selective kinase inhibitor that 
inhibits M, osteoclasts and mast cells, and mice treated with PLX3397 phenocopy mice 
similarly treated with neutralizing mABs against CSF1 or CD11b and CTX. Interestingly, a 
number of studies suggest that TNBC may be relatively resistant to taxanes, particularly 
following prior exposure in the early stage setting. These preclinical data imply that leveraging 
either inhibition of the bioactivity of Ms or eradicating their presence in tumor tissue will 
provide a survival advantage to women receiving CTX in a neoadjuvant setting, and may benefit 
women in an adjuvant setting when treated in combination with CTX. The combination of 
PLX3397 with CTX, therefore, is an entirely novel treatment strategy that has the potential to 
improve outcome not just for pts with advanced TNBC, which is the main goal for this clinical 
trial, but also as initial, potentially curable therapy in high risk TNBC, which is our long-term 
goal.
1.2 
Clinical Studies
CLINICAL PHARMACOKINETICS PLX3397
PLX3397 human exposure has been evaluated in 8 clinical studies. PLX3397 HCl was 
administered as single agent in 5 studies and in combination with paclitaxel, temozolomide and 
vemurafenib in the other 3 studies. The PK of PLX3397 at dose levels between 200 mg/day and 
1200 mg/day has been evaluated in the dose-escalation and extension study, PLX108-01, using 
QD or BID dosing in the fasting state. The Tmax is approximately 2 hours, and the mean 
accumulation ratio compared to Day 1 values is approximately 2-fold. In general, there is 
doseproportional exposure. In the PLX108-05 acute myeloid leukemia (AML) doseescalation 
study at dose levels between 800 mg/day and 5000 mg/day, saturation of exposure was observed 
at 2000 mg/day. The steady state exposure of 900 mg QD cohort in PLX108-03 Hodgkin’s 
lymphoma study and  of 1000 mg BID cohortsin  all the other single agent studies (PLX108-04 
glioblastoma , PLX108-05 AML, PLX108-06 prostate cancer) were similar to, exposure of the 
respective dose groups in PLX108-01 solid tumors study. 
The mean PLX3397 plasma concentrations for the 800 mg BID cohorts at 2, 4 and 6 hours in the 
combination studies with paclitaxel (PLX108-07), temozolomide (PLX108-08), and vemurafanib 
(PLX108-09) were comparable to those seen in PLX3397 single agent studies. Subjects 
administered 600 mg of PLX3397 HCl with a high-fat, high-calorie meal displayed an 
approximately 2-fold increase in Cmax and AUC compared to subjects administered PLX3397 


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HCl in the fasted state (PLX108-11). When PLX3397 HCl was administered in the  presence of 
esomeprazole, overall exposure was reduced approximately 30%. 
PLX3397 is currently in a Phase 1 trial (ClinicalTrials.gov Identifier: NCT01004861) under 
Protocol PLX108-01 entitled, “A Phase 1 Study to Assess Safety, Pharmacokinetics, and 
Pharmacodynamics of PLX3397 in Patients with Advanced, Incurable, Solid Tumors in which 
the Target Kinases Are Linked to Disease Pathophysiology.”  The PLX3397 clinical formulation 
has demonstrated appreciable bioavailability and dose-dependent exposures to date, and is 
supplied as gel caps of 100 mg each.  The plasma half-life of PLX3397 appears to be greater 
than 10 hours, and the trial has achieved exposures that are within the efficacious range predicted 
by preclinical studies.  Nineteen patients have been enrolled to date, and the current dose level is 
600 mg by mouth given once daily on an empty stomach.  A maximum tolerated dose has not yet 
been defined, and dose escalation is ongoing without consistent clinically significant toxicity. 
One younger patient experienced a reversible change in hair color to white, attributed to 
inhibition of KIT.  The majority of the biomarker studies are ongoing; flow studies have 
demonstrated a reduction in monocytes that appear sensitive to CSF1 stimulation in patients 
treated with PLX3397. 
No clinical studies on drug-drug interactions have been performed.  However, preclinical 
biochemical and cellular studies predict that the drug-drug interaction potential is low.  The 
plasma PK of paclitaxel (measured at multiple time points after 10 mg/kg injection) was 
determined to have a half-life of 1 hour in mice receiving vehicle chow, and was unchanged by 7 
previous days consumption of the PLX3397 drug 
chow (measured 15 and 45 minutes after 
paclitaxel injection.  It is assumed that eribulin 
will 
have 
a 
similar 
profile, 
however 
pharmacokinetics will be performed in the phase I 
portion of this trial.
The ongoing Phase 1 dose escalation study 
PLX108-01 in patients with solid tumors is 
designed to evaluate the safety and PK of 
PLX3397 administered orally in order to establish 
a maximum tolerated dose (MTD). As of June 
2011, a total of 41 patients have been treated with 
PLX3397 PO. The dose levels have been 200 
mg/day (n=3), 300 mg/day (n=6), 400 mg/day 
(n=6), 600 mg/day (n=6), 900 mg/day (n=7), 1000 
mg/day (n=7) and 1200 mg/day (n=6). In 
summary, the Tmax is approximately 2 hr, the 
mean elimination half-life is approximately 20 hr, 
and the mean accumulation ratio compared to Day 
1 values is approximately 1.6. In general, there is 
increasing exposure with increasing dose. On Day 
15, the AUC0-24hr was 62 uM•hr for the 200 
Fig 6: A) Increased CD4 and CD8 T cells in 
tumors of PLX3397/PTX treated MMTV-PyMT 
mice. B) Mean fold change in cytokine mRNA 
expression of PyMT tumors from mice treated 
with PTX alone or in combination with PLX3397. 
C) 85-day-old MMTV-PyMT mice were treated 
with PTX and/or PLX3397 and anti-CD8 IgG. 
Total tumor burden/animal was assessed every 5 
days. (*) p<0.05, (**) p <0.01.


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mg/day dose group, 122 uM•hr for the 300 mg/day dose group, 98 uM•hr for the 400 mg/day 
dose group, 258 uM•hr for the 600 mg/day dose group, 254 uM•hr for the 900 mg/day dose 
group and 329 uM•hr for the 1200 mg/day dose group (pharmacokinetic data for the 1000 
mg/day cohort is not currently available). Dose-limiting toxicities (DLTs) of Grade 3 AST 
elevation and Grade 4 neutropenia occurred at 1200 mg/day. A 1000 mg/day cohort was opened 
and 1 out of 7 patients experienced a DLT (Grade 3 AST), establishing 1000 mg/day as the 
MTD.
There have been no safety signals in vital signs, physical examinations, or ECGs (including 
careful evaluation of potential QT prolongation). A reduction in hemoglobin (usually G1) has 
been observed in several patients, but this has not resulted in treatment discontinuation in any 
patients. There have been a total of 6 patients with DLTs, as follows:  G3 increased INR 
(300 mg/day) in a patient on warfarin; G3 lymphopenia (600 mg/day), subsequently exempted as 
a DLT; G3 lymphopenia and G4 hyponatremia (600 mg/day); G3 AST (1000 mg/day); G3 AST 
(1200 mg/day) which recovered after study drug discontinuation; and G4 neutropenia (1200 
mg/day) which recovered after holding study drug and management with G-CSF. As this is a 
population of patients with metastatic solid tumors that have been heavily pretreated with 
cytotoxic therapies, adverse events are anticipated due to either the disease or previous 
treatments. The most common AEs have been nausea and fatigue. Please see the Investigator’s 
Brochure for more details on adverse events and tolerability.
Response biomarkers are being assayed in order to profile the inhibitory activity of PLX3397 on 
Fms and Kit activity as a function of dose and exposure. These biomarkers include circulating 
tumor cells (CTCs) and CD14+/CD16+ proinflammatory monocyte cell numbers, IL-6, IL-1β, 
MMP3, and markers of osteoclast activity. Most of the soluble markers are not elevated at 
Baseline in the patients treated to date, so no decrease with treatment can be anticipated. 
However, in 4 patients with elevated CTCs at Baseline, 3 patients have shown a clinically 
relevant reduction during treatment with PLX3397. Marked reductions in the CD14+/CD16+ cell 
populations have also been observed in the majority of patients, with no change in the remainder.
CLINICAL PHARMACOKINETICS PLX3397
 As of June 30, 2014, data are available on 345 patients who have been enrolled in the PLX3397 
clinical program across 8 clinical studies PLX108-01, PLX108-03, PLX108-04, PLX108-05, 
PLX108-06, PLX108-07, PLX108-08, and PLX108-09. Of the 345 patients, 181 patients with 
solid tumors received as studies are a single agent (which included advanced, incurable, solid 
tumors; relapsed or refractory Hodgkin’s lymphoma; recurrent glioblastoma multiforme; or 
progressive castration-resistant prostate cancer with high circulating tumor cell counts). Ninety 
patients received PLX3397 as a single agent for relapsed or refractory AML. Seventy-four 
patients received PLX3397 in combination with other therapies. Most of these studies are 
ongoing. The most frequent TEAEs (>20%) among all treated patients included fatigue, nausea, , 
decreased appetite, diarrhea, anemia, vomiting, and increases in aspartate aminotransferase 
(AST).  Hair color changes (depigmentation) and constipation also commonly occurred in solid 
tumor patients receiving single agent PLX3397. With the exception of febrile neutropenia (which 
occurred at a high rate in the AML study), less than 10% of these common AEs were considered 
as Grade 3 or higher Treatment related SAEs) reported more than once included, neutropenia 


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(including febrile neutropenia), anemia, pneumonia, increased AST or ALT, increased INR, 
dehydration, hyponatremia, and maculo-papular rash.  
ERIBULIN
Eribulin mesylate (E7389) is a nontaxane, microtubule dynamics inhibitor with a novel 
mechanism of action. Eribulin suppresses polymerization, has no effect on microtubule depoly 
merization, and sequesters tubulin into nonfunctional aggregates[70, 71]. Preclinical studies have 
demonstrated antitumor activity in cell lines that are taxane resistant as a result of β-tubulin 
mutations[72]. In addition, eribulin appears to have less neurotoxicity than other microtubule 
antagonists. A murine model compared the effect on nerve conduction of paclitaxel and 
ixabepilone to eribulin. This data, presented by Wozniak and colleagues at the annual European 
Society for Medical Oncology found that treatment with paclitaxel and ixabepilone resulted in a 
reduction in caudal nerve conduction velocity as well as caudal and digital amplitude, but 
eribulin had no deleterious effect on these endpoints. Eribulin also caused less severe 
morphological changes in dorsal root ganglion and sciatic nerves on pathological assessment. 
Nine Phase 1 clinical studies have been completed. The National Institutes of Health (NIH) 
sponsored two Phase 1 studies of E7389 (National Cancer Institute [NCI] Study 5730 and Study 
7444), and Eisai has sponsored seven additional studies: E7389-A001-101 and E7389-A001-102 
in the United States (US); E7389-E044-103, E7389-E044-108, E7389-E044-109, and E7389 
E044-110 in Europe; and E7389-J081-105 in Japan. In general, the PK of E7389 is characterized 
by a rapid distribution phase, with a prolonged elimination phase after intravenous infusion. The 
disposition of E7389 follows linear kinetics over the dose range studied, as shown by consistent 
dose-independent pharmacokinetic parameters (terminal half-life [t½], clearance [CL], steady-
state volume of distribution [Vss]) and similar dose-normalized parameters (Cmax/Dose, AUC0-
t/Dose and AUC0-∞/Dose) between E7389 doses ranging from 0.25 to 1.4 mg/m2 (E7389-A001-
101) and from 0.25 to 4.0 mg/m2 (E7389-A001-102).  NCI Phase 1 Study 5730 included 
subjects with advanced solid tumors and was designed to evaluate the toxicity and PK of E7389 
and to determine the maximum tolerated dose (MTD) using a bolus injection on Days 1, 8 and 15 
of a 28-day cycle. Dose limiting toxicities (DLTs) were observed in approximately one third of 
subjects that received 1.4 mg/m2 and in four out of five subjects at 2 mg/m2. The principal 
investigators considered 1.4 mg/m2 as the MTD. 
This schedule was selected as the initial schedule for the Phase 2 program. Two Phase 1 dose-
finding studies were conducted by Eisai, administering E7389 as a 1-hour infusion. Study 
E7389-A001-101 determined the safety, toxicity, PK, and MTD of E7389 administered on Days 
1, 8, and 15 of a 28-day cycle. The MTD was determined to be 1.0 mg/m2. Dose limiting 
toxicities were primarily Grade 3 and 4 neutropenia, but also included Grade 3 fatigue and Grade 
3 anorexia. Study E7389-A001-102 determined the safety, PK, MTD and tumor response of 
E7389 administered on Day 1 of a 21-day cycle in subjects with advanced solid tumors. The 
MTD was determined to be 2.0 mg/m2 and Grade 4 febrile neutropenia was observed as the 
DLT. The DLT was observed in all three subjects who received 4.0 mg/m2 (Cycle 1, Days 7, 8 
or 11); in two out of three subjects who received 2.8 mg/m2 (Cycle 1, Day 9 or 10); and in two 
out of seven subjects who received 2.0 mg/m2 (Cycle 1, Day 7 or 8).  Although the study was 
not designed or powered to establish efficacy, of 21 subjects, one had an unconfirmed partial 
response (PR) at 12 weeks, and 12 subjects had stable disease (SD).


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Study E7389-J081-105 was conducted at National Cancer Center Hospital East in Japan to 
evaluate the safety, toxicity, PK, and MTD of E7389 administered as a 2 to 5 minute bolus 
infusion on Days 1 and 8 of a 21-day cycle. DLTs were observed in five subjects at 1.4 mg/m2 
and 2.0 mg/m2, and the MTD was determined to be 1.4 mg/m2.  Studies E7389-E044-103, 
E7389-E044-108, E7389-E044-109 and E7389-E044-110 were also performed with E7389 
administered as a 2 to 5 minute bolus infusion on Days 1 and 8 of a 21-day cycle. These studies 
investigated the excretion balance and metabolic pathway of E7389, the influence of hepatic 
impairment on exposure to E7389, the PK and tolerance of E7389 when co-administered with 
oral multiple doses of ketoconazole (a potent CYP3A4 inhibitor) and the impact of E7389 on 
ECG. NCI Phase 1 Study 7444, included subjects with refractory or advanced solid tumors and
was designed to evaluate safety, tolerability, toxicity, and anti-tumor activity of E7389 and 
gemcitabine administered in combination as a 2 to 5 minute intravenous bolus on Days 1, 8, and 
15 of a 28-day cycle or Days 1 and 8 of a 21-day cycle. The 21-day cycle was better tolerated. 
DLTs with E7389 at 1.4 mg/m2 and gemcitabine at 1000 mg/m2 included Grade 3 diarrhea, 
Grade 3 dizziness and fatigue. The recommended Phase 2 dose was E7389 at 1.0 mg/m2 and 
gemcitabine at 1000 mg/m2.
In the clinical setting, eribulin has demonstrated efficacy in patients with heavily pre-treated 
metastatic breast cancer, and is given in a 21 day cycle of an intravenous infusion weekly for two 
weeks followed by one week off. The first phase II trial treated 103 patients with a median of 4 
prior chemotherapy regimens for advanced disease[73].  70 subjects received 1.4 mg/m2 eribulin 
administered as an IV bolus on days 1, 8, and 15 of a 28-day cycle; another 33 subjects received 
eribulin administered as an IV bolus on days 1 and 8 of a 21-day cycle). The 21-day cycle cohort 
was added because 63% of subjects in the 28-day cycle cohort experienced dose delays, 
reductions, or omissions due to neutropenia; in most cases the day 15 dose was being omitted. 
The response rate (RR) was 11.5% (all PR), the clinical benefit rate (CBR) was 17.2%, and 
progression free survival (PFS) was 2.6 months.  The second trial enrolled 299 patients with 
prior therapy or resistance to anthracyclines, taxanes and capecitabine and the same median prior 
number of treatment regimens[74]; all patients received treatment on the day 1 and 8 schedule 
every 21 days.  Results were similar by independent review, with an RR of 9.3%, a CBR of 
17.1% and PFS of 2.6 months.  Between the two trials, overall survival (OS) ranged from 9 to 
10.4 months.  The most common drug-related grades 3 to 4 toxicities were neutropenia (54-
64%), fatigue (5-10%), peripheral neuropathy (5-6.9%), and febrile neutropenia (4-5.5%).
The results of a phase III trial comparing eribulin to treatment of physician’s choice (TPC) in 
patients with anthracyline and taxane pre-treated MBC and at least two prior chemotherapy 
regimens for advanced disease  has recently led to FDA approval of this novel chemotherapy 
agent [75].  The Embrace trial randomized 508 women to eribulin, and 254 women to TPC; the 
primary endpoint was OS, which was prolonged with eribulin to 13.12 months versus 10.65 
months in the TPC arm (HR 0.81, p=0.041).  The RR was also longer in the eribulin arm (12.2 
versus 4.7%, p=0.002), and although PFS was significantly longer by investigator assessment, by 
central review PFS was not significantly different, likely due to the inclusion of patients with 
evaluable rather than solely measurable disease (3.7 versus 2.2 months, HR 0.87, p=0.14).  
Subset analysis suggested benefit from eribulin across identified risk groups. 144 patients were 
identified with ER/PR and HER2 negative disease, determined locally, and in this group the PFS 
for eribulin was 2.23 months, compared to 1.9 months for TPC.  In the overall study, grade 3-4 
toxicities included higher rates of neutropenia (21% versus 14%) and leukopenia (11.7% versus 


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5%) as well as febrile neutropenia (3% versus 0.8%). However, anemia, asthenia/fatigue, nausea, 
mucositis and hand-foot syndrome were more prevalent in the TPC arm.
1.3
Rationale
TNBC is a highly proliferative BC subtype associated with poor outcome, and acquisition of 
CTX resistance. This subtype of BC is found more frequently in young African American 
women, and the presence of Ms correlates with more aggressive tumor biology and worse 
survival. Concordant with this data, the M-associated TH1 signature (CD4lo/CD68lo/CD8hi) 
predicted worse RFS in patients with TNBC (Fig 1). Preclinical data indicate that inhibition of 
CSF1R with PLX3397 enhances responsiveness to standard CTX, including PTX (Fig 3-5). 
However, in humans, therapy with PTX requires premedication with immune-suppressing 
steroids that may negate effects of macrophage-depletion. In addition, the majority of patients 
with TNBC presenting in the pre-treated metastatic setting will have already been exposed to 
taxanes as well as other CTX/targeted agent combinations. Eribulin is a well-tolerated, novel 
halichondrin analogue recently approved by the FDA for treatment of MBC not requiring steroid 
premedication and is therefore an ideal CTX choice to partner with PLX3397 in this population 
of patients. The phase Ib portion of the trial will include all BC subtypes in order to efficiently 
complete accrual and proceed to a phase II trial specifically designed for patients with TNBC.  
Both trials will be conducted at three Comprehensive Cancer Centers, with breast cancer 
investigators who have expertise in all phases of clinical trials, as well as acquisition of tumor 
biopsies. Breast cancer advocates from each center will be actively involved in the study design 
and clinical trial execution, as well as all patient education and recruitment.
Phase I trial results (preliminary)
Twenty-eight patients were enrolled in the Phase Ib trial, with a final MTD of 1000 mg of 
PLX3397 in two divided doses given each day combined with eribulin at 1.4 mg/m2 day 1 and 8 
every 21 days.  The primary toxicities included rash, bone marrow suppression and transaminitis 
which were overall manageable with dose reduction, dose delays, growth factor support, and 
antihistamines and steroids for rash.  
2.0
Objectives
2.1
Primary Objective
2.1.1
Phase Ib: 

To determine the maximum tolerated dose of PLX3397 given in combination with 
standard dose eribulin in patients with metastatic breast cancer.
2.1.2
Phase II 

To determine the percentage of patients with chemotherapy pre-treated triple negative 
metastatic breast cancer treated with PLX3397 in combination with eribulin who are 
progression free at 12 weeks.


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2.2
Secondary Objectives
2.2.1
Phase Ib

To determine the safety and tolerability of PLX3397 in combination with eribulin in 
patients with metastatic breast cancer.

Correlative studies:

To determine the pharmacokinetics of the combination of PLX3397 and eribulin.

To correlate change in CSF1 levels during treatment with specific dose levels of 
PLX3397.

Make a preliminary assessment of the relationship between immune profile, 
tumor subtype, and tumor associated macrophages with response to therapy.

