Clinical trial NCT02303977
Conditions: Patients With Stage IV or Recurrent Adenocarcinoma of the Lung
Sponsor: Abramson Cancer Center at Penn Medicine
Start date: 2015-06-26; Completion date: 2020-04-30
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to see how well the combination of Abraxane and gemcitabine works in people with advanced adenocarcinoma NSCLC who have already had treatment for their disease. Gemcitabine and Abraxane are FDA approved chemotherapies; however, the FDA has not approved this combination in the treatment of this specific type of cancer. Patients may continue to receive the study drugs until their disease gets worse or they have unacceptable side effects.

Detailed description:

Arms: arm 1: All patients were treated intravenously with albumin-bound paclitaxel at 100 mg/m2 plus gemcitabine at 1000 mg/m2 on days 1 and 8 of each three-week cycle.
Interventions: intervention 1: Abraxane intervention 2: Gemcitabine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
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sponsor 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
PHASE II STUDY OF ABRAXANE AND GEMCITABINE IN 
PATIENTS WITH ADVANCED ADENOCARCINOMA NON- 
SMALL CELL LUNG CANCER PROGRESSING AFTER FIRST- 
LINE PLATINUM-BASED CHEMOTHERAPY 
Regulatory Sponsor: 
Christine Ciunci, MD 
Hospital of the University of Pennsylvania 
3400 Civic Center Boulevard 
Philadelphia, Pennsylvania 19104 
215-662-9801 
Christine.Ciunci@uphs.upenn.edu 
 
Funding Sponsor: 
 
 
 
 
Statistician: 
Celgene Corporation 
86 Morris Avenue 
Summit, NJ 07901 
Phone: 908-219-0978 
Fax: 908-673-2779 
 
Rosemarie Mick, MS 
Department of Biostatistics & Epidemiology 
University of Pennsylvania Perelman School of Medicine 
609 Blockley Hall, 423 Guardian Drive 
Philadelphia, PA 19104-6021 
Office: 215-898-9057 
Fax: 215-573-4865 
Email: rmick@mail.med.upenn.edu 
 
Study Product: 
Albumin-bound paclitaxel (Abraxane) 
Gemcitabine (Gemzar) 
 
 
Protocol Number: 
UPCC 21514 
 
IND Number: 
IND-exempt 
 
Initial version:   2/24/2014 
Amended:         6/27/2014 
Amended:         7/29/2016 
Amended:       10/20/2014 
Amended:         3/18/2015 
Amended:           8/3/2015 
Amended:         11/1/2016 
Amended:         2/26/2018 
Amended:         7/16/2018 
Amended:           1/9/2019 


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Phase II Gem-Abraxane 
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Table of Contents 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION ................................................................................................................................ 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 3 
1.3 
PRECLINICAL DATA ........................................................................................................................ 3 
1.4 
CLINICAL DATA TO DATE ................................................................................................................. 4 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 4 
2 
STUDY OBJECTIVES ........................................................................................................................ 5 
3 
STUDY DESIGN ................................................................................................................................. 5 
3.1 
GENERAL DESIGN .......................................................................................................................... 5 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 5 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 6 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 6 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 6 
4.1 
INCLUSION CRITERIA....................................................................................................................... 6 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 6 
4.3 
SUBJECT RECRUITMENT AND SCREENING ........................................................................................ 7 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................. 7 
4.4.1 
When and How to Withdraw Subjects...................................................................................... 7 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 8 
5 
STUDY DRUG .................................................................................................................................... 8 
5.1 
DESCRIPTION ................................................................................................................................. 8 
5.2 
TREATMENT REGIMEN .................................................................................................................... 8 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................ 10 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG.................................................................... 10 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 11 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 12 
5.7 
PACKAGING ................................................................................................................................. 12 
5.8 
BLINDING OF STUDY DRUG ........................................................................................................... 12 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 12 
5.9.1 
Receipt of Drug Supplies ....................................................................................................... 12 
5.9.2 
Storage .................................................................................................................................. 13 
5.9.3 
Dispensing of Study Drug ...................................................................................................... 13 
5.9.4 
Return or Destruction of Study Drug ...................................................................................... 13 
6 
STUDY PROCEDURES ................................................................................................................... 14 
6.1 
PRETREATMENT EVALUATION ....................................................................................................... 14 
6.2 
ON-TREATMENT EVALUATION ....................................................................................................... 14 
6.2.1 
Procedures Before Each Treatment ...................................................................................... 14 
6.2.2 
Other Procedures During the Treatment Period .................................................................... 14 
6.2.3 
Evaluations at End of Last Treatment Cycle .......................................................................... 14 
7 
STATISTICAL PLAN ........................................................................................................................ 15 
7.1 
SAMPLE SIZE DETERMINATION .................................................................................................... 116 
7.2 
STATISTICAL METHODS ............................................................................................................... 116 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 16 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................... 116 


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8.1 
DEFINITIONS .............................................................................................................................. 116 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................. 17 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................... 18 
8.3.1 
Investigator reporting: notifying the study sponsor ................................................................ 18 
8.3.2 
Investigator reporting: notifying the Penn IRB ....................................................................... 19 
8.3.3 
Investigator reporting: Abramson Cancer Center DSMC ....................................................... 22 
8.4 
UNBLINDING PROCEDURES ........................................................................................................... 23 
8.5 
MEDICAL MONITORING .................................................................................................................. 23 
9 
DATA HANDLING AND RECORD KEEPING ....................................................................................... 23 
9.1 
CONFIDENTIALITY ......................................................................................................................... 23 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 23 
9.3 
CASE REPORT FORMS .................................................................................................................. 24 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................... 24 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 24 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 24 
11 
ETHICAL CONSIDERATIONS ........................................................................................................... 24 
12 
STUDY FINANCES ............................................................................................................................ 25 
12.1 
FUNDING SOURCE ........................................................................................................................ 25 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 25 
13 
PUBLICATION PLAN ........................................................................................................................ 25 
14 
REFERENCES ................................................................................................................................... 25 


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List of Abbreviations 
NSCLC- non-small cell lung cancer 


