Clinical trial NCT01620190
Conditions: Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer
Sponsor: University of Washington
Start date: 2012-12-02; Completion date: 2019-04-29
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study examines the use of Abraxane (paclitaxel albumin-stabilized nanoparticle formulation) in patients with lung cancer. Abraxane is a chemotherapy approved to treat patients with breast cancer. Doctors want to know if Abraxane is safe and effective in treating patients with lung cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) and epidermal growth factor receptor (EGFR) mutations.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the overall response rate of weekly nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) in patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations following front-line therapy with EGFR tyrosine kinase inhibitors (TKI).

SECONDARY OBJECTIVES:

I. To evaluate the safety profile of weekly nab-paclitaxel in patients with advanced NSCLC with EGFR mutations following front-line therapy with an EGFR TKI.

II. To evaluate the time-to-progression and overall survival.

OUTLINE:

Patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks and then every 3 months thereafter.

Arms: arm 1: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Paclitaxel Albumin-Stabilized Nanoparticle Formulation
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase II study of weekly Abraxane for patients with advanced NSCLC with EGFR mutations or with 
durable response to an EGFR tyrosine kinase inhibitor following front line therapy with 
EGFR tyrosine kinase inhibitors. 
Principal Investigator: 
Christina Baik, MD, MPH 
Co-investigators: 
Laura Chow, MD 
Bernardo Goulart, MD 
Renato G. Martins, MD, MPH 
Cristina Rodriguez, MD 
Sylvia Lee, MD 
Seattle Cancer Care Alliance Network Office 
825 Eastlake Avenue East, LG-200 
Seattle, WA 98109-1023 
Phone: (206) 288-7232 or (888) 201-0060 
Fax: (206) 288-1310 
sccanetresearch@seattlecca.org 
FHCRC IRB Approval  
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Table of contents 
LIST OF ABBREVIATIONS……………………………………………………………….. 4 
STUDY SCHEMA …………………………………………………………………………...5 
PROTOCOL 
1.
OBJECTIVES
1.1 
Primary……………………………………………………………………….      6 
1.2 
Secondary…………………………………………………………………….      6 
2.
BACKGROUND AND RATIONALE
2.1 
Concept Summary…………………………………………………………… 6 
2.2 
NSCLC with EGFR mutations………………………………………………. 6 
2.3 
Systemic chemotherapy in patients with EGFR mutation positive NSCLC… 7 
2.3.1 Taxane based chemotherapy in patients EGFR mutation positive 
NSCLC………………………………………………………………. 7 
2.4 
ABRAXANE® in advanced NSCLC………………………………………... 7 
2.4.1 Monotherapy………………………………………………………….   7 
2.4.2 Combination therapy…………………………………………………. 8 
2.5 
SPARC, a potential predictive marker of nab-paclitaxel therapy……………. 8 
3.
DRUG INFORMATION, ABRAXANE® (NAB-PACLITAXEL)
3.1 
Description…………………………………………………………………… 9 
3.2 
Mechanism of action…………………………………………………………. 9 
3.3 
Preclinical studies with ABRAXANE® ……………………………………… 9 
3.4 
Toxicology…………………………………………………………………….      10 
3.5 
Study drug administration……………………………..……………………….12 
3.6 
Storage and handling of study drug……………………………………………14 
3.7 
Study drug distribution…………………………………………………………15 
3.8 
Study drug return and destruction………………………………………………15 
4.
PATIENT SELETION
4.1 
Inclusion criteria……………………………………………………………….. 15 
4.2 
Exclusion criteria……………………………………………………………. .... 16 
5.
STUDY TREATMENT PLAN
5.1 
Administration schedule of nab-paclitaxel……………………………………. 17 
5.2 
Nab-paclitaxel premedications…………………………………………………17 
5.3   Dose modifications……………………………………………………………..18 
5.4     Concomitant therapy……………………………………………………………20 
5.5 
Discontinuation of study treatment……………………………………………..20 
5.6 
Treatment      compliance…………………………………………………………..21 
6.
CLINICAL AND LABORATORY ASSESSMENT
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6.1 
Screening      assessment……………………………………………………………21 
6.2 
Assessments, treatment period…………………………………………………..22 
6.3 
Assessments, post-treatment period……………………………………………..22 
7.
EFFICACY ASSESSMENTS
7.1 
Screening evaluation……………………………………………………………. 23 
7.2 
Efficacy evaluations, treatment period…………………………………………. 23 
7.3 
Efficacy evaluations, post-treatment period……………………………………. 24 
7.4 
Definitions………………………………………………………………………      24 
7.5 
Baseline documentation of tumor burden………………………………………. 24 
7.6 
Response      criteria…………………………………………………………………24 
8.
SAFETY ASSESSSMENTS AND ADVERSE EVENT REPORTING ……………… 25 
8.1  Adverse events…………………………………………………………………  25 
8.2      Serious adverse events…………………………………………………………  26 
8.3 
Reporting a serious adverse event……………………………………………...  26 
9.
SPONSOR AND INVESTIGATOR REQUIREMENTS ……………………………..   27 
9.1 
Study initiations………………………………………………………………..  27 
10.
STATISTICAL CONSIDERATIONS
10.1 
Study endpoints 
10.1.1 Primary endpoint: overall response rate………………………………. . 27 
10.1.2 Secondary endpoints: time to progression, overall survival, 
toxicity and correlative tissue study ………………………………….. 
27 
10.2 
Study design …………………………………………………………………… 28 
10.3 
Sample size determination and data analysis …...……………………………. 
28 
10.4 
Exploratory analysis …………………………………………………………...  28 
APPENDIX 1: ECOG Performance Status ……………………………………………………. 29 
APPENDIX 2: Study Calendar …………………………………………………………...…… 30 
APPENDIX 3: Correlative Tissue analysis …………………………………………………… 31 
REFERENCES ….………………………………………………………………………….    32 
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List of Abbreviations 
 
AE 
adverse event 
AUC 
area under curve 
BSA 
body surface area 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events, version 4.0 
EGFR 
epidermal growth factor receptor 
IRB 
Institutional Review Board 
mg 
milligram 
mL 
milliliter 
MTD 
maximum tolerated dose 
Nab-paclitaxel 
nanoparticle albumin-bound paclitaxel 
NSCLC 
non-small-cell lung cancer 
PR 
partial response 
RR 
response rate 
SAE 
serious adverse event 
SOP 
standard operating procedure 
SPARC 
secreted protein acidic and rich in cysteine 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
 
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Study Schema 
 
 
Study synopsis: 
This is a phase II trial of weekly nab-paclitaxel 125mg/m2 in patients with advanced EGFR 
mutation positive NSCLC after front line therapy with an EGFR tyrosine kinase inhibitor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue treatment until disease progression 
Disease assessment with CT scans after every 2 cycles 
Nab-paclitaxel 125mg/m2 
Treatment days #1, 8, 15 
28 day cycle 
Screening 
Stage IV or recurrent EGFR mutation positive NSCLC 
Progressive disease on first line EGFR tyrosine kinase inhibitor 
Sample size = 29 
 