Correlate immune profile and tumor associated macrophages from primary tumor 
blocks with metastatic tumor tissue.
2.2.2
Phase II

To determine the response rate of PLX3397 in combination with eribulin in patients with 
chemotherapy pre-treated triple negative metastatic breast cancer. 

To determine the duration of response from the above therapy in this patient population.

To determine the safety and tolerability of PLX3397 in combination with eribulin in this 
patient population.

Correlative studies:

Correlation of CSF1 levels and response/duration of response to treatment.

Correlation of immune profiling in blood with PLX3397 treatment.

Correlate tumor immune profile before and after therapy with tumor subtype and 
response to therapy.
3.0
Study Design and Eligibility Criteria
3.1
Study Design
This is a nonrandomized, open label phase Ib/II study evaluating the safety and efficacy of 
eribulin in combination with PLX3397, a novel CSF1 inhibitor, in patients with metastatic breast 
cancer.  The phase II portion of this trial will be limited to patients with triple negative disease.
3.1.1
Phase Ib
The phase I portion of this trial is a dose escalation of PLX3397 to determine the maximum 
tolerated dose (MTD) of PLX3397 when given in combination with standard dose eribulin.  
Patients will be enrolled in cohorts of three, using the dose levels and plan outlined in the 
statistical section, with 6 patients enrolled at the MTD.  All patients with accessible tumor will 
be required to have a tumor biopsy at study start before starting therapy.  Pharmacokinetics of 
PLX3397 and eribulin, and blood levels of CSF1 will be obtained as outlined in section 14.  To 
allow rapid accrual to phase Ib, and an earlier start to the phase II trial, patients will be enrolled 
in phase I with both hormone receptor positive and negative disease, and at any line of therapy 
assuming eligibility criteria are otherwise met.


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Dose limiting toxicity (DLT) will be defined as any treatment-related toxicity meeting the 
criteria below and occurring within the first 21 days of combination therapy.  Patients must 
receive at least 14 days of PLX3397 and 2 doses of eribulin during the first cycle in order to be 
considered evaluable for DLT (unless the missed doses are due to a DLT).
Patients discontinuing study therapy in Cycle 1 for reasons other than treatment-related or a DLT 
may be replaced. 
Hematologic DLTs

CTCAEv4 Grade 4 neutropenia lasting for ≥5 days in duration

CTCAEv4 Grade 4 neutropenia with fever >38.5oC and/or infection requiring antibiotic 
or anti-fungal treatment 

CTCAEv4 Grade 4 thrombocytopenia ( platelets ≤25.0/µL)

CTCAEv4 Grade 3 thrombocytopenia associated with significant bleeding
Non-hematologic DLTs

Any CTCAEv4 Grade ≥3 non-hematologic toxicity (except alopecia), unless the event is 
clearly unrelated to treatment with PLX3397 in combination with eribulin

Grade ≥3 nausea, vomiting, or diarrhea that resolves to Grade ≤2 within 48 hours, with or 
without medical intervention or prophylaxis, will not be considered a DLT

Grade 3 fatigue that resolves within 14 days, with or without medical intervention or 
prophylaxis, will not be considered a DLT

Grade ≥3 hyperglycemia will not be considered a DLT
A treatment delay of greater than 7 days for PLX3397 or inability to get two doses of 
eribulin, even if a dose reduction is required on day 8 in the first cycle due to toxicity that is 
not related to cancer worsening or intercurrent illness will be considered a DLT.
A dose reduction required on Day 8 is not considered a DLT.
Patients in each cohort will be followed for at least 3 weeks (one full cycle) before opening 
accrual to the next dose level.  If one patient in any cohort develops a DLT, an additional 3 
patients will be enrolled at that level. A minimum of 12 patients will be enrolled in the phase I 
study.  The phase II trial will not open until the last patient in the phase I study has been 
followed for at least 3 weeks.
3.1.2
Phase II
The phase II portion of this trial will evaluate PFS in patients with TNBC treated with PLX3397 
and eribulin, using the dose of PLX3397 determined in the phase Ib study in a two-step design.  
Please see the statistical section for details regarding enrollment and statistical design.  
Treatment is preceded by a 6 to 7 day lead-in phase, in which patients will take PLX3397 800mg 
(400 mg in the morning and 400 mg at night) for 5 days, followed by 1 to 2 days off before 
starting eribulin combined with PLX3397.  PLX3397 will continue to be given on a 5 days on, 2 
days off schedule, repeated weekly, throughout the course of treatment. Patients with accessible 


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tumor will undergo a core biopsy of tumor before the start of PLX3397 treatment, and then a fine 
needle aspiration or core biopsy will be performed on the day of or the day before the start of 
eribulin (day -2 to day 0). 
3.2
Inclusion Criteria

Pathologically confirmed diagnosis of breast cancer with documented progressive 
disease. 

Patients with stable brain metastases are eligible for this trial. Stable brain metastases 
defined as stable disease for one month and not on active treatment including steroids.

Concomitant therapy with bisphosphonates is allowed.

Stable dose coumadin anticoagulation is allowed, providing that anticoagulation can be 
safely held to an INR within normal range for the purpose of tumor biopsy. LMWH is the 
preferred method of anticoagulation.

PT/INR and PTT ≤ Grade 1 within two weeks before initial biopsy of visceral organs.

Measurable disease, as defined by RECIST v1.1 guidelines or evaluable disease. Bone 
metastases must be evaluable.

Disease amenable to core biopsy.  Patients with pulmonary metastases as their only site 
of disease may enroll on this trial and will not undergo biopsy.

For Phase Ib: patients with HER2 overexpressing disease must have been previously 
treated with trastuzumab (patients with HER2 overexpressing disease are not eligible for 
the Phase II trial).

Age eighteen years or older.

ECOG performance status <2.

Life expectancy of > 12 weeks.

Patients with ≤ Grade 1 peripheral neuropathy are eligible for this trial using the CTCAE 
v4.0, regardless of use of therapy for neuropathy including gabapentin.

Adequate bone marrow reserve: ANC > 1000, platelets > 100,000.

Adequate renal function: serum creatinine < 1.5x upper limit of normal OR calculated 
creatinine clearance ≥ 50 ml/min.

Sodium and potassium levels ≤ Grade 1.

Adequate hepatic function: AST and ALT <2.5 x ULN, and total bilirubin < 1.5x upper 
limit of normal.  In patients with liver dysfunction due to hepatic metastases, AST and 
ALT are permitted to be < 5 times the ULN.No clinical evidence of heart failure or 
history of untreated ejection fraction below the lower limit of normal per institutional 
standards, or significant QT prolongation (> Grade 1, 480 msec)  no history of 
congenital long QT syndrome, and no use of drugs known to increase the risk of 
Torsades de Point - patients may be eligible for study if the drug can be changed to 
another agent with less risk.

Able to take oral medications and maintain hydration.


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
Ability to give written informed consent and willingness to comply with the 
requirements of the protocol.

Women of child-bearing potential must agree to use an effective method of birth control 
during treatment and for six months after receiving their last dose of study drug.
Specific inclusion criteria for Phase II

Patients enrolling on the phase II portion of this trial must have ER, PR and HER2 
negative disease defined as less than 10% staining for ER and PR, and HER2 0-1+ by 
IHC, or 2+ by IHC and no evidence of amplification by FISH using local laboratory 
testing.
3.3
Exclusion Criteria

Treatment with another chemotherapy or hormonal therapy within the past 2 weeks.

Treatment with trastuzumab, bevacizumab or other targeted therapies within the past 2 
weeks.

Concurrent radiation therapy is not allowed with the exception of brain metastases 
developing on study treatment (see section 5.2 for details).

Ongoing treatment with any other investigational therapy.

Prior treatment with eribulin.

Severe, concurrent illness including congestive heart failure, significant cardiac disease 
and uncontrolled hypertension, that would likely prevent the patient from being able to 
comply with the study protocol.

Inadequate bone marrow, renal, or hepatic function as defined above, or an active 
coagulopathy that precludes tissue biopsy.

Pregnant or lactating women and women of child-bearing potential who are not using an 
effective method of birth control.  Women of childbearing potential must undergo a 
pregnancy test within seven days of starting the study drug.
4.0
Patient Registration
4.1
Stratification
No stratification will be performed in this study.
4.2
Randomization and Blinding
No randomization or blinding will be performed in this study.
4.3
Registration
4.3.1
UCSF Helen Diller Family Comprehensive Cancer Center 
Patients who have consented and are eligible for the study will be registered in the UCSF 
Comprehensive Cancer Center Clinical Trials Management System (CTMS).  The CTMS is 
password protected and complies with HIPAA standards.  The assigned CRC at UCSF will issue 
the patient a unique study number.


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A log of patients who are screened but ineligible for the study will also be kept at each site.  
4.3.2
Participating sites
To register patients on study, the site CRC will complete an eligibility form and fax it to the 
designated UCSF CRC (contact information to be provided by the start of study).  Written 
confirmation of enrollment will be faxed to the enrolling site within 24 hours, along with 
assigned study number.  Study numbers for each patient will be assigned serially. 
Pertinent 
information will be entered from the patient medical record.
5.0
Investigational Treatment Plan
5.1
Dose and Schedule
Phase Ib:  In the phase Ib study, patients will start both PLX3397 and eribulin on day 1.  Patients 
will take PLX3397 in two divided doses (twice daily), the first dose immediately followed by the 
IV administration of eribulin.  A tumor biopsy will be obtained before treatment start.  
Pharmacokinetics will be obtained as outlined in section 14.4. The study will use a single-arm, 
open-label, phase I trial design with expanded cohort for response assessment. Eligible patients 
must have confirmed metastatic carcinoma of the breast and have received at least one prior 
cytotoxic chemotherapy regimen for advanced disease. 
The study will follow a standard dose-escalation schema with 3 to 6 patients per cohort (3+3 
design). The starting dose level will consist of PLX3397 at 600 mg by mouth daily. Enrollment 
to successive cohorts up to dose level 2 will be performed according to the table shown below, to 
establish the MTD. If 2 or more dose-limiting toxicities (DLTs) are observed at level 0, one dose 
reduction (to level -1) is built in to the study design. All patients at a given dose level will be 
followed on treatment for at least 3 weeks before accrual to the next cohort can commence. 
There will be no intra-patient dose escalation allowed. For any dose cohort, if a patient is 
removed from study for reasons that are clearly not treatment-related, then an additional patient 
will be accrued to that dose level. For the purposes of Phase Ib dose escalation, DLTs will be 
defined as any treatment-related toxicity occurring within the first 21 days of combination 
therapy as noted in section 3.1.1.
Dose Escalation Schedule
Dose
Dose Level
PLX3397
 Eribulin
Level -2
400 mg
(200 mg BID)
0.7 mg/m2, 2-5 min IV
Day 1, 8 q21 days
Level -1
400 mg
(200 mg BID)
1.1 mg/m2, 2-5 min IV
Day 1, 8 q21 days
Level 0 
(starting dose)
600 mg
(400 mg AM; 
200 mg PM)
1.4 mg/m2, 2-5 min IV
Day 1, 8 q21 days
Level 1
800 mg
(400 mg BID)
1.4 mg/m2, 2-5 min IV
Day 1, 8 q21 days


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Level 2
(MTD)
1000 mg
(600 mg AM; 
400 mg PM)
1.4 mg/m2, 2-5 min IV
Day 1, 8 q21 days
Due to the bone marrow suppression known to occur with eribulin, patients may receive myeloid 
growth factors at any time, at physician discretion (for guidelines regarding use of neupogen, see 
section 6.1). An eribulin premedication regimen of intravenous dexamethasone (6 mg, or 
physician-selected dose), or other equivalent steroid, <60 minutes prior to eribulin. This may be 
tapered with subsequent doses per investigator discretion.
Note:  Patients enrolled on to the trial under protocol version 6.0 which allowed for Eribulin 
dosing schedule of Day 1 and Day 15 every 28 days will remain on that treatment and 
assessment schedule.  
Phase II:  The phase II portion will begin after the MTD for PLX3397 is determined and we will 
enroll a total of 56 patients with triple (ER/PR/HER2) negative metastatic breast cancer to 
evaluate the safety and efficacy of the proposed treatment. In the phase II study, treatment is 
preceded by a 6 to7 day lead-in phase, in which patients will take PLX3397 800mg (400 mg in 
the morning and 400 mg at night) alone for 5 days, followed by 1 to 2 days off before starting 
eribulin combined with PLX3397.  PLX3397 will continue to be given on a 5 days on, 2 days off 
schedule, repeated weekly, throughout the course of treatment. Concomitant antihistamines are 
recommended to reduce the incidence of rash. A tumor core biopsy will be obtained before 
treatment start, and then again before the start of eribulin.  Patients will be treated until clinical 
or radiographic disease progression or cumulative toxicity and will be evaluated regularly in 
clinic.  Evaluation of disease response or progression will be accomplished with CT scans, and 
bone scans as indicated, every 6 weeks. Visits will take place before each dose of eribulin (Day 1 
and Day 8) during cycle 1, and then on Day 1 before cycle 2 and beyond.  
5.2
Duration of Therapy
Treatment with the combination of PLX3397 and eribulin will continue until patients experience 
disease progression based on RECIST v1.1 criteria, toxicity that prevents continued treatment, or 
in the case of patient decision. 
Patients who have evidence of systemic response or disease control after at least one full cycle of 
eribulin and PLX3397 and who develop brain metastases may stay on study with a break in study 
therapy of up to one month in order to complete brain directed therapy. Brain directed therapy 
may include whole brain radiation or stereotactic radiosurgery.  Eribulin should be held during 
whole brain radiation but need not be adjusted for stereotactic radiation.  Stereotactic radiation 
should be scheduled for the week off of eribulin if at all possible. Patients may resume treatment, 
if deemed safe per the PI.
6.0
General Concomitant Medication and Supportive Care Guidelines
Concomitant treatment is permitted if the medication is not expected to interfere with the 
evaluation of safety or efficacy of the study drug. During the study, if the use of any concomitant 
treatment becomes necessary (e.g., for treatment of an adverse event), the treatment must be 


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recorded on the CRF, including the reason for treatment, generic name of the drug, dosage, route, 
and start and stop dates of administration.  Antihistamines (i.e. loratadine or cetirizine) are 
recommended as pre-meds for all pts to prevent rash, and growth factor use is strongly 
recommended as prophylaxis for patients who have a history of bone marrow suppression on 
past chemotherapy and is allowed at the treating physicians discretion.
Although PLX3397 does not appear to inhibit CYP drug-metabolizing enzymes to an important 
extent, caution is warranted when administering PLX3397 to subjects taking drugs that are 
highly dependent on CYP3A4 for metabolism and have a narrow therapeutic index.
Of the five major CYP isoforms, 3A4 (BFC) may be involved in phase I metabolism (first pass) 
of PLX3397, with possibly CYP1A2 playing a minor role. Until information regarding exposure-
toxicity and exposure-response relationships are available with PLX3397, concomitant CYP3A4 
inhibitors and inducers should be administered with caution, in the event they alter the systemic 
exposure to PLX3397 (see Appendix I for a list of common CYP3A4 inhibitors and inducers). In 
general, strong inhibitors or inducers of CYP3A4 should be avoided unless absolutely clinically 
necessary without effective alternatives. These include anticonvulsants, mycin antimicrobials, 
and antiretrovirals. Some common examples include inhibitors such as erythromycin, fluoxetine, 
gemfibrozil, and inducers such as rifampicin, carbamazepine, phenytoin, efavirenz, and 
nevirapine.
6.1
Use of Myeloid Growth Factors
The primary toxicity of eribulin is bone marrow suppression, specifically neutropenia. Patients 
enrolling on this study will have had prior exposure to chemotherapy so will be at risk for bone 
marrow suppression. Myeloid growth factors will be allowed at physician discretion at any time, 
including during the DLT period. It is recommended that NCCN guidelines are followed.  
Myeloid growth factors will be allowed at any time following NCCN guidelines.
In particular, prophylactic neupogen should be considered for patients requiring growth factor 
support with prior systemic chemotherapy.  
7.0
Toxicity Management & Dose Modifications
The following dose modification rules will be used with respect to potential toxicity.  Toxicity 
will be assessed continuously according to the NCI Common Terminology Criteria for Adverse 
Events Version 4.0 (CTCAE v4.0) 
The AE may be due to PLX3397 or eribulin alone in which case the respective agent should be 
reduced. If overlapping toxicity is suspected both drugs may be reduced with the potential to re-
escalate the non-offending agent. Given the different nature of PLX3397 and eribulin toxicities, 
separate tables are shown for individual agents. 
7.1
PLX3397
Phase I


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PLX3397 dose reductions and interruptions will be permitted during the first 21 days of Cycle 1 
only if a patient experiences a protocol-defined DLT. If a patient experiences a DLT during 
Cycle 1, PLX3397 treatment continuation at a lower dose may be permitted at the discretion of 
the Investigator including following Cycle Day 1 chemotherapy.  In particular, prophylactic 
neupogen should be considered for patients requiring growth factor support with prior systemic 
chemotherapy.  After Cycle 1 Day 21, dose reductions or interruptions for adverse events may 
take place at any time.
Phase II
Guidelines for dosage modification for PLX3397–related toxicities as well as guidelines for their 
management are noted in Table 7-1. Please notify the Principal Investigator or UCSF study 
coordinator  about all dose modifications. Dose reductions should occur in increments of 200 
mg. These parameters are only suggestions and are not intended to supersede the clinical 
judgment of the treating physician. All adjustments should be made in consultation with the site 
specific Principal Investigator.
Table 7-1.  Dose Modifications Guidelines for PLX3397
Toxicity Grade
(CTCAE v4)
PLX3397 dose changes during 
current treatment period
Dose adjustments for 
resumption of treatment
Non-Hematologic Toxicity
Drug Related Grade 3 (start symptomatic treatment when possible)
1st Appearance
Continue treatment and provide 
supportive care
Reduce by one dose level if symptoms persist 
for  ≥5 days despite supportive management.
2nd Appearance
Interrupt until resolved (grade 0 -1 
or baseline)
Reduce by an additional dose level. 
3rd Appearance 
Discontinue permanently
N/A
Drug Related Grade 4 (start symptomatic treatment when possible)
1st Appearance
Interrupt until resolved (grade 0 -1 
or baseline)
Reduce by one dose level. 
2nd Appearance 
Discontinue permanently
N/A
Hematologic Toxicity
Grade 4 neutropenia
1st Appearance
Interrupt until ANC recovers; 
provide growth factor support
Once recovered to ANC ≥500X106/L, resume 
at same dose. If ANC does not recover to ≥ 
1X109/L after 7 days, reduce dose by one  dose 
level
2nd Appearance
Interrupt until ANC recovers; 
provide growth factor support
Once resolved to ANC ≥500X106/L, reduce 
dose by one dose level. If ANC does not 
recover to ≥1X109/L after 7 days, reduce dose 
by an additional dose level . 
3rd Appearance
Interrupt until ANC recovers; 
provide growth factor support
If ANC does not recover to ≥500X106/L after 
14 days, discontinue permanently.
Grade 2 and > 2x Baseline elevation of  liver enzymes (ALT, AST, AlkPhos)
1st Appearance
Interrupt until recovers to less than 
No Change


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Table 7-1.  Dose Modifications Guidelines for PLX3397
Toxicity Grade
(CTCAE v4)
PLX3397 dose changes during 
current treatment period
Dose adjustments for 
resumption of treatment
Grade 2
2nd Appearance
Interrupt until recovers to less than 
Grade 2
Reduce byone dose level 
3rd Appearance
Interrupt until recovers to less than 
Grade 2
Reduce by an additional dose level 
4th Appearance
Discontinue permanently
Grade 3 or Grade 4 febrile neutropenia
1st Appearance
Interrupt until ANC and fever 
recovery; provide growth factor 
support
Once resolved to ANC ≥500X106/L and T ≤ 
38˚C, reduce dose by one dose level
2nd Appearance
Interrupt until ANC and fever 
recover; provide growth factor 
support
Once resolved to ANC ≥500X106/L and T
 ≤38˚C, reduce dose by an additional dose level 
3rd Appearance
Discontinue permanently
N/A
Grade 4 thrombocytopenia
1st Appearance
Interrupt until PLT ≥ 25X109/L
Reintroduce at same dose
2nd Appearance
Interrupt until PLT ≥ 25X109/L
Reduce dose by one dose level
3rd Appearance
Interrupt until PLT ≥ 25X109/L
Reduce dose by one dose level
4th Appearance
Discontinue permanently
N/A
Dose interruptions for Grade 2 non-hematologic toxicity for up to 1 week can be implemented at 
the discretion of the treating physician to manage intolerable or clinically significant toxicity. No 
dose reduction is required when resuming treatment.
A dose delay of greater than 21 days from the intended date of eribulin administration or a 21 
day hold in administration of PLX3397 requires removal from study therapy.
Every effort should be made to adhere to the intended schedule whenever possible.
7.2
Eribulin
Phase I
Eribulin dose reductions will be permitted during the first 21 days of Cycle 1 only if a patient 
experiences a protocol-defined DLT.  Patients starting at 1.4 mg/m2, eribulin dose reductions 
will be permitted at physician discretion on Cycle 1, Day 8 – this will not be considered a DLT.
If a patient experiences a protocol-defined DLT during Cycle 1, eribulin dose reduction will be 
permitted at physician discretion. After Cycle 1 Day 21, dose reductions or interruptions for 
adverse events may take place at any time.
Phase II