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Study Summary 
 
Title 
Phase II study of albumin-bound paclitaxel and gemcitabine in patients with 
advanced adenocarcinoma non-small cell lung cancer progressing after first- 
line platinum-based chemotherapy 
Short Title 
Phase II albumin-bound paclitaxel and gemcitabine 
Protocol Number 
UPCC 21514 
Phase 
Phase II 
Methodology 
Single arm, open label 
Study Duration 
2 - 2.5 years 
Study Center(s) 
Single-center 
Objectives 
The primary objective is overall response rate. Secondary objectives include 
clinical benefit, overall survival, and progression-free survival. 
Number of Subjects 
37 (12 in stage 1 and 25 in stage 2, in an optimal Simon 2-stage design) 
Diagnosis 
and 
Main 
Inclusion Criteria 
Patients with stage IV or recurrent adenocarcinoma of the lung, age 18 or 
older, with an ECOG performance status of 0 to 1, who have progressive 
disease on or after a first-line, platinum-based chemotherapy 
Study  Product,  Dose, 
Route, Regimen 
albumin-bound paclitaxel (Abraxane) 100 mg/m2 intravenously days 1 and 8 
of a 21 day cycle 
Gemcitabine 1000 mg/m2 intravenously, days 1 and 8 of a 21 day cycle 
Duration 
of 
administration 
Drugs  will  be  administered  until  documented  progression  of  disease  or 
intolerable toxicity 
Reference therapy 
The study  product  is  being  compared  to  historical  controls  of  second-line 
treatment of non-small cell lung cancer. 
Statistical 
Methodology 
This optimal Simon 2-stage phase II trial will reject the albumin-bound 
paclitaxel and gemcitabine combination if the objective response rate is <5% 
and will accept the combination if the objective response rate is >20%, with 
10% type I error rate and 90% power. Objective response rate will be 
examined by K-ras mutation status. Median PFS and OS will be estimated by 
Kaplan-Meier method. 


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1 Introduction 
 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference 
on Harmonization guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
1.1 Background 
 
Three agents are currently FDA approved for use for non-small cell lung (NSCLC) cancer that has 
progressed following platinum-based chemotherapy: docetaxel, pemetrexed or erlotinib. However, 
response rates to second-line treatment are consistently low, and survival benefits remain modest. Better 
therapeutic strategies are needed. One option to consider is a combination of albumin-bound paclitaxel 
and gemcitabine. 
 
Platinum-based doublet chemotherapy in the first-line treatment of advanced non-small cell lung cancer 
has consistently proved superior to single agent chemotherapy in terms of improving overall survival, 
even in elderly and poor performance status patients [1-3]. While single-agent treatment has shown a 
survival advantage over best supportive care in the second-line setting [4, 5], outcomes and response 
rates for single agent therapies remain poor, with response rates for the three approved agents of less 
than 10% in randomized clinical trials. Cytotoxic doublet therapy in the second-line setting can improve 
response rates and progression free survival [6], but it has yet to improve overall survival relative to 
single-agent treatment. 
 
The taxanes are consistently active agents in the treatment of NSCLC and are approved for use with 
platinum compounds in the first-line treatment of non-small cell lung cancer (paclitaxel, docetaxel, and 
albumin-bound paclitaxel). In addition, docetaxel is an approved second-line agent with a demonstrated 
survival benefit. Gemcitabine shows efficacy in the treatment of NSCLC [7, 8] and is approved for use 
with platinum in the first-line setting, though it lacks formal approval in second-line treatment. Albumin- 
bound paclitaxel plus gemcitabine is a well-tolerated doublet with important clinical activity in patients with 
advanced pancreatic cancer [9]. In a preclinical therapeutic study, the combination of albumin-bound 
paclitaxel and gemcitabine was shown in a mouse model of pancreatic ductal adenocarcinoma to 
overcome the resistance mechanism of suboptimal intra-tumoral concentrations of gemcitabine, leading 
to tumor regression [10]. This suggests one possible mechanism for the notable anti-tumor activity of the 
drug combination. In a pivotal phase III trial, this combination proved superior to single agent gemcitabine 
in patients with advanced pancreatic cancer with a statistically significant improvement in overall 
response rate, progression free survival, and overall survival [11]. 
 
In addition, in patients with NSCLC, the combination of gemcitabine and docetaxel has previously been 
shown to have activity in the second-line setting after progression on platinum, with median overall 
survival exceeding one year [12]. Although albumin-bound paclitaxel has not been formally compared to 
docetaxel in non-small cell lung cancer, weekly albumin-bound paclitaxel in combination with carboplatin 
every three weeks yielded a higher response rate compared to standard paclitaxel administered every 
three weeks in combination with carboplatin [13]. 
 
In summary, single chemotherapy agents have remained the standard of care for NSCLC in the second 
line setting. However, given albumin-bound paclitaxel and gemcitabine’s potential ability to overcome 
important chemotherapy resistance mechanisms, this combination may be more effective than doublets 
that have been studied in the past. In addition, this combination has been notably well tolerated even in 
patients with advanced cancer. Therefore, we propose a phase II trial of albumin-bound paclitaxel and 
gemcitabine in patients with advanced NSCLC progressing after first-line platinum-based chemotherapy. 
Because there are now treatment distinctions for non-small cell lung cancer patients based on histology, 
we are limiting our study population to those with adenocarcinoma. The  majority of patients  with 
squamous cell histology receive either a taxane or gemcitabine in combination with platinum in the first- 


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line setting. However, a significant percentage of patients with adenocarcinoma receive pemetrexed with 
platinum in the first-line setting and are therefore often naïve to both the taxanes and gemcitabine in the 
second-line setting and are therefore more likely to benefit from the combination. 
 
 
1.2 Investigational Agent 
 
Albumin-bound paclitaxel (Abraxane, Celgene) 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 intraluminal 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 [14]. A protein 
specifically secreted by the tumor (SPARC) binds albumin, allowing release of the hydrophobic drug to 
the tumor cell membrane [15]. 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. 
 
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. 
 
Gemctabine (GEMZAR, Eli Lilly) is a nucleoside metabolic inhibitor indicated in combination with cisplatin 
for the treatment of non-small cell lung cancer and as a single agent for the treatment of pancreatic 
cancer. Gemzar (gemcitabine for injection USP) is a white to off-white lyophilized powder available in 
sterile single-use vials containing 200 mg or 1 g gemcitabine. Adding 5 mL to the 200-mg vial or 25 mL to 
the 1-g vial yields a Gemzar concentration of 38 mg/mL. Complete withdrawal of the vial contents will 
provide 200 mg or 1 g of Gemzar. Prior to administration the appropriate amount of drug must be diluted 
with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL. 
 
Reconstituted gemcitabine is a clear, colorless to light straw-colored solution. Inspection visually prior to 
administration allows for discarding for particulate matter or discoloration. Gemzar solutions are stable for 
24 hours at controlled room temperature of 20° to 25°C (68° to 77°F) and should not be refrigerated as 
crystallization can occur. No incompatibilities have been observed with infusion bottles or polyvinyl 
chloride bags and administration sets. 
 
The combination of gemcitabine and albumin-bound paclitaxel has been administered to patients with 
advanced pancreatic cancer in phase 1, 2 and 3 clinical trials. 
 