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1.
OBJECTIVES
1.1 
Primary 
To evaluate the overall response rate of weekly nab-paclitaxel in patients with advanced non- 
small cell lung  cancer (NSCLC) with epidermal growth factor receptor (EGFR)  mutations 
following front-line therapy with EGFR tyrosine kinase inhibitors (TKI). 
1.2 
Secondary 
To evaluate the safety profile of weekly nab-paclitaxel in patients with advanced NSCLC with 
EGFR mutations following front-line therapy with an EGFR TKI. 
To evaluate the time-to-progression and overall survival. 
2.
BACKGROUND AND RATIONALE
2.1 
Concept Summary 
Patients with EGFR mutation positive NSCLC represent approximately 10-15% of advanced 
NSCLC and show remarkable sensitivity to EGFR tyrosine kinase inhibitors such as erlotinib 
and gefitinib. However, most patients experience disease progression after approximately one 
year and will require second-line therapy. There is evidence indicating that these patients may 
be particularly sensitive to taxane-based therapies. This study will evaluate the clinical efficacy 
of single agent nab-paclitaxel in a cohort of patients with EGFR mutation positive NSCLC who 
have experienced disease progression during front-line therapy with an EGFR TKI. 
2.2 
NSCLC with EGFR mutations 
NSCLC with EGFR mutations is a well described molecular subgroup of lung cancer which is 
remarkably sensitive to EGFR TKIs. The initial experience with these drugs identified favorable 
outcomes in patients with adenocarcinoma histology, Asian ethnicity, female sex and never 
smokers. Later investigations demonstrated that these populations are enriched for EGFR 
mutated NSCLC, and that the presence of an activating EGFR mutation was highly predictive of 
response to EGFR TKIs [Pao, Rosell]. The most common mutations are exon 19 deletion and a 
leucine-to-arginine substitution at position 858 in exon 21 (L858R) and these comprise 
approximately 90% of the mutations [Rosell]. However, despite the sensitivity of these tumors 
to EGFR TKIs, most patients experience disease progression after a median of 10 to 14 months 
of therapy [Oxnard]. For these patients, no standard therapy exists and research is ongoing to 
identify effective therapeutic options for second line therapy. 
2.3 
Systemic chemotherapy in patients with EGFR mutation positive NSCLC 
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Chemotherapy has clearly been shown to be inferior to EGFR TKIs in EGFR mutation positive 
NSCLC in first line metastatic patients in both response rate and progression free survival; 
however, it also has been observed that these tumors do exhibit significant response to 
chemotherapy. In the Iressa Pan-Asia study (IPASS), a  phase III trial of  gefitinib versus 
carboplatin/paclitaxel in advanced NSCLC in a population composed of never- or light former 
smokers, gefitinib was superior to chemotherapy, but patients treated with chemotherapy did 
exhibit a significant response rate (RR) of 32% and when stratified by mutational status, a RR of 
47% was observed among EGFR mutant tumors [Mok]. Other phase III trials of EGFR mutant 
NSCLC have shown RR ranging from 10.5% to 36% in the chemotherapy arm [Maemondo, 
Rosell, Zhou]. These studies indicate that while EGFR TKIs are clearly superior in the first line 
setting, chemotherapy will likely be beneficial in patients who relapse after TKI treatment. 
 
2.3.1 Taxane-based chemotherapy in patients with EGFR mutation positive NSCLC 
 
While EGFR mutation positive NSCLC does exhibit response to cytotoxic chemotherapy, there 
is no specific regimen that has been shown to be superior in this patient population. However, 
there is evidence indicating that these patients may be particularly sensitive to taxane-based 
therapies. In a retrospective analysis of patients with advanced NSCLC who initially 
experienced disease control  with  EGFR  TKIs  and  subsequently  received  second  line 
chemotherapy for disease progression, taxane-based chemotherapy was associated with higher 
response rate (48% vs. 21%), progression free survival (7 vs. 1.8 months) and overall survival 
(12.6 months vs. 5.1 months) compared to non-taxane based regimens [Kuo]. 
 
2.4 
ABRAXANE® in advanced NSCLC 
 
ABRAXANE® is a solvent-free, albumin-bound form of paclitaxel which is currently indicated 
for the treatment of breast cancer after failure of combination chemotherapy for metastatic 
disease or relapse within 6 months of adjuvant chemotherapy. It also has shown clinical efficacy 
as first-line therapy for NSCLC, both as mono- and combination therapy and its use in the 
treatment of other malignancies is under investigation. 
 
2.4.1 Monotherapy 
 
The efficacy of weekly nab-paclitaxel monotherapy was shown in a phase II study which 
assessed first-line nab-paclitaxel 125mg/m2 weekly given on days 1, 8 and 15 of a 28-day cycle 
in 40 patients with advanced NSCLC. After a median of 4 cycles, the study resulted in an 
overall response rate of 30%, time to progression of 5 months and overall survival of 11 months. 
This study excluded patients who had received previous chemotherapy for advanced disease; 
however, it did allow patients who were previously treated with EGFR TKIs who comprised 
13% of the participants [Rizvi]. 
 
Another study investigated the efficacy of nab-paclitaxel 260mg/m2 given every 3 weeks as 
first-line therapy to 43 patients with advanced NSCLC. After a median of 6 cycles, the response 
rate was 16%, the median time to progression was 6 months and overall survival was 11 months 
[Green].   The most frequently reported Grade 3 and 4 adverse events in these trials were 
 
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neutropenia, peripheral neuropathy and fatigue. No  severe  hypersensitivity  reactions  were 
observed in these trials without corticosteroid premedication. Above studies demonstrate that 
nab-paclitaxel as monotherapy is a promising strategy in advanced NSCLC. 
2.4.2 Combination therapy 
Weekly nab-paclitaxel has also been investigated in combination with carboplatin in both phase 
II and III settings. In a phase II study, 56 patients with advanced NSCLC received weekly nab- 
paclitaxel 100mg/m2 on days 1, 8 and 15 of a 28-day cycle in combination with carboplatin area 
under the curve (AUC) 6 on day 1 of each cycle. Among the 50 evaluable patients, an overall 
response rate of 50% and a median time to progression of 28 weeks was reported [Allerton]. 
In a subsequent phase III study, weekly nab-paclitaxel 100mg/m2 in combination with 
carboplatin AUC 6 was compared with solvent-based paclitaxel 200mg/m2 and carboplatin 
every 3 weeks in 1,052 patients with advanced NSCLC. After a median of 6 cycles, there was 
significantly improved overall response rate in nab-paclitaxel arm with a response rate of 33% 
by independent review compared to 25% in the solvent-based paclitaxel arm. Interestingly, the 
response rate was particularly higher with nab-paclitaxel in the squamous cell histology (41% vs. 
24%). In the final analysis of the study, there was no difference in median progression free 
survival (6.3 months vs. 5.8 months) or overall survival (12.1 months vs. 11.2 months) between 
the two arms [Socinski]. Grade 3 and 4 anemia and thrombocytopenia were more frequent in the 
nab-paclitaxel arm while neutropenia and peripheral neuropathy were more frequent in the 
solvent based paclitaxel arm. The above study shows that nab-paclitaxel is as effective, if not 
superior, to solvent based paclitaxel and is a promising chemotherapeutic agent that warrants 
further investigation in the patient population with EGFR mutation positive NSCLC. 
2.5 
SPARC, a potential predictive marker of nab-paclitaxel therapy 
SPARC (a secreted protein, acidic and rich in  cysteine, also known as osteonectin) is an 
extracellular matrix glycoprotein which has shown to be overexpressed in many different tumors 
including breast, head and neck, and lung cancers, and its overexpression has been associated 
with poor prognosis. This protein can be produced by the tumor or the neighboring stroma. 
SPARC can bind albumin with high affinity and studies have shown that SPARC may play a role 
in concentrating albumin in the areas near a tumor [Gradishar]. Given these observations, 
several studies have investigated the role of SPARC as a predictive tumor marker of nab- 
paclitaxel response with the hypothesis that tumor-secreted SPARC could facilitate the 
accumulation of albumin in the tumor and therefore increase the effectiveness of nab-paclitaxel. 
For instance, a retrospective analysis of nab-paclitaxel monotherapy in head and neck cancers 
showed that the response to nab-paclitaxel was higher in patients whose tumors were SPARC- 
positive by immunohistochemistry compared to SPARC-negative tumors with response rates of 
83% vs. 25%, respectively [Desai 2009]. In another study of metastatic pancreatic 
adenocarcinoma, previously untreated patients were treated with nab-paclitaxel followed by 
gemcitabine and their tumors were evaluated for SPARC status by immunohistochemistry. In 
this study, the high-SPARC group resulted in higher overall survival when compared to the low- 
SPARC group with median survival of 17.8 vs. 8.1 months, respectively. Interestingly, stromal 
SPARC was significantly correlated with overall survival but not tumoral SPARC [Von Hoff]. 
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In lung cancer, the role of SPARC was assessed in a preclinical study of human NSCLC cell 
lines and patient-derived NSCLC tumor xenografts. This study showed that nab-paclitaxel 
resulted in anti-tumor efficacy, however, this was not associated with SPARC expression by 
mRNA and gene methylation [Shao]. Above studies demonstrate that SPARC protein 
expression by immunohistochemistry is a potential predictive biomarker of nab-paclitaxel 
therapy and warrants further investigation. 
 
