Clinical trial NCT00733408
Conditions: Estrogen Receptor-negative Breast Cancer HER2-negative Breast Cancer Progesterone Receptor-negative Breast Cancer Recurrent Breast Cancer Stage IV Breast Cancer Triple-negative Breast Cancer
Sponsor: University of Washington
Start date: 2008-04-23; Completion date: 2017-09-28
Enrollment: 59 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well giving paclitaxel albumin-stabilized nanoparticle (Nab-paclitaxel) formulation together with bevacizumab followed by bevacizumab and erlotinib hydrochloride work in treating patients with metastatic breast cancer. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can prevent cancer growth by blocking the ability of cancer cells to grow and spread. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This trial evaluates a maintenance treatment with erlotinib and bevacizumab after Nab-paclitaxel and bevacizumab which may control cancer growth with biologic therapies.

Detailed description:
PRIMARY OBJECTIVES:

I. Progression free survival.

SECONDARY OBJECTIVES:

I. Response rate.

II. Overall survival.

III. Safety and toxicity.

IV. Exploratory biomarkers will be assessed as potential predictors of response to treatment including: expression of epidermal growth factor receptor (EGFR) and secreted protein acidic and rich in cysteine (SPARC) in the primary tumor and changes in levels of circulating tumor cells (CTCs) and circulating endothelial cells (CECs).

OUTLINE:

INDUCTION THERAPY: Patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients achieving complete response, partial response, or stable disease after completion of induction therapy will receive bevacizumab IV over 30-90 minutes once every 14 or 21 days and erlotinib hydrochloride orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up per physician discretion.

Arms: arm 1: INDUCTION THERAPY: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV on days 1, 8, and 15 and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients achieving complete response, partial response, or stable disease after completion of induction therapy will receive bevacizumab IV over 30-90 minutes once every 14 or 21 days and erlotinib hydrochloride PO QD in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: paclitaxel albumin-stabilized nanoparticle formulation intervention 2: bevacizumab intervention 3: erlotinib hydrochloride
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Department of Medicine, Division of Oncology 
Seattle Cancer Care Alliance 
Harborview Medical Center 
Seattle, Washington 
 
Combined Targeted Therapies for Triple Negative Advanced Breast 
Cancer - A Phase II Trial of Weekly Nab-Paclitaxel and Bevacizumab 
Followed by Maintenance Targeted Therapy with Bevacizumab and 
Erlotinib 
 
NCT00733408 
 
Current Version: April 14, 2014 
 
 
 
   Previous Version:   October 14, 2013 
 
Principal Investigator: 
Jennifer Specht, M.D.; University of Washington 
Associate Professor of Medicine  
 
 
University of Washington  
 
 
 
Seattle Cancer Care Alliance 
 
 
 
P.O. Box 19023 
 
 
 
 
 
825 Eastlake Avenue East  
 
 
 
Mail Stop G3-630 
 
 
 
 
 
Seattle, WA 98109-1023 
 
 
 
 
(206) 288-6889 
 
 
 
 
 
(206) 288-2054 (fax) 
jspecht@u.washington.edu 
 
Co-investigators:  
University of Washington: 
Georgiana Ellis, M.D. 
V.K. Gadi, M.D. 
Julie Gralow, M.D. 
Larissa Korde, M.D. 
Hannah Linden, M.D. 
Lupe Salazar, M.D. 
 
Study Statistician:  
Brenda Kurland, PhD 
Research Associate Professor, Biostatistics 
University of Pittsburgh  
201 North Craig Street 
Pittsburgh, PA 15213 
(412) 383-1128 
BFK10@pitt.edu 


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TABLE OF CONTENTS 
 
 
 
Page 
 
SCHEMA .............................................................................................................................. 3 
1.0 OBJECTIVES ......................................................................................................................... 4 
2.0 BACKGROUND ..................................................................................................................... 4 
3.0 DRUG INFORMATION........................................................................................................... 8 
4.0 STAGING CRITERIA ........................................................................................................... 25 
5.0 ELIGIBILITY CRITERIA ....................................................................................................... 27 
6.0 STRATIFICATION FACTORS .............................................................................................. 29 
7.0 TREATMENT PLAN ............................................................................................................. 29 
8.0 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS ................................. 32 
9.0 STUDY CALENDAR ............................................................................................................ 41 
10.0 CRITERIA FOR EVALUATION AND END POINT DEFINITIONS....................................... 43 
11.0 STATISTICAL CONSIDERATIONS .................................................................................... 46 
12.0 DISCIPLINE REVIEW ........................................................................................................ 49 
13.0 REGISTRATION GUIDELINES .......................................................................................... 49 
14.0 DATA SUBMISSION SCHEDULE ...................................................................................... 50 
15.0 SPECIAL INSTRUCTIONS ................................................................................................ 51 
16.0 ETHICAL AND REGULATORY CONSIDERATIONS ......................................................... 55 
17.0 BIBLIOGRAPHY ................................................................................................................ 61 
18.0 APPENDICES .................................................................................................................... 65 
 
 
 


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SCHEMA 
 
 
 
 
 
REGISTRATION 
 
 
 
 
INDUCTION REGIMEN 
 
Induction therapy with weekly Nab-Paclitaxel 100 mg/m2 IV days 1, 8, and 15 and  
Bevacizumab 10 mg/kg IV days 1 and 15 of each 28 day cycle for 6 cycles 
 
 
 
 
POST INDUCTION DISEASE ASSESSMENT 
 
 
 
 
 
Disease Progression 
Disease Stable or Responding 
 
 
 
 
Off Study 
 
MAINTENANCE REGIMEN 
 
Bevacizumab 10 mg/kg IV Q 14 days or 15 mg/kg 
IV Q 21 days and Erlotinib 150 mg PO daily until 
disease progression 
 
 
 
 
 


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1.0  
OBJECTIVES 
 
1.1 
Primary Objective 
 
The primary objective is progression free survival. 
 
1.2 
Secondary Objectives 
 
The secondary objectives are: 
 
• 
Response rate,  
• 
Overall survival,  
• 
Safety and toxicity,  
• 
Exploratory biomarkers will be assessed as potential predictors of response 
to treatment including: 
• 
Expression of EGFR and SPARC in the primary tumor and 
• 
Changes in levels of circulating tumor cells (CTCs) and circulating 
endothelial cells (CECs). 
 
 
2.0 
BACKGROUND 
 
It is now recognized that patients with breast cancer which expresses the basaloid or 
“triple negative” phenotype (ER negative, PR negative, HER2 non-overexpressing) have 
a particularly aggressive and virulent form of the disease.  In the adjuvant setting, their 
prognosis is worse than that of other subgroups (luminal A, luminal B) defined by DNA 
genotyping [1], and with recent improvements in the outcome of adjuvant therapy for 
HER2 over-expressing patients, it appears they will also have a much worse outcome in 
that setting than the HER2 over-expressing patients.  There is little as yet reported about 
the prognosis or response to chemotherapy of these patients in the setting of advanced 
disease; however, our institutional experience with combination chemotherapy, in pilot 
studies involving antitubulin combinations, indicates a response rate over 50% 
(comparable to other phenotypes) but a relatively short median time to progression of 
4.4 months in the first line setting [2]. 
 
The biology of triple negative disease is under intensive study.  It is known that familial 
cancers with BRCA 1 mutations which involve loss of function, usually express this 
phenotype [3-7].  Further, work from the group at the University of Chicago suggests 
that, even among “sporadic” tumors with the triple negative phenotype, there is often 
down-regulation of expression of the BRCA 1 protein, apparently due to epigenetic 
mechanisms involving suppression of promoter function [8].  There are data from 
preclinical systems which suggest that loss or down-regulation of the function of BRCA 
1, a gene known to be involved in the repair of DNA damage, may predispose to 
alteration in the pattern of chemosensitivity for standard agents, with an increase in 
sensitivity to the platinators [9, 10] and to vinorelbine, but not docetaxel [11].  It is not yet 
known whether these preclinical observations will be borne out in the setting of human 
cancer.   
 
 


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Epidermal Growth Factor Receptor Expression and Significance in Cancer 
 
The control of cell growth is mediated by a complex network of signaling pathways 
responsive to external influences, such as growth factors, as well as to internal controls 
and checks.  Epidermal growth factor (EGF) was one of the first growth factors to be 
described.  It was shown to be mitogenic, an effect mediated by the binding of EGF (or 
other ligands) to the cell surface EGF receptor (EGFR), stimulating autophosphorylation 
of the intracellular tyrosine kinase domain of the receptor.  Subsequent investigations 
revealed EGFR to be one of a family of closely related receptors that includes EGFR 
(HER1), HER2, HER3, and HER4.   Over-expression, at the protein level, of EGFR 
(erbB1), demonstrated by radioligand binding assay [12] and by immunohistochemistry 
[13,14] is another alteration common to the triple negative breast cancer phenotype.  
However, unlike the situation with HER2, where gene amplification occurs in 20% or 
more of human  breast cancers, gene amplification by the same criteria appears to be 
very rare in human breast cancer, even among  specimens selected for expression of 
the triple negative phenotype [15, 16].   
 
EGFR and other HER family members are considered to be important in the 
development, progression, and aggressive behavior of human epithelial malignancies 
and to be relevant therapeutic targets.  A number of human malignancies are associated 
with aberrant or over-expression of EGFR [17].  Stimulation of tumor cells via the EGFR 
is important for both tumor growth and tumor survival in vivo.  Over-expression of EGFR 
in certain human tumors, including non–small cell lung carcinoma (NSCLC), has been 
correlated with both chemo-resistance and poor prognosis [18-30]. Inhibitors of EGFR 
tyrosine kinase activity have been in development for a number of years, and although 
earlier compounds lacked specificity and potency, newer compounds have proven active 
in nonclinical and clinical studies. 
 
Erlotinib (Tarceva, previously known as OSI-774) is an orally active, potent, selective 
inhibitor of the EGFR tyrosine kinase.  Early clinical data with erlotinib indicate that the 
compound is generally safe and well tolerated at doses that provide the targeted 
effective concentration based on nonclinical experiments.  In non-small cell lung cancer, 
for example, there is significant benefit to the administration of small-molecule inhibitors 
of EGFR, such as erlotinib, among patients with disease progression after 
chemotherapy, independent of evidence for gene amplification by the usual criteria, but 
with some relationship to expression of the protein [31-33].  In colorectal cancer, 
administration of cetuximab, a monoclonal antibody directed against EGFR, appears to 
be effective, regardless of the level of expression of EGFR [34].   
 
It is now clear, from randomized trials in metastatic breast cancer [35], non-small cell 
lung cancer [36] and colorectal cancer [37] that the addition of  bevacizumab, a 
monoclonal antibody which targets VEGF, improves response rate and time to 
progression, compared to chemotherapy alone.  However, it has so far been impossible 
to demonstrate consistent correlates of VEGF status with clinical outcome in these 
diseases.  In ECOG 2100, first line therapy for metastatic breast cancer in HER2 non-
amplified patients with paclitaxel and bevacizumab was compared to paclitaxel alone in 
a randomized phase III trial and reported at SABC 2005.  The combination of paclitaxel 
and bevacizumab was associated with a significant improvement in progression free 
survival for patients with ER positive and ER negative disease (11.4 months for 
paclitaxel and bevacizumab versus 6.11 months for paclitaxel alone; HR 0.51, 
p<0.0001).  This outcome in E2100 will serve as a historical control for this trial of 


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combined targeted therapies with continued bevacizumab and erlotinib after induction 
therapy with nab-paclitaxel and bevacizumab. 
 
Unlike the situation with bevacizumab, where concurrent administration with 
chemotherapy appears beneficial, the concurrent administration of erlotinib with 
chemotherapy appeared deleterious in patients with non-small cell lung cancer [38].  The 
reasons for this are not clear, but a sequential approach (chemotherapy, then small 
molecule targeted inhibitor) seems, at present, to be the preferred approach for erlotinib. 
 
Scientific Rationale for Dosing Schema 
 
The dosing for nab-paclitaxel (Abraxane) proposed for this study is 100 mg/m2 
intravenously days 1, 8 and 15 every 28 days until best response.  The rationale for this 
dose is based upon the following: 1) -nab-paclitaxel was superior to paclitaxel in a phase 
III, randomized trial, both for response rate and for time to progression [39]; 2) weekly 
nab-paclitaxel appears to be anti-angiogenic [40, 41], and there are now data which 
establish the optimal tolerated weekly dose for this compound [41].   Bevacizumab will 
be dosed at 10 mg/kg intravenously every 14 days during induction and at either 10 
mg/kg intravenously every 14 days or 15 mg/kg intravenously every 21 days during 
maintenance.  Bevacizumab 10 mg/kg intravenously every 14 days has been previously 
evaluated for toxicity and efficacy in metastatic breast cancer [35].  Erlotinib is being 
administered at its FDA-approved dose and schedule.  
 
Hypothesis/Objectives: 
 
We propose to explore the combination of nab-paclitaxel and bevacizumab in first-line 
therapy for metastatic disease among patients with the triple negative phenotype, based 
on evidence that: 1) nab-Paclitaxel was superior to paclitaxel in a phase III, randomized 
trial, both for response rate and for progression free survival [39]; and 2) the combination 
of paclitaxel on a weekly schedule and bevacizumab was superior to paclitaxel alone, in 
a population of patients with advanced breast cancer whose tumors did not over-express 
HER2 [35]. The schedule proposed for nab-paclitaxel is weekly, since this appears to be 
anti-angiogenic [40, 41], and there are now data which establish the optimal tolerated 
weekly dose for this compound [41].  At the completion of 24 weeks of induction 
chemotherapy, nab-paclitaxel will be discontinued, and patients who remain on study 
without evidence of disease progression will receive combined, targeted “maintenance” 
therapy with bevacizumab and erlotinib, a combination which has been studied with 
acceptable toxicity and promising preliminary results [42].  We hypothesize that the 
combination of targeted, biologic therapies aimed at the critical pathways of 
angiogenesis (VEGF) and signaling via EGFR may result in prolonged progression free 
survival after chemotherapy.    
 
The primary endpoint will be progression free survival with secondary endpoints to 
include response rate, overall survival, safety and toxicity, and correlation of response 
with EGFR and SPARC expression in the primary tumor, changes in levels of circulating 
tumor cells (CTCs), and circulating endothelial cells (CECs) as potential predictors of 
treatment response. 
 
Correlative Studies: 
 


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We propose to study, in patients entered on this trial, the expression of EGFR and 
SPARC (secreted protein acidic and rich in cysteine, also known as BM40 or 
osteonectin) in their primary tumors by immunohistochemistry.  EGFR is the target of 
erlotinib and is often overexpressed at the protein level in triple negative breast cancers.  
SPARC is an albumin-binding protein secreted by tumor cells into the interstitium [43].  
Nab-paclitaxel achieves a high intracellular tumor concentration, and its intracellular 
concentration is at least, in part, achieved by an albumin-mediated transendothelial 
transport via the gp60 pathway [50].  SPARC is a matricellular protein that is upregulated 
in several aggressive tumors, and its presence is associated with poor outcomes.  
Expressed in 40-50% of breast cancers, SPARC also shares sequence homology with 
the C terminus of the gp60 pathway (an important pathway in nab-paclitaxel intracellular 
transport) and binds albumin.  By exploiting both caveolin-1 and the SPARC protein, 
nab-paclitaxel may preferentially enhance drug delivery to tumors.  Expression of EGFR 
and SPARC protein by IHC methodology in primary tumors will be correlated in an 
exploratory fashion to treatment response. 
 
In addition, levels of circulating tumor cells (CTC) and circulating endothelial cells (CEC) 
will be quantitated over time including pre-therapy, prior to weeks 5 and 17 of induction, 
prior to weeks 1 and 9 of maintenance and at disease progression if the patient is 
removed from study treatment due to disease progression.  The number of CTCs 
detectable in patients with metastatic breast cancer prior to initiation of therapy has been 
shown to be an independent predictor of progression-free and overall survival [44] [45], 
however, the predictive value of CTCs in regimens containing targeted, biologic 
therapies has not been well-established.  Flow cytometry studies have indicated that 
circulating endothelial cells (CECs) are significantly increased in number and percentage 
viability in untreated cancer patients compared with healthy subjects [46], and animal 
models and studies in cancer patients suggest that CECs and their putative progenitor 
cells (CEPs) may be used as quantitative surrogate pharmacodynamic markers of 
antiangiogenic therapies [47,48].  In advanced breast cancer patients receiving 
metronomic chemotherapy, an increase in apoptotic CECs after 2 months of therapy 
was associated with prolonged progression-free and overall survival with follow up of 
greater than 2 years [49].   
 
Measurement of circulating endothelial cells (CECs) isolated from peripheral blood will 
be performed in a serial fashion and will be correlated in an exploratory fashion with 
angiogenic factors and with patient clinical response to treatment.  We hypothesize that 
decreases in level of CTC may predict longer time to disease progression, and increases 
in apoptotic CEC may also be predictive of response to chemotherapy and 
bevacizumab. 
 
Based upon the prolongation in PFS observed in E2100 where patients with ER and PR 
negative, HER2 non-overexpressing metastatic breast cancer were treated with the 
combination of bevacizumab and paclitaxel, we would consider a prolongation in the 
median progression free survival (PFS) for these patients from 8 to 13 months to be of 
sufficient interest to warrant further exploration of this combination in the setting of a 
randomized trial.  It will be necessary to enter 63 patients on the trial in order to be able 
to detect this degree of improvement.  Secondary objectives will be the assessment of 
response rate, survival and the proportion of patients with grade 3 or 4 toxicity. 
 