1.3 Preclinical Data 
 
Preclinical studies comparing Abraxane to Taxol® (paclitaxel Cremophor®  EL solvent-based, BMS) 
demonstrated lower toxicities, with an MTD approximately 50% higher for Abraxane 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, Abraxane treated groups showed 
more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At 
equal dose, tumor paclitaxel area under the curve was 33% higher for Abraxane versus solvent-based 
paclitaxel, indicating more effective intratumoral accumulation of Abraxane [16]. 


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In a preclinical therapeutic study, the combination of Abraxane and gemcitabine was shown in a mouse 
model of pancreatic ductal adenocarcinoma to overcome the resistance mechanism of suboptimal intra- 
tumoral concentrations of gemcitabine, leading to tumor regression [10]. This suggests one possible 
mechanism for the notable anti-tumor activity of the drug combination. 
 
1.4 Clinical Data to Date 
 
Both albumin-bound paclitaxel and gemcitabine are, in combination with a platinum agent, approved for 
use in the first-line treatment of advanced non-small cell lung cancer based upon established efficacy and 
acceptable tolerability. In a direct comparison of carboplatin and paclitaxel versus carboplatin and 
albumin-bound paclitaxel in the first-line treatment of advanced non-small cell lung cancer, the nab- 
paclitaxel combination led to an improved response rate and decreased neuropathy and 
myalgias/arthralgias [13]. The taxanes are a class of cytotoxic agents that function by inhibiting 
microtubule function. Three taxanes (paclitaxel, docetaxel, and albumin-bound paclitaxel) have 
demonstrated efficacy in non-small cell lung cancer and are approved for use with platinum in the first-line 
setting. Docetaxel is approved in the second-line setting based upon demonstrated survival benefit 
relative to best supportive care. 
 
The combination of two effective agents in the first-line treatment of non-small cell lung cancer (platinum 
in combination with a taxane, gemcitabine, vinorelbine, or pemetrexed) has established superiority over 
single-agent treatments [1-3, 17, 18]. However, in the second-line setting, no combination has yet 
demonstrated clear superiority over single agent treatment. Because both albumin-bound paclitaxel and 
gemcitabine have activity in non-small cell lung cancer, pre-clinical evidence of synergy, and established 
tolerability when used in combination, this study proposes to use the combination in the second-line 
setting. 
 
The most relevant clinical data for this approach are studies evaluating the efficacy of gemcitabine and 
docetaxel in the second-line treatment of NSCLC [12] as well as studies of gemcitabine and albumin- 
bound paclitaxel in patients with advanced pancreatic cancer discussed previously [9, 11]. 
 
 
1.5 Dose Rationale and Risk/Benefits 
 
The maximum tolerated dose of Abraxane plus gemcitabine in patients with advanced pancreatic cancer 
is 125 mg/m2 of Abraxane plus 1,000 mg/m2 of gemcitabine once a week for 3 weeks, every 28 days [9]. 
The doses were tolerable in this population of patients with an advanced solid malignancy. The same 
dosing was used in the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study [11]. 
Abraxane has been used safely and effectively at 100 mg/m2 weekly in combination with carboplatin in 
non-small cell lung cancer patients with advanced disease [13]. 
 
Gemcitabine has been safely used at 1000 mg/m2 on days 1, 8, and 15 of a 28 day cycle in patients with 
metastatic non-small cell lung cancer as a single agent [19], and when combined with agents such as 
cisplatin [20]. 
 
Given this data, patients will receive Abraxane at 100 mg/m2 intravenously plus gemcitabine at 1000 
mg/m2 intravenously on days 1 and 8 of each cycle. One cycle will be defined as 3 weeks. The risks to 
subjects are reasonable in relation to the anticipated benefits and also the knowledge that might 
reasonably be expected from the results given that this combination has been notably well tolerated in 
patients with very advanced cancer, and also given the poor response rates to second line treatment of 
advanced NSCLC. 


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2 Study Objectives 
 
Primary Objective 
To assess the overall response rate in subjects treated with Abraxane and gemcitabine as measured by 
RECIST 1.1 criteria. 
 
Secondary Objective 
To assess progression-free survival, disease control rate (complete response, partial response or stable 
disease), and overall survival in subjects treated with Abraxane and gemcitabine. 
 
 
3 Study Design 
3.1 General Design 
 
 The design of this study is a phase II non-randomized, single-arm, and single institution study. 
 
Figure 1: Schema of drug schedule. 
 
 
 
 
 Treatment duration: Subjects with remain on the study drugs until they have documented 
progressive disease or intolerable side effects. Subjects will be followed for progression-free and 
overall survival following completion of therapy. 
 
3.2 Primary Study Endpoints 
 
The primary endpoint is overall response rate, which is the percentage of patients with a partial response 
or complete response recorded from the start of the treatment until disease progression/recurrence by 
RECIST 1.1 criteria. 


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3.3 Secondary Study Endpoints 
 
Secondary endpoints include the following: 
1. Progression-free survival: measures the length of time from the first day of therapy until progressive 
disease, death from any cause, or last patient contact. 
2. Disease  control  rate:  measures  the  percentage  of  patients  with  a  partial  response,  a  complete 
response, or stable disease during the study. 
3. Overall survival: measures the length of time from the first day of therapy to death from any cause or 
last patient contact. 
 
3.4 Primary Safety Endpoints 
 
The safety and tolerability of Abraxane and gemcitabine in patients with adenocarcinoma NSCLC will be 
evaluated. Clinical assessment and laboratory evaluation of Adverse Events and Dose Limiting Toxicities 
will be done according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.02 
of the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP). 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. Histologic or cytologic diagnosis of adenocarcinoma non-small cell lung cancer 
2. Stage IV non-small cell lung cancer or recurrent disease which cannot be approached with 
curative intent. 
3. First-line treatment with a standard platinum doublet chemotherapy regimen (carboplatin or 
cisplatin at standard dosing plus one of the following drugs at standard dosing: paclitaxel, 
docetaxel, vinblastine, vinorelbine, pemetrexed, or etoposide). Patients who received platinum- 
based chemotherapy for localized lung cancer (either adjuvant chemotherapy following surgery or 
chemotherapy given in conjunction with definitive radiation) are eligible if their cancer  has 
recurred within 6 months of platinum-based chemotherapy. 
4. Must have recovered from toxic effects of prior chemotherapy 
5. ECOG performance status of 0-1 
6. Life expectancy of at least 12 weeks 
7. Age 18 or greater 
8. Must have measurable disease defined as at least one lesion that can be accurately measured in 
at least one dimension (longest diameter to be recorded as > 20 mm with conventional 
techniques or > 10 mm with spiral CT scanning). 
9. Patients with prior malignancies are allowed, provided they have been treated with curative intent 
and have no evidence of active disease. 
10. Patients must be capable of giving informed consent and be willing and able to comply with 
scheduled visits, treatment plan and laboratory testing. 
11. Bilirubin < 1.5 mg/dL 
12. 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 
13. Patients must have adequate bone marrow function: Platelets >100,000 cells/mm3, Hemoglobin 
> 9.0g/dL and ANC > 1,500 cells/mm3 
14. Patients must have adequate renal function: creatinine <1.5 mg/dL 
15. Women of childbearing potential and sexually active males must use an effective contraception 
method during treatment and for three months after completing treatment 
16. Negative serum β-hCG pregnancy test at screening for patients of childbearing potential. 
17. Patients must have < Grade 2 pre-existing peripheral neuropathy (per CTCAE) 