 
3. 
DRUG INFORMATION, ABRAXANE® (NAB-PACLITAXEL) 
 
3.1 
Description 
 
ABRAXANE® for Injectable Suspension (also known as ABI-007, nab-paclitaxel, paclitaxel 
protein-bound particles for injectable suspension) is an albumin-bound form of paclitaxel with a 
mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a non- 
crystalline, amorphous state. ABRAXANE is supplied as a white to yellow, sterile, lyophilized 
powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to 
intravenous infusion. Each single-use vial contains 100 mg of paclitaxel and approximately 900 
mg of human albumin. Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. 
ABRAXANE is free of solvents.  The active agent in ABRAXANE is paclitaxel. 
 
 
3.2 
Mechanism of action 
 
ABRAXANE is a 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 concentrations of the drug by a receptor-mediated transport process 
allowing transcytosis across the endothelial cell. This albumin-specific receptor mediated 
process involves the binding of albumin to a specific receptor (gp60) on the intralumminal 
endothelial cell membrane, resulting in activation of a protein (caveolin-1), which initiates an 
internalization process in the endothelial cell through the formation of caveolae, with transport 
of the intact albumin-bound chemotherapeutic complex via these caveolae to the underlying 
tumor interstitium [Desai 2004]. A protein specifically secreted by the tumor (SPARC) binds 
albumin, allowing release of the hydrophobic drug to the tumor cell membrane [Desai 2004]. 
ABRAXANE is the first biologically interactive nanoparticle product leveraging this gp- 
60/caveolin-1/caveolae/SPARC pathway to increase intra-tumoral concentration of the drug and 
reducing toxic effects in normal tissue. 
 
3.3 
Preclinical studies with ABRAXANE 
 
Preclinical studies comparing nab-paclitaxel to Taxol® (paclitaxel Cremophor® EL solvent-based, 
BMS) demonstrated lower toxicities, with an 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 paclitaxel, 
nab-paclitaxel treated groups showed more complete regressions, longer time to recurrence, 
longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the 
 
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curve was 33% higher for nab-paclitaxel versus solvent based paclitaxel, indicating more 
effective intratumoral accumulation of nab-paclitaxel [Desai 2006]. 
3.4 
Toxicology 
Myelosuppression, nausea and vomiting, diarrhea, mucositis, infections, hypotension, abnormal 
ECG changes, cough, dyspnea, edema, peripheral neuropathy, bilirubin/liver enzyme elevations, 
allergic reactions, alopecia, asthenia, arthralgia, and myalgia. During post marketing 
surveillance, rare cases of severe hypersensitivity reactions have occurred. 
a 
Table 1: Frequency of Important Treatment Emergent Adverse Events in 
the Randomized Study on an Q3W Schedule 
Percent of Patients 
ABRAXANE 
b 
260/30min 
(n=229) 
Paclitaxel Injection 
c,d 
175/3h 
(n=225) 
Bone Marrow 
Neutropenia 
80 
82 
9 
< 2.0 x 10 /L 
9 
22 
9 
< 0.5 x 10 /L
Thrombocytopenia 
9 
< 100 x 10 /L 
9 
< 50 x 10 /L 
2 
<1 
3 
<1 
Anemia 
33 
25 
< 11 g/dL 
1 
<1 
< 8 g/dL 
Infections 
24 
20 
Febrile Neutropenia 
2 
1 
Bleeding 
2 
2 
e
Hypersensitivity Reaction 
All 
4 
12 
f 
Severe 
0 
2 
Cardiovascular 
g 
Vital Sign Changes 
Bradycardia 
<1 
<1 
Hypotension 
5 
5 
Severe Cardiovascular 
f 
Events 
3 
4 
Abnormal ECG 
All patients 
60 
52 
Patients with Normal 
35 
30 
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Baseline 
Respiratory 
Cough 
7 
6 
Dyspnea 
12 
9 
Peripheral Neuropathy 
Any Symptoms 
71 
56 
f
Severe Symptoms 
10 
2 
Myalgia / Arthralgia 
Any Symptoms 
44 
49 
f
Severe Symptoms 
8 
4 
Asthenia 
Any Symptoms 
47 
39 
f
Severe Symptoms 
8 
3 
Fluid Retention/Edema 
Any Symptoms 
10 
8 
f
Severe Symptoms 
0 
<1 
Gastrointestinal 
Nausea 
Any symptoms 
30 
22 
f 
Severe symptoms 
3 
<1 
Vomiting 
Any symptoms 
18 
10 
f
Severe Symptoms 
4 
1 
Diarrhea 
Any Symptoms 
27 
15 
f
Severe Symptoms 
<1 
1 
Mucositis 
Any Symptoms 
7 
6 
f
Severe Symptoms 
<1 
0 
Alopecia 
90 
94 
Hepatic (Patients with Normal Baseline) 
Bilirubin Elevations 
7 
7 
Alkaline Phosphatase 
Elevations 
36 
31 
AST (SGOT) Elevations 
39 
32 
Injection Site Reaction 
<1 
1 
a 
Based on worst grade 
b 
2 
ABRAXANE dose in mg/m /duration in minutes 
c 
2 
paclitaxel injection dose in mg/m /duration in hours 
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d 
paclitaxel injection pts received premedication 
e 
Includes treatment-related events related to hypersensitivity (e.g., flushing, 
dyspnea, chest pain, hypotension) that 
began on a day of dosing. 
f 
Severe events are defined as at least grade 3 toxicity 
g 
During study drug dosing. 
 
3.5 
Study drug administration 
 
ABRAXANE will be supplied by Celgene. ABRAXANE is a solvent-free, protein-bound 
particle form of paclitaxel injection with a mean particle size of approximately 130 nanometers. 
ABRAXANE is supplied as a white-to-yellow, sterile, lyophilized cake containing 100 mg of 
paclitaxel and approximately 900mg (800 mg theoretical) of human albumin solution as a 
stabilizer in a 50-mL vial. Each vial of the lyophilized product is reconstituted with 20 mL of 
0.9% Sodium Chloride Injection (USP) to create a suspension. Each mL of reconstituted 
suspension contains 5 mg of paclitaxel. 
 
Vials of ABRAXANE provided for clinical trials are labeled according to country-specific 
regulatory requirements for labeling of investigational products. ABRAXANE contains 
paclitaxel, a taxane with the Anatomical Therapeutic Chemical (ATC) code L01C D01. 
 