 


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3.0 
DRUG INFORMATION 
 
3.1 
Nab-Paclitaxel: (ABI-007, Abraxane, albumin-bound paclitaxel) 
 
Nab-paclitaxel for Injectable Suspension (paclitaxel albumin-bound particles for 
injectable suspension) is indicated for the treatment of  
 
• 
Metastatic breast cancer after failure of combination chemotherapy for 
metastatic disease or relapse within 6 months of adjuvant chemotherapy. 
Prior therapy should have included an anthracycline unless clinically 
contraindicated. 
• 
Locally advanced or metastatic non-small cell lung cancer (NSCLC), as first-
line treatment in combination with carboplatin, in patients who are not 
candidates for curative surgery or radiation therapy. 
• 
Metastatic adenocarcinoma of the pancreas as first-line treatment, in 
combination with gemcitabine. 
 
Nab-paclitaxel is a Cremophor EL-free, albumin-bound form of paclitaxel with a 
mean particle size of approximately 130 nanometers. Each 50-mL single-use vial 
contains 100 mg of paclitaxel, and approximately 900 mg of human albumin. 
Nab-paclitaxel is supplied as a white to off-white sterile lyophilized powder for 
reconstitution with 20 mL of 0.9% Sodium Chloride Injection USP. 
 
3.1.1 Introduction 
 
Nab-paclitaxel (Abraxane) is a novel biologically interactive albumin-
bound paclitaxel combining a protein with a chemotherapeutic agent in 
the particle form. This composition provides a novel approach of 
increasing intra-tumoral concentration of the drug by a receptor-mediated 
transport process allowing transcytosis across the endothelial cell wall, 
thereby breaching the blood/tumor interface. This albumin-specific 
receptor mediated process involves the binding of a specific receptor 
(gp60) on the endothelial cell wall, resulting in activation of a protein 
caveolin-1, which initiates an opening in the endothelial wall with 
formation of a little caves or caveolae, with transport of the albumin-
bound chemotherapeutic complex via these caveolae to the underlying 
tumor interstitium [50]. A protein specifically secreted by the tumor 
(SPARC) binds and entraps the albumin, allowing release of the 
hydrophobic drug to the tumor cell membrane [50]. Nab-paclitaxel is the 
first biologically interactive nanoparticle leveraging this gp-60/caveolin-
1/caveolae/SPARC pathway to increase intra-tumoral concentration of 
the drug and reducing toxic drug in normal tissue. 
3.1.2 Preclinical Studies with Nab-Paclitaxel  
 
Preclinical studies comparing nab-paclitaxel to Taxol demonstrated lower 
toxicities, with a MTD approximately 50% higher for nab-paclitaxel 
compared to Taxol.  At equal doses there was less myelosuppression 
and improved efficacy in a xenograft tumor model of human mammary 
adenocarcinoma.  At equitoxic doses of nab-paclitaxel was found to be 
markedly more efficacious than Taxol [51] 


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3.1.3 Clinical Studies with Nab-Paclitaxel  
 
Every 3 Week Schedule 
 
In a phase I study, the maximum tolerated dose (MTD) of nab-paclitaxel 
was determined to be 300 mg/m2 by 30 minute infusion every 3 weeks, 
without premedication or G-CSF support [52]  No severe hypersensitivity 
reactions 
occurred 
with 
nab-paclitaxel 
despite 
the 
absence 
of 
premedication.  Dose-limiting toxicities included sensory neuropathy, 
stomatitis, and superficial keratopathy, which occurred at a dose of 
375 mg/m2.  
 
Two multicenter phase II studies have evaluated 2 dose levels of nab-
paclitaxel (300 mg/m2, n=63, and 175 mg/m2, n=43) in patients with 
metastatic breast cancer [53]  The overall response rates in these 2 
phase II trials were 40% (95% CI 25-54%) for the 175 mg/m2 dose, and 
48% (95% CI 35-60%) for the 300 mg/m2 dose.  Of 39 patients receiving 
300 mg/m2 as first-line therapy for metastatic breast cancer, 64% (95% CI 
49-79%) responded.  This was contrasted with a 45% response rate in 
similar patients at the lower dose level. Grade 4 neutropenia was noted in 
24% of patients at the higher dose level, occurred primarily during the first 
cycle and resolved rapidly. 
 
A Phase III trial in patients with metastatic breast cancer compared nab-
paclitaxel 260 mg/m2 to Taxol 175 mg/m2 given every 3 weeks [39]  
Efficacy analyses were based on the ITT population. The ORR was 
significantly greater for nab-paclitaxel than for Taxol for all patients (33% 
v 19%, respectively; P = 0.001), patients who received first-line therapy 
(42% v 27%, respectively; P = 0.029), patients who received second-line 
or greater therapy (27% v 13%, respectively; P = 0.006), and patients 
who 
had 
received 
prior 
anthracycline 
therapy 
in 
either 
the 
adjuvant/metastatic setting (34% v 18%, respectively; P = 0.002) or the 
metastatic setting only (27% v 14%, respectively; P = 0.010). Tumor 
response rate was also significantly higher for nab-paclitaxel than for 
Taxol in patients with visceral dominant lesions (34% v 19%, respectively; 
P = 0.002) and in patients aged younger than 65 years (34% v 19%, 
respectively; P < 0.001). ORR also was greater for nab-paclitaxel 
compared with standard paclitaxel in patients with nonvisceral dominant 
lesions (34% v 19%, respectively) and in patients  65 years old (27% v 
19%, respectively), but the results did not reach statistical significance 
because of the small number of patients in these subsets. 
 
Median TTP was significantly longer with nab-paclitaxel than with 
paclitaxel for all patients (23.0 v 16.9 weeks, respectively; hazard ratio 
[48] = 0.75; P = 0.006). 
 
At the time of these analyses (October 2004), the median censoring time 
for overall patient survival was 103 weeks for the nab-paclitaxel group 
and 101 weeks for the Taxol group. There was a trend for greater median 


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survival for all patients treated with nab-paclitaxel than with paclitaxel 
(65.0 v 55.7 weeks, respectively; P = 0.374). Although no difference in 
survival was observed in first-line patients, the difference was statistically 
significant in patients who received nab-paclitaxel , compared with 
paclitaxel, as second-line or greater therapy (56.4 v 46.7 weeks, 
respectively; HR = 0.73; P = .024). 
 
The incidence of hypersensitivity reactions (any grade) was low for both 
arms (1% for nab-paclitaxel and 2% for Taxol). No severe (grade 3 or 4) 
treatment-related hypersensitivity reactions occurred in any of the 
patients in the nab-paclitaxel group despite the absence of premedication. 
In contrast, grade 3 hypersensitivity reactions occurred in the paclitaxel 
group despite standard premedication (chest pain, two patients; allergic 
reaction, three patients). Per protocol, corticosteroids and antihistamines 
were not administered routinely to patients in the nab-paclitaxel group; 
however, premedication was administered for emesis, myalgia/arthralgia, 
or anorexia in 18 patients (8%) in the nab-paclitaxel group in 2% of the 
treatment cycles, whereas 224 patients (> 99%) in the paclitaxel group 
received premedication in 95% of the cycles. 
 
Although the patients in the nab-paclitaxel group received an average 
paclitaxel dose-intensity 49% greater than that received by patients in the 
paclitaxel group, the incidence of treatment-related grade 4 neutropenia 
was significantly lower in the nab-paclitaxel group than in the Taxol group 
(9% v 22%, respectively; P < 0.001), with a higher mean neutrophil nadir 
(1.67 v 1.31x109/L, respectively; P = 0.046), suggesting that polyethylated 
castor oil may have contributed to this toxicity in patients who received 
standard paclitaxel.  
 
As expected with a higher dose of paclitaxel, treatment-related grade 3 
sensory neuropathy occurred more frequently in the nab-paclitaxel arm 
than in the paclitaxel arm (10% v 2%, respectively; P <  0.001); however, 
these episodes improved with interruption of treatment to grade 2 or 1 in 
a median 22 days and were easily managed with treatment interruption 
and dose reduction. By day 28 after its first occurrence, the number of 
patients with persistent grade 3 sensory neuropathy was the same (n = 4) 
in both study arms. No episodes of motor neuropathy or grade 4 sensory 
neuropathy were reported in either group.  
 
The only clinical chemistry value that was notably different between the 
two treatment arms was higher serum glucose levels in the paclitaxel–
treated patients, who also had a higher incidence of hyperglycemia 
reported as an AE compared with nab-paclitaxel–treated patients (7% v 
1% respectively; P =0.003).  
 
Subgroup analyses revealed that the safety profiles of nab-paclitaxel and 
paclitaxel in patients who received the drugs as first-line therapy were 
similar to those in the overall study population. In subgroup analyses by 
age, the reported AEs were similar in patients less than 65 years old and 
patients  65 years old in both groups. Of the patients  65 years old, the 
incidences of the following AEs were notably lower in the nab-paclitaxel 


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group than in the paclitaxel group: neutropenia (23% v 59%, 
respectively), leukopenia (10% v 31%, respectively), nausea (20% v 38%, 
respectively), hyperglycemia (0% v 19%, respectively), and flushing (0% v 
16%, respectively). These data indicate no additional safety concerns for 
nab-paclitaxel in patients  65 years old compared with younger patients.  
 
Six patients (3%) in the nab-paclitaxel group and eight patients (4%) in 
the standard paclitaxel group died during the study, all as a result of 
disease progression. No treatment-related deaths occurred in the nab-
paclitaxel group; one patient (< 1%) in the paclitaxel group died of 
multiorgan failure, which was considered by the investigator to be 
possibly related to treatment but may also have been a result of sepsis 
and/or progressive disease. 
Weekly for 3 Weeks, Every 4 Weeks Schedule 
 
Thirty-nine patients were enrolled into A Phase I study of  nab-paclitaxel 
administered weekly for 3 weeks followed by a 1 week rest in patients 
with advanced solid tumors [54].  The MTDs for heavily and lightly pre-
treated patients were 100 and 150 mg/m2 respectively.  Dose limiting 
toxicities included grade 4 neutropenia and grade 3 sensory neuropathy.  
Premedication was not required, and unexpected, non-taxane associated 
toxicities were not observed. 
 
In a Phase II trial in heavily pretreated patients with taxane-refractory 
metastatic breast cancer, objective antitumor responses occurred in 15% 
of women treated with  nab-paclitaxel100 mg/m2 on this schedule [55]  
Nab-paclitaxel weekly regimen was well tolerated. 91% of patients were 
treated at the full dose of 100 mg/m2 of nab-paclitaxel without dose 
reductions. Based on the activity and low toxicity documented with the  
nab-paclitaxel 100 mg/m2 weekly regimen, this study was expanded to 
evaluate the efficacy and safety/tolerability of a higher dose of  nab-
paclitaxel 125 mg/m2 weekly regimen in 75 additional patients. Results of 
this dose-finding study confirm the dose of  nab-paclitaxel 100 mg/m2 as 
the appropriate dose for further study in this patient population [56] 
 
3.1.4 Potential Risks of Nab-Paclitaxel 
 
Please refer to the FDA approved prescribing information for risk and 
safety information for Nab-Paclitaxel. 
 
Advantages of Nab-Paclitaxel 
 
Nab-Paclitaxel is a novel Cremophor EL-free, non-crystalline, amorphous, 
albumin-bound particle form of paclitaxel suspended in normal saline with 
several advantages over Taxol:  
 
• 
Preclinical models consistently demonstrated improved tolerability, 
increased antitumor activity and higher intratumor paclitaxel levels for 
nab-paclitaxel compared to paclitaxel.  Recent mechanistic studies 
indicate that this increased antitumor activity may be due to increased 


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tumor uptake of paclitaxel that is mediated through albumin-receptors 
on tumor neovasculature (Desai et al, 2006). 
 
• 
Nab-Paclitaxel does not require steroid co-medication and can be 
administered weekly or every 3 weeks. 
 
• 
Nab-Paclitaxel is better tolerated than paclitaxel. In a Phase I trial 
using an every 3 week schedule of administration, the maximum 
tolerated dose of nab-paclitaxel (300 mg/m2) was substantially higher 
than the labeled dose for paclitaxel (175 mg/m2) (Investigator’s 
Brochure 8th Ed).  Improved tolerability compared to Taxol was also 
demonstrated using a schedule of weekly administration for 3 weeks 
with a week of rest in which a recently completed Phase I study found 
the MTDs and recommended Phase II doses to be 100 and 
150 mg/m2 in heavily and minimally pretreated patients respectively 
[54]. 
 
• 
The antitumor activity of nab-paclitaxel is greater than that of 
paclitaxel.  In Phase II trials, antitumor activity was documented in 
metastatic breast cancer (Ibrahim et al 2005 and Investigator’s 
Brochure 7th Ed) and a Phase III study utilizing  nab-paclitaxel at a 
dose of 260 mg/m2 every 3 weeks demonstrated increased objective 
response rates and time to tumor progression compared to standard 
doses of Taxol in women with metastatic breast cancer [39]. Antitumor 
activity with very little toxicity has also been seen in a Phase II trial of 
100 mg/m2 weekly in heavily pretreated patients with paclitaxel-
refractory metastatic breast cancer [55]. 
 
• 
The major components of nab-paclitaxel are unmodified paclitaxel 
and human serum albumin. The absence of Cremophor EL in the 
formulation allows the infusion of nab-paclitaxel in approximately 30 
minutes. 
 
• 
Nab-Paclitaxel is Cremophor EL-free and therefore associated with a 
reduced 
risk 
of 
hypersensitivity 
and 
no 
requirements 
for 
premedication as compared to Taxol. 
 
• 
The Cremophor EL constituent in Taxol requires special non-DEHP 
tubing and in-line filters for intravenous administration, since 
Cremophor EL causes leaching of the tubing plasticizers.   Nab-
Paclitaxel requires no special tubing or in-line filters. 
 
3.1.5 Packaging, Labeling, and Storage of Study Drug 
 
Nab-Paclitaxel is commercially available in single-use vials, but will be 
supplied free of charge by Celgene for patients who are enrolled after the 
IRB approves modification to the study design.   
 
3.1.6 Study Medication Administration 
 


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Nab-Paclitaxel will be stored, reconstituted and administered per FDA 
approved package insert instructions and administered to the patient at 
the study site. 
3.2 
Bevacizumab (Avastin®) 
 
Bevacizumab is a monoclonal antibody that has been studied in a multitude of 
Phase I, II, and III clinical trials in more than 5000 patients and in multiple tumor 
types. The following discussion summarizes bevacizumab’s safety profile and 
presents some of the efficacy results pertinent to this particular trial. Please refer 
to the Bevacizumab Investigator Brochure for descriptions of all completed 
Phase I, II, and III trials reported to date. 
 
3.2.1 Description 
 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, 
sterile 
liquid 
concentrate 
for 
solution 
for 
intravenous 
(IV) 
infusion.  Bevacizumab may be supplied in 20-cc (400-mg), and 50-cc 
(1000-mg) glass vials containing 4 mL or 16 mL of bevacizumab, 
respectively (all at 25 mg/mL).  Vials contain bevacizumab with 
phosphate, trehalose, polysorbate 20, and Sterile Water for Injection 
(SWFI), USP.  Vials contain no preservative and are suitable for single 
use only. 
 
For further details and molecule characterization, see the Bevacizumab 
Investigator Brochure. 
 
3.2.2 Clinical Data 
 
In a large phase III study (AVF2107g) in patients with metastatic 
colorectal cancer, the addition of bevacizumab, a monoclonal antibody 
directed against vascular endothelial growth factor (VEGF), to 
irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy resulted in a 
clinically and statistically significant increase in duration of survival, with a 
hazard ratio of death of 0.67 (median survival 15.6 vs. 20.3 months; 
p < 0.001).  Similar increases were seen in progression-free survival (6.2 
vs. 10.6 months; p < 0.001), overall response rate (35% vs. 45%; 
p < 0.01) and duration of response (7.1 vs. 10.4 months; p < 0.01) for the 
combination arm versus the chemotherapy only arm [57] 
 
Based on the survival advantage demonstrated in Study AVF2107g, 
bevacizumab was designated for priority review and was approved on 26 
February 2004 in the United States for first-line treatment in combination 
with IV 5-FUbased chemotherapy for subjects with metastatic colorectal 
cancer. 
 
3.2.3 Safety Profile 
 
In the initial Phase I and II clinical trials, four potential bevacizumab-
associated safety signals were identified: hypertension, proteinuria, 
thromboembolic events, and hemorrhage.  Additional completed Phase II 


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and Phase III studies of bevacizumab as well as spontaneous reports 
have further defined the safety profile of this agent.  Bevacizumab-
associated adverse events identified in phase III trials include congestive 
heart failure (CHF), gastrointestinal perforations, wound healing 
complications, and arterial thromboembolic events (ATE). These and 
other safety signals are described in further detail as follows and in the 
Bevacizumab Investigator Brochure. 
 
Hypertension: Hypertension has been commonly seen in bevacizumab 
clinical trials to date and oral medications have been used to manage the 
hypertension when indicated. Grade 4 and 5 hypertensive events are 
rare. Clinical sequelae of hypertension are rare but have included 
hypertensive 
crisis, 
hypertensive 
encephalopathy, 
and 
reversible 
posterior leukoencephalopathy syndrome (RPLS) [58], Glusker, 2006 
#78].  RPLS may include signs and symptoms of headache, altered 
mental function, seizures, and visual disturbances / cortical blindness and 
requires treatment, which should include control of hypertension, 
management of specific symptoms, and discontinuation of bevacizumab. 
 