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Guidelines for dosage modification for eribulin–related toxicities as well as guidelines for their 
management are noted in Table 7-2.
Table 7-2. Guidelines for dosage modification for eribulin–related toxicities
Toxicity
NCI-CTC grade, 
unless otherwise 
specified
Management of 
eribulin
Dose upon resumption
Neutropenia 
(ANC <1000) +/- fever (T>38)
1st episode
Hold until afebrile and 
ANC >1000
No change and add filgrastim
 
2nd episode
Hold until afebrile and 
ANC >1000
No change
If ANC does not recover to ≥ 
1X109/L after 7 days despite 
growth factor use, reduce  by 
one dose level 
 
3rd episode
Hold until afebrile and 
ANC >1000
  Reduce by one dose level
 
4th episode
Remove from study
Remove from study
Thrombocytopenia
Grade 2 or greater 
(<75K)
Hold until >75K
No change
 
Recurrent grade 2 
or greater
Hold until >75K
Reduce by one dose level
 
3rd occurrence 
grade 2 or greater
Hold until >75K
No change
 
4th occurrence 
grade 2 or greater
Remove from study
Remove from study
Rash
Grade 1 or 2
Continue treatment; 
supportive care
No change**
 
Grade 3
Hold until grade1 or 
less; supportive care
No change**
 
Second episode 
grade 3
Hold until grade1 or 
less; supportive care
Reduce by one dose level
 
3rd occurrence  
grade 3
Remove from study; 
supportive care
Remove from study
GI toxicity: diarrhea, nausea, 
vomiting
Grade 1, 2
Continue treatment
No change; maximize 
supportive treatment
 
Grade 3
Hold until grade 1 or 
less 
No change; maximize 
supportive treatment
 
Recurrent grade 3 
Hold until grade 1 or 
less 
No change
 
3rd occurrence 
Hold until grade 1 or 
less 
Reduce by one dose level
 
4th occurrence 
grade 3 or 4
Remove from study
Remove from study
Liver function abnormalities 
(ALT, AST, Alk Phos only)
Grade 1, 2
Continue treatment
No change
Grade 3 and >2x 
baseline
Hold until less than 
grade 3
No change
recurrent 3 and 
>2x baseline
Hold until less than 
grade 3
Reduce by one dose level
Neuropathy (motor and 
Grade 1, 2
Continue treatment
No change


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Table 7-2. Guidelines for dosage modification for eribulin–related toxicities
Toxicity
NCI-CTC grade, 
unless otherwise 
specified
Management of 
eribulin
Dose upon resumption
sensory)
Grade 3 
Hold until less than 
grade 3
No change
Recurrent grade 3
Hold until less than 
grade 3
Reduce by one dose level
3rd occurrence 
grade 3
Remove from study
Remove from study
Dose interruptions for Grade 2 non-hematologic toxicity for up to 1 week can be implemented at 
the discretion of the treating physician to manage intolerable or clinically significant toxicity. No 
dose reduction is required when resuming treatment.
A dose delay of greater than 21 days from the intended date of eribulin administration or a 21 
day hold in administration of PLX3397 requires removal from study therapy.
Every effort should be made to adhere to the intended schedule whenever possible.
Dose Reduction Levels for PLX3397 and Eribulin 
Dose
Dose Level
PLX3397
 Eribulin
Starting Dose
800 mg x 5 days/week
(400 mg BID x 5days, 
followed by 2 days off, 
repeated weekly)
1.4 mg/m2, 2-5 min IV
Day 1, 8 q21 days
1st dose reduction
600 mg x 5 days/week
(400mg AM and 200mg PM x 
5days, followed by 2 days 
off, repeated weekly)
1.1 mg/m2, 2-5 min IV
Day 1, 8 q21 days
2nd dose reduction
400 mg x 5 days/week
(200mg BID x 5days, 
followed by 2 days off, 
repeated weekly)
0.7 mg/m2, 2-5 min IV
Day 1, 8 q21 days


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8.0 
Schedule of Assessments 
Table  8-1 Study Calendar: Phase Ib
Cycle 
(1 cycle = 
21 days)
Comment
Screening
Cycle 1
Cycle 2
Cycle 3 & 
Beyond
EOT 
Real life 
time clock
≤4 
wks
≤2 
wks
D 11
D 2
D 8 D 15
D 11
D 8
D15
D 11
D 8
D15
≤ 30 
days
Informed 
Consent 
X
Registration
X
History & Exam
X
X
X
X
X
X
ECOG
X
X
X
X
X
ConMed 
Review
X
X
X
X
X
X
X
X
Peripheral
Neuropathy 
X
X
X
X
CBC w/ 5 part 
diff.
X
X
X
X
X
X
X
X
Chemistry
Panel 
BUN, CO2, Cl, K, 
Na, Creatinine, 
Glucose (non-
fasting), & 
Magnesium
X
X
X
X
X
Liver Function 
Tests
ALT, AST, AlkPhos, 
Total Bilirubin, & 
Albumin
X10
X10
X10
PT/PTT
Completed prior to 
tumor biopsy
X
Urine Pregnancy 
Test 2
Within 7 days of 
beginning treatment
X
X
EKG 3
X
X
Eribulin 
Therapy, IV4
Day 1 & 8, 
q 21 days 
X
X5
X
X
X
X
PLX3397 
Therapy
Oral
Beginning Cycle 1, Day 1: Daily 
(self-administered)
Bone Scan & 
other imaging 
Baseline, then as 
indicated 
X
CT (C/A/P)
Every 6 weeks 
X
X
X
PK Draws
X6
X7
X8
Blood for 
CSF19
X
X
X
Blood for 
Leukocyte 
Subtyping9
X
Tumor biopsy 
Required for patients 
w/ accessible tumor
X
Archived Tumor 
Tissue 
Requested of all 
participants
X


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1.
Allowed a window of ± 3 days for Day 1 procedures
2.
In women of child bearing potential
3.
EKGs performed at the start of every other cycle (even numbered), at 6 week intervals
4.
The following eribulin treatment delays are allowed for patient coordination:
C1 D8 (up to 3 days), C2+ D1 (up to 14 days), and C2+ D8 (up to 3 days)
5.
A delay in C1 D8 of up to 7 days is allowed for resolution of toxicity
6.
Plasma samples for PK on C1 D1 will occur pre-PLX3397 administration 
and at 1, 2, and 5 hours post treatments (± 15 minutes)
7.
Plasma samples for PK on C1D2 will occur 24 hours post eribulin treatment, 
but pre-PLX3397 administration (± 30 minutes)
8.
Plasma samples for PK on C2D1 will occur pre-PLX3397 and at 2 hours post treatment (± 15 minutes)
9.
All blood should be drawn before administration of IV eribulin
10. Liver function tests will be completed on D15 of the firsts three cycles only (C1D15, C2D15, and C3D15).


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Table 8-2 Study Calendar: Phase II
Cycle 
(1 cycle = 
21 days)
Comment
Screenin
g
Lead-In 
Phase
Cycle 1
Cycle 2
Cycle 3 
& 
Beyond
EO
T 
Real life 
time clock
≤4 
wks
≤2 
wks
Day
 -7 to -6
D 11
D 8
D15
D 11
D 8
D15 D 11 D 8 D15
≤ 30 
days
7
Informed 
Consent 
X
Registration
X
History & Exam
X
X
X
X
X
X
ECOG
X
X
X
X
X
ConMed Review
X
X
X
X
X
X
X
X
Peripheral
Neuropathy 
X
X
X
X
CBC w/ 5 part 
diff.
X
X
X
X
X
X
X
X
Chemistry
Panel 
BUN, CO2, Cl, K, 
Na, Creatinine, 
Glucose (non-
fasting), & 
Magnesium
X
X
X
X
X
Liver Function 
Tests
ALT, AST, 
AlkPhos, Total 
Bilirubin, & 
Albumin
X
X
X
X10
X
X
X10
X
X
X10
X
PT/PTT11
Completed prior to 
tumor biopsy 
X
Pregnancy Test 2
Within 7 days of 
beginning treatment
X
X
EKG 3
X
X
Eribulin 
Therapy, IV4
Day 1 & 8, 
q 21 days 
X
X5
X
X
X
X
PLX3397 
Therapy
Oral
Beginning With Lead-In Phase (Day -7 to -6):
 Daily (self-administered)
Bone Scan & 
other imaging 
Baseline, then as 
indicated 
X
CT (C/A/P)
Every 6 weeks9 
X
X
X
Blood for 
CSF16
X
X
X
X8
Blood for 
Leukocyte 
Subtyping6
X
X
X
X8
Tumor biopsy 
Required for 
patients w/ 
accessible tumor
X
X 
(Day 
0/ -1)
Archived Tumor 
Tissue 
Requested of all 
participants
X
1.
Allowed a window of ± 3 days for Day 1 procedures
2.
In women of child bearing potential. Urine or Serum test allowed. 
3.
EKGs performed at the start of every other cycle (even numbered), at 6 week intervals
4.
The following eribulin treatment delays are allowed for patient coordiantion:
C1 D8 (up to 3 days), C2+ D1 (up to 14 days), and C2+ D8 (up to 3 days)
5.
A delay in C1 D8 of up to 7 days is allowed for resolution of toxicity


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6.
Blood should be drawn before the first dose of PLX3397 during the lead-in phase, and before each administration of 
eribulin. 
7.
EOT procedures should occur within 30 days of last dose, after which the patient will be Off-Study.
8.
Cycle 4 Day 1 only
9.
Patients with either CR or PR and who have received at least 6 cycles of therapy may reduce the frequency of scans to 
every 9 weeks.
10. Liver function tests will be completed on D15 of the first three cycles only (C1D15, C2D15, and C3D15).
11. PT/PTT is only required for patients getting visceral organ biopsies
8.1
Screening Assessments (same for both the Phase Ib and Phase II study)
The following screening procedures must be performed within 2 weeks (or 4 weeks where noted) 
of entering the clinical trial:

Patients must have reviewed and signed the consent form (within 4 weeks)

Complete medical history and physical to determine if patient meets the study entry 
criteria  

Review of concomitant medications

Baseline laboratories, including: complete blood count with 5 part differential, chemistry 
panel, liver functions tests, PT/INR, and PTT

Pregnancy test if patient has childbearing potential (within 7 days) 

Tumor imaging, including a CT scan of the chest, abdomen, and pelvis and bone scan, or 
a whole body PET CT for patients with measurable disease.    PET CT scans must 
include a diagnostic CT to be study eligible (cannot use CT scans for attenuation only 
purposes).

12-lead EKG

Request archived tumor tissue

Tumor biopsy for patients with accessible tumor

Blood for correlative studies 
8.2
Assessments During Treatment 
Once the patient is confirmed to be eligible based on screening assessments, the following study 
assessments will be performed. See Table 8-1 and 8-2 for summary. One cycle is defined as 21 
days.  Day 1 visit procedures for any cycle of therapy are allowed a window of ± 3 days unless 
otherwise noted.  Following the first cycle of therapy, patients may delay the start of a new cycle 
of therapy up to 2 weeks as necessary for personal activities, such as travel or vacation although 
every attempt should be made to keep patients on schedule.  Treatment or visit delays due to 
public holidays, weather conditions, or natural disasters, do not constitute protocol violations.  
The following treatment delays are allowable for patient coordination:

Cycle 1, Day 8 – delay eribulin administration up to 3 days

Cycle 2+, Day 1 – delay eribulin administration up to 14 days

Cycle 2+, Day 8 – delay eribulin administration up to 3 days
8.2.1
Lead in Phase - Phase II only, Day -7/-6

Blood for CSF1 and leukocyte phenotyping 
o
For CSF1: 5 cc of blood will be drawn into a serum separator tube (gold top)
o
For leukocyte phenotyping:  10 cc of blood will be drawn into an EDTA tube 
(purple top)


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
Tumor Biopsy Day 0/-1
8.2.2
During Cycle 1 (same for Phase Ib and Phase II except where noted below)
The following assessments will be performed prior to receiving treatment on Day 1: 

Medical history and physical examination

Review of concomitant medications

Laboratories, including complete blood count, chemistry panel and liver function tests.

Blood for CSF1 and leukocyte phenotyping

Blood for pharmacokinetics (Phase I only) 
The following assessments will be performed after receiving treatment on Day 1 (Phase Ib only):

Blood  for pharmacokinetics will be drawn at 1 hour, 2 hours and 5 hours post treatment
    
 The following assessment will take place on Day 2 (Phase Ib only):

Blood for pharmacokinetics and CSF1 will be drawn 24 hours post Day 1 treatment 
The following assessment will take place on Day 8: 

Medical history and symptom-driven physical examination

Laboratories, including complete blood count with differential

Review of concomitant medications
The following assessment will take place on Day 15: 

Liver function tests
8.2.3
During Subsequent Cycles (Cycle 2 and beyond) 
The following assessments will be performed prior to receiving treatment on Day 1: 

Medical history and physical examination

Review of concomitant medications

Laboratories, including complete blood count, chemistry panel

and liver function tests. Urine Pregnancy test will only be done for women of 
childbearing potential (Cycle 3+)

Blood for CSF1 and leukocyte phenotyping (Cycle 2 and 4 Day 1only)

Blood for pharmacokinetics (Cycle 2, Phase Ib only) 
The following assessments will be performed after receiving treatment on Day 1: 

Blood  for pharmacokinetics will be drawn at 2 hours post treatment (C2, Phase Ib only)
The following assessments will take place on Day 8: 

Laboratories, including complete blood count with differential

Review of concomitant medications
The following assessment will take place on Day 15: 

Liver function tests (Cycles 2 and 3 only)


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Scans including all measurable and/or evaluable disease will be obtained every 6 weeks and at 
End of Treatment. Patients with either CR or PR and who have received at least 6 cycles of 
therapy may reduce the frequency of scans to every 9 weeks.
8.3
Follow-Up Assessments
Patients will be permitted to stay on treatment until they have disease progression.
Patients who develop progressive disease or Grade 3/4 toxicity that does not resolve after 
discontinuation of all study medications for 14 days will be removed from the study.  All patients 
who leave the study must have a follow up visit within 30 days after their last dose of study 
medication.  At this time, patients will have the following:

Full medical history and physical exam for assessment of residual toxicities

Blood draw for complete blood count with differential, chemistry panel, and liver
function tests
If patients continue to have evidence of persistent toxicities at the first follow up visit, they will 
have continued monitoring at the discretion of the principal investigator until these symptoms are 
resolved or considered stable.  
9.0
Criteria for Evaluation
9.1
Response Definitions
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with PLX3397
Evaluable for objective response:  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-
target disease.  The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions.
Disease Parameters
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 (≥2 cm) by chest x-ray or 
as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 


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node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in follow-up, 
only the short axis will be measured and followed.
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 
short axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 


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(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable. 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.  
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 
2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000].
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 


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during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
Response Criteria
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm).
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is 
also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis).
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator).
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.


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


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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
9.2
Toxicity Definitions
All study toxicities will be graded by the NCI Common Terminology Criteria for Adverse Events 
Version 4.0.
10.0
Criteria for Termination
10.1
Conditions for Terminating the Study
The Principal Investigator may terminate the study for any of the following reasons:

Significant toxicities: Patients with any grade 3/4 toxicity that persists and does not 
improve 21 days after discontinuation of all study medications, despite pharmacologic 
management, will be removed from the study.  Any patient who experiences any grade 4 
toxicity can be removed from the study at the discretion of the study investigator.

If it becomes clear that the study treatment is less effective than standard treatment.  The 
phase II study has a two-stage design (see section 3 for more details).  If fewer than 8 out 
of the first 20 pts are progression-free at 12 weeks, this would be considered an 
unacceptably low PFS rate (<39%), the study will not continue and accrual will cease. 
Study accrual will continue while efficacy is being determined. Conversely, if at least 7 
patients in the first stage of the phase II study are free of progressive disease at 12 weeks, 
then enrollment will continue to the second stage of the study. .

Once all data collection has been completed.
10.2
Conditions for Individual Patient Termination
The Principal Investigator may terminate the participation of an individual patient for any of the 
following reasons:

Disease progression

Need for exclusionary concurrent treatment

Withdrawn consent

Protocol non-compliance

Lost to follow-up
11.0
Drug Information
Eribulin is supplied in single-use vials containing 1 mg of the drug at a concentration of 0.5 
mg/mL. The single-vial cartons should be stored at 25 °C.


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The recommended dosage of eribulin is 1.4 mg/m2 administered intravenously over two to five 
minutes on days 1 and 8 of a 21-day cycle. Eribulin may be administered undiluted or diluted in 
100 mL of 0.9% Sodium Chloride Injection, USP. The drug should not be administered through 
an IV line that is delivering a dextrose-containing solution. 
Syringes containing undiluted eribulin and containers of diluted eribulin may be stored up to 4 
hours at room temperature or up to 24 hours refrigerated at 25 °C.
The labeling includes recommendations for dosage reductions in patients with liver or kidney 
impairment.
Also included in the labeling are recommendations for reducing and delaying scheduled doses in 
response to blood-count abnormalities that develop during treatment.
The labeling states that febrile or afebrile neutropenia occurred in 82% of eribulin recipients in 
the company's pivotal Phase III clinical trial, compared with 53% of patients in the control 
group. Other adverse events that affected at least 25% of eribulin recipients were anemia, 
weakness or tiredness, alopecia, peripheral neuropathy, nausea, and constipation.
According to the labeling, blood-cell counts should be monitored during eribulin therapy and 
dosages reduced or delayed in patients with low red- or white-blood-cell counts. Patients should 
also be periodically assessed for peripheral neuropathy.
QT-interval assessments are recommended during eribulin therapy for patients who have heart 
failure, bradyarrhythmia, or electrolyte abnormalities or are receiving concomitant treatment 
with drugs that prolong the QT interval.
PLX3397 is supplied in 200 mg gelcaps. 
11.1
Eribulin mesylate (E7389)
11.1.2 Classification
Eribulin mesylate (E7389) is a synthetic analog of Halichondrin B (HalB), a natural product 
isolated from the marine sponge Halichondria okadai.1 HalB is a large polyether macrolide that 
exerts potent anticancer effects in cell-based and animal models of cancer. The structurally 
simplified synthetic analog eribulin mesylate (E7389) encompasses the biologically active 
macrocyclic portion of HalB, and shows similar or identical anticancer properties in preclinical 
models.
11.1.3 Mode of Action
E7389 exerts its antiproliferative effects via a tubulin-based antimitotic mechanism. Currently-
available data indicate that its mechanism of action is similar or identical to that of HalB.4,5 Like 
HalB, E7389 was shown to be a potent inhibitor of tubulin polymerization into microtubules as 
well as microtubule dynamics in vitro and in whole cells.4,6 Nonclinical data show that sub- to 
low-nmol/L levels of E7389 inhibit cancer cell proliferation via induction of irreversible cell 
cycle blocks at G2/M, disruption ofmitotic spindles, and initiation of apoptosis.
Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and 
sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based 