Preparation for intravenous administration 
At any given dose of paclitaxel in mg/m2, the total mg of paclitaxel to be administered should be 
calculated by the physician, using the height/weight conversion chart or other standard method 
for calculation of the patient’s body surface area (BSA). 
Reconstitution 
ABRAXANE is supplied as a sterile, lyophilized powder for reconstitution before use. To avoid 
errors, read preparation instructions prior to reconstitution. 
 
1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% sodium chloride injection. 
 
2. Slowly inject the 20 mL of 0.9% sodium chloride injection over a minimum of 1 minute, using 
the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL. 
 
3. DO NOT INJECT the 0.9% sodium chloride injection directly onto the lyophilized cake as 
this will result in foaming. 
 
4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure 
proper wetting of the lyophilized cake/powder. 
 
5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of 
any cake/powder occurs. Avoid generation of foam. 
 
6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. 
 
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Administration 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration whenever the solution and container permit. The reconstituted sample 
should be milky and homogenous, without visible particulates. If particulates are visible or 
settling occurs, the vial should be gently inverted to ensure complete resuspension before use. 
Discard the reconstituted suspension if precipitates are observed. Discard any unused portion. 
 
Each vial of the reconstituted formulation will contain 5 mg of paclitaxel per mL. The exact total 
dosing volume of 5 mg/mL suspension required for the patient is calculated using this formula: 
 
Dosing volume (mL) = Total dose (mg) / 5 (mg/mL) 
 
The appropriate amount of reconstituted ABRAXANE is injected into an empty, sterile, PVC- or 
non−PVC-type IV bag. The use of an in-line filter is not recommended. 
 
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for 
possible infiltration during drug administration. Limiting the infusion of ABRAXANE to 30 
minutes (or as directed according to the protocol) reduces the likelihood of infusion-related 
reactions. No premedication to prevent solvent-related HSRs is required with ABRAXANE. 
 
ABRAXANE should be administered under the supervision of a physician experienced in the use 
of chemotherapeutic agents. Appropriate management of complications is possible only when 
adequate diagnostic and treatment facilities are readily available. 
 
Because of the possibility of myelosuppression with ABRAXANE and the exclusion of patients 
with a baseline neutrophil count < 1,500 cells/mm3 or a platelet count < 100,000 cells/mm3 from 
the Phase III trial, ABRAXANE should not be administered to such patients. Blood cell counts 
should be monitored weekly during ABRAXANE therapy. For patients being treated on  
protocols using weekly dosing schedules, investigators should consult the requirements in the 
study-specific protocol concerning dose modifications and withholding treatment. 
 
In addition, patients who experience severe neutropenia (neutrophil count <500 cells/mm3 for ≥  
1 week) or severe peripheral neuropathy during ABRAXANE therapy should have their dosage 
reduced for subsequent courses of ABRAXANE. For recurrence of severe episodes of either AE, 
the dosage should be further reduced. For grade 3 peripheral neuropathy, treatment should be 
withheld until resolution to grade 1 and then reduced for all subsequent courses of ABRAXANE 
therapy. In addition, investigators should consult the requirements in the study-specific protocol 
for dose reductions and withholding treatment. 
 
An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to 
those of drug in solution. Do not substitute for or with other paclitaxel formulations. 
 
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3.6 
Storage and handling of study drug 
 
ABRAXANE is a cytotoxic anticancer drug and, as with other potentially toxic paclitaxel 
compounds, caution should be exercised in handling ABRAXANE. The use of gloves is 
recommended. 
 
Procedures for proper handling and disposal of anticancer drugs should be followed. Several 
guidelines on this subject are available [Clinical Oncological Society of Australia, Jones, 
American Medical Association, American Society of Hospital Pharmacists, Occupational Safety 
and Health Administration, Jeffrey]. There is no general agreement that all of the procedures 
recommended in these guidelines are necessary or appropriate. However, according to the Active 
Pharmaceutical Ingredient manufacturer’s safety data for paclitaxel, the product should not be 
released into the environment despite the fact that it is a natural, biodegradable product. It is 
recommended that the material be recovered, if possible, and incinerated under controlled 
conditions in compliance with the local and national regulations currently in force. 
 
No reports of accidental exposure to ABRAXANE have been received; however, tingling, 
burning, and redness have been reported after topical exposure to Cremophor-based paclitaxel. If 
ABRAXANE (lyophilized cake or reconstituted suspension) comes in contact with the skin, the 
skin should be washed immediately and thoroughly with soap and water. Dyspnea, chest pain, 
burning eyes, sore throat, and nausea have been reported after inhalation of solvent-based 
paclitaxel. If ABRAXANE comes in contact with mucous membranes, the membranes should be 
flushed thoroughly with water. 
 
Unopened vials of ABRAXANE are stable until the date indicated on the package when stored in 
the original cartons at USP Controlled Room Temperature (25ºC [77ºF], excursions permitted 
between 15°-30°C [59°-86°F]), or as specified on the vial label and as per the country 
requirements. 
 
Stability of reconstituted suspension in the vial 
From a microbiological point of view, the reconstituted suspension in the vial should be filled 
into an infusion bag immediately. If not filled immediately, storage times and conditions are the 
responsibility of the user and should not normally be longer than 8 hours at 2−8°C (36−46°F). If 
not used immediately, each vial of reconstituted suspension should be replaced in the original 
carton to protect it from bright light. 
 
Stability of the reconstituted suspension in the infusion bag 
From a microbiological point of view, the reconstituted suspension in the infusion bag should be 
used immediately. If not used immediately, in-use storage times and conditions prior to 
administration are the responsibility of the user and should not normally be longer than 8 hours 
at ambient temperature (approximately 25°C [77°F]) and lighting conditions. 
 
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3.7 
Study drug distribution 
 
ABRAXANE® will be distributed by Celgene Corporation. No supplies will be shipped to any 
site until regulatory approval has been obtained. Investigational sites will be supplied with 
ABRAXANE® upon identification and screening of a potential trial subject. 
 
Upon identification of a potential subject, sites must fax a completed Drug Request Form to 
Celgene Corporation. Allow at least 5 working days for drug shipment. There are no shipments 
on Fridays or holidays. 
 
For re-supply of drug, please complete and fax the Drug Request Form to Celgene Corporationat 
908-673-2779. 
 
3.8 
Study drug return and destruction 
 
If the investigational site does not have a policy, procedure or SOP detailing the process to 
follow for study drug destruction, the study drug must then be returned to Celgene using the 
Drug Return Form provided in the package containing the study drug. The following 
information must be recorded on the site’s pharmacy drug accountability log: quantity of vials to 
be returned, expiration date and lot number. A copy of the Drug Return Form and the study drug 
should be returned to Celgene Clinical Supplies Dept. using the mailing address on the 
packaging slip that came with the original study drug order. A copy of the Drug Return Form 
should be retained at the clinical site. In the event of study completion or termination, a copy of 
all pharmacy records (drug dispensing log, drug accountability log and any destruction memos) 
must be mailed to Celgene Medical Operations. 
 
If the investigational site has a policy, procedure or SOP detailing the process to follow for study 
drug destruction, the pharmacist or designee can choose to destroy the study drug on site. The 
following information must be recorded on the site’s pharmacy drug accountability log: quantity 
of vials destroyed, expiration date and lot number. The pharmacist must document that the study 
drug was destroyed in accordance with their institution’s drug destruction policy or SOP. A drug 
destruction memo and the site’s drug destruction SOP/policy should be sent to Celgene Medical 
Operations Dept. A copy of the drug destruction memo should be retained at the clinical site. In 
the event of study completion or termination, a copy of all pharmacy records (drug dispensing 
log, drug accountability log and any destruction memos) must be mailed to Celgene Medical 
Operations. 
 