Proteinuria: Proteinuria has been commonly seen in bevacizumab 
clinical trials to date. The severity of proteinuria has ranged from 
asymptomatic and transient events detected on routine dipstick urinalysis 
to nephrotic syndrome; the majority of proteinuria events have been 
grade 1 or 2. In study AVF2107g, none of the 118 patients receiving 
bolus-IFL plus placebo, three of 158 patients (2%) receiving bolus-IFL 
plus  bevacizumab, and two of 50 (4%) patients receiving 5-FU/LV plus  
bevacizumab who had a 24-hour collection experienced grade 3 
proteinuria (> 3.5 g protein/24 hr). Rare events of nephrotic syndrome 
have occurred, and bevacizumab should be discontinued in patients with 
nephrotic syndrome.  
 
Thromboembolic Events: Both venous and arterial thromboembolic (TE) 
events, ranging in severity from catheter-associated phlebitis to fatal, 
have been reported in patients treated with bevacizumab in the colorectal 
cancer trials and, to a lesser extent, in patients treated with bevacizumab 
in NSCLC and breast cancer trials. In the phase III pivotal trial in 
metastatic CRC, there was a slightly higher rate of venous TE events 
that was not statistically significant in patients treated with bevacizumab 
plus chemotherapy compared with chemotherapy alone (19% vs. 16%). 
There was also a higher rate of arterial TE events (3% vs. 1%) such as 
myocardial 
infarction, 
transient 
ischemia 
attack, 
cerebrovascular 
accident/stroke and angina/unstable angina. A pooled analysis of the rate 
of arterial TE events from 5 randomized studies (1745 patients) showed 
that treatment with chemotherapy plus bevacizumab increased the risk of 
having an arterial TE event compared with chemotherapy alone (3.8% vs. 
1.7%, respectively) [59] Furthermore, subjects with certain baseline 
characteristics (age ≥ 65 years and/or a history of a prior arterial TE 
event) may be at higher risk of experiencing such an event.  See the 
Bevacizumab Investigator Brochure for additional information on risk 
factors. 
 


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15 
Aspirin is a standard therapy for primary and secondary prophylaxis of 
arterial thromboembolic events in patients at high risk of such events, and 
the use of aspirin ≤ 325 mg daily was allowed in the five randomized 
studies discussed above. Use of aspirin was assessed routinely as a 
baseline or concomitant medication in these trials, though safety analyses 
specifically regarding aspirin use were not preplanned. Due to the 
relatively small numbers of aspirin users and arterial thromboembolic 
events, retrospective analyses of the ability of aspirin to affect the risk of 
such events were inconclusive. However, similarly retrospective analyses 
suggested that the use of up to 325 mg of aspirin daily does not increase 
the risk of grade 1-2 or grade 3-4 bleeding events, and similar data with 
respect to metastatic colorectal cancer patients were presented at ASCO 
[60]. Further analyses of the effects of concomitant use of bevacizumab 
and aspirin in colorectal and other tumor types are ongoing. 
 
Gastrointestinal perforation Patients with metastatic carcinoma may be 
at increased risk for the development of gastrointestinal perforation when 
treated with bevacizumab and chemotherapy.  Bevacizumab should be 
permanently discontinued in patients who develop gastrointestinal 
perforation. A causal association of intra-abdominal inflammatory process 
and gastrointestinal perforation to bevacizumab has not been established. 
Nevertheless, caution should be exercised when treating patients with 
intra-abdominal 
inflammatory 
processes 
with 
bevacizumab. 
Gastrointestinal perforation has been reported in other trials in non-
colorectal cancer populations (e.g., ovarian, renal cell, pancreas, and 
breast) and may be higher in incidence in some tumor types. 
 
Wound healing complications: Wound healing complications such as 
wound 
dehiscence 
have 
been 
reported 
in 
patients 
receiving 
bevacizumab. In an analysis of pooled data from two trials in metastatic 
colorectal cancer, patients undergoing surgery 28-60 days before study 
treatment with 5-FU/LV plus bevacizumab did not appear to have an 
increased risk of wound healing complications compared to those treated 
with chemotherapy alone [61] Surgery in patients currently receiving 
bevacizumab is not recommended. No definitive data are available to 
define a safe interval after bevacizumab exposure with respect to wound 
healing risk in patients receiving elective surgery; however, the estimated 
half-life of bevacizumab is 20 days.  Bevacizumab should be discontinued 
in patients with severe wound healing complications. 
 
Hemorrhage: Overall, grade 3 and 4 bleeding events were observed in 
4.0% of 1132 patients treated with bevacizumab in a pooled database 
from eight phase I, II, and III clinical trials in multiple tumor types [57]. The 
hemorrhagic events that have been observed in bevacizumab clinical 
studies were predominantly tumor-associated hemorrhage (see below) 
and minor mucocutaneous hemorrhage.  
 
Tumor-associated hemorrhage – was observed in phase I and phase II 
bevacizumab studies. Six serious events, of which 4 had fatal outcome, 
were observed in a phase II trial of patients with non-small cell lung 
cancer receiving bevacizumab. These events occurred suddenly and 


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presented as major or massive hemoptysis in patients with either 
squamous cell histology and/or tumors located in the center of the chest 
in close proximity to major blood vessels. In five of these cases, these 
hemorrhages were preceded by cavitation and/or necrosis of the tumor. 
Tumor-associated hemorrhage was also seen rarely in other tumor types 
and locations, including central nervous system (CNS) bleeding in a 
patient with hepatoma with occult CNS metastases and continuous 
oozing of blood from a thigh sarcoma with necrosis.  
 
Across all bevacizumab clinical trials, mucocutaneous hemorrhage has 
been seen in 20%-40% of patients treated with bevacizumab. These were 
most commonly grade 1 epistaxis that lasted less than 5 minutes, 
resolved without medical intervention and did not require any changes in 
bevacizumab treatment regimen. There have also been less common 
events of minor mucocutaneous hemorrhage in other locations, such as 
gingival bleeding and vaginal bleeding.  
 
Congestive heart failure: In clinical trials CHF was observed in all 
cancer indications studied to date, but predominantly in patients with 
metastatic breast cancer.  In the Phase III clinical trial of metastatic breast 
cancer (AVF2119g), 7 (3%) bevacizumab-treated patients experienced 
CHF, compared with two (1%) control arm patients.  These events varied 
in severity from asymptomatic declines in left ventricular ejection fraction 
(LVEF) to symptomatic CHF requiring hospitalization and treatment.  All 
the patients treated with bevacizumab were previously treated with 
anthracyclines (doxorubicin cumulative dose of 240360 mg/m2).  Many 
of these patients also had prior radiotherapy to the left chest wall.  Most of 
these patients showed improved symptoms and/or left ventricular function 
following appropriate medical therapy (Miller et al. 2005). 
 
In a randomized, Phase III trial of patients with previously untreated 
metastatic breast cancer (E2100), the incidence of LVEF decrease 
(defined as NCI-CTC Grade 3 or 4) in the paclitaxel  bevacizumab arm 
was 0.3% versus 0% for the paclitaxel alone arm.  
 
No information is available on patients with preexisting CHF of New York 
Heart Association (NYHA) Class IIIV at the time of initiating 
bevacizumab therapy, as these patients were excluded from clinical trials. 
 
Prior anthracyclines exposure and/or prior radiotherapy to the chest wall 
may be possible risk factors for the development of CHF.  Caution should 
be exercised before initiating bevacizumab therapy in patients with these 
risk factors. 
 
A Phase II trial in patients with refractory acute myelogenous leukemia 
reported 5 cases of cardiac dysfunction (CHF or LVEF decrease to 
 40%) 
among 
48 patients 
treated 
with 
sequential 
cytarabine, 
mitoxantrone, and bevacizumab. All but 1 of these patients had significant 
prior exposure to anthracyclines as well (Karp et al. 2004).  
 


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Patients receiving anthracyclines or with prior exposure to anthracyclines 
should have a baseline MUGA or ECHO with a normal ejection fraction. 
 
Additional Adverse Events: See the Bevacizumab Investigator Brochure 
for additional details regarding the safety experience with bevacizumab. 
 
3.2.4  Bevacizumab Administration 
 
Bevacizumab will be diluted in a total volume of 100 mL of 0.9% Sodium 
Chloride Injection, USP.  Administration will be as a continuous IV 
infusion.  Anaphylaxis precautions should be observed during study drug 
administration. 
 
The initial dose will be delivered over 90  15 minutes.  If the first infusion 
is tolerated without infusion-associated adverse events (fever and/or 
chills), the second infusion may be delivered over 60  10 minutes.  If the 
60-minute infusion is well tolerated, all subsequent infusions may be 
delivered over 30 10 minutes. 
 
If a subject experiences an infusion–associated adverse event, he or she 
may be premedicated for the next study drug infusion; however, the 
infusion time may not be decreased for the subsequent infusion.  If the 
next infusion is well tolerated with premedication, the subsequent infusion 
time may then be decreased by 30 10 minutes as long as the subject 
continues to be premedicated.  If a subject experiences an 
infusion-associated adverse event with the 60-minute infusion, all 
subsequent doses should be given over 90 15 minutes.  Similarly, if a 
subject experiences an infusion-associated adverse event with the 
30-minute infusion, all subsequent doses should be given over 60 
10 minutes. 
 
3.2.5  Bevacizumab Storage 
 
Upon receipt of the study drug, vials are to be refrigerated at 2C–8C  
(36F–46F) and should remain refrigerated until just prior to use.  DO 
NOT FREEZE.  DO NOT SHAKE.   Vials should be protected from light. 
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE 
USE ONLY.  Vials used for 1 subject may not be used for any other 
subject.  Once study drug has been added to a bag of sterile saline, the 
solution must be administered within 8 hours. 
 
3.2.6 Supplier and Drug Accountability 
 
 
Bevacizumab is commercially available but will be supplied by Genentech 
free of charge for the study.  
 
The investigator, or an approved representative, e.g. pharmacist, will 
ensure that all study drugs are stored in a secured area, under 
recommended storage conditions and in accordance with applicable 
regulatory requirements.  All study drug supplies must be kept in a locked 


6628p 
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limited access room.  The study drug must not be used outside the 
context of the protocol.  Under no circumstances should the investigator 
or other site personnel supply study drug to other investigators, patients, 
or clinics, or allow supplies to be used other than directed by this protocol.  
 
The investigator must maintain adequate records documenting the 
receipt, use, loss or other deposition of the investigational product, 
including batch or code numbers, and account for its disposition on 
patient-by-patient basis, including specific dates and quantity per 
institutional guidelines. The prescribed dose should also be recorded in 
the patient’s medical records. 
 
Destruction must be adequately documented. 
 
3.3 
Erlotinib (Tarceva®) 
 
Erlotinib is an EGFR tyrosine kinase inhibitor that has been investigated in 
several Phase III studies.  An overview of relevant nonclinical and clinical 
information is presented below; complete details are available in the Erlotinib 
(Tarceva®) Investigator Brochure. 
 
3.3.1 Non-clinical Data 
 
3.3.1.1 Pharmacology 
 
Erlotinib, a quinazoline, directly and reversibly inhibits the human 
EGFR tyrosine kinase with an IC50 of 2 nM (0.79 ng/mL) in an in 
vitro enzyme assay and reduces EGFR autophosphorylation in 
intact tumor cells with an IC50 of 20 nM (7.9 ng/mL).  This potent 
inhibition is selective for the EGFR tyrosine kinase both in assays 
assessing the effects of erlotinib on a variety of other isolated 
tyrosine kinases and in cellular bioassays designed to isolate this 
functional pathway. Erlotinib is designed to inhibit EGF-dependent 
proliferation of cells at submicromolar concentrations and blocks 
cell cycle progression in the G1 phase.  
 
Data on drug exposure and anti-tumor responses in human tumor 
xenograft models (HN5 and A431) were analyzed in order to 
estimate the plasma concentration of erlotinib associated with 
anti-tumor activity.  Based on these efficacy models, the minimum 
steady-state plasma concentration targeted for clinical activity in 
humans is projected to be 500 ng/mL. 
 
3.3.1.2 Toxicology 
 
Toxicology studies have been performed in mice, rats (up to 6 
months), dogs (up to 1 year), and monkeys (1 week).  Treatment-
related effects observed in at least one species or study included 
effects on the cornea (atrophy, ulceration), skin (follicular 
degeneration and inflammation, redness, and alopecia), ovary 
(atrophy), liver (necrosis), kidney (papillary necrosis and tubular 


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dilatation), lacrimal glands (atrophy), salivary glands (atrophy), 
mandibular lymph nodes (inflammation), spleen (hematopoiesis), 
gastrointestinal tract (delayed gastric emptying and diarrhea), and 
embryo-fetal toxicity.  Red blood cell parameters were decreased, 
and white blood cells (primarily neutrophils) were increased.  
There were treatment-related increases in ALT, AST, triglyceride 
and bilirubin; and decreases in albumin.  Increases in bilirubin 
were likely caused by a treatment-related impairment of bilirubin 
metabolism.  
 
3.3.2 Clinical Trial Experience 
 
As of April 2004, erlotinib has been studied clinically in more than 4000 
healthy subjects and patients (excluding patients exposed to placebo) in a 
number of Phase I, II, and III studies. 
 
3.3.2.1 Dose Selection for Single Agent Trials of erlotinib 
 
Phase I trials of erlotinib explored both schedule and dose to 
evaluate the safety, tolerability, and pharmacokinetic profile of the 
compound given as a single agent.  A number of pharmacokinetic 
trials in healthy subjects have been conducted, along with three 
classic Phase I trials in patients with advanced cancer.  The 
single-agent maximum tolerated dose (MTD) was estimated to be 
150 mg administered once daily. 
 
The primary toxicities of single-agent erlotinib consisted of rash 
(dermatosis), diarrhea, nausea, fatigue, stomatitis, vomiting, and 
headache.  When given daily, dose-limiting toxicity (diarrhea) was 
observed at 200 mg/day.  At 150 mg/day, diarrhea was 
manageable with the addition of loperamide therapy; this dose 
was considered the maximal tolerated dose. 
 
Rash (variously referred to as dermatitis, acneiform rash, or 
maculopapular rash) has been variable in onset, duration, and 
severity, but typically appears on the face, neck, scalp, chest, and 
back starting after ~1 week of treatment.  The mechanistic basis of 
the rash remains uncertain; histopathologic examination of 
biopsies of the rash demonstrated inflammatory cell infiltrate and 
mild epidermal hyperproliferation.  In some cases, the rash 
gradually improved despite continued dosing and, in general, 
resolved without sequelae following erlotinib discontinuation.  The 
rash did not result in study discontinuation in patients with cancer 
in the Phase I trials. 
 
Laboratory abnormalities observed infrequently with single-agent 
erlotinib involved primarily liver function tests, including elevation 
of ALT, AST, and/or bilirubin. 
 
Selection of the 150 mg/day dose of erlotinib for subsequent 
single-agent studies was based on pharmacokinetic parameters, 


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as well as the safety and tolerability profile of this dose in Phase I 
trials in heavily pretreated patients with advanced cancer.  Drug 
levels seen in patients with cancer receiving the 150 mg/day dose 
were consistently above the average plasma concentration of 500 
ng/mL targeted for clinical efficacy.  
 
3.3.2.2 Pharmacokinetics 
 
Oral erlotinib is well absorbed and has an extended absorption 
phase, with mean peak plasma levels occurring at 3 hours after 
oral dosing of 150 mg/dL at steady state.  A study in healthy 
subjects provided an estimate of bioavailability of 59% (95% CI:  
55%, 63%).  The time to reach steady-state plasma concentration 
was ~5 days.  The accumulation ratio with daily dosing of erlotinib 
was estimated to be 2.0.  From a population pharmacokinetic 
analysis of 708 patients, the median trough concentration (Cmin) 24 
hours following the previous dose was 1041 (697) ng/mL.  
Median AUC achieved during the dosing interval at steady state 
was 19,801 ng • hr/mL.  Exposure after an oral dose is increased 
by food.   
 
There is extensive binding of erlotinib and metabolites to both 
serum albumin and AAG (alpha-1-acid glycoprotein), with total 
plasma protein binding for erlotinib and OSI-420 of ~95% and 
91%, respectively.  Erlotinib is extensively metabolized in the liver 
by the hepatic cytochromes in humans–primarily by CYP3A4 and 
to a lesser extent by CYP1A2.  The primary metabolite of erlotinib, 
OSI-420, has potency comparable to that of erlotinib, but is 
present at levels that are  10% of erlotinib levels.  Erlotinib is 
excreted predominantly via the feces ( 90%).  The elimination 
half-life after a 150-mg oral dose is ~30 hours.  In population-
based data analyses, no relationships were identified between 
predicted steady-state trough concentration and patient age, body 
weight, sex, ethnicity, or creatinine clearance. 
 
3.3.2.3 Phase II and III Trials in Patients with Advanced Breast Cancer 
 
Multiple Phase II trials evaluating the safety, tolerability, and 
antitumor activity of erlotinib have been conducted in patients with 
advanced, refractory malignancies including cancer of the head 
and neck, lung, aerodigestive tract, ovary, breast, central nervous 
system (glioma), and others. Erlotinib has been evaluated both as 
a single agent and administered concurrently with conventional 
chemotherapy agents using various doses and schedules. 
 
Evidence of activity has been observed in squamous cell 
carcinoma of the head and neck, ovarian, breast and pancreatic 
carcinoma, non–small cell lung cancer (NSCLC), and glioblastoma 
multiforme (GBM).  Patients received 150 mg/day of erlotinib in all 
of these studies except the GBM study where dose escalation was 


6628p 
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allowed until limited by rash and where a higher starting dose was 
tested in subjects receiving concomitant enzyme inducing anti-
epileptic drugs.  Dose reduction was allowed in all studies in the 
case of intolerance.  Diarrhea was treated with loperamide therapy 
and/or dose reduction.  Rash was treated with a variety of agents, 
including oral and topical antibiotics, corticosteroids, and other 
agents. 
 