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antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, 
ultimately, apoptotic cell death after prolonged mitotic blockage.
11.1.4 Storage and Stability
The long-term storage condition for E7389 drug product is to store at 2°C to 8°C (do not freeze). 
Clinical supplies labeled for storage at temperatures up to 25°C have been reassigned to 
refrigerated storage (2°C to 8°C) to provide an extended provisional shelf life.
The drug product may be administered without dilution or diluted with 0.9% Sodium Chloride 
Injection to concentrations between 0.005 mg/mL and 0.2 mg/mL, and administered per Eisai’s 
directions.  
Photostability studies have demonstrated that protection from light is not necessary for the 
E7389 drug product.
11.1.5 Metabolism
Cytochrome 3A4 (CYP3A4) appears to be the major enzyme responsible for the human hepatic 
metabolism of E7389, and forms mainly isomeric monohydroxylates in vitro.
11.1.6 Preparation & Administration
Aseptically withdraw the required amount of HALAVEN from the single-use vial and administer 
undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. Do not dilute in or 
administer through an intravenous line containing solutions with dextrose. Do not 
administer in the same intravenous line concurrent with the other medicinal products. Store 
undiluted HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 hours 
under refrigeration (40°F or/ 4°C). Store diluted solutions of HALAVEN for up to 4 hours at 
room temperature or up to 24 hours under refrigeration. Discard unused portions of the vial.
11.1.7 Side Effects
The most common adverse reactions (≥25%) reported in patients receiving eribulin were 
neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. 
The most common serious adverse reactions reported in patients receiving eribulin were febrile 
neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in 
discontinuation of eribulin was peripheral neuropathy (5%). Because clinical trials are conducted 
under widely varying conditions, the adverse reaction rates observed in the clinical trials of a 
drug cannot be directly compared to rates in other clinical trials and may not reflect the rates 
observed in clinical practice. In clinical trials, eribulin has been administered to 1,222 patients 
with multiple tumor types, including 240 patients exposed to eribulin for 6 months or longer. The 
majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 
years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and 
other (5%). The adverse reactions were identified in 750 patients treated in Study 1 [see Clinical 
Studies (14)]. In Study 1, patients were randomized (2:1) to receive either eribulin (1.4 mg/m2 on 
Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician(control 
group). A total of 503 patients received eribulin, and 247 patients in the control group received 
therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, 
gemcitabine 19%, taxanes 15%, vinorelbine 25%, and other chemotherapies 10%)] or hormonal 


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therapy (3%). The median duration of exposure was 118 days for patients receiving eribulin and 
63 days for patients receiving control therapy. Table 2 reports the most common adverse 
reactions occurring in at least 10% of patients in either group.
11.1.8 Nursing Implications
There are no premedications required for eribulin infusion and eribulin is not a significant 
vesicant.
11.2
PLX3397
11.2.1 PLX3397 Administration
PLX3397 will be administered orally using a capsule formulation (200 mg per capsule). 
PLX3397 will be administered only to patients who have signed and dated an informed consent 
form. PLX3397 will be administered on a 5 day on, 2 day off schedule, repeated weekly, , 
beginning C1D1 (baseline) for Phase Ib, or Day -7/-6 for Phase II. PLX3397 should be taken 
orally with 240 mL (8 oz) of room-temperature water in the fasting state. The patient should 
fast at least 1 hour before administration and 1 hour after administration of PLX3397. 
Patients will be permitted to eat a low-fat, bland snack (e.g., crackers, toast, tea) during the 
fasting period if needed.
PLX3397 should be taken by the patient at approximately the same time of day. 
Instructions for BID Dosing:
The time between BID doses should be approximately 12 hrs. Dosing may occur once daily 
(QD) under certain circumstances (e.g. dose reductions) and at the discretion of the Investigator 
in consultation with the Principal Investigator. 
On C1D1, C1D2 and C2D1, the patients should take the morning dose of PLX3397 at the 
clinical site after the pre-dose PK blood sample is obtained– patients should be instructed not to 
take the study drug at home prior to these clinic visits. The time of dosing will be recorded in the 
clinic. The evening dose of PLX3397 should be taken by the patient at home. On all other visit 
days, patients may administer the study drug at home and record dosing information in the 
PLX3397 administration diary. 
Missed doses of greater than 2 hrs before or after the appropriate dosing time should be 
skipped and not taken as a double dose at the next dosing timepoint. For example, a patient 
who takes their PLX3397 at 8 a.m. and 8 p.m. each day should not take their dose if they are 
outside of the ±2 hr window period.
Patients who vomit their dose should be instructed to NOT make up that dose. 
11.2.2 PLX3397 Packaging and Labeling
PLX3397-HCl capsules (200 mg strength of the active free base of PLX3397) are manufactured, 
packaged, and labeled according to GMP and GCP at the following address:


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11.2.3 PLX3397 Storage and Stability
PLX3397-HCl capsules will be stored at the clinical site, as indicated on the study drug label, 
i.e., room temperature (between 15-30ºC, or 59-86ºF).
Patients will be requested to store PLX3397 at the recommended storage conditions noted on the 
label, out of the reach of children or other cohabitants.
11.2.4 PLX3397 Accountability, Reconciliation, and Return
The investigator is accountable for all test article supplied by the Sponsor. Copies of the 
completed source dispensing and inventory record(s) will be returned to the Sponsor (or 
designee) after the Sponsor (or designee) has performed accountability procedures. PLX3397 
accountability will also be captured in the EDC throughout the course of the trial.
All PLX3397 capsules must be returned to the contract distribution center with the appropriate 
form if there is evidence that the product has been tampered within transit. Returned and unused 
PLX3397 capsules may also be destroyed and documented at the investigative site in accordance 
with GCP.
11.2.5 PLX3397 Compliance
At each clinic visit, patients will be questioned about their PLX3397 compliance. PLX3397 
compliance will also be tracked through a patient diary.
11.2.6 PLX3397 Toxicity
PLX3397 treatment-emergent Adverse Events occurring in ≥10% of patients with solid tumors 
are listed in the table on the following page (combined data from 5 studies, including Phase I, 
Phase I/II, and Phase II studies).


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8 serious adverse events (SAEs) possibly or probably related to study drug have been reported in 
5 patients in the pooled solid tumor studies (listed in table below). No SAE has been reported 
more than once.
Please refer to the PLX3397 Investigator’s Brochure (version 6 dated October 27, 2014) for 
more detailed information.
One patient experienced constrictive pericarditis.  The finding was seen on one echocardiogram 
and resolved on the first follow-up echocardiogram 2 weeks later.  This patient had cancer cells 
in the fluid around the heart, which may have contributed to the inflammation.  The study doctor 
could not rule out the possibility of this event being related to study drug.
12.0
Statistical Considerations
12.1
Endpoint Definitions
Phase I
The study will follow a standard dose-escalation schema (Phase Ib portion) with 3 to 6 patients 
per cohort (3+3 design). The starting dose level will consist of PLX3397 600 mg. Enrollment to 
successive cohorts up to dose Level 2 will be performed according to the table shown below, to 
establish the MTD. If 2 or more dose-limiting toxicities (DLTs) are observed at level 0, one dose 
reduction (to Level -1) is built in to the study design. All patients at a given dose level will be 
followed on treatment for at least 3 weeks before accrual to the next cohort can commence. 
There will be no intra-patient dose escalation allowed. For any dose cohort, if a patient is 
removed from study for reasons that are clearly not treatment-related, then an additional patient 
will be accrued to that dose level. 
Dose Escalation Schedule
Dose
Dose Level
PLX3397
 Eribulin


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Dose Escalation Schedule
Level -2
400 mg
(200 mg BID)
0.7 mg/m2, 2-5 min IV
Day 1, 8 q21 days
Level -1
400 mg
(200 mg BID)
1.1 mg/m2, 2-5 min IV
Day 1, 8 q21 days
Level 0 
(starting dose)
600 mg
(400 mg AM; 
200 mg PM)
1.4 mg/m2, 2-5 min IV
Day 1, 8 q21 days
Level 1
800 mg
(400 mg BID)
1.4 mg/m2, 2-5 min IV
Day 1, 8 q21 days
Level 2
1000 mg
(600 mg AM; 
400 mg PM)
1.4 mg/m2, 2-5 min IV
Day 1, 8 q21 days
Phase II
The Phase II portion will begin after MTD is determined and we will enroll a total of 56 patients 
with TNBC to evaluate the safety and efficacy of the proposed treatment. Patients will be treated 
until clinical or radiographic disease progression or cumulative toxicity. Patients will be 
evaluated regularly in clinic with history, physical examination, and CT scans every 6 weeks. 
Visits will take place weekly during the first cycle (one cycle = 21 days) of study treatment, and 
then on day 1 and 8 of every 3 week cycle during the second cycle and beyond. 
For Phase II, sample size is based under the Simon’s 2-stage optimal design for progression-free 
survival at 3 months as a single proportion. The study is designed to determine the following 
hypothesis with >80% power and 2-sided type I error of 5% using binomial approximation: H0: 
PFS% <39% versus Ha: PFS% > 57% (with PLX3397), where PFS% is the proportion of 
progression-free (PFS) at 3 months. The PFS% of >57% would represent a clinically relevant 
improvement with the treatment in triple-negative patients with locally recurrent or metastatic 
breast cancer. Based on these considerations, a sample size of 51 evaluable patients is required 
for the study. We plan for a targeted enrollment of 56 patients with 10% dropout rate.
Interim assessment and stopping rules for Safety and efficacy 
Safety and SAE data will be routinely monitored. Because of the possibility of unacceptable or 
excessive defined serious adverse events during treatment or the study enrollment period, 
stopping rules for safety/tolerability are also developed. We have set the maximum rate of 
treatment-related SAE at 15% in patient enrollment. Thus, we may consider terminating the 
study if the number of patients with SAE is greater than the number expected under the binomial 
distribution. The following table shows the early stopping guideline based on the number of SAE 
observed under the rate of unacceptable SAE in the group sequential enrolment for the study. For 
example, assuming the unacceptable rate of SAE is greater than 15%, if the study observes 3 or 
more SAE in the first 17 treated patients, then we may consider if the study should be stopped 
early.
Safety Stopping Rules: 
Number of enrolled patients with excessive SAE to consider early study termination.


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Number patients in study
1-17
18-29
30-41
Unacceptable SAE – 15%
3
4
6
Efficacy Stopping Rules
Failure to obtain early responses at the scheduled tumor assessments will be taken as evidence 
that the regimen in question is ineffective. If fewer than 8 out of the first 20 pts are progression-
free at 12 weeks, this would be considered an unacceptably low PFS rate (<39%), the study will 
not continue and accrual will cease. Accrual will contiue while efficacy data is being determined. 
If 25 or fewer pts are progression free at 12 weeks at full accrual, then the treatment would be 
deemed ineffective. If the true PFS rate at 12 weeks is 39% for TNBC pts, the probability of 
terminating the study during the interim evaluation is 0.63; if the true PFS rate is 57% for TNBC 
pts, the probability that the trial will be stopped in the first stage is 0.10. 
12.2
Analysis Plan
Primary Efficacy Endpoint 
Demographics and Baseline Characteristics
Demographic data (age, sex, race, ethnicity, body weight) and baseline disease characteristics will be 
tabulated and summarized and presented in data listings.
Progression Free Survival 
Progression-free survival at 3 months (PFS) is defined as the proportion of patients alive and 
progression-free 90 days after Study Day 1. Duration of PFS is defined as the time from Study 
Day 1 to the earlier of disease progression or death due to any cause. 
Progression free survival will be calculated from the first administration of PLX3397 with 
eribulin. The analyses of PFS will be performed using the Per Protocol population. These 
analyses are designed to include only objective progression events per the RECIST v1.1 criteria. 
Patients who do not have any post-baseline tumor assessments will be right censored on the date 
of Study Day 1. Patients who receive subsequent anti-cancer therapy before experiencing an 
event will be right censored at the date of the last tumor assessment prior to the date of initiation 
of subsequent therapy. Patients who have not experienced an event (and are not otherwise 
censored) at the time of data cutoff will be right censored on the date of their last tumor 
assessment 
PFS will be estimated as a simple proportion based upon the results of the 12-week tumor 
assessment. Patients for whom this assessment is not performed will be included as failures, even 
if known to be alive at this timepoint. Confidence intervals will be provided. PFS and duration of 
PFS will also be estimated using Kaplan-Meier methods with associated confidence intervals. 
Secondary and Supportive Efficacy Endpoints 
Objective Response Rate 
The objective response rate (ORR) is defined as the proportion of patients for whom the best 
overall response at the time of data cutoff is confirmed CR or confirmed PR as assessed per 
RECIST v 1.1criteria. A table defining the derivation of best overall response to be applied will 
be provided in the SAP. 


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The analysis of ORR will employ the Per Protocol population. Patients who do not have any 
post-baseline tumor assessments will be counted as non-responders. 
Point estimates of ORR and confidence intervals will be provided. As a basic measure of dose-
response, ORR in the escalation phase will also be presented by dose cohort. Objective response 
will be assessed using the RECIST v 1.1 response criteria. The response will be collected on 
CRFs. The number and percent of subjects with each type of response will be summarized and 
presented in data listings. A 95% confidence interval will also be calculated using exact 
bionomial method. The 95% confidence interval for the difference in objective response rates 
will be calculated using exact binomial method. Time to onset of the response and duration of 
response will be also summarized using descriptive statistics.
Duration of Response 
Duration of response is defined as the time from first documentation of objective response that is 
subsequently confirmed to PD by the criteria or death due to any cause. Responders who have 
not been documented to have progressed or died at time of data cutoff will be right censored at 
the last available adequate tumor assessment.  Median duration of response for each treatment 
arm and its associated confidence interval will be estimated using the Kaplan-Meier method. 
Time to Progression
Time to progression will be estimated using the Kaplan-Meier method. Efficacy responses, 
disease progression and relapse classified based on RECIST v1.1 criteria will be used to 
determine progression. Time to progression will be calculated from the first administration of 
PLX3397 with eribulin. Patients who do not have disease progression will be censored at the 
date of the last evaluation for study disease or at the time of initiation of the new therapy, 
whichever is earlier. Patients lacking any response assessment after randomization will be 
censored at Day 1.
12.3
Accrual Objectives
Phase I
A minimum of 12 patients will enroll in the Phase I trial, following a 3+3 design for 3 cohorts.  
We estimate that 10 patients will enroll at UCSF, and 7 patients each at Duke and Vanderbilt.
Phase I completed at UCSF with 28 patients enrolled as 03/10/2015
Phase II
This study will enroll 56 patients (n=22 in the first stage and n=34 in the second stage) in the 
Phase II portion with the assumed 10% dropouts.  We estimate that 26 patients will enroll at 
UCSF and 15 each at Vanderbilt and Duke.
12.4
Estimated Duration of Study
The Phase I study is expected to complete accrual within 1.25 years, and the Phase II  study is 
expected to complete accrual over a time course of 2.5 years.
12.5
Data Safety Monitoring
See Section 16.0.


Pr ot o c ol V er si o n  # 1 0
P a g e 5 3 of 8 5
0 3/ 0 3/ 2 0 1 6
Pr ot o c ol #:  1 2 7 5 1
1 2. 6  
Re pl ace me nt  P olic y
P h ase I
F or a n y  d ose c o h ort, if a patie nt is re m o ve d fr o m st u d y f or reas o ns t hat are clearl y n ot treat me nt-
relate d, t he n a n a d diti o nal patie nt will be accr ue d t o t hat d ose le vel. 
P h ase II
Patie nts w h o  ha ve n o e val uati o n meas ures after starti n g t hera p y, a n d st o p t hera p y f or reas o ns 
ot her t ha n pr o gressi o n or t o xicit y will be re place d.  Patie nts w h o recei ve o nl y o ne d ose of 
eri b uli n or less t ha n 1 4 da ys of P L X 3 3 9 7 f or reas o ns ot her t ha n pr o gressi o n or t o xicit y will be 
re place d.
1 2. 7 
P h ar m ac o ki netic  st u dies
P har mac o ki netic st u dies will  be perf or me d as o utli ne d i n secti o n 1 4. 4. Ser u m c o nce ntrati o ns of 
P L X 3 3 9 7 wit h eri b uli n will be assesse d b y E LI S A at Ple x xi k o n I nc. a n d will be use d t o calc ulate 
t he val ues of P K para meters, i ncl u di n g ma xi m u m ser u m dr u g c o nce ntrati o n ( C ma x), area u n der 
t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o t o i nfi nit y ( A U C 0-i nf), s yste mic cleara nce ( C L), 
v ol u me of distri b uti o n ( V), a n d eli mi nati o n half-life (t 1/ 2). Descri pti ve statistics (i ncl u di n g 
n u m ber, mea n a n d/ or me dia n, sta n dar d de viati o n, a n d c oefficie nt of variati o n) will be use d t o 
descri be t he c o nce ntrati o n ti me data. W here a p pr o priate, t hese data ma y be c o m bi ne d wit h data 
fr o m ot her st u dies as part of a metaa nal ysis. T he i nfl ue nce of e x p os ure o n cli nical safet y 
para meters (e. g., selecte d A Es) will be e x pl ore d. Res ults of t he P K a nal ysis will be e val uate d i n 
c o nj u ncti o n wit h a vaila ble safet y a n d p har mac o d y na mic data.
1 2. 7  
C orrel ati ve st u dies
D ue t o  t he s mall sa m ple sizes e x pecte d fr o m t he pr o p ose d st u d y desi g n, t he c orrelati ve st u dies 
will be h y p ot hesis ge nerati n g, b ut will als o hel p pr o vi de pil ot data t o i nf or m eli gi bilit y a n d 
f oll o w u p of f ut ure trials usi n g a n M O tar geti n g  strate g y. C S F 1 le vels will be a nal yze d as a 
c o nti n u o us varia ble a n d cate g orical varia ble base d o n me dia n C S F c ha n ge wit h treat me nt. Mea n 
a n d 9 5 % c o nfi de nce i nter vals of C S F 1 le vels will be esti mate d a n d c o m pare d f or differe nces 
bet wee n d ose c o h orts. As a c o nti n u o us meas ure, A N O V A a n d Pears o n c orrelati o n will c o m pare 
C S F 1 le vels bet wee n P L X 3 3 8 9 d ose c o h orts a n d res p o nse gr o u ps. As a cate g orical meas ure, 
C hi-s q uare tests will deter mi ne t he ass ociati o ns bet wee n t u m or s u bt y pe ( m olec ular pr ofile) a n d 
i m m u ne pr ofile ( dic h ot o m o us varia ble) a n d bet wee n t u m or m olec ular pr ofile a n d C S F 1 gr o u ps. 
F A C S a nal ysis of le u k oc yte p o p ulati o ns as a perce nt of t otal C D 4 5 + cells will be e val uate d 
a m o n g t he o utc o me gr o u ps, P F S a n d O R R. T he relati o ns hi p bet wee n mea n a n d me dia n i m m u ne 
i nfiltrate a n d c o nti n u o us q ua ntitati ve meas ure me nts of t u m or classificati o n will be re p orte d usi n g 
eit her para metric ( Pears o n) a n d Fis her’s e xact tests or n o n para metric ( S pear ma n) c orrelati o n 
c oefficie nts a n d Ra n k tests a n d 9 5 % c o nfi de nce i nter vals f or eac h statistic.
1 3. 0
D at a  C ollecti o n a n d M a n a ge me nt
T he St u d y  C hair a n d/ or her desi g nee, will pre pare a n d 
mai ntai n a de q uate a n d acc urate 
partici pa nt case hist ories wit h o bser vati o ns a n d data perti ne nt t o t he st u d y.  St u d y s pecific Case 
Re p ort F or ms ( C R Fs) will d oc u me nt safet y a n d treat me nt o utc o mes f or safet y m o nit ori n g a n d 
data a nal ysis.  All st u d y data will be e ntere d i nt o O n C ore ®  via sta n dar dize d C R Fs i n acc or da nce 
wit h t he C T M S st u d y cale n dar, usi n g si n gle data e ntr y wit h a sec ure access acc o u nt.  T he 


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Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible upon 
completion of the study visit; the Investigator will review and approve the completed CRFs. 
Each participating site will complete study specific CRFs for safety monitoring and data 
analysis.  Each site will enter the study data into OnCore® via standardized CRFs in accordance 
with the CTMS study calendar, using single data entry with a secure access account. The 
participating site’s Clinical Research Coordinator (CRC) will complete the CRFs; the 
Investigator will review and approve the completed CRFs – this process must be completed 
within 3 business days of the visit. Study data from the participating site will be reported and 
reviewed in aggregate with data from patients enrolled at the coordinating center, UCSF.  All 
source documentation and CTMS data will be available for review/monitoring as needed.
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for each 
patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The Study Chair will approve 
all completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by Plexxikon 
or the designated CRO and regulatory agencies.
The Study Chair will be responsible for ensuring the accurate capture of study data.  At study 
completion, when the CRFs have been declared to be complete and accurate, the database will be 
locked.  Any changes to the data entered into the CRFs  after that time can only be made by joint 
written agreement among the Study Chair, the Trial Statistician, and the Protocol Project 
Manager.
14.0
Correlative studies
14.1
Tumor biopsies
Tumor biopsies will be obtained from accessible tumor tissue following the guidelines provided 
below before treatment start in all eligible patients.  Patients enrolled on the Phase II trial will be 
asked to have a second core biopsy or FNA, depending on ease and site of biopsy.  Patients who 
refuse the second biopsy will be allowed to stay on study treatment.  Every attempt will be made 
to obtain tumor tissue at the time of a clinical procedure, if possible.  Patients with lung only 
metastases will not be required to have biopsies, but will be allowed to enroll on this trial.
Core biopsies of the breast will be performed by a qualified radiologist or surgeon, according to 
institutional guidelines for a diagnostic biopsy.  Biopsies of other sites may be done by 
radiology, pathology or qualified surgeons. When required, radiographic coordination will be 
arranged.  Tissue specimens will be collected from recurrent or metastatic lesions using standard 
institutional procedures.  The goal is to obtain 2 to 4 core needle biopsies using an 18 gauge 
needle. If a fine needle aspiration is performed, 3-6 passes should be obtained.  Less than the 
goal amount of tissue is acceptable, and should be based upon the clinical judgment of the 