 
4. 
PATIENT SELECTION 
 
4.1 
Inclusion criteria 
 
Patients are eligible to be included in the study only if they meet all of the following criteria: 
 
• Age > 18 years 
 
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• Pathologically confirmed non-small cell lung cancer with documented EGFR mutation in 
tumor DNA or complete / partial response to first line EGFR tyrosine kinase inhibitors with 
> or = to 6 months duration of response in patients who do not have a confirmed EGFR 
mutation 
• At least one site of measurable disease as determined by the Investigator, using RECIST 1.1 
criteria 
• Progressive disease with radiographic evidence of disease progression per investigator 
assessment during therapy with an EGFR tyrosine kinase inhibitor in the metastatic setting. 
Patients may continue EGFR inhibitor therapy throughout the screening period until the day 
prior to nab-paclitaxel treatment initiation 
• ECOG performance status 0, 1 or 2 at the time of informed consent (Appendix 1) 
• Adequate renal, hepatic, hematologic function: 
o Platelet count >100,000/uL 
o Absolute neutrophil count >1,500/uL 
o Hemoglobin >9g/dL 
o AST and ALT <2.5 times upper limit of normal 
o Alkaline phosphatase <2.5 times upper limit of normal, unless bone 
metastasis is present in the absence of liver metastasis 
o Bilirubin <1.5mg/dL 
o Creatinine <1.5mg/dL 
• Women of child-bearing potential (WOCP) and sexually active men must agree to use 
adequate contraception (hormonal or barrier method of birth control or abstinence) prior to 
study entry, during treatment and for three months after completing treatment 
• Negative serum or urine β-hCG pregnancy test at screening for patients of childbearing 
potential 
• Life expectancy of > 12 weeks. 
• Signed and dated informed consent document indicating that the patient has been informed of 
all the pertinent aspects of the trial prior to enrollment. 
 
4.2 
Exclusion criteria 
 
• Prior conventional cytotoxic chemotherapy for metastatic or recurrent disease. Prior adjuvant, 
neoadjuvant or chemoradiotherapy for NSCLC is permitted, provided at least 6 months 
elapsed prior to documented metastatic recurrence. 
• A single dose of a platinum doublet discontinued due to intolerability without evidence of 
disease progression is permitted. 
 
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• Patient is < 5 years free of another primary malignancy, except: a) if the other malignancy is 
basal cell carcinoma or cervical carcinoma in situ or b) if the other primary malignancy is not 
considered clinically significant and is requiring no active intervention 
 
• Progressive or symptomatic CNS metastases. Patients with known brain metastasis must 
have stable disease following treatment with surgery, radiation or both. In addition, they 
must be off corticosteroids. 
• Radiotherapy within 7 days of study treatment 
• Peripheral neuropathy grade 2 or greater 
• Grade III/IV congestive heart failure, as defined by NYHA criteria or myocardial infarction 
within 6 months. 
 
• Any serious or uncontrolled concomitant disorder that, in the opinion of the investigator, 
would compromise the patient’s ability to complete the study. 
 
• Patient has known chronic liver disease, e.g. diagnosis of chronic active hepatitis or cirrhosis. 
 
• Major surgery within 21 days of study treatment. Minor surgery within 2 weeks of study 
treatment. Placement of vascular access device and biopsies allowed and is not considered 
major or minor surgery. 
 
• Patient with any significant history of non-compliance to medical regimens or with inability 
to grant reliable informed consent 
 
• Pregnant or breast feeding females 
 
 
5. 
STUDY TREATMENT PLAN 
 
Patients enrolled on study will be treated with weekly nab-paclitaxel until disease progression or 
intolerance of treatment. Nab-paclitaxel will be administered in the infusion center of the 
treating physician. 
 
5.1 
Administration of schedule of nab-paclitaxel 
 
A treatment cycle is defined as one 28-day period and includes three weekly doses of 
intravenous nab-paclitaxel, administered on days 1, 8 and 15. Each nab-paclitaxel dose will be 
calculated based upon patient’s body surface area (BSA), with maximum body surface area 
capped at 2.0m2. Each nab-paclitaxel dose is 125mg/m2, and will be infused over 30 minutes, or 
per standard pharmacy protocol. Total dose of nab-paclitaxel will be calculated by BSA 
determination on the first day of each cycle, using actual weight. A delay of cycle as a result of 
holidays, weekends, bad weather, or other unavoidable circumstances will be permitted and not 
counted as a protocol violation. 
 
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5.2 
Nab-paclitaxel premedications 
 
Patients do not require premedication prior to ABRAXANE administration, as hypersensitivity 
reactions are rare. 
 
Although the solubilizing agents Cremophor® EL and Tween® 80 have long been implicated in 
adverse events including hypersensitivity reactions due to their detergent-like nature and known 
ability to induce histamine release [Ten Tije], the administration of solvent-based  taxanes 
(Taxol and Taxotere) requires premedication with corticosteroids and histamine receptor 
blocking agents to prevent the occurrence of hypersensitivity reactions. However, the 
hypersensitizing role of the taxane molecules themselves cannot be ruled out. 
 
In the unlikely event of a mild hypersensitivity reaction, premedication for subsequent doses 
may be administered using the premedication regimen the institution typically uses for solvent 
based paclitaxel. 
 
In the rare event of a severe hypersensitivity reaction, discontinue ABRAXANE. 
 
5.3 
Dose modifications 
 
Administration of Study Drug to Patients with Abnormal Hematologic Function 
ABRAXANE dosing should not be administered at the start of each cycle until the absolute 
neutrophil count (ANC) returns to ≥1.0 x 109 cells/L and the platelet count returns to >100 x 109 
cells/L. For patients receiving weekly ABRAXANE, for each subsequent dose of ABRAXANE 
within a cycle (Days 8 and 15), patients must have an ANC ≥ 1.0 x 109 cells/L and platelets > 75 
x 109 cells/L. 
o If the ANC and platelets are not adequate for treatment on Day 8 and/or 15, the dose 
will be omitted and the total cycle length remains the same. 
o If the ANC and platelets are not adequate for treatment on Day 15 the dose will be 
omitted and a new treatment cycle will commence the following week, as long as the 
ANC count has returned to ≥1.0 x 109 cells/L and the platelet count has returned to 
>100 x 109 cells/L. 
Administration of Study Drug to Patients with Abnormal Hepatic Function 
Study drug should only be administered if hepatic function is within the parameters established 
in the eligibility criteria. 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. 
 
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Dose Modification Table 
Use this table as a guideline to determine any necessary dose modifications. The modification is 
dependent on the starting dose for the study. 
 