Patients 
receiving 
erlotinib 
in 
combination 
with 
various 
chemotherapy agents have generally experienced the same type 
of adverse events (AEs) as with either agent alone. 
 
The first randomized placebo controlled trial to demonstrate a 
survival advantage for an EGFR inhibitor was the Phase III study, 
BR21.  This international trial, conducted by the National Cancer 
Institute of Canada Clinical Trial Group (NCIC CTG), included 731 
patients with incurable Stage IIIb/IV NSCLC who have failed 
standard therapy for advanced or metastatic disease.  Patients 
randomized in a 2:1 ratio to single-agent erlotinib 150 mg/day 
obtained a 42.5% improvement in median survival over placebo, 
from 4.7 to 6.7 months.  The one-year survival increased 
significantly (from 22% to 31%) as did the median and 6 month 
PFS, response rate, and the time to deterioration of tumor related 
symptoms of pain, cough, and dyspnea [63]. 
 
In BR-21, of the 727 patients evaluable for safety (485 erlotinib, 
242 placebo), the most common AEs in the erlotinib arm were 
rash (75% erlotinib, 17% placebo), diarrhea (54% erlotinib, 18% 
placebo) and stomatitis (17% erlotinib, 18% placebo) events.  The 
majority of these events were mild to moderate in severity.  The 
incidence of interstitial lung disease (ILD) reported was the same 
in the placebo and erlotinib groups at 0.8% in each arm. 
 
Two large, Phase III, randomized studies in first-line NSCLC 
patients evaluated erlotinib in combination with platinum-based 
two-drug combination chemotherapy.  A total of 1079 previously 
untreated patients received carboplatin/paclitaxel with either 
erlotinib or placebo in the TRIBUTE trial (OSI2298g) conducted in 
the United States.  An additional 1172 patients received 
cisplatin/gemcitabine plus either erlotinib or placebo in the 
TALENT trial (BO16411) conducted in 27 countries in Europe and 
other ex-U.S. locations.  Neither study met its primary endpoint of 
improved overall survival or a secondary endpoint of improved 
time to disease progression or overall response rate.  Overall, the 
number of adverse events and serious adverse events were well 
balanced between the two arms of each study, with two 
exceptions.  As expected, rash and diarrhea occurred more 
frequently in the erlotinib arms.  In the TRIBUTE study, more 
serious adverse events resulting in death were seen in the 
erlotinib arm compared with the placebo arm (53 vs. 27).  Most of 


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the apparent imbalance was due to events reported as pneumonia 
or progression of underlying cancer  [36]. 
 
3.3.2.4 Patients with Hepatic or Renal Impairment 
 
The influence of hepatic metastases and/or hepatic dysfunction on 
the pharmacokinetics of erlotinib is not yet known.  However, 
erlotinib is cleared predominately by the liver, and caution should 
be used when administering erlotinib to patients with hepatic 
dysfunction. Erlotinib is also a strong inhibitor of the UDP-
glucuronosyltransferase UGT1A1 enzyme responsible for the 
glucuronidation of bilirubin.  Hyperbilirubinemia appears most 
often to be a side effect related to genetic polymorphisms of 
UGT1A1.  Rare cases of hepatic failure (including fatalities) have 
been reported during the postmarketing use of erlotinib.  
Confounding factors for severe hepatic dysfunction have included 
pre-existing liver disease such as cirrhosis, viral hepatitis, 
hepatocellular carcinoma, hepatic metastases or concomitant 
treatment with potentially hepatotoxic drugs. 
 
Rare cases of myocardial infarction (including fatalities) have been 
reported during the postmarketing use of erlotinib. 
 
No clinical studies have been conducted in patients with 
compromised renal function since erlotinib and its metabolites are 
not significantly excreted by the kidneys. 
 
3.3.3 Adverse Event Using Erlotinib 
 
Common adverse events associated with erlotinib administration include 
rash 
and 
diarrhea. 
 
Other 
common 
adverse 
events 
include 
nausea/vomiting, mucositis/stomatitis, headache, and fatigue. 
 
A rash occurred in 75% of erlotinib-treated NSCLC patients enrolled in 
BR.21.  Similar incidences of rash have occurred when erlotinib was 
administered concurrently with chemotherapy including gemcitabine, 
paclitaxel/carboplatin and gemcitabine/cisplatin.  Other dermatologic 
manifestations reported in clinical studies or postmarketing use of 
erlotinib include nail changes, paronychia, painful fissures or cracking of 
the skin on the hands and feet and hair growth abnormalities (alopecia, 
thinning hair, eyelash/eyebrow changes, hirsutism). A pustular rash 
manifesting most often on the face and upper trunk was common across 
all studies, but rash was rarely the cause of study drug discontinuation. 
Wearing of contact lenses while receiving erlotinib therapy is not 
recommended.  The incidence of diarrhea in BR.21 was 54% of erlotinib-
treated NSCLC patients.  The median time to onset of skin rash was 8 
days and median time to occurrence of first diarrheal symptom was 9 
days. 
 
There have been infrequent reports of serious (including fatal) interstitial 
lung disease (ILD) in patients receiving erlotinib for treatment of NSCLC 


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or other advanced solid tumors.  In Study BR.21, the incidence of ILD 
(0.8%) was the same in the placebo and erlotinib groups.  The overall 
incidence in erlotinib-treated patients from all studies (including 
uncontrolled studies and studies with concurrent chemotherapy) is 
approximately 0.6%.  Included in this rate of ILD are reported diagnoses 
of pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, 
interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, 
pulmonary fibrosis, acute respiratory distress syndrome, alveolitis, and 
lung infiltration, irrespective of investigator assessed causality.  Most of 
the cases were associated with confounding or contributing factors such 
as concomitant/prior chemotherapy, prior radiotherapy, preexisting 
parenchymal lung disease, metastatic lung disease, or pulmonary 
infections. 
 
Rare cases of acute renal failure or renal insufficiency have been 
reported (including fatalities).  Many of these cases have been associated 
with dehydration associated with nausea, vomiting, diarrhea and/or 
anorexia.  There have been rare reports of renal failure in patients 
receiving erlotinib in combination with platinum-containing chemotherapy 
regimens. Febrile neutropenia has been reported in patients receiving 
concomitant chemotherapy. 
 
Co-administration of erlotinib with omeprazole, a proton pump inhibitor, 
decreased the exposure of erlotinib (AUC) by 46% and the maximum 
concentration (Cmax) by 61%.  There was no change to Tmax or half-life.  
Therefore, drugs that alter the pH of the GI tract may alter the solubility of 
erlotinib and hence its bioavailability. 
 
The exposure to erlotinib (AUC) increased to a moderate extent, by 39%, 
and the maximum concentration (Cmax) by 17%, when erlotinib was co-
administered with ciprofloxacin, an inhibitor of both CYP3A4 and 
CYP1A2. 
 
Co-administration of erlotinib with an inhibitor of CYP3A4 metabolism 
(ketoconazole, 200 mg po BID for 5 days) resulted in increased exposure 
to erlotinib as measured by an 86% increase in median erlotinib AUC and 
a 69% increase Cmax, compared with administration of erlotinib alone. 
 
Induction of CYP3A4 metabolism by a known enzyme inducer (rifampin, 
600 mg po QD for 7 days) resulted in a 69% decrease in the median 
erlotinib AUC, compared with administration of erlotinib alone.  However, 
the effect of rifampin on Cmax was negligible.  In another study, rifampicin 
pretreatment followed by co-administration of rifampicin with a single 450 
mg dose of erlotinib resulted in a mean erlotinib exposure (AUC) that was 
57.6% of that observed following a single 150 mg erlotinib dose in the 
absence of rifampicin treatment.  Therefore, a potential for drug-drug 
interaction exists when erlotinib is co-administered with drugs that are 
highly protein bound or that are potent CYP3A4 inhibitors or inducers. 
 
International normalized ratio (INR) elevations and/or bleeding events 
have been reported in some cancer patients while on erlotinib alone and 


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24 
in combination with other chemotherapeutic agents, and concomitant 
NSAIDS or anticoagulants including warfarin. 
 
3.3.4 General Plan to Manage Safety Concerns 
 
Skin toxicities will be monitored by routine physical examination and 
managed symptomatically.  The following agents may be used to treat 
rash: diphenhydramine, topical or oral corticosteroids and topical 
(clindamycin) or oral antibiotics (tetracycline, minocycline, doxycycline).  
Topical drying agents are not recommended. 
 
Liver function abnormalities, including elevated serum ALT, AST and/or 
bilirubin, have been observed infrequently with single agent erlotinib and 
occasionally with erlotinib in combination with concomitant chemotherapy.  
Periodic monitoring of liver function is recommended.  Erlotinib dosing 
should be interrupted if changes in liver function are severe. 
 
Women of childbearing potential should have a negative pregnancy test 
prior to starting therapy with erlotinib and should use adequate 
contraceptive methods during and for at least 2 weeks after erlotinib 
therapy.  Treatment should only be continued in pregnant women if the 
potential benefit to the mother outweighs the risk to the fetus.  If erlotinib 
is used during pregnancy, the patient should be apprised of the potential 
hazard to the fetus or potential risk for loss of the pregnancy. 
 
It is not known whether erlotinib is excreted in human breast milk.  
Because many drugs are excreted in human milk and because the effects 
of erlotinib on infants have not been studied, women should be advised 
against breast-feeding while receiving erlotinib therapy. 
 
3.3.5 Supplier and Drug Accountability 
 
 
Erlotinib is commercially available but will be supplied by Genentech free 
of charge for the study.  
 
The investigator, or an approved representative, e.g. pharmacist, will 
ensure that all study drugs are stored in a secured area, under 
recommended storage conditions and in accordance with applicable 
regulatory requirements.  All study drug supplies must be kept in a locked 
limited access room.  The study drug must not be used outside the 
context of the protocol.  Under no circumstances should the investigator 
or other site personnel supply study drug to other investigators, patients, 
or clinics, or allow supplies to be used other than directed by this protocol.  
 
The investigator must maintain adequate records documenting the 
receipt, use, loss or other deposition of the investigational product, 
including batch or code numbers, and account for its disposition on 
patient-by-patient basis, including specific dates and quantity per 
institutional guidelines. The prescribed dose should also be recorded in 
the patient’s medical records. 
 


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Destruction must be adequately documented. 
 
 
4.0  
STAGING CRITERIA 
 
4.1   
Definition of TNM 
 
Primary Tumor (T) 
 
Definitions for classifying the primary tumor (T) are the same for clinical and for 
pathologic classification.  The telescoping method of classification can be 
applied.  If the measurement is made by physical exam, the examiner will use the 
major headings (T1, T2).  If other measurements, such as mammographic or 
pathologic, are used, the telescoped subsets of T1 can be used.* 
 
T1 
Tumor 2 cm of less in greatest dimension 
 
T1a 
0.5 cm or less in greatest dimension 
T1b 
More than 0.5 but not more than 1 cm in greatest dimension 
T1c 
More than 1 cm but not more than 2 cm in greatest dimension 
 
T2 
Tumor more than 2 cm but not more than 5 cm in greatest dimension 
 
T3 
Tumor more than 5 cm in greatest dimension 
 
T4 
Tumor of any size with direct extension to the chest wall or skin 
 
T4a 
Extension to the chest wall† 
T4b 
Edema (including peau d’orange) or ulceration of the skin of the 
breast or satellite skin nodules confined to the same breast 
T4c 
Both (T4a and T4b) 
T4d 
Inflammatory carcinoma 
 
*Note:  Paget’s disease associated with a tumor is classified according to 
the size of the tumor. 
†Note: Chest wall includes ribs, intercostal muscles and serratus anterior 
muscle but not pectoral muscle 
 
Regional Lymph Nodes (N) 
 
N0 
No regional lymph node metastasis 
 
N1 
Metastasis to movable ipsilateral axillary lymph node(s) 
 
N2 
Metastasis in ipsilateral axillary lymph nodes(s) fixed or matted, or in 
clinically apparent* ipsilateral internal mammary nodes in the absence of 
clinically evident axillary lymph node metastasis. 
 
N2a 
Metastasis in ipsilateral axillary lymph nodes fixed to one another 
(matted) or to other structures. 


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N2b 
Metastasis only in clinically apparent* ipsilateral internal mammary 
nodes in the absence of clinically evident axillary lymph node 
metastasis 
 
N3 
Metastasis in ipsilateral infraclavicular lymph node(s), with or without 
axillary node involvement, or in clinically apparent* ipsilateral internal 
mammary lymph nodes in the presence of clinically evident axillary lymph 
node metastasis; or metastasis in ipsilateral supraclavicular lymph 
node(s), with or without axillary or internal mammary lymph node 
involvement. 
 
N3a 
Metastasis in ipsilateral infraclavicular lymph node(s). 
N3b 
Metastasis in ipsilateral internal mammary lymph node(s) and 
axillary lymph node(s). 
N3c 
Metastasis in ipsilateral supraclavicular lymph node(s). 
 
Clinically apparent is defined as detected by imaging studies (excluding 
lymphoscintigraphy) or by clinical examination or grossly visible 
pathologically. 
 
Distant Metastasis (M) 
 
 
Clinical history and routine imaging studies including CT chest, abdomen and 
bone scan will be obtained prior to protocol therapy to assess for presence of 
distant metastasis prior to initiation of protocol therapy. 
  
MX 
Distant metastasis cannot be assessed 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
4.2 
Stage Groupings 
 
Stage I 
 
T1 
N0 
 
M0 
 
Stage IIA 
 
T0 
N1 
 
M0 
 
 
 
T1 
N1 
 
M0 
 
 
 
T2 
N0 
 
M0 
 
Stage IIB  
  
T2 
N1 
 
M0 
 
 
 
 
  
T3 
N0 
 
M0 
 
Stage IIIA  
  
T0 
N2 
 
M0 
 
 
 
 
 
  
T1 
N2 
 
M0 
 
T2 
N2 
 
M0 
 
T3 
N1, N2  
M0 


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Stage IIIB  
 
T4 
N0, N1, N2 
M0 
 
 
Stage IIIC 
  
Any T N3 
 
M0 
 
Stage IV  
  
Any T Any N  
M1 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
5.1 
Patients must meet the following criteria to be included: 
 
5.1.1 Have histologically confirmed invasive breast cancer that is ER negative 
(<10%), PR negative (< 10%) and HER-2 normal (< 10% of cells) by IHC 
or FISH. 
5.1.2 Be receiving first-line therapy for metastatic disease.  
5.1.3 Patients must satisfy either 5.1.3.1 or 5.1.3.2: 
5.1.3.1 Measurable disease by RECIST criteria (see Section 10.1.1).  X-
rays, scans or physical examinations used for tumor measurement 
must have been completed within 28 days prior to registration.  X-
rays, scans or other tests for assessment of non-measurable 
disease must have been performed within 42 days prior to 
registration. 
5.1.3.2 Non-measurable disease only (see Section 10.1.2), with rising 
serum CA15-3 or CA 27.29 or CEA documented by two 
consecutive measurements taken at least 14 days apart with the 
most recent measurement being within 42 days prior to 
registration.  The second CA 15-3 or CA 27.29 or CEA value must 
have at least a 20% increase over the first and for CA 15-3 or CA 
27.29 be greater than or equal to 40 units/mL or for CEA be 
greater than or equal to 4 ng/mL. 
5.1.4 Subjects with brain metastases as their first site of disease recurrence 
may be eligible if treated by definitive radiation (stereotactic radiosurgery 
or whole brain) with clinically controlled neurologic symptoms for a period 
of 21 days prior to study treatment.  
5.1.5 Bilirubin < 1.5 mg/dL 
5.1.6 Patients must have adequate liver function: AST and ALT < 2.5 X upper 
limit of normal, alkaline phosphatase < 2.5 X upper limit of normal, unless 
bone metastasis is present in the absence of liver metastasis 
5.1.7 Patients must have adequate bone marrow function: Platelets >100,000 
cells/mm3, hemoglobin > 9.0g/dL and ANC > 1,500 cells/mm3 
5.1.8 Patients must have adequate renal function: creatinine <1.5 mg/dL is 
recommended; however, institutional norms are acceptable.  


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5.1.9 If of childbearing potential must have a negative pregnancy test and use 
an effective method to avoid pregnancy for the duration of the trial and for 
at least 6 months after completion of study therapy. 
5.1.10 Pre-existing peripheral neuropathy, if present, must be < grade 2 (per 
CTCAE Version 3.0) 
5.1.11 Patients must be informed of the investigational nature of this study and 
must sign and give informed consent in accordance with institutional 
standards and federal guidelines. 
 
5.2 
Patients who fulfill any of the following criteria will be excluded: 
 
5.2.1 Recurrent disease within 12 months after completion of adjuvant 
chemotherapy containing a weekly taxane. 
5.2.2 CNS metastases that are symptomatic and/or requiring steroids. 
5.2.3 Pre-existing nephritic syndrome. 
5.2.4 Serious intercurrent medical or psychiatric illness including serious active 
infection. 
5.2.5 Inadequately controlled hypertension (defined as systolic blood pressure 
150 and/or diastolic blood pressure > 100 mmHg on antihypertensive 
medications). 
5.2.6 Any prior history of hypertensive crisis or hypertensive encephalopathy. 
5.2.7 New York Heart Association (NYHA) rgade II or greater congestive heart 
failure (see Appendices). 
5.2.8 History of myocardial infarction or unstable angina within 6 months prior 
to study enrollment. 
5.2.9 History of stroke or transient ischemic attack within 6 months prior to 
study enrollment. 
5.2.10 Significant vascular disease (e.g., aortic aneurysm, aortic dissection). 
5.2.11 Symptomatic peripheral vascular disease. 
5.2.12 Evidence of bleeding diathesis or coagulopathy. 
5.2.13 Major surgical procedure, open biopsy, or significant traumatic injury 
within 28 days prior to study enrollment or anticipation of need for major 
surgical procedure during the course of the study. 
5.2.14 Core biopsy or other minor surgical procedure, excluding placement of a 
vascular access device, within 7 days prior to study enrollment. 
5.2.15 History of abdominal fistula, gastrointestinal perforation, or intra-
abdominal abscess within 6 months prior to study enrollment. 
5.2.16 Serious, non-healing wound, ulcer, or bone fracture. 
5.2.17 Proteinuria at screening as demonstrated by either 
o Urine protein:creatinine (UPC) ratio   1.0 at screening OR  


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o Urine dipstick for proteinuria > 2+ (patients discovered to have > 2+ 
proteinuria on dipstick urinalysis at baseline must have a UPC ratio 
done that is <1.0 to be eligible.  If the UPC ratio is > 1.0 then the 
patient should undergo a 24-hour urine collection which must 
demonstrate < 1g of protein in 24 hours for the patient to be eligible.) 
5.2.18 Known hypersensitivity to any component of bevacizumab or to nab-
paclitaxel. 
 