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Investigator and the clinician performing the procedure.  The study coordinator will be present at 
the time of the biopsy to collect and process the tissue samples.  Samples will be delivered to the 
laboratory of 
.  Specific processing and delivery instructions will be provided 
to all sites in the Laboratory Manual, which contains all details for specimen processing and 
handling.
14.2
CSF1 levels
Patients on both trials will have CSF1 levels drawn to assess the impact of PLX3397.  5 cc of 
blood will be obtained in a serum separator tube.  For patients on the phase I trial, CSF1 levels 
will be drawn at Cycle 1, days 1 and 2, and Cycle 2, day 1. For patients on the phase II trial, 
CSF1 levels will be drawn at the start of the PLX3397 lead-in, at day 5 to 7 before the start of 
eribulin, at Cycle 1, day 1, and Cycle 2, day 1.
14.3
Blood for leukocyte subtyping
Blood will be drawn for flow cytometric analysis at baseline for patients in phase I, and at day -
7/5 and day 0/1 for patients on the phase II trial.  10 cc of blood will be drawn into an EDTA 
tube and evaluated by flow cytometry.  Processing will take place at each site. See Lab Manual 
for more details.
14.4
Pharmacokinetic sampling
Limited pharmacokinetic sampling will be performed in the phase I portion of this trial.  PK 
sampling will occur on C1D1 (pre-PLX3397 administration and at 1, 2, 5, and 24 hours post 
treatment and on C2D1 (pre-PLX3397 administration and at 2 hours post treatment).  Serum 
concentrations of PLX3397 with eribulin will be assessed by ELISA at Plexxikon Inc. and will 
be used to calculate the values of PK parameters, including maximum serum drug concentration 
(Cmax), area under the concentration-time curve from time zero to infinity (AUC 0-inf), 
systemic clearance (CL), volume of distribution (V), and elimination half-life (t1/2). Descriptive 
statistics (including number, mean and/or median, standard deviation, and coefficient of 
variation) will be used to describe the concentration time data. Where appropriate, these data 
may be combined with data from other studies as part of a metaanalysis. The influence of 
exposure on clinical safety parameters (e.g., selected AEs) will be explored. Results of the PK 
analysis will be evaluated in conjunction with available safety and pharmacodynamic data.
Blood Collection
Approximately 5 mL of blood will be collected via peripheral venipuncture into a lithium 
heparin tube. This blood sample will be used to measure concentrations of PLX3397 for each PK 
blood collection, as noted in the Study Calendar. Samples will be collected, processed and stored 
according to the study-specific laboratory manual. 
Blood samples for PK analysis should be collected at the requested time but within a ±15 minute 
window (or ± 30 minute window where specified) of the requested time. The exact actual time of 
collection should be noted in the source documents and eCRFs. 


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Bioanalytical Methodology
The plasma samples will be analyzed for PLX3397 by using a validated method (high 
performance liquid chromatography (HPLC) with tandem quadruple mass spectrometric 
detection) of appropriate specificity and sensitivity.
14.5.
Archival tumor samples
All patients will be asked to provide a sample of their original tumor pathology, if it is available.
14.6
Details of the correlative studies
The main goal of the correlative studies accompanying this trial will be to identify tissue
and serum biomarkers capable of 1) predicting likelihood of response to macrophage-targeted 
therapy, or 2) providing an early indication of response to PLX3397 treatment likely to be seen 
at 12 wks of therapy. Both predictive and response biomarker assessment of tissue (core biopsy 
or FNA) and blood will be conducted as previously described[76, 77]. Phase I studies will be 
performed on all tumor subtypes, while Phase II studies will be performed on pts with TNBC. 
The lead-in period in Phase II will allow evaluation of the effect of PLX3397 alone on serum 
CSF1 levels and leukocyte subsets in blood and tissue prior to administration of eribulin.
14.6.1 Evaluation of baseline biomarkers most likely to predict response to M∅-targeted 
therapy
We will establish baseline values and variability of immune, and CSF1 measures in pts enrolled 
in phase I and phase II trials, and correlate these measures to magnitude of change in serum 
CSF1 levels and clinical response. Pts will be categorized as “good” or “poor” responders based 
on median change in serum CSF1, clinical response based in RECIST v1.1 imaging criteria at 12 
wks and TTP. We will determine whether the tumor phenotype (ER, PR, HER2, and ki67), 
immune signature (CD68lo/CD4lo/CD8hi vs. CD68hi/CD4hi/CD8lo) and CSF1 signature at 
initial diagnosis (obtained from archived tumor blocks) correlates with response. In addition, we 
propose to explore whether the baseline immune and CSF1 signature differ between the early 
stage setting (derived from ongoing studies) and pts with MBC enrolled on this trial.
14.6.2 Evaluation of dynamic tissue and blood biomarkers most likely to show early 
biologic changes that predict clinical response
Identify whether leukocyte subpopulations are altered with PLX3397 treatment alone in a cohort 
of pts with metastatic TNBC. The lead-in design of the trial will allow evaluation of systemic 
response to PLX3397 alone in the absence of systemic chemotherapy (CTX). We will determine 
whether this single-agent therapy modulates leukocyte complexity in blood, with serum CSF1 
measured between day -7/-5 and day 0/1. In addition, if ongoing studies demonstrates that core 
biopsy or FNA can reliably recapitulate the immune signature obtained from surgical samples, 
repeat biopsies will be used to determine whether immune infiltrate in tissue is modulated with 
PLX3397 treatment. This will provide confirmation that PLX3397 results in the expected 
macrophage, DC and T cell modulation at the tissue level.
14.6.3 Determine magnitude of change in serum CSF1
Determine whether magnitude of change in serum CSF1 is associated with: 1) dose levels of 
PLX3397 and 2) response to therapy.   For patients on the phase I trial, CSF1 levels will be 


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drawn at Cycle 1, days 1 and 2, and Cycle 2, day 1. For patients on the phase II trial, CSF1 levels 
will be drawn at the start of the PLX3397 lead-in, at day 5 to 7 before the start of eribulin, at 
Cycle 1, day 1, and Cycle 2, day 1.. Baseline CSF1 and magnitude of change in CSF1 will be 
correlated to dose of PLX3397 and treatment response group.
15.0
Reporting Adverse Drug Reactions
15.1
Adverse Event Definitions
Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related.  
More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, 
without any judgment about causality.  An adverse event can arise from any use of the drug (e.g., 
off-label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose. 
Adverse reaction
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude that 
the drug caused the event.
Suspected
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship between 
the drug and the adverse event.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction.
Unexpected
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
investigator brochure or package insert(s), or is not listed at the specificity or severity that has 
been observed, or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure.  For example, a certain number of non-acute deaths in a cancer trial would be 
anticipated as an outcome of the underlying disease, but such deaths would generally not be 
listed as a suspected adverse reaction in the investigator brochure.


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Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class effect, 
the first case of angioedema observed with the drug under investigation should be considered 
unexpected for reporting purposes.
Serious
An adverse event or suspected adverse reaction is considered serious if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 

Death

Life-threatening adverse event

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function

Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
Life-threatening
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
15.2
Recording of an Adverse Event
During Phase Ib, all adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug.  During Phase II, all grade 3 and above 
adverse events will be entered into OnCore®, whether or not the event is believed to be 
associated with use of the study drug.  Data about these events and their severity will be recorded 
using the NCI CTCAE v4.0.  
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 


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Relationship 
Attribution 
Description 
Unrelated
The AE is clearly NOT related to the 
intervention 
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the 
intervention 
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Related to investigational 
drug/intervention
Definite
The AE is clearly related to the intervention 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions:
Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL
Grade 4:
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE
15.3
Follow-up of Adverse Events
Reportable SAEs are those that occur after the first dose of PLX3397 and until 21 days after the 
last dose of combined therapy.  All adverse events will be followed with appropriate medical 
management until resolved.  Patients removed from study for unacceptable adverse events will 
be followed until resolution or stabilization of the adverse event.  For selected adverse events for 
which administration of the investigational drug was stopped, a re-challenge of the subject with 
the investigational drug may be conducted if considered both safe and ethical by the Investigator.
15.4
Adverse Events Monitoring 
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC); UCSF’s Institutional Review Board, the 
Committee on Human Research (CHR); and to the Food and Drug Administration (FDA) if it 
meets the FDA reporting criteria.
Adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis during Phase Ib and on a 
monthly basis during Phase II.  The Site Committee will review and discuss at each meeting the 
selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s).


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In addition, all adverse events and suspected adverse reactions considered “serious,” entered into 
OnCore® will be reviewed and monitored by the Plexxikon or the designated CRO every six (6) 
weeks, and prior to dose escalation.  At the time of dose escalation, a written report will be 
submitted to the DSMC Chair (or qualified alternate) describing the cohorts, dose levels, adverse 
events, safety reports, and any Dose Limiting Toxicities observed, in accordance with the 
protocol.  The report will be reviewed by the DSMC Chair (or qualified alternate).  Approval for 
the dose escalation by the DSMC must be obtained prior to implementation.  For a detailed 
description of the Data and Safety Monitoring Plan please see section 16.
15.5
Expedited Reporting 
Participating Sites Reporting to Sponsor-Investigator (UCSF)
In addition to complying with all applicable regulatory reporting laws and regulations, each site 
will report the following information in writing to the Sponsor-Investigator within one business 
day of the Investigator’s awareness of occurrence:

All SAEs

Reports of pregnancy exposure (pregnancy encompasses the entire course of pregnancy 
and delivery, perinatal and neonatal outcomes, even if there were no abnormal findings; 
both maternal and paternal exposure is collected);

Reports of lactation exposure;

Overdose (with or without an SAE);

Abuse (use for non-clinical reasons with or without an SAE);

Inadvertent or accidental exposure; and

Follow-up information regarding any of the above. 

The participating investigator should include his or her assessment of the causal 
relationship between each SAE and the Grantor product.
Reports will include the cover page provided, and reference the Protocol Number.  
A copy of the report should be sent to the coordinating center CRC at UCSF.  Information will 
be provided.
Sponsor-Investigator Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or 
to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail.
Sponsor-Investigator 
Reporting 
to 
UCSF 
Committee 
on 
Human 
Research
(Institutional Review Board)
The Sponsor-Investigator must report events meeting the UCSF CHR definition of 
“Unanticipated Problem” (UP) within 5 business days of his/her awareness of the event. 


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Sponsor-Investigator Expedited Reporting to the Food and Drug Administration
The Sponsor-Investigator is responsible for determining whether or not the suspected adverse 
reaction meets the criteria for expedited reporting in accordance with Federal Regulations 
(21 CFR §312.32). 
The Sponsor-Investigator must report in an IND safety report any suspected adverse reaction that 
is both serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets 
all three definitions: 

Suspected adverse reaction (as defined in 6.1.30)

Unexpected (as defined in 0)

Serious (as defined in 6.1.5)
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report 
will be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
Sponsor-Investigator Reporting to Pharmaceutical Companies Providing Study Drug
The Sponsor-Investigator will report all Serious Adverse Events (SAEs) that occur during the 
SAE reporting period to the investigational drug manufacturer (Plexxikon) within 24 hours after 
first becoming aware of the event (immediately if the event is fatal or life-threatening).  The 
Coordinating Center will report the SAE using an FDA MEDWATCH form and the Serious 
Adverse Event Fax Cover Sheet provided by the pharmaceutical partners for this trial.  Events 
should be reported as soon as they are determined to meet the definition of an SAE, even if 
complete information is not yet available.
The medical monitor contact information for Plexxikon is listed below:
 
Follow-Up Information.  
Coordinating center and participating sites will assist the 
pharmaceutical partners in investigating any SAE and will provide any reasonable follow-up 
information requested.


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15.6
Reporting DLTs
The investigator at the originating site must report suspected DLTs to the Study Chair or 
designee immediately, not more than 24 hours after awareness of the event. The Study Chair will 
determine whether the event meets the protocol criteria for DLT and may consult with the 
monitoring CRO, DSMC, UCSF Phase I Site Committee, and/or co-investigators to do so.  All 
investigators and the CRC at both sites will be notified immediately if a DLT determination is 
made. Dose level assignments for any patients scheduled to begin treatment and cohort 
expansion must be determined as per protocol criteria by the Study Chair or designee based upon 
the new DLT results. See Section 5.0 for dose escalation rules and decision process.
The coordinating center CRC will utilize the CTMS to track enrollment of subject(s) at each 
dose level, as well as dose limiting toxicities (DLTs).  
16.0
Data Safety Monitoring Plan 
16.1
Oversight and Monitoring Plan
Under the IND Transfer of Obligations executed between UCSF and Plexxikon, Plexxikon will 
monitor all clinical investigations.  The UCSF-CCC Data Safety Monitoring Committee (DSMC) 
will review the monitoring SOPs and subsequent monitoring reports from Plexxikon or the 
designated CRO.  The DSMC will not be involved in the direct monitoring or auditing of this 
trial.  DSMC activities for this study includes: 

Review of subject data in each cohort 

Review of suspected adverse reactions considered “serious”
16.2
Monitoring and Reporting Guidelines
All institutional Phase Ib therapeutic studies are designated with a high risk assessment.  All 
subject data will be monitored at 6 week intervals data by the designated CRO.  At the time of 
dose escalation, a written report will be submitted to the DSMC Chair outlining the cohort dose, 
all adverse events and suspected adverse reactions considered “serious,” and any Dose Limiting 
Toxicity as described in the protocol.  The report will be reviewed by the DSMC Chair or 
qualified alternate.  Written authorization to proceed will be granted by the DSMC.
 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites.  During Phase 1, the Study Chair will conduct continuous 
review of data and subject safety and discuss each subject’s treatment at weekly UCSF Site 
Committee meetings.  During Phase 2, the Study Chair will conduct continuous review of data 
and subject safety and discuss each subject’s treatment at monthly UCSF Site Committee 
meetings.  The discussions are documented in the UCSF Site Committee meeting minutes.  For 
each dose level, the discussion will include the number of patients, significant toxicities in 
accordance with the protocol, doses adjustments, and observed responses.


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Dose Level Considerations
The PI/Study Chair, participating investigators, and research coordinators from each site will 
review enrollment for each dose level cohort during the regularly scheduled conference calls.  
The dose level for ongoing enrollment will be confirmed for each subject scheduled to be 
enrolled at a site.  Dose level assignments for any subject scheduled to begin treatment must be 
confirmed by the UCSF Coordinating Center via fax or e-mail.
If a Dose Limiting Toxicity (DLT) arises in a subject treated at a study site, all sites must be 
notified immediately by the UCSF Coordinating Center.  The Study Chair has 1 business day 
(after first becoming aware of the event at either the UCSF Coordinating Center or the 
participating site) in which to report the information to all participating sites.  If the DLT occurs 
at a participating site, the local investigator must report it to the UCSF Coordinating Center 
within 1 business day, after which the UCSF Coordinating Center will notify the other 
participating sites.
16.3
Review and Oversight Requirements
Adverse Event Monitoring
During Phase 1, all clinically significant adverse events (AEs), whether or not unexpected, and 
whether or not considered to be associated with the use of study drug, will be entered into 
OnCore®, UCSF’s Clinical Trial Management System.  During Phase 2, all clinically significant 
grade 3 and above adverse events (AEs), whether or not unexpected, and whether or not 
considered to be associated with the use of study drug, will be entered into OnCore®, UCSF’s 
Clinical Trial Management System.
  
During Phase 1, all clinically significant adverse events entered into OnCore® will be reviewed 
on a weekly basis at the UCSF Coordinating Center’s Site Committee.  During Phase 2, all 
clinically significant grade 3 and above adverse events entered into OnCore® will be reviewed on 
a monthly basis at the UCSF Coordinating Center’s Site Committee,  All clinically significant 
adverse events must be reported to the UCSF Coordinating Center by the participating sites 
within 10 business days of becoming aware of the event.  The Site Committee will review and 
discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the adverse 
event to the administration of the study drug(s).
For Phase I patients, toxicity data must be entered into OnCore® by noon (Pacific Standard 
Time) on Wednesday of each week for review by Site Committee at UCSF. 
For Phase II patients, toxicity data must be entered into OnCore® by noon (Pacific Standard 
Time) of the second Monday of each month for review by Site Committee at UCSF.
In addition, all suspected adverse reactions considered “serious” are entered into OnCore® and 
will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing 
basis and discussed at the DSMC meetings, which take place every six (6) weeks.


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All suspected adverse reactions considered “serious” should be reported to the UCSF 
Coordinating Center within 1 business day of becoming aware of the event or during the next 
scheduled conference call, whichever is sooner.  
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or the 
assigned designee must be notified within 1 business day from the participating site(s) and the 
Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of 
this notification.  The contact may be by phone or e-mail.
UCSF Data and Safety Monitoring Committee Contacts:
DSMC 
Chair: 
 
 
 
 
 
 
 
Study Management
17.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
17.2
Independent Ethics Committees/Institutional Review Board
This protocol and the informed consent will be approved by the Committee on Human Research 
(the UCSF IRB).  The Principal Investigator is responsible for keeping the IRB advised of the 
progress of the study and of any changes made in the protocol.  The Principal Investigator will 
also keep the IRB informed of any significant adverse reactions, and any protocol exceptions or 
deviations.  Records of all study review and approval documents must be kept on file by the 


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Principal Investigator and are subject to FDA inspection during or after completion of the study.  
The IRB will receive notification of the termination of the study.
17.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  The 
original signed copy of the consent document must be retained in the medical record or research 
file. 
17.4
Oversight and Monitoring Plan
This study is a multi-institution, investigator-initiated trial which will be coordinated by UCSF 
and conducted at both the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) 
and the participating site.  The Principal Investigator at the coordinating center (UCSF) holds the 
role of Study Chair.  The responsibilities of the Study Chair are described in the Code of Federal 
Regulations (Title 21, Subpart D, 312.50 through 312.69).
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, biweekly (during Phase 1) or monthly 
(during Phase 2) conference calls with the participating sites at the completion of each cohort or 
more frequently as needed to discuss risk assessment.  The following issues will be discussed as 
appropriate:

Enrollment information 

Cohort updates (i.e. DLTs)

Adverse events (i.e. new adverse events and updates on unresolved adverse events and new 
safety information)

Protocol violations

Other issues affecting the conduct of the study
The coordinating center CRC will insure that participating sites are notified of safety events.  
Questions regarding the study or reporting of adverse events may be directed to the designated 
coordinating center (UCSF) CRC (contact information to be provided by the start of study).  
 
 
 the IND Transfer of Obligations executed between UCSF and Plexxikon, Plexxikon or a 
designated CRO will monitor all clinical investigations.  The DSMC will not be involved in the 
monitoring and auditing of this trial.  Please refer to Section 16.0 for additional details.