Table 2:  Dose Modification 
Dose Level 
ABRAXANE 
(mg/m2) 
0 
125 
-1 
100 
-2 
80 
 
Dose Reductions and guidelines for optional use of Growth Factors for Hematologic Toxicity 
The table below provides a guideline for implementing dose reductions and optional use of 
growth factor treatment for hematologic toxicity: 
Table 3:  Use of G-CSF and Dose reductions for Hematologic Toxicity 
Adverse Event 
Occurrence 
Action to be Taken 
ANC < 500 cells/mm3 (nadir 
count) with neutropenic fever 
> 38° 
OR 
Delay of next cycle due to 
persistent neutropenia (ANC < 
1000 cells/mm3) 
OR 
For patients on weekly 
treatment whose next 
treatment within the cycle 
(Day 8 or Day 15) is omitted 
due to persistent neutropenia 
(ANC < 1000 cells/mm3). 
OR 
Neutropenia < 500 cells/mm3 
for > 1 week 
Any 
Occurrence 
At the first occurrence of a hematological 
toxicity (as outlined in the Adverse Event 
column), dose reduction to the next lower level 
will be required for subsequent cycles once 
ANC is ≥ 1000 cells/mm3. 
In the event that a hematological toxicity re- 
occurs, dose reduction to the next lower level 
will be required for subsequent cycles once 
ANC is ≥ 1000 cells/mm3. 
Alternatively, the same dose may be maintained 
and G-CSF is given as outlined below in the 
event of reoccurrence. In the event that a 
hematological toxicity re-occurs in the face of 
G-CSF, dose reduction to the next lower level 
will be required for subsequent cycles once 
ANC is ≥ 1000 cells/mm3. 
If G-CSF is given concurrently with weekly 
ABRAXANE, administration may begin the day 
after ABRAXANE is given and should stop at 
least 48 hours prior to when ABRAXANE is 
given the following week. 
 
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Thrombocytopenia Grade 3 or 
Grade 4* 
1st 
Occurrence 
Dose reduction to next lower level 
Recurrence 
Dose reduction to next lower level 
*See NCI Toxicity Criteria Scale for definition of Grade 3 and Grade 4 events. 
 
G-CSF Administration 
For weekly study drug administration administer G-CSF 5 mcg/kg/day (rounded to the nearest 
vial size per investigator/institution’s standard of care) 24 hours after chemotherapy and hold 48 
hours prior to the next dose 
 
Peripheral Neuropathy 
ABRAXANE should be withheld in patients who experience ≥ Grade 3 peripheral neuropathy. 
Treatment may be resumed at the next lower dose level (see Table 2) in subsequent cycles after 
the peripheral neuropathy improves to ≤ Grade 1. The time to resolution to Grade ≤ 1 should be 
the adverse event duration used for adverse event reporting. In those patients who experience 
Grade 4 peripheral neuropathy, study drug should be withheld, and treatment resumed at a 
reduction of 2 dose levels (Dose Level -2; see Table 2) in subsequent cycles after the peripheral 
neuropathy improves to ≤ Grade 1. 
 
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 reactions to ABRAXANE should not be re-challenged. It is 
not recommended to administer ABRAXANE to patients with prior hypersensitivity to a taxane. 
Other Toxicities 
A dose hold and / or dose reduction is permissible for any grade 2 drug-related adverse events at 
the treating investigator’s discretion, until satisfactory resolution of the AE. If drug related 
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 Table 2). 
 
5.4 
Concomitant therapy 
 
Supportive care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the site investigator. Concurrent treatment with bisphosphonates or other bone 
sparing agents are allowed. G-CSF may be administered at the discretion of the investigator, 
consistent with institutional guidelines. 
 
Patients may have interruption in their treatment schedule for palliative radiotherapy and/or 
brain radiotherapy for progressive brain metastasis during the course of treatment.  Patients may 
 
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resume study treatment after one week of completion of radiotherapy at the discretion of the 
investigator if their systemic disease remains stable or continues to respond to study treatment. 
 
No other concurrent investigational drugs or other anticancer drugs will be allowed. Also, 
concurrent treatment with any of the following may not be administered: Ritonavir, Saquinavir, 
Indinavir and Nelfinavir. 
 
 
5.5 
Discontinuation of study treatment 
 
Patients will be discontinued from study treatment under the following circumstances: 
 
• The patient may withdraw from the study, at any time and for any reason, without 
prejudice to future care from the investigator or the institution. 
• The investigator decides the patient should be withdrawn from the study. If a serious 
adverse event, or clinically significant laboratory value, form the basis for this decision, 
then the investigator will discontinue the study treatment and take appropriate measures. 
• Disease progression, as defined by RECIST 1.1 criteria 
o Patients will be able to continue on study if they have progressive brain metastasis 
as discussed in section 5.4. 
• Death 
• The study treatment is associated with excess toxicity, such that a third dose reduction 
would be indicated. (See Tables 2 and 3) 
• The study treatment is associated with excess toxicity, such that treatment has been 
delayed longer than 21 days. 
• Peripheral neuropathy ≥ Grade 3 ≥ 21 days 
• Significant non-compliance to protocol, as judged by the investigator 
 
5.6 
Treatment compliance 
 
Records of study medication used, dosage administered, and intervals between visits will be kept 
during the study. Drug accountability will be noted at the completion of the trial. 
 
 
6. 
CLINICAL AND LABORATORY ASSESSMENT 
 
Patient must be followed at the study center according to the visit schedule, with assessments as 
outlined in the Study Calendar (Appendix 2). Special attention should be given to the patients 
with bulky tumors or tumors involving or close to vital organs. These patients should be 
monitored very closely during the first months of treatment, as judged appropriate by the treating 
physician. 
 
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6.1 
Screening assessment 
 
Written, informed consent must be obtained before any study-specific medical procedures are 
performed. The following screening assessments and laboratory evaluation must be performed 
within 30 days prior to starting study treatment: 
 
Screening assessments 
 
Assessment 
Includes 
Inclusion/exclusion criteria 
Patient eligibility is to be assessed 
Demographics 
Medical History / Current 
Medical Conditions 
Date of birth, sex and race. 
Medical history, disease history, and current medical conditions 
Tumor Sample 
Obtain tissue from prior biopsy in patients that sign consent for optional 
correlative tissue study. 
Previous NSCLC treatment 
Previous surgery, radiotherapy and systemic therapy. 
Physical Examination / 
Vital Signs/ Performance 
Status/ Body weight 
Total body examination, including height, weight, pulse rate, blood pressure 
and performance status according to ECOG criteria (see Appendix 1). 
Tumor measurements 
CT scan as appropriate (classification of measurable and non-measurable 
disease according to RECIST 1.1 criteria).1 
Hematology 
Complete blood count with platelets and absolute neutrophil count 
Serum chemistry 
BUN, creatinine, sodium, potassium, bicarbonate, chloride, calcium, glucose, 
total protein, albumin, total bilirubin, alkaline phosphatase, AST (SGOT) and 
ALT (SGPT) 
EKG 
Electrocardiogram2 
Pregnancy test 
Negative serum or urine β-hCG pregnancy test at screening for patients of 
childbearing potential2 
1 Tumor measurement may occur no more than 30 days prior to study start. 
2 Pregnancy test and EKG must be obtained within 7 days of study start. 
 
6.2 
Assessments, treatment period 
 
During study treatment, patients will undergo the following physical and laboratory assessments. 
Patients will undergo CT scans of known sites of disease after every 2 cycles of therapy (see 
Study Calendar, Appendix 2). 
 
Days of nab-paclitaxel infusion (Days 1, 8 and 15) 
o Notation of concurrent illnesses and changes in baseline medications 
o Assessment of adverse events and toxicity rating using NCI CTCAE version 4.0 
o Physical examination on Day 1 only 
o Vital signs including weight, blood pressure and pulse. 
o ECOG performance status on Day 1 only 
o Complete blood count, with absolute neutrophil count and platelet count 
 
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o Serum chemistries including BUN, creatinine, sodium, potassium, bicarbonate, chloride, 
calcium, glucose, total protein, albumin, total bilirubin, alkaline phosphatase, AST 
(SGOT) and ALT (SGPT) on Day 1 only. 
o CT scan of chest and other known sites of disease after every two cycles of therapy (end 
of cycle 2, 4, etc.) 
End of Treatment Visit 
o Notation of concurrent illnesses and changes in baseline medications 
o Assessment of adverse events and toxicity rating using NCI CTCAE version 4.0 
o Physical examination 
o Vital signs including weight, blood pressure, and pulse. 
o ECOG performance status 
o Complete blood count, with absolute neutrophil count and platelet count 
o Serum chemistries including BUN, creatinine, sodium, potassium, bicarbonate, chloride, 
calcium, glucose, total protein, albumin, total bilirubin, alkaline phosphatase, AST 
(SGOT) and ALT(SGPT) 
o CT scan of chest and other known sites of disease if not done within past four to six 
weeks. 
 