6.0 
STRATIFICATION FACTORS 
 
There is no stratification.   
 
 
7.0 
TREATMENT PLAN 
 
For protocol related questions, please contact Dr. Jennifer Specht at (206) 288-6889 (e-
mail: jspecht@u.washington.edu). 
 
A number of measures will be taken to ensure the safety of patients participating in this 
trial.  These measures will be addressed through routine monitoring as follows. 
 
Patients enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study.  Safety 
evaluations will consist of medical interviews, recording of adverse events, physical 
examinations, blood pressure, and laboratory measurements.  Patients will be evaluated 
for adverse events (severity grade 2 or greater), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation at each study visit for the 
duration of their participation in the study.  Patients discontinued from the treatment 
phase of the study for any reason will be evaluated ~30 days (28–42 days) after the 
decision to discontinue treatment. 
 
7.1 
Good Medical Practice 
 
The following pre-study tests should be obtained prior to registration in 
accordance with good medical practice.  Results of these tests do not determine 
eligibility and minor deviation are acceptable if they do not impact on patient 
safety in the clinical judgment of the treating physician.  Dr. Specht must be 
contacted if there are significant deviations in the values of these tests. 
 
a. Patients should have normal left ventricular ejection fraction by MUGA or 
transthoracic echocardiogram at study entry.  Reassessment is required only 
if clinical symptoms arise. 
 
7.2 
Induction Therapy:  Nab-Paclitaxel and Bevacizumab 
 
In this single-arm, phase II trial, patients will receive induction therapy with nab-
paclitaxel 100 mg/m2 IV days 1, 8 and 15 and bevacizumab 10 mg/kg IV days 1 
and 15 of each 28 day cycle for 6 cycles.  All attempts should be made to 
maintain treatment schedule; however, deviation in weekly treatment + or – one 


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day is permitted. Patients who develop toxicity and require discontinuation of 
nab-paclitaxel prior to completing all six cycles of induction and who have 
evidence of disease response or stability may transition to maintenance therapy 
after a discussion between the treating physician and the principal investigator. 
   
 
Induction Therapy: 
 
DRUG 
DOSE 
FREQUENCY 
# of DOSES 
Route of 
Administration 
Nab-Paclitaxel 
100 mg/m2 
Days 1, 8, and 
15 of each 28 
day cycle 
18 doses 
IV 
Bevacizumab 
10 mg/kg 
Days 1 and 15 of 
each 28 day 
cycle  
12 doses  
IV 
 
Patients do not require premedication prior to nab-paclitaxel administration, as 
hypersensitivity reactions are not expected.  In the unlikely event of a 
hypersensitivity reaction, premedication may be administered using the 
premedication regimen the institution typically uses for paclitaxel. 
 
If patients on treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4-8 weeks prior to the surgical 
procedure. Patients undergoing a major surgical procedure should not 
begin/restart  bevacizumab until 4 weeks after that procedure (in the case of high 
risk procedures such as liver resection, thoracotomy, or neurosurgery, it is 
recommended that chemotherapy be restarted no earlier than 6 weeks and  
bevacizumab no earlier than 8 weeks after surgery). 
 
Dose modifications for adverse events are allowed as described in Sections 8.1, 
8.2 and 8.3.  Treatment is continued until disease progression or other reason for 
termination of study therapy (Section 7.4). 
 
7.3 
Maintenance Therapy 
 
At the completion of induction chemotherapy, nab-paclitaxel will be discontinued, 
and patients with CR, PR, SD will remain on study and receive combined, 
targeted “maintenance” therapy with bevacizumab 10 mg/kg IV Q 14 days or 15 
mg/kg Q 21 days and erlotinib 150 mg PO daily until disease progression or 
unacceptable toxicity.  The choice of dosing schedules for bevacizumab (Q14 
days or Q21 days) during the maintenance period is at the discretion of the 
treating physician and allowed to accommodate flexibility for patients.   
 
 
Maintenance Therapy  
For patients with CR, PR or stable disease following induction therapy: 
DRUG 
DOSE 
FREQUENCY 
# of DOSES 
Route of 
Administration 
Bevacizumab 
10 mg/kg or 
15 mg/kg 
Q 14 days or 
Q 21 days 
Until 
progression 
IV 


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Erlotinib 
150 mg 
daily 
Until 
progression 
PO 
 
Patients who develop toxicity and require discontinuation of bevacizumab or 
erlotinib and who continue to have evidence of disease response or stability may 
continue maintenance therapy after a discussion between the treating physician 
and the principal investigator. 
 
Erlotinib will be self-administered in an open-label, unblinded manner to all 
patients enrolled in the study. During the treatment period, patients will receive 
erlotinib 150 mg/day.  Tablets should be taken at the same time each day with 
200 mL of water at least 1 hour before or 2 hours after a meal.  Patients who are 
unable to swallow tablets may dissolve the tablets in distilled water for 
administration. 
 
Erlotinib tablets will be supplied in white, high-density polyethylene (HDPE) 
bottles with child-resistant closures and should be stored at temperatures 
between 15°C and 30°C (59°F and 86°F). 
 
Dose reductions for adverse events will be permitted (see Sections 8.3 and 8.4).  
Treatment is continued daily until disease progression or other reason for 
termination of study therapy (see Section 7.4). 
 
If patients on treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4-8 weeks prior to the surgical 
procedure. Patients undergoing a major surgical procedure should not 
begin/restart bevacizumab until 4 weeks after that procedure (in the case of high 
risk procedures such as liver resection, thoracotomy, or neurosurgery, it is 
recommended that bevacizumab be restarted no earlier than 8 weeks after 
surgery). 
 
7.4 Criteria For Removal From Protocol Treatment 
 
Patients have the right to withdraw from the study at any time for any reason.  
The investigator also has the right to withdraw patients from the study in the 
event of intercurrent illness, treatment related toxicity, treatment failure, protocol 
violations, administrative reasons or other reasons. 
 
Should a patient decide to withdraw prematurely, all efforts will be made to 
complete and report the end of treatment observations as thoroughly as possible. 
 
Subjects will be removed from protocol treatment for the following reasons: 
 
▪ 
Progressive disease. 
• 
Inability of subject to comply with study requirements. 
▪ 
Pregnancy. 
▪ 
Patient wishes. 
▪ 
Physician discretion. 
• 
Nephrotic syndrome. 
• 
Gastrointestinal perforation. 
• 
Clinically significant deterioration of the patient’s condition. 


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• 
Wound dehiscence requiring surgical intervention. 
• 
Any grade arterial thromboembolic event. 
• 
Grade ≥ 2 pulmonary or CNS hemorrhage; any Grade 4 hemorrhage. 
▪ 
Persistent (> 3 weeks) NCI-CTCAE version 3.0 Grade 3 or Grade 4 
adverse event or any significant adverse event that compromises the 
patient’s ability to participate in the study. 
• 
Symptomatic Grade 4 venous thromboembolic event. 
• 
Grade 4 hypertension or reversible posterior leukoencephalopathy 
syndrome (RPLS). 
• 
Grade 4 congestive heart failure. 
• 
All Grade 4 events thought to be related to nab-paclitaxel, bevacizumab 
or erlotinib by the investigator. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
8.1 
The following general principles apply in all cases. 
 
8.1.1 This study will use the NCI CTC (Common Terminology Criteria) Version 
3.0 for treatment related toxicity and adverse event reporting.  A copy of 
the CTC Version 3.0 can be down loaded from the CTEP home page 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
ctcaev3.pdf). 
 
8.1.2 Dose adjustments are to be made according to the system showing the 
greatest degree of treatment related toxicity.   
 
8.1.3 For any event present at baseline, the dose modification will apply 
according to the corresponding shift in toxicity grade if the investigator 
feels it is appropriate (e.g. if a patient has a grade 1 asthenia at baseline 
which increases to grade 2 during treatment, this will be considered a 
shift of 1 grade and treated as a grade 1 treatment related toxicity for 
dose modification purposes). 
 
8.1.4 If in the opinion of the Investigator, a specific treatment related toxicity is 
considered solely due to one drug, dose modification of the other drug is 
not required. 
 
8.1.5 For treatment related toxicities which are considered by the Investigator 
unlikely to develop into serious or life-threatening events (e.g. alopecia, 
altered taste, etc.), treatment will be continued at the same dose without 
reduction or interruption.  In addition, no dose reductions or interruptions 
will be required for anemia as it can be satisfactorily managed by 
transfusions or erythropoietic growth factors. 
 
8.1.6 Patients will be evaluated for adverse events at each study visit for the 
duration of their participation in the study and for 30 days after the 
discontinuation. 
 


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8.2 
Dose Modifications – Nab-Paclitaxel  
 
Use the table below to determine a patient’s dose: 
 
Dose Modification Table 
Dose Level 
Nab-Paclitaxel 
(mg/m2) 
0 
100 
-1 
80 
-2 
65 
 
8.2.1 Abnormal Hematologic Function 
 
Nab-paclitaxel dosing should not begin unless the absolute neutrophil 
count is  1500 cells/mm3 and the platelet count is >100,000 cells/mm3.  
For each subsequent dose of nab-paclitaxel patients must have an ANC  
1000 cells/mm3 and platelets > 75,000 cells/mm3.  If the ANC or platelets 
are not adequate for treatment, the dose is to be omitted.  If the dose is 
omitted for ANC < 1000 cells/mm3 institute G-CSF as outlined in the table 
below. 
 
8.2.2 Dose Reductions and Use of Growth Factors for Hematologic Toxicity 
 
The table below provides a recommended guideline for implementing 
dose reductions and growth factor treatment for hematologic toxicity: 
 
Use of G-CSF and Dose reductions for Hematologic Toxicity 
Adverse Event 
Occurrence 
Action to be Taken 
Neutropenia 
(ANC < 1000 cells/mm3). 
1st  
Occurrence 
 
 
 
Recurrence 
Nab-paclitaxel is held and G-CSF is started.  Nab-
paclitaxel dose is maintained when ANC recovers to 
> 1000 cells/mm3.   Prophylactic antibiotics may be 
given at physician’s discretion in the setting of ANC < 
500 or neutropenic fever.  
In the event that neutropenia (ANC < 1000 
cells/mm3) re-occurs in the face of G-CSF, dose 
reduction to the next lower level will be required for 
subsequent doses once ANC is  1000 cells/mm3.   
Thrombocytopenia Grade 3 
(platelet count at least 25,000 
but less than 50,000/mm3) or 
Grade 4 (platelet count <25,000) 
1st 
Occurrence 
Dose reduction to next lower level 
Recurrence 
Dose reduction to next lower level 
 
8.2.3 G-CSF Administration: should be given according to NCCN guidelines 
and the treating physician’s clinical judgment.   When G-CSF is given with 


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weekly nab-paclitaxel it should begin the day after the nab-paclitaxel is 
given. 
 
8.2.4 Abnormal Hepatic Function 
 
Nab-paclitaxel should not begin unless AST and ALT < 2.5 x upper limit 
of normal and alkaline phosphatase < 2.5 x upper limit of normal, unless 
bone metastasis is present in the absence of liver metastasis, and 
bilirubin < 1.5 mg/dL.  Hepatic toxicity from taxanes may occur but it is 
uncommon.  Therefore, hepatic dysfunction that occurs while the patient 
is on study should prompt an evaluation to determine the cause, including 
the possibility of progressive metastatic disease and hepatotoxicity from 
concurrent medications. 
 
8.2.5 Sensory Neuropathy 
 
Nab-paclitaxel should be withheld in patients who experience  Grade 2 
sensory neuropathy.  Treatment may be resumed at the next lower dose 
level (see Dose Modification Table in Section 8.2 above) in subsequent 
cycles after the sensory neuropathy improves to  Grade 1.  In those 
patients who experience Grade 4 sensory neuropathy, study drug should 
be withheld, and treatment resumed at a reduction of 2 dose levels (Dose 
Modification Table in Section 8.2) in subsequent cycles after the sensory 
neuropathy improves to  Grade 1. 
 
8.2.6 Hypersensitivity Reactions 
 
Hypersensitivity reactions rarely occur.  If they do occur, minor symptoms 
such as flushing, skin reactions, dyspnea, lower back pain, hypotension, 
or tachycardia may require temporary interruption of the infusion. 
However, severe reactions, such as hypotension requiring treatment, 
dyspnea requiring bronchodilators, angioedema or generalized urticaria 
require immediate discontinuation of study drug administration and 
aggressive symptomatic therapy. Patients who experience a severe 
hypersensitivity reaction to nab-paclitaxel should not be re-challenged.  
 
8.2.7 Other Toxicities  
 
If toxicities are  grade 2, manage symptomatically if possible, and retreat 
without dose reduction. 
 
If toxicities are  grade 3, except for anemia, treatment should be 
withheld until resolution to  grade 1 or baseline if baseline was greater 
than grade 1, then reinstituted, if medically appropriate, at the next lower 
dose level (see Dose Modification Table in Section 8.2 above). 
 
8.3 
Dose Modifications –  Bevacizumab 
 


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There are no reductions in the bevacizumab dose. If adverse events occur that 
require holding bevacizumab, the dose will remain the same once treatment 
resumes. 
 
Any toxicities associated or possibly associated with bevacizumab treatment 
should be managed according to standard medical practice.  Bevacizumab has a 
terminal half-life of 2 to 3 weeks; therefore, its discontinuation results in slow 
elimination over several months. There is no available antidote for bevacizumab.  
Subjects should be assessed clinically for toxicity prior to, during, and after each 
infusion. If unmanageable toxicity occurs because of bevacizumab at any time 
during the study, treatment with bevacizumab should be discontinued. 
  
Infusion Reaction: Infusion of bevacizumab should be interrupted for subjects 
who develop dyspnea or clinically significant hypotension. Subjects who 
experience a NCI CTCAE v. 3.0 Grade 3 or 4 allergic reaction/hypersensitivity, 
adult respiratory distress syndrome, or bronchospasm (regardless of grade) will 
be discontinued from bevacizumab treatment. 
 
The infusion should be slowed to 50% or less or interrupted for subjects who 
experience any infusion-associated symptoms not specified above. When the 
subject’s symptoms have completely resolved, the infusion may be continued at 
no more than 50% of the rate prior to the reaction and increased in 50% 
increments every 30 minutes if well tolerated. Infusions may be restarted at the 
full rate during the next cycle. 
 
Adverse events requiring delays or permanent discontinuation of bevacizumab 
are listed in the table below.  Regardless of the reason for holding study drug 
treatment, the maximum allowable length of treatment interruption is 2 months. 


6628p 
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 Bevacizumab Dose Management Due to Adverse Events 
 
Event 
Action to be Taken 
Hypertension 
 
Grade 3 
At treating physician’s discretion, treatment may be held for a 
maximum duration of two months. 
If not controlled to 150/100 mmHg with medication, discontinue 
bevacizumab. 
 
Grade 4 (including RPLS 
(confirmed by MRI) or 
hypertensive 
encephalopathy) 
Discontinue bevacizumab. 
Hemorrhage 
 
Grade ≥ 2 pulmonary or 
CNS hemorrhage 
 
Discontinue bevacizumab. 
Grade 3  nonpulmonary 
and non-CNS 
hemorrhage 
Subjects who are also receiving full-dose anticoagulation will be 
discontinued from receiving bevacizumab.   
All other subjects will have study treatment held until all of the 
following criteria  are met: 
• 
The bleeding has resolved and hemoglobin is stable. 
• 
There is no bleeding diathesis that would increase the risk 
of therapy. 
• 
There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage recurrence. 
Subjects who experience a repeat Grade 3 hemorrhagic event will be 
discontinued from receiving bevacizumab. 
 
Grade 4 
Discontinue bevacizumab. 
Venous Thrombosis 
 
Grade 3/ Asymptomatic  
Grade 4 
Hold study drug treatment.  If the planned duration of full-dose 
anticoagulation is <2 weeks, study drug should be held until the full-
dose anticoagulation period is over.  If the planned duration of full-
dose anticoagulation is >2 weeks, study drug may be resumed 
during the period of full-dose anticoagulation if all of the following 
criteria  are met: 
• 
The subject must have an in-range INR (usually between 
2 and 3) on a stable dose of warfarin (or other 
anticoagulant) prior to restarting study drug treatment. 
• 
The subject must not have had a Grade 3 or 4 
hemorrhagic event while on anticoagulation. 
• 
The subject must not have had evidence of tumor 
involving major blood vessels on any prior CT scan. 
 
Symptomatic Grade 4 
Discontinue bevacizumab. 