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4.2 Exclusion Criteria 
 
1. Patients with common activating EGFR (deletions in exon 19 and L858R mutation in exon 21) or 
EML4-ALK mutations  
2. Patients previously treated with gemcitabine or Abraxane for metastatic or recurrent disease 
3. Uncontrolled intercurrent illness including, but not limited to: uncontrolled ongoing infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
4. Known HIV or Hepatitis C 
5. Untreated central nervous system metastases. Patients are eligible if they are clinically stable, off 
all steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, 
stereotactic radio surgery) ending at least 2 weeks prior to enrollment, or after surgical resection 
performed at least 2 weeks prior to enrollment. 
6. Concurrent treatment with other anticancer therapy, including other chemotherapy, 
immunotherapy, hormonal therapy, radiotherapy, chemo-embolization, targeted therapy, or an 
investigational agent 
7.  Pregnant or breast-feeding patients, as chemotherapy is thought to present substantial risk to the 
fetus/infant. Men and women of reproductive potential may not participate in this study unless 
they have agreed to use an effective contraceptive method while in this study. (Postmenopausal 
woman must have been amenorrheic for at least 12 months to be considered of non-childbearing 
potential). Patients must agree to continue contraception for 3 months from the date of the last 
study drug administration 
 
 
4.3 Subject Recruitment and Screening 
 
Subjects will be recruited for this study from the clinical practices of the Abramson Cancer Center at the 
University of Pennsylvania. Subjects will be required to give written informed consent to participate in the 
study before any screening tests or evaluations are conducted that are not  part  of standard care. 
Screening laboratories will include a complete blood count and serum comprehensive metabolic panel. 
 
 
4.4 Early Withdrawal of Subjects 
 
4.4.1 When and How to Withdraw Subjects 
Subjects who do not complete the study protocol will be considered to have prematurely discontinued the 
study. The reasons for premature discontinuation (for example, voluntary withdrawal, toxicity, death) must 
be recorded on the case report form (CRF). Final study evaluations will be completed at the time of 
discontinuation. Reasons for withdrawal include, but are not limited to, the following: 
 
 
1. Inter-current illness that would, in the judgment of the investigator, affect assessments of clinical 
status to a significant degree or require discontinuation of study drugs; 
2. Unacceptable toxicity: Patients will be followed until resolution or stabilization; 
3. Disease progression; 
4. Withdrawal of patient consent; 
5. Treatment delay greater than four weeks for any toxicity 
6. Non- compliance with study procedures that cannot be resolved; 
7. Major protocol violations, including, but not limited to: 
1. failure to meet inclusion/exclusion criteria; 
2. failure to complete evaluations as required by protocol; 


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3. use of concomitant therapies other than specified above. 
 
The reason(s) for withdrawal should be noted in the case report form and in the patient’s medical record. 
Standard supportive therapy should be maintained for subjects withdrawn from active treatment. Long- 
term follow-up data, including survival and progression data, will be collected. 
 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Patients taken off study due to toxicity will be followed until resolution or stabilization. All patients will 
be followed for progression-free and overall survival data. 
 
5 Study Drug 
5.1 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. 
 
 
Gemctabine (GEMZAR, Eli Lilly) is a nucleoside metabolic inhibitor indicated in combination with cisplatin 
for the treatment of non-small cell lung cancer and as a single agent for the treatment of pancreatic 
cancer. Gemzar (gemcitabine for injection USP) is a white to off-white lyophilized powder available in 
sterile single-use vials containing 200 mg or 1 g gemcitabine. Adding 5 mL to the 200-mg vial or 25 mL to 
the 1-g vial yields a Gemzar concentration of 38 mg/mL. Complete withdrawal of the vial contents will 
provide 200 mg or 1 g of Gemzar. Prior to administration the appropriate amount of drug must be diluted 
with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL. 
 
 
5.2 Treatment Regimen 
 
Patients will receive Abraxane at 100 mg/m2 intravenously plus gemcitabine at 1000 mg/m2 intravenously 
on days 1 and 8 of each 21 day cycle. One cycle will be defined as 3 weeks. 
 
Dose Modifications/Reductions 
 
Dose level reductions, as referenced in Tables 2 and 3, are provided in Table 1. 
Table 1: Dose level reductions 
Dose level 
Abraxane (mg/m2) 
Gemcitabine (mg/m2) 
Full dose 
100 
1000 
1st dose reduction 
75 
800 
2nd dose reduction 
Discontinue 
600 
If additional dose reduction 
required 
Discontinue 
Discontinue 
 
 
Recommended dose modifications for neutropenia and thrombocytopenia are provided in Table 2. 


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Table 2: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start 
of a Cycle or within a Cycle 
 
Cycle day 
ANC (cells/mm3) 
Platelet Count (cells/mm3) 
Abraxane/Gemcitabine 
Day 1 
<1500 
OR 
<100,000 
Delay dose until recovery 
Day 8 
500 to <1000 
OR 
50,000 to < 75,000 
Reduce 1 dose level 
<500 
OR 
<50,000 
Withhold dose 
* If patient counts recover and at the discretion of the investigator Abraxane can be restarted at the lowest dose on Day 1 of the next cycle. 
 
Abbreviations: ANC = Absolute Neutrophil Count 
Recommended dose modifications for other adverse drug reactions are provided in Table 3. 
Table 3: Dose Modifications for Other Adverse Drug Reactions 
Adverse Drug Reaction 
Abraxane 
Gemcitabine 
Febrile Neutropenia: 
Grade 3 or 4 
Withhold until fever resolves and ANC ≥ 1500; resume at next lower 
dose level 
Peripheral Neuropathy: 
Grade 3 or 4 
Withhold until improves to ≤ Grade 
1; resume at next lower dose level 
No dose reduction 
Cutaneous Toxicity: 
Grade 3 or 4 
Reduce to next lower dose level; discontinue treatment if toxicity persists 
Gastrointestinal Toxicity: 
Grade 3 mucositis or diarrhea 
Withhold until improves to ≤ Grade 1; resume at next lower dose level 
 
Abraxane and gemcitabine dosing should not be administered at the start of each cycle until the 
absolute neutrophil count returns to 1.5 x 109 cells/L and the platelet count returns to >100 x 109 cells/L. 
If the ANC and platelets are not adequate for treatment on Day 8, the dose will be omitted and the total 
cycle length remains the same. 
 