6.3 
Assessments, post-treatment period 
 
Four week visit: The patient will undergo evaluation for toxicity four weeks (+/- 7 days) after 
the last dose of nab-paclitaxel. This evaluation will occur, regardless of reason for stopping nab- 
paclitaxel treatment (i.e. completion of study treatment, disease progression, withdrawal from 
study). Patients will undergo the following tests and procedures: 
• Notation of concurrent illnesses and changes in baseline medications 
• Assessment of adverse events and toxicity rating using NCI CTCAE version 4.0 
• Physical examination, including weight, blood pressure and pulse 
• ECOG performance status 
• Complete blood count, with absolute neutrophil count and platelet count 
• Serum chemistries including BUN, creatinine, sodium, potassium, bicarbonate, chloride, 
calcium, glucose, albumin, total bilirubin, alkaline phosphatase, AST (SGOT) and ALT 
(SGPT) . 
• If a treatment-related adverse effect has not stabilized or resolved to ≤ Grade 1 or 
baseline, the patient will be seen monthly until such resolution has been documented or 
another anti-neoplastic therapy has begun. 
 
Monthly assessment, post-treatment period: Patients who have stopped study treatment without 
documentation of disease progression, will be seen monthly by the study physician. Patients will 
undergo the following evaluation monthly until disease progression is documented, at which 
time they may be followed by telephone. 
• Radiographic efficacy assessment every eight weeks 
 
Telephone follow up: If disease progression is documented, follow-up may thereafter occur by 
telephone. A study investigator, nurse or coordinator will contact each patient every three 
months (+/- 2 weeks), until death or the study is stopped by the investigator. The following will 
be documented: 
 
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• Global health status (alive or deceased) 
 
7. EFFICACY ASSESSMENTS 
 
Please see Study Calendar (Appendix 2) for timing of radiographic efficacy assessments. 
 
7.1 
Screening evaluation 
 
Within 30 days prior to the first dose of nab-paclitaxel, baseline tumor measurement(s) will be 
performed for each patient. Conventional computed tomography (CT) scan of the chest and 
upper abdomen should be performed. In addition to imaging of the chest and upper abdomen, 
other known sites of measurable disease should be quantified by CT. 
 
7.2 
Efficacy evaluations, treatment period 
 
An objective assessment of all measurable and unmeasurable disease will be performed 
according to the Study Calendar (See Appendix 2). Tumor response or progression will be 
defined by RECIST 1.1 criteria, as detailed below. Objective responses will include both partial 
and complete responses (PR and CR). 
 
All tumor assessments should be performed within 14 days of the scheduled assessment date. 
Radiological studies must account for all lesions that were present at baseline. All known 
disease (measurable and non-measurable, as defined below, section 7.4) must be accounted for 
when assessing objective tumor status. 
 
The first tumor assessment will occur after two 4-week cycles of study treatment, and every two 
cycles thereafter. After first documentation of disease progression, no further radiographic 
assessment is required. 
 
At any time, radiological evaluation may be ordered based on clinical symptoms or signs, 
prompting concern for disease progression. 
 
7.3 
Efficacy evaluations, post-treatment period 
 
Patients who stop study treatment due to toxicity or other circumstances specified in Section 5.6 
but continue to exhibit response or stable disease at the end of study treatment will be scheduled 
for further radiographic efficacy assessments.  Tumor assessment by CT will be conducted every 
2 months (+/- 2 weeks) until documentation of disease progression. 
 
7.4 
Definitions 
 
Measurable disease: the presence of at least one lesion that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as ≥10 mm with spiral CT scan for non- 
lymph nodes or ≥ 1.5 cm in short-axis diameter for lymph nodes 
 
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Non-measurable disease:  all other lesions, including small lesions (longest diameter <10 mm 
with spiral CT scan or pathological lymph nodes with >10 to <15mm short axis). 
 
7.5 
Baseline documentation of tumor burden 
 
Target lesions: All measurable lesions up to a maximum of two lesions per organ and five 
lesions in total, representative of all involved organs, should be identified as target lesions. 
These should be recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (those with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest diameter for all 
target lesions will be calculated and reported as the baseline sum longest diameter (SLD). The 
baseline SLD will be used as the reference by which to characterize the objective tumor response. 
Non-target lesions: All other lesions (or sites of disease) should be identified as non-target 
lesions, and should also be recorded at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up. 
 
7.6 
Response criteria 
 
Radiological response will be defined according to the modified RECIST criteria, as follows: 
 
Evaluation of target lesions: 
• Complete response (CR): disappearance of all target lesions 
• Partial response (PR): at least a 30% decrease in the sum of the longest diameter of the 
target lesions, taking as reference the baseline SLD 
• Progressive disease (PD): at least a 20% increase in the SLD of target lesions, taking as 
reference the smallest SLD recorded since the treatment started, or the appearance of one 
or more new lesions 
• Stable disease (SD): neither  sufficient  shrinkage to  qualify  for  PR,  nor  sufficient 
increase to qualify for progressive disease, taking as reference the smallest SLD since the 
treatment started. 
 
Evaluation of non-target lesions: 
• Complete Response (CR): disappearance of all non-target lesions 
• Incomplete Response/Stable Disease (SD): persistence of one or more non-target 
lesion(s) 
• Progressive Disease: appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
 
8. 
SAFETY ASSESSMENT AND ADVERSE REPORTING 
 
Investigators are responsible for monitoring the safety of patients who have entered this study, 
and for alerting both the Fred Hutchinson/University of Washington Cancer Consortium IRB and 
Celgene Drug Safety to any event that seems unusual. 
 
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Safety assessments will occur on the day of each nab-paclitaxel infusion. Safety measurements 
include history, evaluation for side effects and other adverse events, physical examination, 
review of concomitant medications and laboratory tests. Toxicities will be graded according to 
NCI CTCAE version 4.0. Adverse events will be recorded after the first dose of study therapy 
has been given. Only the following adverse events will be recorded in the case report forms 
(CRF): 
• 
All grade 3 and higher adverse events 
• 
Any other adverse event that requires a dose reduction or a dose delay 
 
8.1 
Adverse events 
 
An adverse event (AE) is any undesirable medical condition (sign, symptom or diagnosis) or 
worsening of a preexisting medical condition, which occurs after initiating study treatment, 
whether or not considered causally related to the investigational product. Abnormal laboratory 
values or test results constitute AEs only if deemed clinically significant by the investigator, e.g. 
they induce clinical signs or symptoms, or require therapy. 
 
AEs are collected from first dose of study drug until 30 days after the last dose of study drug. An 
event that, in the judgment of the investigator, is unequivocally due to progression of disease 
should not be reported as an adverse event. 
 