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17.5
Coordinating Center Processing and Documenting FDA Correspondence
This study will be conducted under an IND #114838 held by the Sponsor-Investigator.  A copy 
of all files pertaining to this IND will also be maintained by the centralized regulatory staff of the 
HDFCCC.  It is the responsibility of the Study Chair to relay to HDFCCC centralized regulatory 
staff any correspondence to or from the FDA regarding the IND.
17.6
Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study.
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified.
17.7
Regulatory Documentation
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF Committee on Human Research (CHR).  Prior to implementing this protocol at the 
participating sites, approval for the UCSF CHR approved protocol must be obtained from the 
participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants: 

Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 

Participating Site IRB approved consent form 

Participating Site IRB membership list 

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 


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
Curriculum vitae and medical license for each investigator and consenting professional 

Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site 

Participating site laboratory certifications and normals 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment.
17.8
Patient Enrollment
Patients can be registered only after the pretreatment evaluation is complete and all eligibility 
criteria have been met. Patients must meet all inclusion criteria and no exclusion criteria should 
apply. The patient must have signed and dated an approved, current version of all applicable 
consent forms.
The participating site should fax a completed eligibility checklist and all supporting source 
documentation to the designated coordinating center CRC at UCSF (contact information to be 
provided by the start of study). The CRC will check the forms for completeness and contact the 
participating site with any discrepancies. Eligibility must be confirmed by the Study Chair, or 
designee before patient ID number is assigned.
The coordinating center will provide a study-specific patient ID number to the participating site.  
All future study documentation related to that patient should include the assigned patient ID 
number.
17.9
Study Drug Supply and Accountability
Study drug will be shipped directly to the participating site from Plexxikon for direct distribution 
of the drugs to the study patients in accordance with the IND Transfer of Obligations executed 
between UCSF and Plexxikon.  The participating site will be responsible for drug accountability 
at their site.  Plexxikon CRAs will monitor the participating sites to ensure that appropriate 
records are kept regarding drug accountability.  All documentation will be provided by 
Plexxikon CRA to the coordinating center.  See Section 11 for specific instructions regarding 
study drug availability. Eribulin is FDA approved and should be available through the infusion 
center at each institution.
17.10 Coordinating Center Documentation of Distribution
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that the 
Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, 
drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.


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At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
17.10.1
Approval of Protocol and Amendments
All protocol amendments must be approved by the participating sites’ IRBs within 90 days of 
receipt. Failure to do so can result in the suspension of study activities at that site. 
Upon approval of the protocol or amendment by a participating site’s IRB, a copy of the 
approval documentation must be submitted (electronically or in hard form) to the office of the 
Study Chair. Documentation of participating sites’ protocol approvals will be maintained in the 
correspondence files by the Study Chair or his/her designee.


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18.0
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Appendix 1:  Strong CYP3A4 Inhibitors and Inducers
Strong Inhibitors
Strong Inducers
Protease inhibitors 

Ritonavir

Indinavir

Nelfinavir
Macrolide antibiotics

Erythromycin

Telithromycin

Clarithromycin
Azole antifungals

Fluconazole

Ketoconazole

Itraconazole
Chloramphenicol (antibiotic)
Nefazodone (antidepressant)
Bergamottin (constituent of grapefruit juice)
Aprepitant (antiemetic)
Verapamil (calcium channel blocker)
Anticonvulsants, mood stabilizers 

Phenytoin

Carbamazepine

Oxcarbazepine
Non-nucleoside reverse transcriptase inhibitors 

Efavirenz

Nevirapine

Etravirine
Phenobarbital (barbiturate)
Rifampicin (bactericidal)
Modafinil (stimulant)
Hyperforin (constituent of St Johns Wort)
Cyproterone (antiandrogen, progestin)


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Appendix 2:  Drugs With A Risk Of Torsades De Pointes
Generic Name
Brand Name
Class/Clinical Use
Comments
Amiodarone 
Cordarone®
Anti-arrhythmic / abnormal heart 
rhythm
Females>Males,TdP risk regarded 
as low
Amiodarone 
Pacerone®
Anti-arrhythmic / abnormal heart 
rhythm
Females>Males,TdP risk regarded 
as low
Arsenic trioxide 
Trisenox®
Anti-cancer / Leukemia
Bepridil 
Vascor®
Anti-anginal / heart pain
Females>Males
Chloroquine
Aralen®
Anti-malarial / malaria infection
Chlorpromazine 
Thorazine®
Anti-psychotic/ Anti-emetic / 
schizophrenia/ nausea
Cisapride
Propulsid®
GI stimulant / heartburn
No longer available in the U.S.; 
available in Mexico
Citalopram
Celexa®
Anti-depressant / depression
Clarithromycin
Biaxin®
Antibiotic / bacterial infection
Disopyramide 
Norpace®
Anti-arrhythmic / abnormal heart 
rhythm
Females>Males
Dofetilide 
Tikosyn®
Anti-arrhythmic / abnormal heart 
rhythm
Droperidol 
Inapsine®
Sedative;Anti-nausea / anesthesia 
adjunct, nausea
Erythromycin 
Erythrocin®
Antibiotic;GI stimulant / bacterial 
infection; increase GI motility
Females>Males
Erythromycin 
E.E.S.® 
Antibiotic;GI stimulant / bacterial 
infection; increase GI motility
Females>Males
Flecainide
Tambocor®
Anti-arrhythmic / abnormal heart 
rhythm
Halofantrine 
Halfan®
Anti-malarial / malaria infection
Females>Males
Haloperidol 
Haldol®
Anti-psychotic / schizophrenia, 
agitation
When given intravenously or at 
higher-than- recommended doses, 
risk of sudden death, QT 
prolongation and torsades 
increases. 
Ibutilide
Corvert®
Anti-arrhythmic / abnormal heart 
rhythm
Females>Males
Mesoridazine
Serentil®
Anti-psychotic / schizophrenia
Methadone
Methadose®
Opiate agonist / pain control, 
narcotic dependence
Females>Males
Methadone
Dolophine®
Opiate agonist / pain control, 
narcotic dependence
Females>Males
Moxifloxacin 
Avelox®
Antibiotic / bacterial infection
Pentamidine 
Pentam®
Anti-infective / pneumocystis 
pneumonia
Females>Males
Pentamidine 
NebuPent®
Anti-infective / pneumocystis 
pneumonia
Females>Males
Pimozide
Orap® 
Anti-psychotic / Tourette's tics
Females>Males
Procainamide 
Pronestyl®
Anti-arrhythmic / abnormal heart 
rhythm
Procainamide 
Procan® 
Anti-arrhythmic / abnormal heart 


Protocol Version #10
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Protocol #: 12751
Appendix 2:  Drugs With A Risk Of Torsades De Pointes
Generic Name
Brand Name
Class/Clinical Use
Comments
rhythm
Quinidine
Cardioquin® 
Anti-arrhythmic / abnormal heart 
rhythm
Females>Males
Quinidine
Quinaglute®
Anti-arrhythmic / abnormal heart 
rhythm
Females>Males
Sotalol 
Betapace® 
Anti-arrhythmic / abnormal heart 
rhythm
Females>Males
Sparfloxacin 
Zagam® 
Antibiotic / bacterial infection
Thioridazine
Mellaril® 
Anti-psychotic / schizophrenia
Vandetanib
Caprelsa®
Anti-cancer / Thyroid cancer
Fluconazole
Diflucan®
Anti-arrhythmic / abnormal heart 
rhythm
Ciprofloxacin
Ciloxan, 
Cipro, 
Neofloxin
Anti-arrhythmic / abnormal heart 
rhythm


Protocol Version #10
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Protocol #: 12751
Appendix 3:  Drug Diaries
PLX3397 QD - Patient Drug Diary – Phase Ib, Cycle #____
CC#12751:  Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like Breast Cancer by Targeting 
Macrophages:  A Phase Ib/II study of PLX 3397 and Eribulin in Patients with Metastatic Breast Cancer
Study Subject ID #:____________ _______ Patient Name:  _______________________
Current Assigned dose: ______________________   Start Date:__________________
Reminders:      

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).

Take your dose of study medication every24 hours (± 2 hours) If it is after 2 hours from when your dose was due, 
skip that dose and continue with the subsequent dose.Fast for at least 1 hour prior to taking the study medication 
and 1 hour after you take the study medication.  You are allowed to have a low-fat, bland snack (crackers, toast, 
tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.

Medication should be taken with at least 8 ounces (1 cup) of room temperature water.

Missed doses should be skipped and not taken as a double dose at the next dosing timepoint.  If you vomit your 
dose, you should not make-up that dose or take extra study drug at the next dosing timepoint.  

Write down the time each dose is taken.

Bring your study medication and study diary with you every time you visit the clinic.

Contact your study doctor if you have any questions/concerns.
Patient Signature:
Cycle #
Day
Date
mm/dd/yyyy
Time of Dose
Were you fasting before 
and after to your 
dose?(circle one)
# of 
capsules 
taken
Reason for 
missed 
dose
Cycle __
Day 1*
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 2**
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 3
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 4
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 5
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 6
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 7
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 8
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 9
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 10
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 11
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 12
/          /
Before:  
Yes/No
After:  
Yes/No


Protocol Version #10
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03/03/2016
Protocol #: 12751
PLX3397 QD - Patient Drug Diary – Phase Ib, Cycle #____
CC#12751:  Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like Breast Cancer by Targeting 
Macrophages:  A Phase Ib/II study of PLX 3397 and Eribulin in Patients with Metastatic Breast Cancer
Study Subject ID #:____________ _______ Patient Name:  _______________________
Current Assigned dose: ______________________   Start Date:__________________
Reminders:      

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).

Take your dose of study medication every24 hours (± 2 hours) If it is after 2 hours from when your dose was due, 
skip that dose and continue with the subsequent dose.Fast for at least 1 hour prior to taking the study medication 
and 1 hour after you take the study medication.  You are allowed to have a low-fat, bland snack (crackers, toast, 
tea, etc.) if needed (if you are feeling nauseous or weak) during this 2 hour period.

Medication should be taken with at least 8 ounces (1 cup) of room temperature water.

Missed doses should be skipped and not taken as a double dose at the next dosing timepoint.  If you vomit your 
dose, you should not make-up that dose or take extra study drug at the next dosing timepoint.  

Write down the time each dose is taken.

Bring your study medication and study diary with you every time you visit the clinic.

Contact your study doctor if you have any questions/concerns.
Patient Signature:
Cycle #
Day
Date
mm/dd/yyyy
Time of Dose
Were you fasting before 
and after to your 
dose?(circle one)
# of 
capsules 
taken
Reason for 
missed 
dose
Cycle __
Day 13
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 14
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 15
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 16
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 17
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 18
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 19
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 20
/          /
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 21
/          /
Before:  
Yes/No
After:  
Yes/No
*  For Cycle 1 and Cycle 2, Day 1, do not take your morning dose of PLX3397 until you are instructed to do so during your clinic 
visit.
** For Day 2 of Cycle 1 ONLY, do not take your morning dose of PLX3397 until you are instructed to so during your clinic visit.


Protocol Version #10
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03/03/2016
Protocol #: 12751
PLX3397 BID - Patient Drug Diary – Phase Ib, Cycle #____
CC#12751:  Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like Breast Cancer by Targeting 
Macrophages:  A Phase Ib/II study of PLX 3397 and Eribulin in Patients with Metastatic Breast Cancer
Study Subject ID #:____________ _______ Patient Name:  _______________________
Current Assigned dose: ______________________   Start Date:__________________
Reminders:

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).

Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, 
skip that dose and continue with your next scheduled dose. 

Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication.  You 
are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) 
during this 2 hour period.

Medication should be taken with at least 8 ounces (1 cup) of room temperature water.

Missed doses should be skipped and not taken as a double dose at the next dosing timepoint.  If you vomit your 
dose, you should not make-up that dose or take extra study drug at the next dosing timepoint.  

Write down the time each dose is taken.

Bring your study medication and study diary with you every time you visit the clinic.

Contact your study doctor if you have any questions/concerns.
Patient Signature:
Cycle #
Day
Date
mm/dd/yyyy
Time of 
Dose**
Were you fasting before 
and after to your 
dose?(circle one)
# of 
capsule
s taken
Reason for 
missed 
dose
Cycle __
Day 1*
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 1
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 2**
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 2
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 3
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 3
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 4
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 4
/          /
:         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 5
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 5
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 6
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 6
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 7
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 7
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No


Protocol Version #10
Page 80 of 85
03/03/2016
Protocol #: 12751
Study Subject ID #:____________ _______ Patient Name:  _______________________
Current Assigned dose: ______________________   Start Date:__________________
Reminders:

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).

Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, 
skip that dose and continue with your next scheduled dose. 

Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication.  You 
are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) 
during this 2 hour period.

Medication should be taken with at least 8 ounces (1 cup) of room temperature water.

Missed doses should be skipped and not taken as a double dose at the next dosing timepoint.  If you vomit your 
dose, you should not make-up that dose or take extra study drug at the next dosing timepoint.  

Write down the time each dose is taken.

Bring your study medication and study diary with you every time you visit the clinic.

Contact your study doctor if you have any questions/concerns.
Patient Signature:
Cycle #
Day
Date
mm/dd/yyyy
Time of 
Dose**
Were you fasting before 
and after to your 
dose?(circle one)
# of 
capsule
s taken
Reason for 
missed 
dose
Cycle __
Day 8
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 8
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 9
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 9
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 10
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 10
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 11
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 11
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 12
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 12
/          /
:         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 13
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 13
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 14
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 14
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 15
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 15
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No


Protocol Version #10
Page 81 of 85
03/03/2016
Protocol #: 12751
Study Subject ID #:____________ _______ Patient Name:  _______________________
Current Assigned dose: ______________________   Start Date:__________________
Reminders:

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).

Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, 
skip that dose and continue with your next scheduled dose. 

Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication.  You 
are allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) 
during this 2 hour period.

Medication should be taken with at least 8 ounces (1 cup) of room temperature water.

Missed doses should be skipped and not taken as a double dose at the next dosing timepoint.  If you vomit your 
dose, you should not make-up that dose or take extra study drug at the next dosing timepoint.  

Write down the time each dose is taken.

Bring your study medication and study diary with you every time you visit the clinic.

Contact your study doctor if you have any questions/concerns.
Patient Signature:
Cycle #
Day
Date
mm/dd/yyyy
Time of 
Dose**
Were you fasting before 
and after to your 
dose?(circle one)
# of 
capsule
s taken
Reason for 
missed 
dose
Cycle __
Day 16
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 16
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 17
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 17
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 18
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 18
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 19
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 19
/          /
:         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 20
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 20
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 21
/          /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 21
/          /
  :         PM
Before:  
Yes/No
After:  
Yes/No
*For Cycle 1 and Cycle 2, Day 1, do not take your morning dose of PLX3397 until you are instructed to do so during your 
clinic visit.
**For Day 2 of Cycle 1 ONLY, do not take your morning dose of PLX3397 until you are instructed to so during your 
clinic visit.


Protocol Version #10
Page 82 of 85
03/03/2016
Protocol #: 12751
 PLX3397 BID -  Patient Drug Diary – Phase II, Cycle #____
CC#12751:  Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like Breast Cancer by Targeting 
Macrophages:  A Phase Ib/II study of PLX 3397 and Eribulin in Patients with Metastatic Breast Cancer
Study Subject ID #:____________ _______ Patient Name:  _______________________
Current Assigned dose: ______________________   Start Date:__________________
Reminders:

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).

Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, 
skip that dose and continue with your next scheduled dose. 

Take your study medication daily for 5 days, followed by 2 days off, then restart each week with the same schedule

Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication.  You are 
allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) 
during this 2 hour period.

Medication should be taken with at least 8 ounces (1 cup) of room temperature water.

Missed doses should be skipped and not taken as a double dose at the next dosing timepoint.  If you vomit your dose, 
you should not make-up that dose or take extra study drug at the next dosing timepoint.  If you miss or hold a dose, 
maintain the 5 days on/2 days off schedule marked on the study calendar.

Write down the time each dose is taken.

Bring your study medication and study diary with you every time you visit the clinic.

Contact your study doctor if you have any questions/concerns.
Patient Signature:
Cycle #
Day
Date
mm/dd/yyyy
Time of Dose
Were you fasting before 
and after to your dose? 
(circle one)
# of 
capsules 
taken
Reason for 
missed 
dose
In Cycle 1, you will start taking PLX3397 six to seven days before starting eribulin.  
Cycle 1
Day -7
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle 1
 Day-7
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle 1
Day-6
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle 1
Day-6
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle 1
Day-5
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle 1
Day-5
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle 1
Day-4
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle 1
Day-4
/         /
:         PM
Before:  
Yes/No
After:  
Yes/No
Cycle 1
Day-3
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle 1
Day-3
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle 1
Day-2
/         /
DO NOT TAKE 
STUDY DRUG
Cycle 1
Day-2
/         /
DO NOT TAKE 
STUDY DRUG


Protocol Version #10
Page 83 of 85
03/03/2016
Protocol #: 12751
Study Subject ID #:____________ _______ Patient Name:  _______________________
Current Assigned dose: ______________________   Start Date:__________________
Reminders:

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).

Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, 
skip that dose and continue with your next scheduled dose. 

Take your study medication daily for 5 days, followed by 2 days off, then restart each week with the same schedule

Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication.  You are 
allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) 
during this 2 hour period.

Medication should be taken with at least 8 ounces (1 cup) of room temperature water.

Missed doses should be skipped and not taken as a double dose at the next dosing timepoint.  If you vomit your dose, 
you should not make-up that dose or take extra study drug at the next dosing timepoint.  If you miss or hold a dose, 
maintain the 5 days on/2 days off schedule marked on the study calendar.

Write down the time each dose is taken.

Bring your study medication and study diary with you every time you visit the clinic.

Contact your study doctor if you have any questions/concerns.
Patient Signature:
Cycle #
Day
Date
mm/dd/yyyy
Time of Dose
Were you fasting before 
and after to your dose? 
(circle one)
# of 
capsules 
taken
Reason for 
missed 
dose
Cycle 1
Day-1
/         /
DO NOT TAKE 
STUDY DRUG
Cycle 1
Day-1
/         /
DO NOT TAKE 
STUDY DRUG
Cycle __
Day 1
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 1
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 2
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 2
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 3
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 3
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 4
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 4
/         /
:         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 5
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 5
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 6
/         /
DO NOT TAKE 
STUDY DRUG
Cycle __
Day 6
/         /
DO NOT TAKE 
STUDY DRUG
Cycle __
Day 7
/         /
DO NOT TAKE 
STUDY DRUG


Protocol Version #10
Page 84 of 85
03/03/2016
Protocol #: 12751
Study Subject ID #:____________ _______ Patient Name:  _______________________
Current Assigned dose: ______________________   Start Date:__________________
Reminders:

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).

Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, 
skip that dose and continue with your next scheduled dose. 

Take your study medication daily for 5 days, followed by 2 days off, then restart each week with the same schedule

Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication.  You are 
allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) 
during this 2 hour period.

Medication should be taken with at least 8 ounces (1 cup) of room temperature water.

Missed doses should be skipped and not taken as a double dose at the next dosing timepoint.  If you vomit your dose, 
you should not make-up that dose or take extra study drug at the next dosing timepoint.  If you miss or hold a dose, 
maintain the 5 days on/2 days off schedule marked on the study calendar.

Write down the time each dose is taken.

Bring your study medication and study diary with you every time you visit the clinic.

Contact your study doctor if you have any questions/concerns.
Patient Signature:
Cycle #
Day
Date
mm/dd/yyyy
Time of Dose
Were you fasting before 
and after to your dose? 
(circle one)
# of 
capsules 
taken
Reason for 
missed 
dose
Cycle __
Day 7
/         /
DO NOT TAKE 
STUDY DRUG
Cycle __
Day 8
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 8
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 9
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 9
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 10
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 10
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 11
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 11
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 12
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 12
/         /
:         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 13
/         /
DO NOT TAKE 
STUDY DRUG
Cycle __
Day 13
/         /
DO NOT TAKE 
STUDY DRUG
Cycle __
Day 14
/         /
DO NOT TAKE 
STUDY DRUG
Cycle __
Day 14
/         /
DO NOT TAKE 
STUDY DRUG


Protocol Version #10
Page 85 of 85
03/03/2016
Protocol #: 12751
Study Subject ID #:____________ _______ Patient Name:  _______________________
Current Assigned dose: ______________________   Start Date:__________________
Reminders:

Study medication should be stored at room temperature (Temperature storage range 15-30 oC or 59-86 oF).

Take your dose of study medication every 12 hours (± 2 hours). If it is after 2 hours from when your dose was due, 
skip that dose and continue with your next scheduled dose. 

Take your study medication daily for 5 days, followed by 2 days off, then restart each week with the same schedule

Fast for at least 1 hour prior to taking the study medication and 1 hour after you take the study medication.  You are 
allowed to have a low-fat, bland snack (crackers, toast, tea, etc.) if needed (if you are feeling nauseous or weak) 
during this 2 hour period.

Medication should be taken with at least 8 ounces (1 cup) of room temperature water.

Missed doses should be skipped and not taken as a double dose at the next dosing timepoint.  If you vomit your dose, 
you should not make-up that dose or take extra study drug at the next dosing timepoint.  If you miss or hold a dose, 
maintain the 5 days on/2 days off schedule marked on the study calendar.