Administration of Study Drug to Patients with Abnormal Hepatic Function 
Abraxane 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. 
 
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 
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 Table 2). 


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Concomitant Medications 
 
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. Erythropoietin 
and G-CSF may be administered at the discretion of the investigator, consistent with institutional 
guidelines. 
 
 
 
5.3 Method for Assigning Subjects to Treatment Groups 
 
This trial is not randomized. 
 
 
5.4 Preparation and Administration of Study Drugs 
 
Abraxane 
A research supply of Abraxane will be supplied by Celgene. It will be shipped, stored and dispensed from 
the Outpatient Clinic Pharmacy in the Perelman Center for Advanced Medicine (2nd floor, West Pavilion) 
of the Hospital of the University of Pennsylvania as well as to the infusion center of Penn Presbyterian for 
patients enrolled at that site. The drug preparation will be done in the pharmacy. 
 
Study Medication Administration 
Abraxane is injected into a vein (intravenous (I.V.) infusion) over 30 minutes.  The use of an in-line liter is 
not recommended. Abraxane will be administered per institutional guidelines 
 
Reconstitution and use of Abraxane 
1. Calculate the patient’s body surface area at the beginning of the study and if the weight 
changes by > 10% by using the formula provided in the study manual. 
2. Calculate the total dose (in mg) to be administered by: 
 
Total Dose (mg) = BSA x (study dose mg/m2 ) 
3. Calculate the total number of vials required by: 
Total Number of Vials = Total Dose (mg) 
100 (mg/vial) 
Round up the number of vials to be reconstituted to the next higher whole number when a 
fractional number of vials is obtained by the above formula (eg, if the total number of vials = 
4.05 or 4.5, then 5 vials would be reconstituted). 
4. Using sterile technique, prepare the vials for reconstitution. 
5. Swab the rubber stoppers with alcohol. 
6. Aseptically, reconstitute each Abraxane vial by injecting 20 mL of 0.9% Sodium Chloride 
Injection, USP. 
 
Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 
minute, using the sterile syringe directing the solution flow onto the inside wall of the 
vial. 
 
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP solution directly onto the 
lyophilized cake as this will result in foaming. 
 
Once the injection is complete, allow the vial to sit for a minimum of 5 (five) minutes to 
ensure proper wetting of the lyophilized cake/powder. 


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 
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. Rapid agitation or shaking will 
result in foaming. 
 
If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. 
 
Each ml of reconstituted product will contain 5 mg of paclitaxel. 
7. Calculate the exact total dosing volume of 5 mg/ml suspension required for the patient: 
 
Dosing volume (ml) = Total dose (mg) / 5 (mg/ml) 
8. The reconstituted suspension should be milky and homogeneous without visible particulates. 
If particulates or settling are visible, the vial should be gently inverted again to ensure 
complete resuspension prior to use. Discard the reconstituted suspension if precipitates are 
observed. 
9. Once the exact volume of reconstituted Abraxane has been withdrawn from the vials, discard 
any excess solution left over in accordance with standard operating procedures. 
10. Further dilution is not necessary. Inject the calculated dosing volume of reconstituted Abraxane 
suspension into an empty sterile, standard PVC IV bag using an injection port. Inject 
perpendicularly into the center of the injection port to avoid dislodging plastic material into the 
IV bag. 
11. Administer the calculated dosing volume of reconstituted Abraxane suspension by IV infusion 
over 30 minutes. The use of in-line filters is not recommended because the reconstituted 
solution may clog the filter. 
 
 
Study Medication Administration 
NOTE: It is not a requirement to use filter needles in the preparation of, or in-line filters during the 
administration of Abraxane. In any event, filters of pore-size less than 15 micrometers must not be used. 
 
Abraxane Premedication 
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 [21], 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 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. 
 
Gemcitabine 
Gemcitabine will be prepared and administered per institutional guidelines. Gemcitabine wil be obtained 
commercially. 
 
5.5 Subject Compliance Monitoring 
The study team will track subject compliance with the treatment regimen at each visit and note the dose, 
date, and time of study medication administration on the case report form. If there are any significant 
irregularities in compliance (in the opinion of the investigator), the subject should be withdrawn from the 
study. 


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5.6 Prior and Concomitant Therapy 
A reasonable effort will be made to document any medications the subject received within 30 days prior to 
Day 1. Any medication taken within 7 days of study medication administration must be recorded in the 
CRF as a prior medication. All concomitant medications taken during the study will be recorded in the 
CRF with indication, dose information, including any changes in dose, as well as start and stop dates and 
frequency of administration. The minimum requirement is that drug name, dose, and the dates of 
administration are to be recorded. 
 
Concomitant Therapy: Growth Factor 
Erythropoiesis-stimulating agents (ESAs) are allowed for anemia during the study as per accepted 
standards. G-CSF is allowed during the study for subjects with severe neutropenia and recurrent 
infections. 
 
Any change in dosage of any concomitant medication (change in dose or frequency) MUST be recorded 
in the eCRF, to include: drug name, dose, frequency of administration, start and stop dates  and 
indication. 
 
 
5.7 Packaging 
 
Abraxane will be supplied by Celgene Corporation. 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. 
 
Standard, commercially-availablegemcitabine will be used. 
 
5.8 Blinding of Study Drug 
The drugs will not be blinded. 
 
5.9 Receiving, Storage, Dispensing and Return of Abraxane 
 
5.9.1 Receipt of Drug Supplies 
 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug receipt 
log filled out and signed by the person accepting the shipment. It is important that the designated study 
staff counts and verifies that the shipment contains all the items noted in the shipment inventory. Any 
damaged or unusable study drug in a given shipment (active drug or comparator) will be documented in 
the study files. The investigator must notify Celgene of any damaged or unusable study treatments that 
were supplied to the investigator’s site. 
 
Drug Distribution and Destruction 
 
Supplier 
Celgene Corporation 
86 Morris Avenue 
Summit, NJ 07901 
 
Industry Contact: 
Norma Powers 
Director, Medical Operations 
Celgene Corporation 
86 Morris Avenue 
Summit, NJ 07901 
Mobile: 267-337-2720 


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Fax: 908-673-2779 
Email: npowers@celgene.com 
 
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 
Corporation at 908-673-2779. 
 
 
5.9.2 Storage 
 
Storage and Stability 
Storage: Store the vials in original cartons at 20º C to 25º C (68º F to 77ºF). Retain in the original 
package to protect from bright light. 
Stability: Unopened vials of Abraxane are stable until the date indicated on the package when stored 
between 20ºC to 25ºC (68ºF to 77ºF), in the original package. Neither freezing nor refrigeration 
adversely affects the stability of the product. 
 