The following attributes must be recorded by the study personnel for each adverse event: 
• Description 
• Severity 
• Causality 
• Action taken 
 
8.2 
Serious adverse events 
 
A serious adverse event is defined by regulatory agencies as one that suggests a significant 
hazard or side effect, regardless of the investigator’s opinion regarding relationship to the 
investigational treatment. This includes any undesirable sign, symptom or medical condition 
which: 
 
• Is fatal or immediately life-threatening 
• Requires or prolongs inpatient hospitalization 
• Results in severe or permanent disability or incapacity 
• Constitutes a congenital anomaly or a birth defect 
• Is medically significant, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
 
Events not considered to be serious adverse events are hospitalizations for the: 
 
• Routine  treatment  or  monitoring  of  the  studied  indication,  not  associated  with  any 
deterioration in condition 
 
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• Treatment, which was elective or pre-planned, for a pre-existing condition that did not 
worsen 
• Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions given above and not resulting in hospital admission 
 
An event that, as judged by the investigator, is unequivocally due to progression of disease 
should not be reported as a serious adverse event. 
 
8.3 
Reporting a serious adverse event 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient 
has initiated study therapy and until 30 days after the last dose of drug must be reported. Any 
SAEs experienced after this 30-day period should only be reported to Celgene Drug Safety if the 
investigator suspects a causal relationship to the study drug. SAEs that occur at a Network site 
will be reported to the Network office within 24 hours of learning of its occurrence. The 
Network Office will then forward the SAE reports to both the Coordinating Center Principal 
Investigator (or designee) and Celgene Drug Safety within 24 hours of learning of its occurrence. 
SAEs will be reported to the Fred Hutchinson/University of Washington Cancer Consortium IRB 
in accordance with applicable AE reporting policies. 
 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Drug Safety 
86 Morris Avenue 
Summit, N.J. 07901 
 
Toll Free: (800)-640-7854 
Phone: 
(908) 673-9667 
Fax: 
(908) 673-9115 
 
E-mail: 
drugsafety@celgene.com 
 
9. SPONSOR AND INVESTIGATOR REQUIREMENTS 
 
Sponsors are responsible for selecting qualified investigators, providing them with the 
information they need to conduct an investigation properly, ensuring proper monitoring of the 
investigation(s), ensuring that the investigation(s) is conducted in accordance with the general 
investigational plan and protocols ensuring that all participating investigators are promptly 
informed of significant new adverse effects or risks with respect to the drug. 
 
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9.1 
Study initiations 
 
Before the start of this study and the shipment of investigational agent to the main site and any 
sub-site, the following documents must be on file at the coordinating center (University of 
Washington). 
1. 
U.S.  Food  and  Drug  Administration  (FDA)  Form 1572,  signed  by  the  Principal 
Investigator 
• The names of any sub-investigators must appear on this form. 
2. 
Current curricula vitae and license of the Principal Investigator 
3. 
A financial disclosure statement from the Principal Investigator 
4. 
Delegation of Authority 
5. 
Written documentation of IRB approval of protocol and ICF (identified by title and 
date of approval) for each site 
 
 
10. STATISTICAL CONSIDERATIONS 
10.1 
Study endpoints 
10.1.1 Primary endpoint: Overall response rate 
The primary endpoint will be overall response rate. Responses include both complete and partial 
responses, as defined by RECIST 1.1 criteria. 
 
10.1.2 Secondary endpoints: Time to progression, overall survival, toxicity 
 
Time to tumor progression is defined as time elapsed from date of informed consent, until the 
first documentation of progressive disease. Overall survival is defined as time elapsed from date 
of informed consent, until death. Both time to progression and overall survival will be reported 
as median values.  Toxicity rates will be described as percentage of patients experiencing Grade 
3 or higher toxicity. Toxicity rates will be presented in two ways: 1) overall percentage of 
patients experiencing Grade 3 or higher toxicity; 2) overall percentage of patients experiencing 
toxicity within a clinically significant category – including neutropenia, neutropenic fever and 
neuropathy. 
 
10.2 
Study design 
This study is a single-arm, phase 2 study of weekly nab-paclitaxel in patients with advanced 
EGFR mutation positive NSCLC after front line therapy with an EGFR TKI. 
10.3 
Sample size determination and data analysis 
This is a single-arm, phase 2 study and a total of 29 patients will be enrolled in this trial. We 
will utilize Fleming’s single stage design where there is a level of response, P0, below which the 
treatment would not be considered for further study, and a higher level, P1, above which the 
treatment warrant further investigation [Girling]. Phase II published response rates to single- 
 
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agent nab-paclitaxel range from 16-30%, with weekly therapy resulting in a 30% response rate 
[Rizvi]. Therefore, a response rate <10% (P0) will be considered null and we would not be 
interested in pursuing this therapy further. If the response rate were 30% (P1) or better, this 
therapy would be considered worth further study. With this design, we have 90% power to 
detect a true response rate of 30%. If the true response rate is 10%, then we have a 5% chance of 
falsely rejecting the null rate of 10% (α = 0.05, β = 0.10, P0 = 10%, P1 = 30%). We will 
calculate the response rate as the proportion and 95% confidence interval of patients who 
achieved a complete response or partial response. We will also report time to progression and 
overall survival as median values with their respective 95% confidence intervals. We will 
estimate time to event distributions using the Kaplan-Meier method. 
 
10.4 
Exploratory analysis 
 
An exploratory analysis will examine the response rates stratified by the following histologic 
subtypes if available: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, NSCLC 
others. However, it is expected that the adenocarcinoma subtype will comprise the majority of 
lung cancers in this study. Given the lack of sufficient statistical power to assess response rates 
by the stratified subtypes, no formal statistical analysis will be performed. 
Also, a correlative 
tissue analysis of SPARC expression will be assessed on available tissue specimens if reliable 
detection methodology is available at the end of study recruitment (Appendix 3). 
 
 
 
 
 
 
 
 
 
Appendix 1: ECOG Performance Status 
Score: 
Description of functional status: 
0 
Fully active, able to carry on all pre-disease performance without restrictions 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g. light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care, and confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair 
5 
Deceased 
 
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Appendix 2:  Study Calendar 
 
 
 
 
 
 
Screening 
Screening 
 
Every 28 days 
 
 
End of 
Treatment 
(EOT) 
 
 
 
30 day 
post 
 
Procedure 
within 30 
days 
within 7 
days 
tmt 
+/- 7 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 CBC with platelets and absolute neutrophil count. (Can be done within 2 days of 
  Day1)  
 
2 Includes sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, 
calcium, total bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, 
phosphorus. (Can be done within 2 days of Day1) 
3 CT scan of known sites of involvement after every 2 cycles of therapy. 
4 If not done within 4-6 weeks of the EOT visit 
 
 
Appendix 3.  Correlative tissue analysis 
 
Paraffin blocks/slides will be collected from patients who sign the optional correlative tissue 
study informed consent form. Expression of SPARC and other potential predictive markers will 
be performed on all samples received if reliable detection methodology is available at the end of 
study recruitment. We will conduct an exploratory analysis, correlating SPARC expression with 
response rate and survival in patients treated with nab- paclitaxel. Analysis of all tissue samples 
for SPARC will be blinded with respect to the treatment assignment and to the patient response 
to treatment. The number and percentage of responding patients (i.e., patients that achieve an 
objective confirmed complete or partial overall response) and non-responding patients will be 
tested for association with SPARC expression (i.e., SPARC positive vs. SPARC negative) for 
each treatment group. 
Day 1 
+/- 3 days 
Day 8 
+/- 2 days 
Day 15 
+/- 2 days 
Informed Consent 
X 
Physical Exam 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
ECOG Status 
X 
X 
X 
X 
Medical History 
X 
Pregnancy Test 
X 
CBC 1 
X 
X 
X 
X 
X 
X 
Serum Chemistries 2 
X 
X 
X 
X 
EKG 
X 
CT scans 3,4 
X 
(X) 
X 
ABRAXANE 
X 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
 
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