6628p 
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 Bevacizumab Dose Management due to Adverse Events (continued) 
 
Arterial Thromboembolic event  (Angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, and any other arterial thromboembolic event) 
 
 Any grade 
Discontinue bevacizumab. 
Congestive Heart Failure (Left ventricular systolic dysfunction) 
 
Grade 3 
Hold bevacizumab until resolution to Grade ≤ 1. 
Grade 4 
Discontinue bevacizumab. 
Proteinuria should be monitored by urine dipstick or urine protein creatinine (UPC) ratio every 8 
weeks.  If dip is >2+ then a UPC ratio should be performed 
 
Grade 3 
(UPC > 3.5)  
 
Hold  bevacizumab treatment until UPC recovers to < 3.5  
 
Grade 4 (nephrotic 
syndrome) 
Discontinue bevacizumab 
GI Perforation 
 
Discontinue bevacizumab. 
Bowel Obstruction 
Grade 1 
 
Continue patient on study for partial obstruction NOT requiring medical 
intervention. 
Grade 2 
Hold bevacizumab for partial obstruction requiring medical intervention.  
Patient may restart upon complete resolution. 
Grade 3/4 
Hold bevacizumab for complete obstruction.  If surgery is necessary, 
patient may restart bevacizumab after full recovery from surgery, and 
at investigator’s discretion. 
Wound dehiscence 
requiring surgical 
therapy 
Discontinue bevacizumab. 
Other Unspecified  Bevacizumab-Related Adverse Events 
Grade 3 
 
Grade 4 
Hold bevacizumab until recovery to ≤ Grade 1 
 
Discontinue bevacizumab. 
 
8.4 
Dose Modifications – Erlotinib 
 
Skin toxicities will be monitored by routine physical examination and managed 
symptomatically.  Because secondary bacterial infections are common and can 
lead to more serious complications, topical or systemic antibiotics may be 
considered.  Anecdotally, topical or a short course of systemic corticosteroids 
can be helpful.  See tables below for management guidelines, including erlotinib 
dose reduction/interruption. 


6628p 
38 
Management of a tolerable Grade 2 or 3 rash should include continuation of 
erlotinib at the current dose and symptomatic management.  If skin rash is 
intolerable, dose reduction according to the table below should be considered.  
When skin toxicity improves by at least one grade level, the dose may be 
re-escalated as tolerated.  In Phase II trials, this approach enabled dose 
re-escalation for the majority of patients requiring dose reduction for skin toxicity.  
Patients experiencing Grade 4 skin toxicity should be discontinued from study 
treatment. 
 
Diarrhea will be monitored and managed symptomatically.  Guidelines for 
management 
include 
administration 
of 
loperamide 
and 
erlotinib 
dose 
reduction/interruption as described in the tables below. 
 
For Grade 1 or 2 diarrhea, early intervention should include continuation of 
erlotinib at the current dose and initiation of loperamide therapy as described in 
in the table below.  Grade 2 diarrhea that persists over 48–72 hours, despite 
optimal medical management, should be managed by dose reduction as 
specified in the tables below.  Patients experiencing Grade 3 diarrhea should 
interrupt erlotinib until resolution to Grade 1 and re-start at a reduced dose as 
described in the table below.  Patients should be maintained at the reduced dose 
without attempt at dose re-escalation.  Patients experiencing Grade 4 diarrhea 
should be discontinued from erlotinib. 
 
Although quite rare, interstitial lung disease (ILD) can be life threatening.  
Therefore, patients should be monitored closely for symptoms consistent with 
ILD, such as new onset dyspnea without an obvious cause.  In the event that ILD 
is suspected, erlotinib treatment should be discontinued and the patient should 
receive appropriate medical management.  Although there is no proven therapy, 
systemic corticosteroids are often provided.  Erlotinib should not be restarted in 
those patients suspected of having drug-related ILD.  See tables below for 
management guidelines, including erlotinib dose interruption. 
 
Erlotinib should not be restarted in those suspected of having drug-related ILD. 
 
If a patient becomes pregnant despite contraceptive precautions, she should be 
apprised of the potential risk of fetal morbidity or loss. 
 
Dose reduction or interruption of erlotinib for toxicity may take place at any time 
during the study.  Dose level reductions are presented in the table below.  If 
patients do not tolerate the second dose reduction, erlotinib is to be discontinued.  
 
Erlotinib Dose Level Reductions 
Starting Dose 
First Reduction 
Second Reduction 
150 mg/day 
100 mg/day 
50 mg/day 
 
 


6628p 
39 
Dosage Modifications and Management Guidelines for Erlotinib-Related Toxicities 
NCI-CTCAE (v 3.0) Grade 
Erlotinib Dose Modification 
Guideline for Management 
Diarrhea 
Grade 1 
None 
Consider loperamide (4 mg at 
first onset, followed by 2 mg q 
2–4 hours until free of diarrhea 
for 12 hours) 
Grade 2 
None 
(Dose reduction of erlotinib is 
necessary if diarrhea persists 
over 48–72 hours despite 
optimal medical management) 
Loperamide (4 mg at first onset, 
followed by 2 mg q 2–4 hours 
until diarrhea free for 12 hours) 
Grade  3 
Interrupt then dose reduce 
erlotinib.  Erlotinib should not be 
re-escalated. 
Interrupt erlotinib until resolution 
to Grade 1, and restart at next 
reduced dose 
Grade 4 
Discontinue study treatment. 
 
Pulmonary Events if possibly ILD 
All Grades 
Temporarily interrupt erlotinib 
pending the diagnostic 
evaluation.  If the pulmonary 
adverse event is assessed as 
related to erlotinib, discontinue 
the patient from study treatment. 
Unexplained dyspnea, either 
new or progressive, should be 
aggressively evaluated.   
Rash 
Grade 1 and 2 
Tolerable rash 
None 
Any of the following: oral 
antibiotics (tetracycline, 
minocycline, doxycycline), 
topical clindamycin, 
diphenhydramine, topical or oral 
corticosteroids at discretion of 
investigator 
Grade 3 
Intolerable rash 
Consider interruption and or 
dose reduction if unresponsive to 
symptomatic management.  
Re-escalation is allowed. 
Manage as described above 
Grade 4 
Discontinue erlotinib. 
Manage as described above 
 
 
8.5 
Concomitant Medications 
 
Irradiation is not allowed during the study.  Administration of other chemotherapy, 
immunotherapy, or anti-tumor hormonal therapy during the study is not allowed.  
Use of concurrent investigational agents is not permitted.  Supportive care, 
including but not limited to anti-emetic medications, may be administered at the 
discretion of the Investigator.  Concurrent treatment with bisphosphonates is 
allowed.  All concomitant treatments, including blood and blood products, must 
be reported on the case report form. Erythropoietin may be administered at the 
discretion of the investigator, consistent with institutional guidelines. G-CSF 
should be administered according to the guidelines in this protocol. 
 


6628p 
40 
Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for 
arterial thromboembolic disease. Subjects developing signs of arterial ischemia 
or bleeding on study should be evaluated for possible bevacizumab 
discontinuation per Table 1, Bevacizumab Dose Management Due To Adverse 
Events. 
 
There are potential interactions between both nab-paclitaxel and erlotinib and 
CYP3A4 inhibitors and CYP3A4 promoters.  Although caution and careful 
monitoring are recommended when use of these compounds is necessary, use 
of these compounds does not exclude patients from participating in this trial (see 
Appendices for a list of CYP3A4 inhibitors and inducers). 
 
Grapefruit juice is a CYP3A4 inhibitor, therefore, consumption of grapefruit or 
grapefruit juice should be avoided during nab-paclitaxel and erlotinib treatment. 
 
The solubility of erlotinib is pH dependent.  Erlotinib solubility decreases as pH 
increases. Co-administration of erlotinib with omeprazole, a proton pump 
inhibitor, decreased the exposure of erlotinib (AUC) by 46% and the maximum 
concentration (Cmax) by 61%.  There was no change to Tmax or half-life.  
Therefore, drugs that alter the pH of the GI tract may alter the solubility of 
erlotinib and hence its bioavailability. 
 
The exposure to erlotinib (AUC) increased to a moderate extent, by 39%, and the 
maximum concentration (Cmax) by 17%, when erlotinib was co-administered with 
ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2. 
 
Erlotinib clearance can be induced by smoking via CYP1A2 induction. Potential 
drug-drug interaction is expected when erlotinib is taken with CYP1A2 inducers 
or inhibitors.  In a single-dose study in healthy volunteers, the AUC was reduced 
by 64% in smokers when compared with nonsmokers.  In BR.21, current 
smokers 
achieved 
erlotinib 
trough 
plasma 
concentrations 
that 
were 
approximately 2-fold lower than never smokers.  Smokers should be advised to 
stop smoking while taking erlotinib as plasma concentrations of erlotinib are 
reduced due to the effect of cigarette smoking. 
 
Pretreatment or co-administration of erlotinib did not alter the clearance of a 
prototypical CYP3A4 substrate, midazolam.  Therefore, significant metabolic 
interactions with other CYP3A4 substrates are unlikely.  However, the oral 
bioavailability of midazolam decreased by up to 24% following erlotinib treatment, 
which was not attributed to a metabolic interaction. 
 
Patients taking warfarin or other warfarin-derivative anticoagulants should be 
monitored regularly for changes in prothrombin time or INR. 
 
 
9.0 Study Calendar


6628p 
41 
Required Procedures 
Pre-
study 
Induction 
Maintenance 
Follow up9 
 
 
 Weeks 
1, 2 & 3 
Every 2 
Weeks 
Monthly 
Every 8 
Weeks 
Daily 
 Each 
Bevacizumab 
Infusion 
Monthly 
Every 8 
Weeks 
Vital Signs 
X 
 
X 
 
 
 
X 
 
 
X 
Blood Pressure1 
 
 
X1 
 
 
 
X1 
 
 
X1 
Clinic Visit 
X 
 
 
X 
X 
 
 
X 
 
X 
Adverse Event Notation 
X 
 
 
X 
X 
 
 
X 
 
X 
Disease Assessment 
X 
 
 
 
X 
 
 
 
X 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
CBC/ANC/Platelets 
X 
X 
 
 
 
 
 
X 
 
X 
Metabolic Panel2 
X 
 
 
X 
 
 
 
X 
 
X 
AST/ALT 
X 
 
 
X 
 
 
 
X 
 
X 
Alkaline Phosphatase 
X 
 
 
X 
 
 
 
X 
 
X 
Bilirubin 
X 
 
 
X 
 
 
 
X 
 
X 
CEA and CA 27.29 or  
CEA and CA 15-3 
X 
 
 
 
X 
 
 
 
X 
X 
Pregnancy Test3 
X 
 
 
 
 
 
 
 
 
 
Assessment for Proteinuria4 
X 
 
 
 
X 
 
 
 
X 
 
IMAGING 
 
 
 
 
 
 
 
 
 
 
X-rays/scans 
if 
required 
for 
disease assessment 
X 
 
 
 
X 
 
 
 
X 
X 
MUGA/Echocardiogram 
X5 
 
 
 
 
 
 
 
 
 
RESEARCH SPECIMENS 
 
 
 
 
 
 
 
 
 
 
CEC 
X 
 
 
X6 
 
 
 
X7 
 
 
CTC 
X 
 
 
X6 
 
 
 
X7 
 
 
EGFR/SPARC 
X 
 
 
 
 
 
 
 
 
 


6628p 
42 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
Nab-Paclitaxel  
 
X8 
 
 
 
 
 
 
 
 
Bevacizumab 
 
 
X 
 
 
 
X 
 
 
 
Erlotinib 
 
 
 
 
 
X 
 
 
 
 
 
1 Hypertension will be monitored through evaluation of blood pressure prior to each bevacizumab treatment.  Optimal control of blood pressure according to standard 
public health guidelines is recommended for patients on bevacizumab. 
 
2 Basic Metabolic Panel includes sodium, potassium, chloride, glucose, BUN, creatinine and calcium. 
 
3 Women of childbearing potential only. 
 
4 Urine should be assessed via dipstick or random urine creatinine and protein every 8 weeks.  If dipstick is >2+, then a UPC ratio should be performed.  See appendices 
for instructions for calculating the ratio.  During screening if UPC > 1.0, patient should undergo a 24-hour urine collection which must demonstrate < 1g of protein in 24 
hours for patient to be eligible.  During study treatment if dipstick or UPC demonstrates proteinuria, see table on page 37 for instructions for holding or discontinuing 
bevacizumab due to proteinuria. 
 
5 Assessment of left ventricular ejection fraction by MUGA or transthoracic echocardiogram at study entry is considered good medical practice.  Reassessment is only 
required if clinical symptoms arise. 
 
6 Prior to weeks 5 and 17 of nab-paclitaxel and bevacizumab and at time of disease progression.  If the patient is removed from protocol treatment for reasons other 
than disease progression, CTC and CEC assays do not need to be done at the time of disease progression. 
 
7 Prior to weeks 1 and 9 of bevacizumab and erlotinib and at time of disease progression.  If the patient is removed from protocol treatment for reasons other than 
disease progression, CTC and CEC assays do not need to be done at the time of disease progression. 
 
8 Days 1, 8 and 15 of each 28 day cycle  
 
9 Follow up per physician discretion. Patients with on-going treatment related grade 4 or serious adverse event at the time of discontinuation from study treatment will 
continue to be followed until resolution of the event or until event is considered irreversible. 
 


6628p 
43 
10.0 
CRITERIA FOR EVALUATION AND END POINT DEFINITIONS 
 
10.1 
Measurability of Lesions 
 
10.1.1 Measurable Disease:  Lesions that can be accurately measured in at 
least one dimension by 1) medical photograph (skin or oral lesion), 
palpation, plain x-ray, CT, MRI or other conventional technique with 
longest diameter 2 cm or greater in the axial plane (bone lesions not 
included) or 2) spiral CT scan with longest diameter 1 cm or greater.  
Ultrasound is suitable only for superficial disease (superficial palpable 
nodes, subcutaneous lesions, thyroid nodules). 
 
Conventional CT and MRI should be performed with cuts of 10 mm or 
less in slice thickness contiguously.  Spiral CT should be performed using 
a 5 mm contiguous reconstruction algorithm. 
 
10.1.2 Non-measurable disease:  All other lesions including lesions too small to 
be considered measurable, pleural or pericardial effusions, ascites, bone 
disease, 
inflammatory 
breast 
disease, 
leptomeningeal 
disease, 
lymphangitis, pulmonitis, abdominal masses not confirmed and followed 
by imaging techniques, cystic lesions or disease documented by indirect 
evidence only (e.g. lab values), previously radiated lesions that have not 
progressed. 
 
10.2 
Objective Status at Each Evaluation:  Objective status is to be reported at 
each evaluation.  All measurable lesions up to a maximum of 5 lesions per organ 
and 10 lesions in total, representative of all involved organs, should be identified 
as target lesions at baseline.  All measurable lesions not identified as target 
lesions are non-target lesions and are included as non-measurable disease.  
Measurements must be provided for target measurable lesions, while presence 
or absence must be noted for non-target measurable and non-measurable 
lesions. 
 
10.2.1 Complete Response (CR):  Complete disappearance of all measurable 
and non-measurable disease.  No new lesions.  No disease related 
symptoms.  Normalization of markers and other abnormal lab values.  All 
disease must be assessed using the same technique as baseline. 
 
10.2.2 Partial Response (PR):  Applies only to patients with at least one 
measurable lesion.  Greater than or equal 30% decrease under baseline 
of the sum of longest diameters of all target lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target 
measurable lesions must be assessed using the same techniques as 
baseline. 
 
10.2.3 Stable:  Does not qualify for CR, PR, Progression or symptomatic 
deterioration.  All target measurable lesions must be assessed using the 
same techniques as baseline. 
 
10.2.4 Progression:  Either of the following must occur. 
 


44 
10.2.4.1 RECIST Progression:  One or more of the following must 
occur: 20% increase in the sum of longest diameters of target 
measurable lesions over smallest sum observed (over baseline 
if no decrease during therapy) using the same techniques as 
baseline.  Unequivocal progression of non-measurable disease 
in the opinion of the treating physician (an explanation must be 
provided).  Appearance of any new lesion/site, although some 
exceptions may be allowed if the treating physician feels that the 
area was inadequately evaluated on baseline imaging (an 
explanation must be provided).  Death due to disease without 
prior documentation of progression and without symptomatic 
deterioration. 
 
10.2.4.2 Confirmed bone disease progression:  Confirmed bone 
disease progression is defined as development of one or more 
new bone lesions from baseline (an increase in size or intensity 
of known lesions will not constitute progression) confirmed by a 
subsequent bone scan with further development of new lesions 
at least 6 weeks after the first.  Patients will also be deemed to 
progress if they require therapy for a bone lesion such as 
surgery, radiation therapy, radiofrequency ablation or other local 
therapy.  Date of progression will be defined as the date of the 
scans that first indicated new bone lesions. 
 
10.2.5 Symptomatic Deterioration:  Global deterioration of health status 
requiring discontinuation of treatment without objective evidence of 
progression.  Efforts should be made to obtain objective evidence of 
progression after discontinuation. 
 
10.2.6 Assessment Inadequate, Objective Status Unknown:  Progression or 
symptomatic deterioration has not been documented, and one or more 
target measurable lesions have not been assessed or inconsistent 
assessment methods were used. 
 
10.2.7 Objective Status Notes 
 
10.2.7.1 Non-measurable and non-target measurable disease do not 
affect objective status except in determination of CR (must be 
absent).  A patient who otherwise has a CR, but who has non-
measurable or non-target measurable disease present or not 
assessed will be classified as having a PR.  Non-measurable 
and non-target measurable disease will also affect determination 
of progression if new sites of disease develop or if unequivocal 
progression occurs in the opinion of the treating physician. 
 
10.2.7.2 An objective status of PR or stable cannot follow one of CR.  
Stable can follow PR only in the rare case that tumor increases 
too little to qualify as progression, but enough that a previously 
documented 30% decrease no longer holds. 
 