Stability of Reconstituted Suspension in the Vial 
Reconstituted Abraxane should be used immediately, but may be refrigerated at 2ºC to 8ºC (36ºF to 
46ºF) for a maximum of 4 hours if necessary. If not used immediately, each vial of reconstituted 
suspension should be replaced in the original carton to protect it from bright light. Discard any unused 
portion. 
 
Stability of Reconstituted Suspension in the Infusion Bag 
The suspension for infusion prepared as recommended in an infusion bag should be used 
immediately, but may be stored at ambient temperature (approximately 25º C) and lighting conditions 
for up to 4hours. 
 
 
5.9.3 Dispensing of Study Drug 
Regular study drug reconciliation will be performed to document drug assigned, drug used, and drug 
remaining. This reconciliation will be logged on the drug reconciliation form, and signed and dated by the 
study team. 
 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and 
drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and dated. Any 
discrepancies noted will be investigated, resolved, and documented prior to destruction of unused study 
drug. Drug destroyed on site will be documented in the study files. 
 
Drug Destruction 
The investigational site will follow its internal drug destruction policy. 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 


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(drug dispensing log, drug accountability log and any destruction memos) must be mailed to Celgene 
Medical Operations. 
 
 
6 Study Procedures 
 
Study procedures are detailed below. See Table 4 for complete details 
 
 
6.1 Pretreatment Evaluation 
 
1. Signed written informed consent before any study procedure. 
2. Complete medical history 
3. Complete physical examination including, but not limited to, vital signs, height, weight, ECOG 
Performance Status, and tumor measurements (within 28 days prior to enrollment; tumor measurements 
will need to be repeated if cycle1/day 1 occurs more than 28 days following tumor measurements). 
4. Tumor Evaluation: Confirmation of diagnosis of NSCLC and staging Radiological Evaluation by CT scan 
should be performed within 28 days prior to cycle 1/day 1 of treatment. MRI abdomen/pelvis is allowed 
as an alternative modality at the discretion of the treating physician. The same modality should be used 
throughout to assess disease. 
5. Clinical laboratory testing: CBC with differential and platelet count, Serum Chemistries (total serum 
bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum creatinine, serum electrolytes, serum 
calcium, serum albumin, magnesium), and a pregnancy test for female patients of childbearing potential. 
Creatinine clearance should be calculated by the Cockroft-Gault formula or directly measured if clinically 
indicated (within 28 days before enrollment). 
 
6.2 
On-Treatment Evaluation 
 
6.2.1 Procedures before each treatment 
 
1. Laboratory assessment: Hematology: CBC with differential and platelet count and Serum chemistries: 
alkaline phosphatase, total serum bilirubin, SGOT, SGPT, creatinine or creatinine clearance, serum 
electrolytes, serum albumin, calcium and magnesium. 
2. Vital signs and weight 
3. Interim history, including documentation of concomitant medications, and solicitation of adverse event 
(AE) information if not volunteered by the patient, specifically inquiring as to the known AEs attributed 
in the past to any of the study drugs. Other documentation  will include performance status, 
concomitant medications, and treatment-related toxicity (acute and cumulative),. Mid-level providers, 
including CRNPsand PAs, will be allowed to see patients and perform history and physical in lieu of 
the physician. 
4. A complete physical examination prior to each study treatment . 
5. Any other clinically indicated procedure(s) 
6. During any study drug infusion, patients must be carefully checked so that immediate intervention can occur 
should an adverse event (i.e. hypersensitivity) occur. 
 
6.2.2 Other procedures during the treatment period 
1. Patients will be followed with CBC, differential, and serum chemistries (required weekly during Cycle 1 
and subsequently as clinically indicated between treatment cycles). 
2. Radiologic evaluation with CT Chest, abdomen and pelvis to be performed after every 2 cycles. Patients 
who stop treatment and/or come off study prior to developing progressive disease will continue to be 
followed for progression with CT of chest/abdomen/pelvis performed every 6 weeks until disease 
progression for one year of therapy and then every 9 weeks until disease progression. Patients who 
remain on treatment longer than a year may also have scans done every 9 weeks to minimize scan 
burden. 


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Patients who develop progressive disease and have completed study treatment will be followed for 
overall survival only. Their follow-up status will be assessed q6 months until death or the study ends. 
 
6.2.3 
Evaluations at End of Last Treatment cycle 
The following assessments will be completed no less than 30 days after the patient's last study drug 
infusion: 
1. Interim medical history with adverse event evaluation. 
2. Complete physical examination with vital signs including temperature, weight and estimated 
ECOG Performance Status. 
3. Laboratory testing: CBC with differential and platelet count, serum chemistries. 
4. Following end of treatment/early termination visit, patients will be followed 
 
 
Table 4: Study procedures by visit 
 
Assessment 
Pre- 
treatmenta 
Cycle 1, 
Days 1 & 
8e 
Cycle 2 
on, 
Days 1  
& 8e 
Every other 
cycle, 
beginning 
with Cycle 
3be 
End of 
treatment/early 
terminationc 
Consent 
X 
Serum pregnancy test 
X 
PE, including ECOG PS 
X 
X 
X 
X 
CBC w/ differential and serum 
chemistriesd 
X 
X 
X 
X 
Imaging (CT or MRI) 
X 
X 
Abraxane and gemcitabine 
X 
X 
Adverse event assessment 
X 
X 
X 
Review of concomitant medications 
X 
X 
X 
X 
a: Pre-treatment evaluations must be performed within 28 days of first dose of study treatment (cycle 
1/day 1) 
b: Patients will radiologic assessment of measurable disease (CT chest/abdomen/pelvis) performed every 
other cycle while undergoing treatment for one year, then every 3 cycles until disease progression. 
Patients who discontinue treatment/come off study prior to disease progression will have radiographic 
assessment (CT chest/abdomen/pelvis) performed every 6 weeks until disease progression occurs. 
c: Patients who have experienced progression of disease will be followed for overall survival only. Their 
survival status will be assessed q6 months until death or the study ends. 
d: comprehensive metabolic profile including electrolytes (Na, K, bicarconate, chloride), liver function 
tests, BUN and creatinine, serum albumin and magnesium. 
e: Day 8 assessment may occur one day prior or one day after scheduled.  Day of subsequent cycles 
may occur 2 days before or 2 days after scheduled. 
 
 
PE= physical exam, PS= performance status, w/= with 


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7 Statistical Plan 
7.1 Sample Size Determination 
The sample size will be 12- 37 evaluable patients based on a standard optimal Simon 2-stage phase II 
trial. 
 