Write down the time each dose is taken.

Bring your study medication and study diary with you every time you visit the clinic.

Contact your study doctor if you have any questions/concerns.
Patient Signature:
Cycle #
Day
Date
mm/dd/yyyy
Time of Dose
Were you fasting before 
and after to your dose? 
(circle one)
# of 
capsules 
taken
Reason for 
missed 
dose
Cycle __
Day 15
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 15
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 16
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 16
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 17
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 17
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 18
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 18
/         /
  :         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 19
/         /
  :         AM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 19
/         /
:         PM
Before:  
Yes/No
After:  
Yes/No
Cycle __
Day 20
/         /
DO NOT TAKE 
STUDY DRUG
Cycle __
Day 20
/         /
DO NOT TAKE 
STUDY DRUG
Cycle __
Day 21
/         /
DO NOT TAKE 
STUDY DRUG
Cycle __
Day 21
/         /
DO NOT TAKE 
STUDY DRUG

ICF_001.pdf: 
ICF 10-19-2016
Page 1 of 19
CC#12751
Protocol Version 10 (03-03-2016)
Hope Rugo, MD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Study Title:  CC#12751: Enhancing Efficacy of Chemotherapy in Triple Negative/Basal-Like 
Breast Cancer by Targeting Macrophages:  A Multicenter Phase Ib/II study of PLX 3397 and 
Eribulin in Patients with Metastatic Breast Cancer
This is a clinical trial, a type of research study.  Your study doctor, Dr. Hope Rugo, and her 
associates from the UCSF Department of Medicine, will explain the clinical trial to you.
Clinical trials include only people who choose to take part.  Please take your time to make your 
decision about participating.  You may discuss your decision with your family and friends and 
with your health care team.  If you have any questions, you may ask your study doctor.
You are being asked to take part in this study because you have breast cancer that has spread to 
other parts of your body (metastatic breast cancer) and you have had at least one prior 
chemotherapy treatment for the advanced disease.
WHY IS THIS STUDY BEING DONE?
The purpose of the Phase 1b portion of the study is to determine the best dose of PLX3397 when 
given in combination with standard dose eribulin (Halaven™).  The purpose of the Phase 2 
portion of the study is to find out what effects, good and/or bad, these drugs have on you and 
your cancer.
PLX3397 is a new drug that blocks certain receptors, or targets, on cancer cells.  This activity 
will be used to attack tumors in a number of different ways:  by directly preventing cancer 
related cells from turning on, by stopping cancer cells from communicating with each other, and 
by blocking cancer cells from migrating to other parts of your body and the blood supply cancer 
cells need for growth.  
PLX3397 is an investigational drug, which means it has not been approved for use by the US 
Food and Drug Administration (FDA).  Eribulin is a drug that has been approved by the FDA for 
metastatic breast cancer.  However, the combination of eribulin and PLX3397 is considered 
experimental; that means this combination has not been approved by the FDA.
The Susan G. Komen foundation is providing funding to UCSF to conduct the study.  Plexxikon 
Inc., the manufacturers of PLX3397, will provide PLX3397 at no cost to study participants.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Up to 24 patients will participate in this study in the first portion of this study (Phase 1b) at 
UCSF, Vanderbilt University, and Duke University.  About 10 patients will be enrolled at UCSF. 
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017
NCT# 01596751


ICF 10-19-2016
Page 2 of 19
CC#12751
Protocol Version 10 (03-03-2016)
Hope Rugo, MD
Up to 61 patients will participate in the phase 2 portion at UCSF, Vanderbilt University, and 
Duke University. About 26 patients will be enrolled at UCSF.  A total of 85 patients will be 
enrolled for both phases at all sites. 
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY?
This study is a two part study.  Your study doctor will tell you which part and dose group you 
will be participating in prior to your enrollment.
Phase 1b will determine the highest dose level (maximum tolerated dose) of PLX3397 to give in 
combination with eribulin.  The best dose tolerated by patients in Part 1 will be used as the dose 
level in Part 2 of this study. The Phase 1b portion of this study is now closed to accrual.       
Phase 2 will look at how the maximum tolerated dose of PLX3397 in combination with eribulin 
affects your cancer and your body. 
Study Drug
PLX3397 is given in capsule form.  In this research study, each “cycle” of treatment usually lasts 
21 days.  You will be given a supply of PLX3397 on Day 1 of each cycle to last a whole cycle.  
You will take PLX3397 by mouth 5 days on, 2 days off.  You should fast (not eat anything) for 
at least 1 hour before taking your PLX3397 and 1 hour after taking your PLX3397.  You may eat 
a low-fat, bland snack (e.g., crackers, toast, tea) during the fasting period if needed (for example, 
if you are feeling nauseous or weak).
You will be provided with a drug diary where you will record each date you take the study drug. 
If you forget to take your scheduled dose, you should not make up the missed dose. Any missed 
doses should be recorded on the dosing diary. You will be required to bring your dosing diary 
with you to every visit. 
The doses of PLX3397 will be increased throughout the trial in Phase 1b.  Patients participating 
in Phase 1b will be assigned to one specific dose level and will continue receiving that same dose 
while on treatment.  However, if you have side effects that seem to be due to the drug, your study 
doctor may decrease your dose or take you off of study drug.  The dose escalation portion of the 
study will end when it has been determined what dose of the study drugs are determined to be the 
safest for study participants.  This is also called the maximum tolerated dose or MTD.  Patients 
in Phase 2 will receive the MTD of PLX3397.
Eribulin is given intravenously (IV).  You will receive eribulin on days 1 and 8 of each cycle 
during your study visit.  You may be given medications that are chosen by your study doctor 
prior to the eribulin infusion to help with allergic reactions. If you are given these pre-eribulin 
medications, please ask your study doctor about any risks associated with those medications.
(Note: standard dosing of eribulin is Day 1 and Day 8 every 21 days.  For this study, if you 
started on a modified dosing of eribulin (Day 1 and 15 every 28 days), you will remain on the 
modified dosing schedule.  The modified dosing was implemented to make the combination of 
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


ICF 10-19-2016
Page 3 of 19
CC#12751
Protocol Version 10 (03-03-2016)
Hope Rugo, MD
eribulin and PLX3397 more tolerable and to reduce bone marrow suppression from eribulin.  All 
other patients will start on the standard dosing schedule.  Your study doctor will let you know 
which schedule you will be on.)
Before you begin the study...
If you choose to participate in this study you will have several screening tests to see if you can 
take part.  Most of these are procedures that you would have as part of your regular cancer 
treatment even if you did not participate in this study.  You will also have some procedures that 
are only being done because you are in the study.  These are called research procedures and are 
noted as “research purposes” in the list of procedures below.  If you have had some of these 
procedures recently, they may not need to be repeated. This will be up to your study doctor.  
You must complete your Screening procedures within 14 days prior to receiving the study drug. 
Your screening visit may take up to 6 hours depending on which procedures you have.

Medical history - You will be asked about your health, any current and past illnesses, and
medications you are taking and those you have taken 

Physical exam, including measurements of vital signs, height, and weight

Questions about how your disease is affecting your daily life

Electrocardiogram (ECG) - An ECG records the electrical activity of your heart. Wires or
“leads” will be attached to your chest with an adhesive and you will be asked to lie still while 
the machine prints out an electrical “record” of your heart activity.  This takes about 15-30 
minutes – research purposes

Blood (about 2 tablespoons) will be drawn:
o
For routine laboratory tests
o
To classify different white blood cells in your blood

Pregnancy test - if you are a woman of childbearing age

Tumor assessment by CT (Computed Tomography) scan, PET CT (Positron Emission
Tomography) scan, or Bone Scan.  Patients with bone-only disease will have a CT scan and 
bone scan or PET CT scan.  Your doctor will let you know which scan you will need to have.
o
A CT scan uses special x-ray equipment to make detailed pictures of body tissues and
organs.  For the CT scan, you may be given a "contrast material" (a special dye that 
makes it easier for doctors to see different tissues in your body).  The contrast material 
may be given orally, intravenously, or rectally (less likely).  Oral contrast material is 
given to you to drink and is used to help outline the stomach and intestines.  Intravenous 
(IV) contrast material is given to you by injecting the contrast material into a line which
is attached to a needle in your arm, and is used to get clearer pictures of your body cavity.  
A rectal contrast fills up the loops of your lower bowel so the doctors can see your tumor 
better.  After you have been given the contrast material (either by mouth, by vein, or 
rectum), you will lie flat on a table that will move you into the CT scan machine.  You 
will be asked to lie still and may be asked to hold your breath for a few seconds.  The CT 
scan is done in the radiology department and takes about half an hour.
o
For the PET CT, an IV is started in the hand. A small amount of radioactive chemical
(glucose) is injected into the blood stream. Once the glucose is injected, you will be 
asked to wait for about an hour to allow for glucose to distribute in the body. Then you 
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


ICF 10-19-2016
Page 4 of 19
CC#12751
Protocol Version 10 (03-03-2016)
Hope Rugo, MD
will be asked to lie down on a table and the body is scanned. The total time one will 
spend at the clinic is about 2-3 hours.
o A bone scan is a test that makes detailed images of your bones and any tumors on them.
Before the bone scan a small amount of radioactive substance is injected into your vein.
About 3 hours later you will lie on a table under a machine which will make an image of
your bones.  The test itself will take about 1 hour, but the whole process takes up to 4 
hours.

Tumor tissue collection - Your tumor sample (either fresh biopsy tissue collected during the
study or leftover tissue from a previous biopsy or surgery) will be used to identify 
biomarkers (specific traits) of your cancer that may predict a person’s response to this type of 
treatment or possibly response to PLX3397 treatment – research purposes.   
o
Biopsy for patients with accessible tumor - A biopsy procedure will involve removing all
or part of your tumor. Usually, this biopsy involves the use of a small needle which is 
directed into your tumor site with the guidance of an imaging machine such as a CT scan 
or a Doppler ultrasound, if necessary.  A tumor biopsy will take 30-60 minutes depending 
on the location of the biopsy.
o
Leftover tumor tissue collection – If available, the researchers would like to get a sample
of leftover tumor tissue from any biopsy or surgery you may have had as part of your 
regular cancer care.  Any remaining tumor tissue not used for the biomarker study will be 
returned to the clinic/hospital from which they were obtained.
During the main part of the study...
If the screening exams, tests and procedures show that you can be in the main part of the study, 
and you choose to take part, you will have the following procedures.  Patients participating in 
Phase 1b and Phase 2 will have the same procedures listed below performed unless otherwise 
noted.  A schedule of assessments for Phase 1b and Phase 2 has been included at the end of the 
consent form.  Your clinic visits may take about 1 hour.  If your visit includes blood studies to 
determine the levels of study drug in your blood or tumor assessments, your clinic visit may take 
up to 5-6 hours.
Cycle 1, Day -7/-6 (6 to 7 days before starting eribulin treatment) - Phase 2 only

Questions about how your disease is affecting your daily life

Blood (about 1 tablespoon) will be drawn:
o
To classify different white blood cells in your blood – research purposes
o
To monitor CSF1 (proteins produced by cells in your body) levels – research
purposes

You will start taking PLX3397
Cycle 1, Day 0/-2 (0 to 2 days before starting eribulin treatment) – Phase 2 only

Tumor Biopsy
Cycle 1, Day 1

Do not eat for one hour prior to your appointment.  You may be allowed to have a bland,
low-fat snack (crackers, toast, tea, etc.) if needed during this 1-hour period – Phase 1 
only
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


ICF 10-19-2016
Page 5 of 19
CC#12751
Protocol Version 10 (03-03-2016)
Hope Rugo, MD

Medical history - You will be asked about your health, any current and past illnesses, and
medications you are taking and those you have taken

Physical exam, including measurements of vital signs, height, and weight

Questions about how your disease is affecting your daily life

Blood (about 4-5 tablespoons) will be drawn:
o
For routine laboratory tests
o
To monitor CSF1 (proteins produced by cells in your body) levels – research
purposes
o
For pharmacokinetic (PK) studies – The studies will determine the levels of study 
drug in your blood at different time points.  Blood will be drawn before your drug 
dosing and at one, two and 5 hours post dosing – research purposes.  Phase 1 only
o
To classify different white blood cells in your blood – research purposes.

You will receive eribulin (IV)
Cycle 1, Day 2 - Phase 1 only

Do not take your morning dose of PLX3397 until you are instructed to do during your
clinic visit.

Blood (about 1 tablespoon) will be drawn:
o
For PK – blood will be drawn at 24 hours post Day 1dosing – research purposes
To monitor CSF1 (proteins produced by cells in your body) levels – research purposes
Cycle 1, Day 8

Medical history - You will be asked about your health, any current and past illnesses, and
medications you are taking and those you have taken 

If you are having any symptoms, you will have a Physical exam to check those symptoms

Questions about how your disease is affecting your daily life

Blood (about 1 tablespoon) will be drawn:
o
For routine laboratory tests

You will receive eribulin (IV)
**Patients on the modified eribulin dosing schedule will have this visit performed on Day 15.
Cycle 1, Day 15

Blood (about 1 tablespoon) will be drawn:
o
For liver function tests
Cycle 2 and beyond, Day 1

Do not take your morning dose of PLX3397 until you are instructed to do so during your
clinic visit.  Do not eat for one hour prior to your appointment.  You may be allowed to 
have a bland, low-fat snack (crackers, toast, tea, etc.) if needed during this 1-hour period 
– Cycle 2, Phase 1 only

Medical history - You will be asked about your health, any current and past illnesses, and
medications you are taking and those you have taken 

Physical exam, including measurements of vital signs, height, and weight
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


ICF 10-19-2016
Page 6 of 19
CC#12751
Protocol Version 10 (03-03-2016)
Hope Rugo, MD

Questions about how your disease is affecting your daily life

Blood (about 5 tablespoons) will be drawn for:
o
Routine laboratory tests
o
The following blood samples will only be drawn in Cycle 2 and Cycle 4 -
To monitor CSF1 (proteins produced by cells in your body) levels – research
purposes
To classify different white blood cells in your blood – research purposes
For PK studies - blood will be drawn before your drug dosing and two hours post
dosing – research purposes  Phase 1 only 

ECG – Cycle 2, Phase 1 & Phase 2

You will receive eribulin (IV)
Cycle 2 and beyond, Day 8

Blood (about 1 tablespoon) will be drawn for routine laboratory tests

You will receive eribulin (IV)
**Patients on the modified eribulin dosing schedule will have this visit performed on Day 15.
Cycles 2 and 3, Day 15

Blood (about 1 tablespoon) will be drawn:
o
For liver function tests
Every 6 or 8 weeks (Your study doctor will inform you which schedule you will be on.)

Tumor assessment by CT scan, PET CT scan, or Bone Scan

ECG – Phase 1 & Phase 2
When you are finished receiving PLX 3397 and eribulin...
You will be asked to return to the clinic 30 days after your last dose of study medication for the 
following additional tests and procedures:

Medical history - You will be asked about your health, any current and past illnesses, and
medications you are taking and those you have taken

Physical exam, including measurements of vital signs, height, and weight

Questions about how your disease is affecting your daily life

Blood (about 1 tablespoon) will be drawn for routine laboratory tests

Tumor assessment by CT scan, PET CT scan, or Bone Scan
If you experienced any side effects that have not been resolved, you physician may continue to 
monitor you until these symptoms are resolved or considered stable.
Study Location:  UCSF Helen Diller Family Comprehensive Cancer Center.
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


ICF 10-19-2016
Page 7 of 19
CC#12751
Protocol Version 10 (03-03-2016)
Hope Rugo, MD
HOW LONG WILL I BE IN THE STUDY?
You will continue to receive PLX3397 and eribulin as long as your disease does not progress or 
you do not have severe side effects, you experience any bad side effects, you decide to withdraw 
your consent to participate in this study, or the study is closed.  After you are finished taking the 
treatment, the study doctor will ask you to visit the office for follow-up exams within 30 days.  
CAN I STOP BEING IN THE STUDY?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely.
It is important to tell the study doctor if you are thinking about stopping so any risks from 
PLX3397 and eribulin can be evaluated by your doctor. Another reason to tell your doctor that 
you are thinking about stopping is to discuss what follow-up care and testing could be most 
helpful for you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped.
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY?
There are risks and discomforts that you may experience associated with the research study.  
These deserve careful thought.  You should talk to the study doctor if you have any questions. 
By taking PLX3397, you may experience one or more of the side effects listed below.  The side 
effects of taking the study treatments may range from mild to severe.  The side effects may be 
severe enough to be life-threatening or fatal.
If you experience severe side effects, your treatment with study drug may be reduced, 
temporarily discontinued, or permanently discontinued.  
You will receive appropriate 
medications and treatment for any side effects as determined to be best for your health by the 
study doctor. 
Side effects that may be seen with PLX3397 given by itself or in combination with other anti-
cancer treatments:
Common side effects (≥10% by frequency) associated with the use of PLX3397 include the 
following:

Nausea

Vomiting

Diarrhea

Abnormal or altered sense of taste

Decreased or loss of appetite

Rash

Hair or skin color changes, (to white or gray; original color usually returns after stopping
study drug)
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


ICF 10-19-2016
Page 8 of 19
CC#12751
Protocol Version 10 (03-03-2016)
Hope Rugo, MD

Increases in blood tests that monitor for and indicate liver damage (aspartate
aminotransferase and/or alanine aminotransferase)

Anemia (decrease in red blood cells that may make you weak or tired)

Fatigue or tiredness
Less common side effects ( 3% to less than 10%) associated with the use of PLX3397 
include the following:

Constipation

Increase in bilirubin (produced when the liver breaks down red blood cells)

Decrease in white blood cell counts (which could include one or more of the following:
white blood cell counts, lymphocytes, neutrophils, leukocytes; this may lead to increased 
risk of infection)

Febrile neutropenia (fever in a patient with neutropenia, an abnormally low number of
neutrophils, a type of white blood cell) 

Decrease in platelets (cells that help stop bleeding)

Edema (swelling of tissues in limbs, face, or around the eyes)
Additional side effects observed in clinical trials which are less common (3% to less than 10%) 
and for which association with PLX3397 use is under investigation:

Dry mouth

Upset stomach

Stomatitis (inflammation inside of mouth, usually a small sore or ulcer)

Fever and/or chills

Mucosal inflammation (inflammation affecting moist tissue lining parts of the inside of
your body, such as mouth, nose, lungs, and digestive tract)

Pruritus (itching of skin)

Alopecia (loss of hair)

Dry skin

Low levels of electrolytes in blood (which could include one or more of the following:
potassium, phosphorus, or sodium)

Dehydration

Increase in blood enzyme (which could include one or more of the following: creatine
phosphokinase, blood alkaline phosphatase)

Weight decreased

Headache

Dizziness

Hypertension (high blood pressure)

Cough

Dyspnea (difficulty breathing)

Arthralgia (joint pain)

Insomnia

Change in mental abilities such as memory loss and impaired thinking (2%)
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


ICF 10-19-2016
Page 9 of 19
CC#12751
Protocol Version 10 (03-03-2016)
Hope Rugo, MD
PLX3397 may cause liver injury that in some cases can be severe.  In a study where PLX3397 
was administered on its own and in studies where PLX3397 has been given in combination with 
other treatments, a form of liver injury called cholestasis has been seen. This is a type of liver 
injury where the flow of bile from the liver has been impaired causing jaundice (yellowing of the 
skin) and symptoms of liver disease including itching. Your liver function tests will be followed 
weekly for the first 9 weeks on study, and then each time you receive chemotherapy. Taking 
PLX3397 together with other medications may further increase the risk of severe liver injury.  
The liver injury may persist for a prolonged period (potentially many months), despite 
discontinuation of study medication, and there is the potential that the liver damage may be 
permanent or result in liver failure.   You may be required to have additional monitoring and 
evaluation, which may include a liver biopsy. If you develop jaundice, yellowing of the eyes, a 
change in stool color (to a light color), abdominal pain, itching, or persistent nausea and 
vomiting you should inform your study doctor immediately.  
There has been one report of a patient developing a potentially life-threatening rash after taking 
PLX3397 and PLX3397 was identified as a potential cause. This type of rash may sometimes 
include fever and inflammation of internal organs.
Side effects in healthy normal volunteers who received single doses of PLX3397 were all mild or 
moderate, and mostly associated with the digestive system, including constipation and abdominal 
bloating/discomfort. 
Animals treated with PLX3397 showed decrease in the pumping action (contraction) of the heart. 
There have been two reports of reduced ejection fraction (the amount of blood pumped by your 
heart with each beat) in patients receiving PLX3397 at a dose of 3000 mg/day, a much higher 
dose than you will receive. The role of PLX3397 in these events is undetermined at this time.
The severity of the side effects listed above could range from mild to severe or even life-
threatening. In addition, there may be other risks or side effects from PLX3397 that are not listed 
above or unknown at this time.  It is also possible to experience a serious allergic reaction, which 
could become life-threatening or fatal.  Symptoms of an allergic reaction include rash, hives, 
itching, swelling of the mouth, face, lips or tongue, dizziness, tightness in the chest, or trouble 
breathing.
If you do not understand what any of these side effects mean, please ask the study doctor or 
study staff to explain these terms to you. 
Your condition may not improve and could even worsen if you take part in this study.  
When taking any new medication, you should exercise caution and not drive, operate machinery, 
or engage in other activities requiring mental alertness until you know how the medication will 
affect you.
The study drug must be taken only by the person for whom it has been provided.  It also must be 
kept out of the reach of children or persons of limited capacity to read or understand.
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