45 
10.2.7.3 In 
cases 
for 
which 
initial 
flare 
reaction 
is 
possible 
(hypercalcemia, increased bone pain, erythema of skin lesions), 
objective status is not progression unless either symptoms 
persist beyond 4 weeks or there is additional evidence of 
progression. 
 
10.2.7.4 Lesions that appear to increase in size due to presence of 
necrotic tissue will not be considered to have progressed. 
 
10.2.7.5 For bone disease documented on bone scan only, increased 
uptake does not constitute unequivocal progression. 
 
10.2.7.6 Appearance or worsening of pleural effusions does not 
constitute unequivocal progression unless cytologically proven 
of neoplastic origin. 
 
10.2.7.7 If CR determination depends on a lesion for which the status is 
unclear by the required tests, it is recommended the residual 
lesion be investigated with biopsy or fine needle aspirate. 
 
10.3 
Best Response:  this is calculated from the sequence of objective statuses. 
 
10.3.1 CR:  Two or more objectives statuses of CR a minimum of four weeks 
apart documented before progression or symptomatic deterioration. 
 
10.3.2 PR:  Two or more objective statuses of PR or better a minimum of four 
weeks apart documented before progression or symptomatic deterioration 
but not qualifying as CR. 
 
10.3.3 Unconfirmed CR:  One objective status of CR documented before 
progression or symptomatic deterioration but not qualifying as CR or PR. 
 
10.3.4 Unconfirmed PR:  One objective status of PR documented before 
progression or symptomatic deterioration but not qualifying as CR, PR or 
unconfirmed CR. 
 
10.3.5 Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration but not qualifying as anything else above. 
 
10.3.6 Increasing disease:  Objective status of progression or asymptomatic 
deterioration within 12 weeks of registration not qualifying as anything 
else above. 
 
10.3.7 Inadequate 
assessment, 
response 
unknown: 
 
Progression 
or 
symptomatic deterioration greater than 12 weeks after registration and no 
other response category applies. 
 
10.4 
Progression-Free Survival:  Time from date of registration to date of first 
documentation of progression or symptomatic deterioration or death due to any 


46 
cause.  Patients last known to be alive and progression-free are censored at last 
date of contact. 
 
10.5 
Overall Survival:  Time from date of registration to date of death due to any 
cause.  Patients last known to be alive are censored at last date of contact.. 
 
10.6 
Tumor Marker (MUC-1 or CEA) Antigen Response: 
 
10.6.1 Objective status at each evaluation:  Objective tumor marker response is 
to be recorded prestudy and every 8 weeks. 
10.6.1.1 Tumor Marker Complete Response: Reduction in MUC-1 (CA 
15-3 or CA 27.29) or CEA such that MUC- 1 or CEA ≤ ULN. 
10.6.1.2 Tumor Marker Partial Resonse: Greater than or equal to a 50% 
reduction in MUC-1 or CEA from baseline, but not qualifying as 
CR. 
10.6.1.3 Tumor Marker Progression: Greater than or equal to a 50% 
increase in MUC-1 or CEA from baseline. 
10.6.1.4 Tumor Marker Stable Disease: MUC-1 or CEA response not 
qualifying as CR, PR, or Progression. 
10.6.1.5 Tumor Marker Inadequate Assessment, response unknown:  
MUC-1 or CEA response has not been adequately assessed. 
  
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design 
 
This is a single-arm phase II multicenter clinical trial.    The treatment period is 24 
weeks of induction therapy followed by maintenance therapy until disease 
progression.  
 
The primary end point is progression free survival (PFS), which will be compared 
to historical controls of patients with metastatic basaloid breast cancer treated 
with chemotherapy and bevacizumab. 
 
We consider a 60% increase in median PFS (from 8 to 13 months) to represent 
justification for further exploration of this combination. 
   
11.2 
Sample Size 
 
Targeted enrollment will be 59 evaluable patients to detect this degree of 
improvement with one-sided alpha = .05, power = .80. 
 
11.3 
Interim Analysis and Early Stopping Guidelines 
 
Formal interim analyses and stopping rules are not planned.  As this is an open-
label study, data will be reviewed and summarized in an on-going manner.  In 
addition, the principal investigator will review serious adverse events during the 
course of the study as they are reported.   
 


47 
Excluding patients who withdraw from the study due to progression, if 7 of the 
first 30 patients withdraw prior to completion of induction therapy (due to toxicity 
or other reasons beside progression), the study may be terminated if the 
treatment regimen does not appear to be well-tolerated.  Note that dose 
reductions alone are not considered as withdrawal. 
 
11.4 
Methods of Analysis 
 
This study is being conducted to assess the efficacy and safety of a regimen of 
chemotherapy and combined targeted biologic therapy for patients with the triple 
negative phenotype of metastatic breast cancer.  Efficacy data will be collected 
and summarized on all patients who receive at least one dose of study drug and 
some follow up for progression.  Safety data will be collected and summarized for 
all patients who receive at least one dose of study drug.   
 
11.4.1  Efficacy analysis 
 
Assessments of progression and survival will continue for at least 24 
weeks after the last accrued patient has begun study treatment.  Kaplan-
Meier survival curves will be used to describe PFS and overall survival.  
For PFS, patients without documented disease progression or death will 
be treated as censored on the date of the last tumor assessment.  Overall 
survival time will be censored on the last date the patient was known to 
be alive.   Response rate will be summarized and an exact 90% binomial 
confidence interval determined for evaluable subjects. 
 
A 95% confidence interval for the median PFS will be calculated.  A lower 
bound greater than 8 months would be strong evidence that Nab-
Paclitaxel- bevacizumab induction therapy followed by bevacizumab-
erlotinib maintenance therapy is superior to paclitaxel and  bevacizumab.  
However, a median PFS of 13 months or greater (regardless of whether 
the 95% confidence interval for the median extends below 8 months) 
could also indicate promising results. 
 
 
11.4.2 Safety analysis 
 
Safety assessments will consist of monitoring and recording protocol-
defined adverse events (AEs) and serious adverse events (SAEs); 
measurement of protocol-specified hematology, clinical chemistry, and 
urinalysis variables; measurement of protocol-specified vital signs; and 
other protocol-specified tests that are deemed critical to the safety 
evaluation of the study drugs. 
 
Adverse events will be graded using the Cancer Therapy Evaluation 
Program (CTEP) Common Terminology Criteria for Adverse Events 
version 3.0. Adverse events that meet severity grade 2 or greater will be 
collected and reported. The number and percent of subjects reporting 
adverse events (all, severe or worse, serious and related) will be 
summarized for all patients, and stratified by center and other subgroups 
of interest.  Narratives of all serious adverse events and deaths on-study 
will be provided.   


48 
 
The investigator is responsible for ensuring that all reportable AEs and 
SAEs that are observed or reported during the study are recorded on the 
CRF and reported to the funding agencies in accordance with protocol 
instructions.  
 
Death as a result of disease progression is only to be assessed with 
regard to efficacy measures and not as an AE or SAE. 
 
Investigators will assess the occurrence of AEs and SAEs at all patient 
evaluation time points during the study.  All reportable AEs and SAEs 
whether volunteered by the patient, discovered by study personnel during 
questioning or detected through physical examination, laboratory test or 
other means will be recorded in the patient’s medical record and on the 
appropriate AE or SAE case report form page. 
 
Each recorded AE or SAE will be described by its severity (see Table 3), 
regulatory seriousness criteria if applicable, suspected relationship to the 
investigational product and actions taken. 
 
Table 3:  Adverse Event Grading (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild 
(apply 
event-specific 
NCI-CTCAE grading criteria) 
Transient 
or 
mild 
discomfort 
( 48 hours); no interference with 
the patient’s daily activities; no 
medical 
intervention/therapy 
required 
2 
Moderate 
(apply 
event-specific  
NCI-CTCAE grading criteria) 
Mild to moderate interference with 
the patient’s daily activities; no or 
minimal 
medical 
intervention/therapy required 
3 
Severe 
(apply 
event-specific  
NCI-CTCAE grading criteria) 
Considerable interference with the 
patient’s daily activities; medical 
intervention/therapy 
required; 
hospitalization possible 
4 
Very 
severe, 
life 
threatening,  
or disabling (apply event-specific 
NCI-CTCAE grading criteria) 
Extreme 
limitation 
in 
activity; 
significant 
medical 
intervention/therapy 
required, 
hospitalization probable 
5 
Death related to AE 
 
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  
Refer to definitions of an SAE (see Section 16.1). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the 
observed or reported AE is not in the NCI-CTCAE listing. 
 
 
11.4.3  Additional Analyses 
 


49 
The number of subjects who withdraw from study before the scheduled end of 
study will be quantified with the reason for withdrawal and timing of withdrawal. 
 
At a minimum, the following demographic, baseline and on-study characteristics 
will be summarized for all patients and by center: 
 
• 
Age and race 
• 
Clinical stage of disease 
• 
Clinical response to nab-paclitaxel and  bevacizumab 
• 
Clinical response to  bevacizumab and erlotinib 
• 
Relapse rate following nab-paclitaxel and  bevacizumab 
• 
Dose adjustments to nab-paclitaxel,  bevacizumab, and erlotinib (missed, 
withheld, decreased) 
• 
Median dose intensity for nab-paclitaxel and  bevacizumab, and   
bevacizumab and erlotinib 
• 
Cytokine use 
• 
PFS and overall survival (OS) will be summarized with Kaplan-Meier 
curves; the median survival time with 95% confidence limits will be 
provided.  Exploratory subgroup analyses will look at PFS and OS 
separately for groups defined by dose delivered, treatment history, and 
biomarker values. 
 
11.5 
Expected gender, ethnic and racial composition: 
 
 
TARGETED/PLANNED ENROLLMENT:   
NUMB ER OF SUBJECTS  
 
Ethnic Category 
 
 
 
Sex/Gender 
 
Females 
Males 
Total 
Hispanic or Latin o 
2 
0 
2 
Not Hispanic or Latin o 
61 
0 
61 
Ethnic Category Total of All  Subjects*  
63 
0 
63 
 
                  Racial Categories 
Ame rican Indian/Alaska Native 
0 
0 
0 
Asian 
3 
0 
3 
Nativ e Hawaiian or Othe r Pacifi c Islander 
1 
0 
1 
Black or Afr ican Ame rican 
4 
0 
4 
Whi te 
55 
0 
55 
Racial Categories: Total of Al l Subjects *  
63 
0 
63 
 
 
12.0 
DISCIPLINE REVIEW 
 
There is no discipline review. 
 
 
13.0 
REGISTRATION GUIDELINES 
 


50 
13.1 
Before a subject participates in the trial, the investigator or delegate is 
responsible for obtaining written informed consent after adequate explanation of 
the aims, methods, anticipated benefits, potential hazards, and subject 
responsibilities including the use of adequate methods to prevent pregnancy.  
Consent must be obtained before any on-study procedures or any study 
medications are administered. 
 
13.2 
All patients must be registered before the start of treatment. Patients seen at the 
Seattle Cancer Care Alliance (SCCA) are registered by contacting the Breast 
Program Research Coordinator assigned to the study.  Patients who are seen at 
external performance sites are registered by calling the SCCA Network office  at 
206-288-7232), 8:00 AM to 5:00 PM Pacific time, Monday through Friday.  
Materials required to complete the registration may be faxed (206 288-1310) or 
scanned/e-mailed (SCCANetResearch@seattlecca.org) and include: 
 
• 
Consent Form 
• 
HIPAA Authorization 
• 
Registration Form 
• 
Eligibility Checklist and all supporting documentation 
• 
Race and Ethnicity Form 
• 
Medical records documenting eligibility 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
Data forms will be completed by research staff at the Seattle Cancer Care Alliance for all 
subjects registered to the study.  Records may be faxed, e-mailed or mailed to: 
 
Seattle Cancer Care Alliance Network 
825 Eastlake Avenue East 
Mail Stop LG-200 
Seattle, WA 98109-1023 
(206) 288-1310 (fax) 
sccanetresearch@seattlecca.org 
 
Medical records are due at the following time points to allow for completion of study-
specific case report forms: 
 
14.1 
At the time of registration: all medical records from the time of diagnosis of 
breast cancer and the consent form, HIPAA Authorization, Race and Ethnicity 
Form.   
14.2 
At the end of each cycle of treatment: physical exams, laboratory test results, 
radiology examinations, treatment orders, treatment administration records, 
concomitant medication lists. 
14.3 
At the end of each regimen (e.g. nab-paclitaxel bevacizumab or  
bevacizumab/erlotinib): Assessment of response and disease progression 
14.4 
Every three months for the first three years, every six months for the next 
two years, annually thereafter: Clinic notes and disease assessments (if off 
study for reason other than disease progression) 
 


51 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
General Specimen Submission Instructions 
 
15.1.1 All specimens must be labeled with the protocol number (6628), patient 
number, patient initials and date of specimen collection. 
 
15.1.2 The federal guidelines for shipment are as follows: 
 
15.1.2.1 The specimen must be wrapped in an absorbent material. 
 
15.1.2.2 The specimen must be placed in an AIRTIGHT container (like a 
resealable bag). 
 
15.1.2.3 Pack the resealable bag and specimen in a Styrofoam shipping 
container. 
 
15.1.2.4 Pack the Styrofoam shipping container in a cardboard box. 
 
15.1.2.5 The cardboard box must be marked as “BIOHAZARD”. 
 
15.2 
Immunohistochemistries  
 
Tumor tissue that is available from subjects will be analyzed for expression of the 
SPARC (secreted protein and rich in cysteine) protein and for endothelieal 
growth factor receptor (EGFR).  Participation in these additional analyses is 
optional.  Subjects will indicate in the consent form whether they agree to make 
their tissue sample available for these analyses. Subjects may choose not to 
allow their tumor tissue to be used for testing of SPARC and EGFR expression.  
Tumor tissue that is available from biopsy will be used. Additional procedures will 
not be performed for the purpose of obtaining tumor tissue for SPARC or EGFR 
analyses. 
 
15.2.1 EGFR 
 
Immunohistochemistry for assessment of EGFR will be performed at the 
University of Washington Medical Center. 
 
Procedures for Tumor Sample Preparation and Shipping 
 
Tumor samples obtained in accordance with applicable regulations will be 
collected.  
 
Tissue specimens will be prepared as paraffin embedded blocks. Send 
blocks to Dr. Jennifer Specht at the Seattle Cancer Alliance to be 
inventoried and submitted to the pathology department for EGFR staining. 
The pathology department will process the specimens according to 
standard procedures for EGFR assays. Tissue blocks will be returned to 
the sites of origin as soon as EGFR testing is complete. 
 
An alternative, but not preferred, method is to utilize slides generated at 
the specimen collection sites. Ten unstained slides, cut from archival 


52 
paraffin-embedded tumor blocks, will be obtained for evaluation of tumor 
EGFR expression by IHC methodology. Thickness of the sections should 
be at 4 micron.   Tumor specimens must be unstained and placed 
specifically on Super Frost Plus Slides and baked at 55 - 60oC for 1 hour.   
 
All blocks or slides for EGFR analysis will be shipped as follows:  
 
Ship specimens to: 
 
Seattle Cancer Care Alliance Network 
825 Eastlake Avenue East; MS LG-200 
Seattle, WA 98109-1023 
Phone: (206) 288-7232 
 
Samples will be de-identified by   research staff before shipment to 
outside laboratory. Samples will be coded with a unique study identifier 
that will be assigned at study registration.  
 
Data Analysis  
 
Data reports from the IHC analysis will be distributed to the appropriate 
parties when analysis of the entire data set is complete. 
 
15.2.2 SPARC 
 
15.2.2.1 Background and Rationale 
Nab-Paclitaxel achieves a high intracellular tumor concentration, 
and its intracellular concentration is at least, in part, achieved by 
an albumin-mediated transendothelial transport via the gp60 
pathway.  SPARC (secreted protein acidic and rich in cysteine) is 
a matricellular protein (also known as BM40 or osteonectin) that is 
upregulated in several aggressive tumors and its presence is 
associated with poor outcomes.  Expressed in 40-50% of breast 
cancers, SPARC also shares sequence homology with the C 
terminus of the gp60 pathway (an important pathway in Nab-
Paclitaxel intracellular transport) and binds albumin.  By exploiting 
both caveolin-1 and the SPARC protein, nab-paclitaxel may 
preferentially enhance drug delivery to tumors.  Correlative studies 
evaluating the presence of SPARC expression on tumors, disease 
prognosis, and response to therapy are underway.  
 
15.2.2.2 Objective 
 
To investigate a possible correlation between treatment response 
and the expression of tumor SPARC protein by IHC methodology 
 
15.2.2.3   Eligibility 
 
Patients must be eligible for, enrolled to and treated on the current 
protocol.  Patients must sign an informed consent specific for the 


53 
use of their tumor tissue in investigating expression of the 
SPARC. 
 
15.2.2.4 Study Treatment  
 
Patients will receive treatment as outlined in this protocol.  
  
15.2.2.5  Procedures for Tumor Sample Preparation and Shipping 
 
Tumor 
samples 
obtained 
in 
accordance 
with 
applicable 
regulations will be collected.  
 
Tissue specimens will be prepared as paraffin embedded blocks.  
 
An alternative, but not preferred method will be to utilize slides 
generated at the specimen collection sites. Ten unstained slides, 
cut from archival paraffin-embedded tumor blocks, will be obtained 
at baseline for evaluation of tumor SPARC expression by IHC 
methodology. Thickness of the sections should be at 5 
micron.   Tumor specimens must be unstained and placed 
specifically on Super Frost Plus Slides and baked at 55oC for 1 
hour.  If pretreatment archival tissue specimen is inadequate or 
technical difficulties are encountered, tissue processing from the 
post-induction surgery residual tumor will be attempted.  
 