7.2 Statistical Methods 
 
This optimal Simon 2-stage phase II trial will reject the Abraxane and gemcitabine combination if the 
objective response rate is <5% and will accept the combination if the objective response rate is >20%, 
with 10% type I error rate and 90% power. In stage 1, if no responders are observed in 12 evaluable 
patients, the trial will be terminated. If >1 responder is observed, 25 evaluable patients will be enrolled in 
stage 2. At the end of stage 2, if >4 responders are observed in 37 evaluable patients, the combination 
will be considered promising. The chance of terminating the study after evaluating 12 patients is 54%, if 
the objective response rate is <5%. Objective response rate will be examined by K-ras mutation status. 
Median PFS and OS will be estimated by Kaplan-Meier method. The study of 37 evaluable patients will 
actively enroll patients for 2 - 2.5 years. 
 
7.3 
Subject Population(s) for Analysis 
 
Any patient who receives one dose of treatment will be  considered evaluable  for  the  primary  and 
secondary endpoints. Patients who are enrolled in study but do not undergo at least one treatment due to 
failure to meet eligibility or other reason will be considered non-evaluable and will be replaced. 
 
 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria: 
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries should be regarded as adverse events. 
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
   Non-clinically significant labs as deemed by the investigator will not be captured as adverse events. 
 
 
 


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Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is: 
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events. 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedure to the end of the study treatment follow-up. For this study, adverse 
event reporting will begin with the initiation of study treatment (cycle 1/day 1) until the end of the study 
treatment follow-up which is defined as 30 days following the last administration of study treatment. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition. At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an 
adverse event must also be recorded and documented as an adverse event. 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained. At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study. The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study. 
The sponsor should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study. 
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met: 
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 


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Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in  this  protocol.  Any 
condition responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for and adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition. Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within (insert time-frame 
which must be at least 3 months of the subject’s last dose of IP), are considered immediately 
reportable events. IP is to be discontinued immediately. The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to Celgene Drug Safety immediately by facsimile, or 
other appropriate method, using the Pregnancy Initial Report Form, or approved equivalent form. 
The female subject may be referred to an obstetrician-gynecologist (not necessarily one with 
reproductive toxicity experience) or another appropriate healthcare professional for further 
evaluation. 
The Investigator will follow the female subject until completion of the pregnancy, and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form. 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any of 
the serious criteria, it must be reported as an SAE to Celgene  Drug  Safety immediately by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form. 
All neonatal deaths that occur within 3 months of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 3 months that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the  pregnant female partner should be 
advised to call their healthcare provider immediately. 
 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination. Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF). All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period starting on the day of treatment (cycle 1/day 1) will be 
recorded. The clinical course of each event will be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause. Serious adverse events that 
are still ongoing at the end of the study period will be followed up to determine the final outcome.  Any 


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serious adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation will be recorded. 
 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
 
Investigators must conform to the adverse event reporting timelines, formats and requirements of the 
various entities to which they are responsible, but at a minimum those events that must be reported are 
those that are: 
 related to study participation, 
 unexpected, and 
 serious or involve risks to subjects or others 
(see definitions, section 8.1). 
 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of 
the initial report includes: 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason why the event is classified as serious 
 
Investigator 
assessment 
of 
the 
association 
between the event and study treatment 
 
 
8.3.1 Investigator reporting: notifying Celgene 
 
Toxicity will be scored using CTCAE Version 5.0 for toxicity and adverse event reporting. A copy of the 
CTCAE Version 5.0 can be downloaded from the CTEP homepage (HTTP://CTEP.INFO.NIH.GOV). All 
appropriate treatment areas should have access to a copy of the CTCAE Version 5.0. All adverse clinical 
experiences, whether observed by the investigator or reported by the patient, must be recorded, with 
details about the duration and intensity of each episode, the action taken with respect to the test drug, and 
the patient’s outcome. The investigator must evaluate each adverse experience for its relationship to the 
test drug and for its seriousness. 
 
The investigator will appraise all abnormal laboratory results for their clinical significance. If any abnormal 
laboratory result is considered clinically significant, the investigator will provide details about the action 
taken with respect to the test drug and about the patient’s outcome. 
 
Any study-related unanticipated problem posing risk of harm to subjects or others, and any type of 
serious adverse event, must be reported to the Celgene within 24 hours of the event. To report such 
events, a Serious Adverse Event (SAE) form must be completed by the investigator and faxed to Celgene 
within 24 hours. The investigator will keep a copy of this SAE form on file at the study site. Report 
serious adverse events by facsimile to: 
 
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 
 
Within the following 48 hours, the investigator must provide further information on the serious adverse 
event or the unanticipated problem in the form of a written narrative. This should include a copy of the 
completed  Serious  Adverse  Event  form,  and  any  other  diagnostic  information  that  will  assist  the 


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understanding of the event. Significant new information on ongoing serious adverse events should be 
provided promptly to the study sponsor. 
 
8.3.2 Investigator reporting: notifying the Penn IRB 
 
This section describes the requirements for safety reporting by investigators who are Penn faculty, 
affiliated with a Penn research site, or otherwise responsible for safety reporting to the Penn IRB. The 
University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those events related to study 
participation that are unforeseen and indicate that participants or others are at increased risk of harm. 
The Penn IRB will not acknowledge safety reports or bulk adverse event submissions that do not meet 
the criteria  outlined below. The Penn IRB requires researchers  to  submit  reports  of  the  following 
problems within 10 working days from the time the investigator becomes aware of the event: 
 Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-site) 
that occurs any time during or after the research study, which in the opinion of the principal 
investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately reflected 
in the protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent document and other 
relevant sources of information, such as product labeling and package inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be caused by 
the research procedures.) 
 
Deaths occurring for subjects on-study and within 30 days of study drug administration that are 
considered unforeseen and indicates participants or others are at increased risk of harm (i.e. unexpected 
and probably/definitely related), must be reported to the IRB within 24 hours of notification. 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
 Any adverse experience that, even without detailed analysis, represents a serious unexpected 
adverse event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic 
necrosis, Stevens-Johnson syndrome). 
 Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or 
informed consent form, or would prompt other action by the IRB to assure protection of human 
subjects. 
 Information that indicates a change to the risks or potential benefits of the research, in terms of 
severity or frequency. For example: 
– An interim analysis indicates that participants have a lower rate of response to treatment than 
initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more frequent than 
initially expected. 
– A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value. 
 Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in 
a research protocol. 
 Breach of confidentiality 


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 Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
 Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
 Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot 
be resolved by the research team. 
 Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 
protocol) that in the opinion of the investigator placed one or more participants at increased risk, or 
affects the rights or welfare of subjects. 
 
The IRB will accept other reports when the investigator is unsure whether the event should be reported, 
and the IRB will review such reports to determine whether the event meets the threshold for an 
unanticipated event presenting risk to the participant. 
 