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Risks and side effects related to the study drug eribulin:
Likely

Decreased white blood cells (may increase chance of infection)

Decreased red blood cells (may cause weakness and tiredness)

Fatigue

Hair loss

Peripheral neuropathy (a form of damage to the nerves supplying the hands and feet,
which leads to numbness or the feeling of “pins and needles” and/or impairment of 
muscle strength in the hands and feet)

Nausea

Constipation
Less Likely

Eyes watering

Upset Stomach/abdominal pain

Inflammation or ulcers in the mouth (stomatitis)

Dry mouth

Fluid retention

Upper respiratory tract infection

Low potassium in the blood (can cause constipation, weakness, and abnormal heart
rhythms)

Muscle spasms, muscular weakness

Change in taste

Dizziness

Insomnia

Depression

Rash

Liver function test changes
OTHER RISKS
Study Drug Combination risks:  The side effects of the combination of PLX3397 and eribulin 
are not yet known.  It is possible that this combination of drugs will cause new or more serious 
side effects than taking these drugs separately. You will be monitored closely for side effects and 
your doctor may change your medications if it appears that this combination is causing serious 
side effects. You should tell your doctor about any side effects that you experience while on this 
study.  When additional information about side effects is known, you will be notified of any 
further study drug related effects.  
Dose Escalation risks:  Only for patients participating in Phase 1b, since patients will be 
assigned to different doses of study drug, some patients may receive a dose of the drug that is too 
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


ICF 10-19-2016
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Hope Rugo, MD
small to be effective while others may receive a higher dose that may cause increased side 
effects.  You can ask your study doctor what dose you will be given.
Blood drawing (venipuncture) risks:  Drawing blood may cause temporary discomfort from 
the needle stick, bruising, and infection.
Electrocardiogram (EKG/ECG) risks:  The ECG involves placing electrodes on the skin.  You 
may experience an allergic reaction to the adhesive used to attach the electrodes to the skin.  
These symptoms are generally mild and clear up on their own.  Please let your doctor know if 
you are aware of any allergies.
Radiation (x-ray) risks:  The amount of radiation you will be exposed to is relatively small.  
Such doses of radiation may be potentially harmful, but the risks are so small that they are 
difficult to measure.  If you have already had many x-rays, you should discuss this with the 
researchers before agreeing to be in the study.
CT Scan risks:  CT scans involve the risks of radiation.  In addition, if contrast material (iodine 
dye) is used, there is a slight risk of developing an allergic reaction, from mild (itching, rash) to 
severe (difficulty breathing, shock, or rarely, death).  The contrast material may also cause 
kidney problems, especially if you are dehydrated or have poor kidney function.  The study 
doctors will ask you about any allergies or related conditions before the procedure.  If you have 
any of these problems, you may not be allowed to have a CT scan with contrast.  If you are 
taking metformin (or similar drugs by mouth to treat high blood sugar), such treatment will be 
stopped for 2-3 days around the time a scan is planned in order to avoid kidney side effects.
Having a CT scan may mean some added discomfort for you.  In particular, you may be bothered 
by feelings of claustrophobia when placed inside the CT scanner, or by lying in one position for 
a long time.  If contrast material is used, you may feel discomfort when it is injected by vein.  
You may feel warm and flushed and get a metallic taste in your mouth. Rarely, the contrast 
material may cause nausea, vomiting or a headache.
PET/CT Scan risks:  The PET/CT scan exposes your body to radiation, see radiation risk 
above.  The radiation levels come from a tracer which is a radioactive chemical injected into a 
vein in your arm. The tracer lets the doctor see how your cells are functioning and the radiation 
levels are very low. You may have an allergic reaction to the chemical used in the scan. For 
some patients, having to lie still on the scanning table for the length of the procedure may cause 
some discomfort or pain. After the scan your arm may be a little bit sore or have some redness 
where the IV was placed in your arm.  The radioactive solution does not remain in your system 
for a long period of time.  However, you should wait 2 hours before holding an infant or getting 
close to a pregnant woman to avoid exposing them to radiation.  You should drink fluids after the 
scan to help remove the solution from your system.
Bone Scan risks:  Risks include radiation exposure as well as possible bruising from the 
injection of contrast.  Some subjects may be uncomfortable lying flat.
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


I C F 1 0- 1 9- 2 0 1 6
Pa ge 1 2 of 1 9
C C # 1 2 7 5 1
Pr ot oc ol Versi o n 1 0 ( 0 3- 0 3- 2 0 1 6)
H o pe R u g o, M D
o varies w hic h were re versi ble at t he e n d of t he st u d y. P L X 3 3 9 7 ma y t heref ore affect fertilit y i n 
b ot h me n a n d w o me n. If y o u are a male, y o u ma y as k y o ur st u d y d oct or a b o ut s per m ba n ki n g. 
U n k n o w n Ris ks:  T he e x peri me ntal treat me nts ma y ha ve si de effects t hat n o o ne k n o ws a b o ut 
yet.  T he researc hers will let y o u k n o w if t he y lear n a n yt hi n g t hat mi g ht ma ke y o u c ha n ge y o ur 
mi n d a b o ut partici pati n g i n t he st u d y.
S afe H a n dli n g of C he m ot her a py Me dic ati o ns
T he st u d y dr u g P L X 3 3 9 7 is la bele d as a hazar d o us me dicati o n.  Ha n dli n g P L X 3 3 9 7 a n d ha vi n g 
c o ntact wit h a n y uri ne, feces or v o mit fr o m patie nts recei vi n g P L X 3 3 9 7 ma y p ose s o me ris k t o 
y o u a n d y o ur care gi vers.  T o a v oi d e x p os ure t o P L X 3 3 9 7 a n d a n y ass ociate d ris ks, y o u will be 
e d ucate d b y a me m ber of t he st u d y tea m o n h o w t o safel y ha n dle P L X 3 3 9 7, pr o perl y dis p ose of 
P L X 3 3 9 7, a n d h o w t o clea n pr o d ucts t hat ma y be c o nta mi nate d wit h P L X 3 3 9 7.
F or m ore i nf or mati o n a b o ut ris ks a n d si de effects, as k y o ur st u d y d oct or.
A R E T H E R E B E N E FI T S T O T A KI N G P A R T I N T H E  S T U D Y ?
Ta ki n g part i n t his  st u d y ma y or ma y n ot ma ke y o ur healt h better.  W hile d oct ors h o pe P L X 3 3 9 7 
a n d eri b uli n will be  m ore usef ul a gai nst ca ncer c o m pare d t o t he us ual treat me nt, t here is n o pr o of 
of t his.  
We d o k n o w t hat t he i nf or mati o n fr o m t his st u d y will hel p d oct ors lear n m ore a b o ut 
P L X 3 3 9 7 a n d eri b uli n as a treat me nt f or ca ncer.  T his i nf or mati o n c o ul d hel p f ut ure ca ncer 
patie nts.
W H A T O T H E R C H OI C E S D O I H A V E I F I D O N O T T A K E P A R T I N T HI S S T U D Y ?
If y o u c h o ose n ot t o partici pate i n t his researc h st u d y, ot her pr oce d ures or treat me nts f or y o ur 
ca ncer c o ul d i ncl u de:

Getti n g treat me nt or care f or y o ur ca ncer  wit h o ut bei n g i n a st u d y.  Eri b uli n is a sta n dar d
o pti o n f or treat me nt of metastatic breast ca ncer a vaila ble  wit h o ut bei n g i n a st u d y.  Y o ur
d oct or ca n disc uss ot her c he m ot hera p y o pti o ns wit h y o u.
I R B N U M B E R: 1 2- 0 8 4 6 8
I R B A P P R O V A L D A T E: 1 1/ 1 0/ 2 0 1 6
I R B E X PI R A TI O N D A T E: 0 5/ 0 2/ 2 0 1 7
T u m or Bi o ps y ris ks:  T he ge neral ris ks ass ociate d wit h t his pr oce d ure are pai n, disc o mf ort, 
i nfecti o n, blee di n g a n d i nj ur y t o or ga ns near b y.
Re pr o d ucti ve ris ks:  If y o u bec o me pre g na nt or fat her a c hil d w hile i n t his researc h st u d y or 9 0 
da ys f oll o wi n g st u d y c o m pleti o n, y o u m ust n otif y t he st u d y d oct or i m me diatel y.  T he ris k of 
ta ki n g t his pr o d uct i n pre g na nt w o me n has n ot bee n f ull y deter mi ne d fr o m eit her h u ma n st u dies 
or a ni mal st u dies.  T here is n o cli nical e x perie nce i n h u ma ns wit h P L X 3 3 9 7 i n pre g na nt or 
lactati n g w o me n.  P L X 3 3 9 7 ca n ca use fetal defects i n r o de nts a n d ra b bits, a n d s h o ul d be 
c o nsi dere d p ote ntiall y har mf ul t o t he fet us, wit h t he p ote ntial t o ca use fetal malf or mati o ns.  As a 
res ult, P L X 3 3 9 7 V s h o ul d n ot be a d mi nistere d t o pre g na nt w o me n or lactati n g w o me n w h o 
are breastfee di n g.  Y o u s h o ul d a v oi d bec o mi n g pre g na nt o ver t he c o urse of t his st u d y.  Bec o mi n g 
pre g na nt w hile partici pati n g i n t he st u d y will e x p ose y o u t o a p ote ntial l oss of t he pre g na nc y, or 
ot her u n k n o w n effects o n a n u n b or n c hil d, s uc h as b ut n ot li mite d t o, birt h defects a n d pre mat ure 
deli ver y.  Y o u will be wit h dra w n fr o m t he st u d y if y o u bec o me pre g na nt or ha ve a p ositi ve 
pre g na nc y test. I n a ni mal st u dies, P L X 3 3 9 7 ca use d a decrease i n s per m c o u nt a n d c ha n ges i n t he 


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Protocol Version 10 (03-03-2016)
Hope Rugo, MD

Taking part in another study.

Getting no treatment.

Getting comfort care, also called palliative care.  This type of care helps reduce pain,
tiredness, appetite problems and other problems caused by the cancer.  It does not treat
the cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep
you as active and comfortable as possible.
Please talk to your doctor about your choices before deciding if you will take part in this study.
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE?
We will do our best to make sure that the personal information in your medical record is kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be given 
out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include:

Plexxikon Inc. and Eisai, Inc., and their authorized representatives.

Government agencies such as the National Cancer Institute (NCI) and the Food and Drug
Administration (FDA), involved in keeping research safe for people.

UCSF’s Committee on Human Research

UCSF Helen Diller Family Comprehensive Cancer Center

University of California
Participation in research may involve a loss of privacy, but information about you will be 
handled as confidentially as possible.  A medical record will be created because of your 
participation in this study.  Your consent form and some of your research test results will be 
included in this record.  Therefore, your other doctors may become aware of your participation.  
Hospital regulations require that all health care providers treat information in medical records 
confidentially.
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for taking part in 
studies.  Check with your health plan/insurance company to find out what they will pay for.  
Taking part in this study may or may not cost you or your insurance company more than the cost 
of getting regular cancer treatment.
Plexxikon Inc., the makers of PLX3397, is supplying the study drug free of charge.  You will not 
be billed for any clinic visits or any of the tests required specifically by the study.  These are 
procedures noted above as “study test” (such as tumor biopsies, blood draws for PK, CSF1, and 
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


ICF 10-19-2016
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Protocol Version 10 (03-03-2016)
Hope Rugo, MD
white blood cell blood tests) in this consent form.  Other procedures, which are also done in this 
study but are part of your normal care, will be paid for by you or your insurance.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You can 
print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
WILL I BE PAID FOR TAKING PART IN THIS STUDY?
You will not be paid for taking part in this study.
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY?
It is important that you tell your study doctor, Hope Rugo, M.D., if you feel that you have been 
injured because of taking part in this study. You can tell the doctor in person or call her at 415-
353-7070.
Treatment and Compensation for Injury:  If you are injured as a result of being in this study, 
treatment will be available. The costs of the treatment may be billed to you or your insurer just 
like any other medical costs, or covered by the University of California, depending on a number 
of factors. The University does not normally provide any other form of compensation for injury. 
For further information about this, you may call the office of the Committee on Human Research 
at 415-476-1814.
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution.
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY?
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study.  Contact your study doctor Hope Rugo, M.D., at 415-353-7070.
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


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If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the Office of the Committee on Human Research at 415-476-1814.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017


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CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to 
keep.
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of 
health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled.
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Date
Signature of the Person Obtaining Consent
Date
Signature of the witness (required if participant is a non-English speaker)
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017
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Medications and Foods to Avoid
CC#12751:  A Phase Ib/II study of PLX 3397 and Eribulin in Patients with Metastatic Breast Cancer
The following is a list of medications to avoid while you are on this study. If you go to any 
medical visit, please take this list with you for the doctor’s reference.  This list is not all-
inclusive. 
Before you begin treatment, Dr. Rugo or one of her associates will review all medications you 
are taking. Make sure you talk with Dr. Rugo before you start or stop taking any medications, 
whenever possible. This information will be reviewed at each study visit. 
In addition to the listed medications you should also avoid eating or drinking juice from Seville 
(sour) oranges, grapefruit, pomegranate, and starfruit.
Generic Name
Brand Names ®
Generic Name
Brand Names ®
Amiodarone
Cordarone
Mesoridazine
Serentil
Amprenavir
Agenerase
Methadone
Methadose, Dolophine
Atazanavir
Reyataz
Moxifloxacin
Avelox
Carbamazepine
Carbatrol, Tegretol
Nafcillin
Chloramphenicol
Chlormycetin
Nefazodone
Serzone
Chloroquine
Aralen
Nelfinavir
Viracept
Chlorpromazine
Thorazine
Nevirapine
Viramune
Ciprofloxacin
Ciloxan, Cipro, Neofloxin
Nicardipine
Cardene
Cisapride
Propulsid
Oxcarbazepine
Trileptal
Citalopram
Celexa
Pentamidine
Pentam, Nebupent
Clarithromycin
Biaxin
Pentobarbital
Nembutal
Conivaptan
Vaprisol
Phenobarbital
Luminal
Delavirdine
Rescriptor
Phenytoin
Dilantin
Dexamethasone*
Decadron
Pimozide
Orap
Disopyramide
Norpace
Posaconazole
Noxafil
Dofetilide
Tikosyn
Primidone
Mysoline
Droperidol
Inapsine
Procainamide
Pronestyl
Efavirenz
Sustiva
Quinidine
Cardioquin
Erythromycin
Erythrocin
Rifabutin
Mycobutin
Etravirine
Intelence
Rifampin
Rifadin
Flecainide
Tambocor
Rifapentine
Priftin
Fluconazole
Diflucan
Ritonavir
Norvir
Fosamprenavir
Lexiva
Sotalol
Betapace
Fosphenytoin
Cerebyx
St John’s Wort
n/a
Gingko Biloba
n/a
Telithromycin
Ketek
Ginseng
n/a
Thioridazine
Mellaril
Haloperidol
Haldol
Vandetanib
Caprelsa
Ibutilide
Corvert
Voriconazole
VFend
Indinavir
Crixivan
Itraconazole
Sporanox
Ketoconazole
Oral forms only
Lopinavir 
(+ ritonavir =) Kaletra
*Short courses (up to weeks and premedication) is ok.
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017
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Protocol Version 10 (03-03-2016)
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Schedule of Assessments:  Phase 1b
Table  8-1 Study Calendar: Phase Ib
Cycle 
(1 cycle = 
21 days)
Comment
Screening
Cycle 1
Cycle 2
Cycle 3 & 
Beyond
EOT 
Real life 
time clock
≤4 
wks
≤2 
wks
D 1
D 2
D 8
D 1
D 8
D 1
D 8
≤ 30 
days
Informed 
Consent 
X
Registration
X
History & Exam
X
X
X
X
X
X
ECOG
X
X
X
X
X
ConMed Review
X
X
X
X
X
X
X
X
Peripheral
Neuropathy 
X
X
X
X
CBC w/ 5 part 
diff.
X
X
X
X
X
X
X
X
Chemistry
Panel 
BUN, CO2, Cl, K, 
Na, Creatinine, 
Glucose (non-
fasting), & 
Magnesium
X
X
X
X
X
Liver Function 
Tests
ALT, AST, AlkPhos, 
Total Bilirubin, & 
Albumin
X
PT/PTT
Completed prior to 
tumor biopsy
X
Urine Pregnancy 
Test 
Within 7 days of 
beginning treatment
X
X
EKG 
X
X
Eribulin 
Therapy, IV
Day 1 & 8, 
q 21 days 
X
X
X
X
X
X
PLX3397 
Therapy
Oral
Beginning Cycle 1, Day 1: Daily 
(self-administered)
Bone Scan & 
other imaging 
Baseline, then as 
indicated 
X
CT (C/A/P)
Every 6 weeks 
X
X
X
PK Draws
X
X
X
Blood for 
CSF1
X
X
X
Blood for 
Leukocyte 
Subtyping
X
Tumor biopsy 
Required for patients 
w/ accessible tumor
X
Archived Tumor 
Tissue 
Requested of all 
participants
X
*Patients on the modified eribulin dosing schedule will have cycles 28 days long.  Day 8 clinic 
visits will be performed on Day 15 of each cycle. 
Schedule of Assessments:  Phase 2
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017
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Cycle 
(1 cycle = 
21 days)
Comment
Screening Lead-In 
Phase
Cycle 1
Cycle 2
Cycle 3 
& 
Beyond
EOT 
Real life 
time clock
≤4 
wks
≤2 
wks
Day
 -7 to -6
D 11
D 8
D15
D 11
D 8
D15 D 11 D 8
D15
≤ 30 
days
7
Informed Consent 
X
Registration
X
History & Exam
X
X
X
X
X
X
ECOG
X
X
X
X
X
ConMed Review
X
X
X
X
X
X
X
X
Peripheral
Neuropathy 
X
X
X
X
CBC w/ 5 part 
diff.
X
X
X
X
X
X
X
X
Chemistry
Panel 
BUN, CO2, Cl, K, 
Na, Creatinine, 
Glucose (non-
fasting), & 
Magnesium
X
X
X
X
X
Liver Function 
Tests
ALT, AST, 
AlkPhos, Total 
Bilirubin, & 
Albumin
X
X
X
X
X
X
X
X
X
X
PT/PTT
Completed prior to 
tumor biopsy
X
Urine Pregnancy 
Test 2
Within 7 days of 
beginning treatment
X
X
EKG 3
X
X
Eribulin Therapy, 
IV4
Day 1 & 8, 
q 21 days 
X
X5
X
X
X
X
PLX3397 
Therapy
Oral
Beginning With Lead-In Phase (Day -7 to -6):
 Daily (self-administered)
Bone Scan & 
other imaging 
Baseline, then as 
indicated 
X
CT (C/A/P)
Every 6 weeks9 
X
X
X
Blood for 
CSF16
X
X
X
X8
Blood for 
Leukocyte 
Subtyping6
X
X
X
X8
Tumor biopsy 
Required for 
patients w/ 
accessible tumor
X
X 
(Day 
0/ -1)
Archived Tumor 
Tissue 
Requested of all 
participants
X
*Patients on the modified eribulin dosing schedule will have cycles 28 days long.  Day 8 clinic 
visits will be performed on Day 15 of each cycle. 
IRB NUMBER: 12-08468
IRB APPROVAL DATE: 11/10/2016
IRB EXPIRATION DATE: 05/02/2017
V
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