Samples will be de-identified before shipment to outside sites. Samples 
will be coded with a unique study identifier that will be assigned at study 
registration.  
 
Data Analysis  
Data reports from the IHC analysis will be distributed to the 
appropriate parties when analysis of the entire data set is 
complete. 
 
Patient Response Assessment  
Responses will be defined as outlined in protocol section 10.3 for 
correlation with SPARC expression. 
 
Sample Size 
Because patient participation in this tumor tissue SPARC analyses 
are optional, and this analysis is exploratory in nature, a sample 
size will not be determined. 
 
15.3 
Submission of blood for analysis of circulating tumor cells and circulating 
endothelial cells 
   
15.3.1 Investigators are required to submit whole blood for analysis of circulating 
tumor cell (CTC) and circulating endothelial cell (CEC) analysis. 
 
15.3.2 Directions for obtaining, handling and submitting samples for CTC and 
CEC testing 
 


54 
15.3.2.1 All participating sites should have blood collection tubes and 
shipping supplies onsite at the time of registration.  To obtain 
collection tubes, call (206) 288-6355.    The initial supplies you 
receive will include the following: CellSave® tubes, shipping 
containers, pre-printed airbills. 
 
15.3.2.2 Timing of collections:  Blood for testing for all study patients is to 
be obtained at baseline prior to initiation of study treatment, prior 
to weeks 5, 9 and 17 of nab-paclitaxel and  bevacizumab, prior 
to week 1 and 9 of  bevacizumab and erlotinib and at the time of 
disease progression. All samples should be obtained prior to 
infusion of chemotherapy or before taking the first dose of oral 
therapy for the interval. 
 
15.3.2.3 Materials required for blood collections are: two (2) 10 mL 
purple/yellow top CellSave® blood collection tubes, Vacutainer® 
brand adapter and needles.  The blood may be drawn by a 
physician, registered nurse or licensed phlebotomist at the 
clinical site.  NOTE: Clinical labs for the day should be obtained 
prior to filling the CellSave® tube using the same needle stick.  
This decreases the chance of contamination of the CTC or CEC 
sample with skin epithelial cells which may occur when the 
needle enters the skin. 
 
15.3.2.4 Complete the top portion of the CTC and CEC Blood Draw and 
Results CRF noting the lot number and expiration date of each 
of the CellSave® tubes.  For each patient, obtain the blood 
sample via a venous puncture or from a port or other central 
venous catheter using appropriate access needles and 
techniques.  Fill each of the blood collection tubes (minimum 
blood volume of 9 mL for each tube).  Invert each tube a 
minimum of eight (8) times to ensure proper mixing of the 
additives contained in each ®tube.  Write the study number, 
patient number and date of collection on the tubes.  Complete 
the remainder of the CTC and CEC Blood Draw and Results 
CRF. 
 
15.3.2.5 The filled CellSave® tubes must be maintained at ambient (10 – 
30° C) temperature avoiding extremes of heat and cold at all 
times. 
 
15.3.2.6 Place each filled collection tube into the styrofoam shipping 
container.  One shipping container accommodates up to two 
collection tubes.  Place the Styrofoam box into a ziplock bag and 
secure the lid of the outer cardboard box. 
 
15.3.2.7 Complete Section 1 of the airbill and make sure the box under 
“Does this shipment contain dangerous goods?” is checked 
“No”.  Packages may be sent Monday through Thursday for 
Tuesday through Friday delivery only.  Specimens cannot be 
received or processed on the weekend. 
 
15.3.2.8 Place the completed CTC and CEC Blood Draw and Results 
CRF into the express mail envelope. 
 
15.3.2.9 Call the laboratory to alert the lab of the shipment.  Ship all 
blood tubes overnight delivery to: 
 


55 
Daniel Sabath, M.D. 
Seattle Cancer Care Alliance 
825 Eastlake Avenue East 
Mail Stop G7-800 
Seattle, WA 98109-1023 
(206) 288-7060 
 
 
 
  
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
16.1 
Definitions 
 
Adverse Events 
 
An adverse event (AE) is any new, undesirable medical occurrence or worsening 
of a pre-existing condition that occurs during or after treatment, whether or not 
considered to be product related.  Therefore, adverse events are treatment-
emergent signs or symptoms.  
 
This includes the following: 
 
• 
AEs not previously observed in the patient that emerge during the 
protocol-specified AE reporting period 
• 
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as biopsies) 
• 
Preexisting medical conditions (other than the condition being studied) judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period 
• 
Diagnoses and/or symptoms associated with breast cancer should be 
reported as AEs if they worsen or change in character.  Clinical progression 
of breast cancer should not be reported as an AE. 
 
Adverse events that meet severity grade 2 or greater will be collected from the 
initiation of study treatments to 30 days subsequent to study completion or 
withdrawal. Follow up of these events will follow the same procedure as 
described in Section 16.3.1 for AEs observed during the study period. 
 
Life-threatening Adverse Event 
 
Any adverse drug experience that places the research subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred.  This 
does not include a reaction that, had it occurred in a more severe form, might 
have caused death. 
 
Serious Adverse Events (SAE) 
 
To ensure patient safety, every SAE, regardless of suspected causality, 
occurring after the patient has initiated study therapy and until 30 days after the 
patient has stopped study treatment must be reported within 24 hours of learning 
of the event.  Any SAE experienced after the 30-day period should only be 
reported if the investigator suspects a causal relationship to the study drugs.  Dr. 


56 
Specht and her staff will be responsible for reporting to Celgene, Genentech and 
the IRB.   
 
A serious adverse event as defined by IHC is any adverse drug experience that 
at any dose meets any of the following conditions: 
 
• 
Results in death 
• 
Is life-threatening (The patient was at risk of death at the time of the 
event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe) 
• 
Requires 
in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization 
• 
Results in persistent or significant disability or incapacity or 
• 
Is a congenital anomaly or birth defect. 
 
The terms “serious” and “severe” are not synonymous.  The term “severe” is 
often used to describe the intensity (severity) of a specific event (as in mild, 
moderate or severe myocardial infarction).  The event itself, however, may be of 
relatively minor medical significance (such as severe headache).  This is not the 
same as “serious”, which is based on patient/event outcome or action criteria 
usually associated with adverse events, which pose a threat to a patient’s life or 
functionality.  Seriousness (not severity) is the criterion used to define reporting 
obligations.   
 
Severity and seriousness should be independently assessed when recording 
AEs and SAEs on the case report form. 
 
Note: Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations; for example, important 
medical events may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the outcomes listed in the definition above. Any adverse event is 
considered a serious adverse event if it is associated with clinical signs or 
symptoms judged by the investigator to have a significant clinical impact. 
 
Related to Study Treatment 
 
An adverse event is related to a study product, treatment or procedure if it is 
certain or reasonably possible that it was caused by the product, treatment or 
procedure.  An adverse event is not related to a study product, treatment or 
procedure if: (i) it is caused by the subject’s medical condition or concomitant 
therapy that is not part of the study treatment or intervention or (ii) there is no 
plausible temporal, behavioral or biological relationship to the product, treatment 
or procedure.   
 
To ensure consistency of AE and SAE causality assessments, investigators 
should apply the following general guideline: 
 
Related = YES 


57 
There is a plausible temporal relationship between the onset of the AE and 
administration of the investigational product, and the AE cannot be readily 
explained by the patient’s clinical state, intercurrent illness, or concomitant 
therapies; and/or the AE follows a known pattern of response to the 
investigational 
product; 
and/or 
the 
AE 
abates 
or 
resolves 
upon 
discontinuation of the investigational product or dose reduction and, if 
applicable, reappears upon re-challenge. 
 
Related = NO 
Evidence exists that the AE has an etiology other than the investigational 
product (e.g., preexisting medical condition, underlying disease, intercurrent 
illness or concomitant medication); or the AE has no plausible temporal 
relationship to administration of the investigational product (e.g., cancer 
diagnosed 2 days after first dose of study drug). 
 
Unexpected Adverse Event 
 
Any adverse drug experience, the specificity or severity of which is not consistent 
with the applicable product information (e.g., Investigator’s Brochure for an 
unapproved investigational product or package insert/summary of product 
characteristics for an approved product).  For example, under this definition, 
hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure only referred to elevated hepatic enzymes or hepatitis.  
Similarly, cerebral thromboembolism and cerebral vaculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure only listed cerebral 
vascular accidents.  “Unexpected,” as used in this definition, refers to an adverse 
drug experience that has not been previously observed (e.g. included in the 
investigator brochure). 
 
16.2 
SAE Reporting Period 
 
The SAE reporting period is from the date of the first dose of study drug to 30 
days after discontinuation of all study drugs.  After this period, investigators 
should only report SAEs that are attributed to prior study treatment. 
 
16.3 
SAE Reporting Guidelines 
 
16.3.1 All serious adverse events experienced by patients seen at performance 
sites other than the Seattle Cancer Care Alliance (SCCA) Lake Union site 
must be reported by calling (206) 288-6355.  The reporting requirements 
for the IRB and the funding agencies (Celgene and Genentech) differ.  
The SCCA Network office will assist external sites with preparing the 
appropriate reports and will forward the completed reports to the principal 
investigator and Breast Cancer Research Program study staff for 
submission to the appropriate agencies.  SAEs experienced at the SCCA 
or UWMC will be reported to the appropriate agencies by the Principal 
Investigator with assistance from Breast Cancer Research Program study 
staff.     
 
 All SAEs must be followed until resolved or considered stable.  The 
following attributes must be reported:  


58 
 
• 
Description of event;  
• 
Dates of onset and resolution;  
• 
Severity;  
• 
Assessment of relatedness to study drug, and  
• 
Action taken.   
 
The investigator may be asked to provide follow-up information and will 
assist in investigating any SAE and will provide any follow-up information 
reasonably requested by the Principal Investigator. 
 
16.3.2 Reporting Requirements for the IRB  
 
The IRB requires the principal investigator to ensure that adverse events 
that meet the expedited reporting criteria defined below are reported to 
the IRB not later than ten (10) calendar days after she becomes aware of 
them. 
 
• 
All adverse events that are unexpected, related or possibly related to 
the research and serious or suggest that the research places research 
participants or others at greater risk of physical or psychological harm 
than was previously known or recognized. 
• 
Death of the research participant within thirty (30) days from the start 
of administration of the study product, treatment, or procedure 
• 
AEs that must be reported on an expedited basis to comply with the 
protocol on which a research participant is being treated. 
 
Note: If a principal investigator submits an AE that does not meet the 
Expedited Reporting Criteria, the IRB office will log in the AE and then 
return it to the Principal Investigator (PI)/contact person. A copy of the AE 
report not meeting the Expedited Reporting Criteria will not be kept by the 
IRB. At time of Continuation Review, the PI will be responsible for 
submitting a summary of the AE reports. 
 
16.3.3 Reporting Requirements for Celgene 
 
Serious adverse events (SAE) are defined above.  The investigator must 
inform Celgene in writing using a Celgene SAE form or MEDWATCH 
3500A form of any SAE within 24 hours of being aware of the event.  This 
study will use the MEDWATCH 3500A form.  The written report must be 
completed and supplied to Celgene by facsimile within 24 hours/1 
business day.  The initial report must be as complete as possible, 
including an assessment of the causal relationship between the event and 
the investigational product(s), if available.  Information not available at the 
time of the initial report (e.g., an end date for the adverse event or 
laboratory values received after the report) must be documented on a 
follow-up report.  A final report to document resolution of the SAE is 
required.  The Celgene tracking number (AX-CL-BRST-PI-003828) and 
the institutional protocol number should be included on SAE reports (or 
on the fax cover letter) sent to Celgene.  A copy of the fax transmission 


59 
confirmation of the SAE report to Celgene should be attached to the SAE 
and retained with the patient records. 
 
 
 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.   
Suite 6000     
Berkeley Heights, NJ  07922        
Fax: 
(908) 673-9115 
E-mail: drugsafety@celgene.com 
 
16.3.4 Reporting Requirements for Genentech 
 
Investigators will submit written reports of all SAEs, regardless of 
attribution, to Genentech within 48 hours of learning of the events.  For 
initial SAE reports, investigators should record all case details that can be 
gathered within 48 hours on an SAE CRF page.  For this study, the 
MEDWATCH 3500A form will be considered the SAE case report form 
page.  The completed SAE CRF page and SAE Fax Cover Sheet should 
be faxed immediately upon completion to Genentech’s Drug Safety 
Department at: 
 
(650) 225-4682 or 
(650) 225-5288. 
 
and to the GNE Drug Safety Hotline at (888) 835-2555. 
 
Relevant follow-up information should be submitted to Genentech’s Drug 
Safety as soon as it becomes available and/or upon request. 
 
 
16.4 
Monitoring for Data Accuracy and Compliance 
 
Protocol implementation will be reviewed and summarized in an on-going 
manner.  The principal investigator will review (1) all serious adverse events and 
(2) data concerning disease progression. 
 
Teleconferences or videoconferences with performance sites other than the 
SCCA at Southeast Lake Union will occur at regular intervals to discuss the 
progress of the study.  The conversations will be summarized and discussed at 
the monthly of the study team which includes the principal investigator, Breast 
Cancer Research Program study coordinator and staff of the SCCA Network 
office.  The following topics will be discussed and summarized: 
 
• 
Screening activity 
• 
Enrollment 
• 
Status of each patient receiving study treatment (e.g. number of weeks on 
study treatment, toxicity experienced, response to date, etc.) 
• 
Reports of serious, unexpected adverse events related to study treatment 


60 
• 
IND safety reports of serious, unexpected adverse events that are related 
to study drugs 
• 
Instances of disease progression 
• 
Vital status of study participants 
• 
Pending protocol or consent form changes 
• 
Other issues related to accrual or protocol implementation as necessary. 
 
Written summaries of serious, unexpected adverse events occurring on the study 
that are related to the study drugs and IND safety reports received from Celgene 
or Genentech will be distributed by the Coordinating Center to the lead 
investigator at each external (e.g. non-SCCA at Southeast Lake Union) 
performance site.  Protocol modifications and consent form changes will be 
distributed to each performance site as they are approved by the IRB with 
instructions as to whether subjects must be re-consented. 
Formal trial monitoring will be conducted at least annually and in accordance with 
the Cancer Consortium Institutional Data and Safety Monitoring Plan, and 
FHCRC/UW Cancer Consortium Guidelines for Conducting Multi-Center Trials 
where FHCRC/UW serves as the Coordinating Center.  Monitoring visits occur at 
specified intervals determined by the assessed risk level of the study and the 
findings of the previous visits. The purpose of the monitoring visits is to verify the 
accuracy of the study data, assess compliance with the protocol and with Good 
Clinical Practice (GCP) regulations, and assure the timely and complete reporting 
of safety (adverse event) data.  To assure protocol compliance and data 
consistency, the medical records for all patients enrolled to the study will be 
submitted to the Coordinating Center for review, data abstraction and protocol 
monitoring.   
 
Depending on the source of the participant’s registration, the monitoring activities 
will be carried out by: 
 
 For registrations from the Seattle Cancer Care Alliance (SCCA), monitoring 
will be performed by staff of the Research Support Office (RSO) or by 
external contractors engaged by the RSO. 
 For registrations from SCCA Network sites or other Northwest sites managed 
through the SCCA Network Office, monitoring will be performed by staff of the 
SCCA Network or by contractors engaged by the SCCA Network. 
 
Each monitor will be qualified by experience and training to perform these 
services.  
 


61 
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65 
18.0 
APPENDICES 
 
 
18.1 
NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES CHF Guidelines 
 
18.2 
UPC Ratio 
 
18.3 
CYP3A4 Inhibitors 
 
 


66 
18.1 
NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES CHF Guidelines 
 
In order to determine the best course of of therapy, physicians often assess the stage of heart 
failure according to the New York Heart Association (NYHA) functional classification system. 
This system relates symptoms to everyday activities and the patient's quality of life. 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased. 


67 
18.2 
UPC Ratio 
 
Procedure for Obtaining a Urine Protein / Creatinine Ratio  
 
1)  Obtain at least 4 ml of a random urine sample (does not have to be a 24-hour urine) 
  
2)  Determine protein concentration (mg/dL) 
 
3)  Determine creatinine concentration (mg/dL) 
 
4)  Divide #2 by #3 above:  urine protein / creatinine ratio = protein concentration (mg 
/dL) / creatinine concentration (mg /dL) 
 
The UPC directly correlates with the amount of protein excreted in the urine per 24 hrs 
(i.e. a UPC of 1 should be equivalent to 1g protein in a 24hr urine collection) 
 
Protein and creatinine concentrations should be available on standard reports of 
urinalyses, not dipsticks. If protein and creatinine concentrations are not routinely 
reported at an Institution, their measurements and reports may need to be requested. 
 
 


68 
18.3 
CYP3A4 Inhibitors and Inducers 
 
 
The following are known inhibitors of CYP3A4: 
Delaviridine 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir  
Amiodarone  
Cimetidine  
Ciprofloxacin  
Clarithromycin  
Diethyl-dithiocarbamate  
Diltiazem  
Erythromycin  
Fluconazole  
Fluvoxamine  
Gestodene ++  
Grapefruit juice  
Itraconazole  
Ketoconazole  
Mifepristone  
Nefazodone  
Norfloxacin  
Norfluoxetine  
Mibefradil  
Troleandomycin 
Atazanavir 
Indinavir 
Telithromycin 
Voriconazole 
The following are known inducers of CYP3A4: 
Rifampicin 
Phenytoin 
Rifabutin 
Rifapentine 
Carbamazepine 
Phenobarbital 
St. John’s Wort