Office of Regulatory Affairs, Institutional Review Board 
3624 Market Street, Suite 301S, Philadelphia, PA 19104-6006 
Phone: 215-573-2540 
Fax: 215-573-9438 
 
 
8.3.3 Investigator reporting: Abramson Cancer Center DSMC 
 
Grade 3 or higher AEs for Penn Subjects, determined to be related to the study drug regardless of 
expectedness or that affect subject safety, must be submitted to the Abramson Cancer Center’s DSMC 
within 5 days of notification, with the exception of the following. The treating investigator must clearly 
document the relationship of these events. 
• 
Grade 3 or 4 events that are probably or definitely related to the subjects’ underlying disease 
and/or other co-morbidity. 
• 
Grade 3 or 4 events that are probably or definitely related to an FDA approved drug based on 
the current labeling. However if the toxicity is more severe or is occurring more frequently 
than the current labeling, the event would be reportable. If the drug is not being used in 
accordance with the current FDA approval (i.e. dose, disease, route, as part of a treatment 
cocktail) then standard reporting is required. 
• 
Grade 3 or 4 events that are obviously unrelated to the study drug (i.e. events related to a 
standard of care test/procedure). 
Other events should be submitted if clinically significant or if a relationship to the study drug cannot be 
ruled out. 
AEs that are related to the subjects’ disease and/or other co-morbidity are not reportable to the ACC 
DSMC. All unexpected deaths or deaths related to the study drug should be reported within 24 hours of 
notification. All other deaths should be reported within 30 days. 
Deaths of subjects off-study for greater than 30 days from the last study treatment/intervention are not 
reportable with the following exceptions: 
a) Deaths on in-house gene or cellular-therapies 
b) Deaths  on  in-house  studies  utilizing  on-campus  manufacturing  of  the  study  agent(s)  or 
components of the study agent(s) 
c) Deaths on first-in-human studies 
 
AE reports should be sent to the DSMC for 90 days following the last date the last subject received study 
drug, and will not be accepted or processed after that time. 
AEs will be submitted to the DSMC through the Velos Clinical Trial Management System. 


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Data and Safety Monitoring Committee 
3400 Spruce Street, 2017 Penn Tower 
Philadelphia, PA 19104-4283 
 
8.4 Unblinding Procedures 
 
This study will not be blinded. 
 
8.5 Medical Monitoring 
The medical monitor for this study will be Dr. Ursina Teitelbaum from the University of Pennsylvania. Dr. 
Teitelbaum is an Assistant Professor of Clinical Medicine in the Department of Hematology-Oncology at 
Penn with extensive oncology and clinical experience. She is not directly involved in the trial and is not 
collaborating with the Sponsor-Investigator on any other trials. 
 
In the role, Dr. Teitelbaum will review all AEs including grading, toxicity assignments, all other safety data 
and activity data observed in the ongoing clinical trial. This will include a real-time review of safety data in 
the event of any unexpected and related SAE regardless of grade, and any on-study deaths. The Medical 
Monitor will also be consulted in the case of exception requests or the evaluation of deviations that may 
compromise subject safety or disrupt the design of the study. This information will be communicated to 
the Medical Monitor via email and filed in the Regulatory Binder/Subject Chart appropriately. As 
applicable, copies of this correspondence will be included in the corresponding IRB/ACC DSMC 
submission of these events. 
 
The Medical Monitor will also be asked to review study data and comprehensive adverse event data at 
least bi-annually (every 6 months). This meeting will take place in person, and all study/safety information 
will be presented appropriately. This meeting will be clearly documented on a Medical Monitor Review 
Sheet, signed off on by the Medical Monitor. At any point during the course of the study, the Medical 
Monitor may recommend reporting of adverse events and relevant safety data not previously reported and 
may recommend suspension or termination of the trial. 
 
 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a 
signed subject authorization informing the subject of the following: 
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization. For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Examples of these original documents, and data records include: hospital records, 
clinical  and  office  charts,  laboratory  notes,  memoranda,  subjects’  diaries  or  evaluation  checklists, 


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pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. The Velos eCRF 
system will be utilized for this study. All data requested on the CRF must be recorded. All missing data 
must be explained. 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site. This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan. This 
monitoring will include a regular assessment of the number and type of serious adverse events. The PI 
will comply with the CTSRMC approved Monitoring Plan. 
 
 
10.2 Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, government 
regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.). 
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 
This investigator-initiated protocol is considered high risk as per the Abramson Cancer Center Data and 
Safety Monitoring Plan (DSMP). As such, high risk protocols are audited approximately six months from 
the first subject enrolled and approximately every six months thereafter for the duration of the study by 
the ACC Department of Compliance and Monitoring (DOCM). However, this schedule may be changed at 
the discretion of the DSMC. High or quick enrolling studies may be audited more frequently as necessary. 
 
The investigator will be notified in advance of the selection of their protocol for review and cases are 
randomly selected. Three randomly selected subjects or 10% of the total accrual (up to 10 subjects), 
whichever is higher, are audited. A formal report is written to the PI within about 10 business days of the 
audit. The committee may alter the frequency of re-monitoring based on the audit findings and degree of 
deficiencies. 
 
Upon review of inspection findings, the Committee designates the audit outcome as Minor, Moderate, or 
Major deficiencies. The deficiency assigned by the Committee initiates specific follow-up actions. 
 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 


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This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct. The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study. All subjects for this study will be provided a consent form describing this 
study and providing sufficient information for subjects to make an informed decision about their 
participation in this study. This consent form will be submitted with the protocol for review and approval 
by the IRB and CTSRMC for the study. The formal consent of a subject, using the EC/IRB-approved 
consent form, must be obtained before that subject undergoes any study procedure. The consent form 
must be signed by the subject, and the investigator-designated research professional obtaining the 
consent. 
 
The Informed Consent Form shall clearly state the following: 
1. Study Drug will be provided at no charge to the Study Subjects; 
2. Celgene shall have full access to the Study Subject’s data; 
3. Informed Consent must not state or imply that Celgene is the sponsor nor be responsible for any Study 
Subject injury. 
 
 
12 Study Finances 
12.1 Funding Source 
 
The study will be supported by funds through Celgene. 
 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved by the study sponsor prior to participation in this study. All University of 
Pennsylvania investigators will follow the University conflict of interest policy. 
 
13 Publication Plan 
 
Publication policy shall be as provided the Research Support Agreement between the University of 
Pennsylvania and Celgene. 
 
Target meeting ASCO meeting May 23, 2016 
Planned final manuscript Journal of Clinical Oncology Jul 01, 2016 
 
 
14 References 
 
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cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol, 2005. 23(1): p. 
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Quoix, E., et al., Carboplatin and weekly paclitaxel doublet chemotherapy compared with 
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4. 
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Desai N, T.V., Yao R, Labao E, Soon-Shiong P, Increased endothelial transcytosis of 
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