Clinical trial NCT01757288
Conditions: STAGE IIIA/B NSCLC / INOPERABLE LUNG CANCER
Keywords: STAGE IIIA/B NSCLC / INOPERABLE LUNG CANCER
Sponsor: University of Texas Southwestern Medical Center
Start date: 2013-03-25; Completion date: 2019-06-03
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators propose this phase I/II study to use weekly Nab-Paclitaxel (Abraxane) and carboplatin with concurrent radiation in local-regionally advanced lung cancer. There are no published human studies combining Nab-Paclitaxel (Abraxane) with radiation. The investigators will first confirm the tolerated dose (TD) of concurrent Nab-Paclitaxel (Abraxane) at 50mg/m2, and then will begin enrolling patients into the phase II component using either Nab-Paclitaxel (Abraxane) at the TD with carboplatin concurrent with daily radiation or paclitaxel with carboplatin concurrent with daily radiation.

Detailed description:

Arms: arm 1: PACLITAXEL PLUS CARBOPLATIN WITH CONCURRENT RADIATION THERAPY arm 2: NAB-PACLITAXEL PLUS CARBOPLATIN WITH CONCURRENT RADIATION THERAPY nab-Paclitaxel 40 mg/m2 IV/30min/wk x6 wks arm 3: NAB-PACLITAXEL PLUS CARBOPLATIN WITH CONCURRENT RADIATION THERAPY nab-Paclitaxel 50 mg/m2 IV/30min/wk x6 wks
Interventions: intervention 1: NAB-PACLITAXEL intervention 2: PACLITAXEL intervention 3: NAB-PACLITAXEL
Intervention descriptions: intervention 1: nab-Paclitaxel 50 mg/m2 IV/30min/wk x6 wks intervention 2: None intervention 3: nab-Paclitaxel 40 mg/m2 IV/30min/wk x6 wks

Protocol documents:
Prot_SAP_000.pdf: 
Official title: A RANDOMIZED PHASE I/II STUDY OF NAB-
PACLITAXEL, OR PACLITAXEL, PLUS CARBOPLATIN WITH 
CONCURRENT RADIATION THERAPY FOLLOWED BY 
CONSOLIDATION IN PATIENTS WITH FAVORABLE 
PROGNOSIS INOPERABLE STAGE IIIA/B NON-SMALL CELL 
LUNG CANCER (NSCLC) 
 
NCT number:     NCT01757288 
Document date: Version 8 (3/4/2015) 


 
1
A RANDOMIZED PHASE I/II STUDY OF NAB-PACLITAXEL, OR PACLITAXEL, PLUS CARBOPLATIN WITH 
CONCURRENT RADIATION THERAPY FOLLOWED BY CONSOLIDATION IN PATIENTS WITH FAVORABLE 
PROGNOSIS INOPERABLE STAGE IIIA/B NON-SMALL CELL LUNG CANCER (NSCLC) 
 
 
Principal Investigator/Radiation Oncology 
 
 
Medical Oncology Co-Chair 
Hak Choy, M.D. 
Mark A. Socinski, M.D. 
Professor and Chairman  
 
 
 
 
Visiting Professor of Medicine and Thoracic Surgery 
Department of Radiation Oncology 
 
 
 
Director, Lung Cancer Section, Division of University 
of Texas Southwestern Medical School  
 
 
Hematology/Oncology 
University of Texas Southwestern Medical School 
 
University of Pittsburgh 
5801 Forest Park Rd.  
 
 
 
 
UPMC Cancer Pavilion 
Dallas, Texas 75390-9183  
 
 
 
 
5150 Centre Avenue, 5th Floor 
214-645-7600  
 
 
 
 
 
Pittsburgh, PA 15232 
Fax: 214-645-7622  
 
 
 
 
 
412.623.4083 
Hak.Choy@UTSouthwestern.edu  
 
 
 
412.648.6579 
 
socinskima@upmc.edu 
 
David Gerber, M.D. 
Aaron Laine, M.D., Ph.D. 
Assistant Professor 
Radiation Oncology  
Division of Hematology and Oncology 
Department of Radiation Oncology 
Simmons Comprehensive Cancer Center 
University of Texas Southwestern Medical School 
5323 Harry Hines Blvd 
5801 Forest Park Rd. 
Dallas, Texas 75390-8852 
Dallas, Texas 75390-9183 
214-648-4180  
 
 
 
 
 
214-645-8525 
FAX: 214-648-1955 
Aaron.laine@UTSouthwestern.edu 
David.Gerber@UTSouthwestern.edu 
 
 
Project Manager/Research Coordinator 
Biostatistician 
Jean Wu  
Xian-Jin Xie, Ph.D.  
Clinical Research Manager 
Associate Professor of Biostatistics 
Department of Radiation Oncology 
Department of Clinical Sciences 
University of Texas Southwestern Medical School 
& Simmons Comprehensive Cancer Center 
5641 Southwestern Medical Ave 
UT Southwestern Medical Center 
Dallas, Texas 75235-8808 
5323 Harry Hines Blvd 
214-633-1753 
Dallas, Texas 75390-8590 
Fax: 214-645-8913 
Tel: 214 648 4017 
Jean.Wu@UTSouthwestern.edu 
xian-jin.xie@utsouthwestern.edu  
 
 
 
 
 
 
 
 
 
Protocol Version History 
Version 1 
10/10/2012 
Version 2 
12/10/2012 
Version 3 
02/06/2013 
Version 4 
07/03/2013 
Version 5 
09/04/2013 
Version 6 
03/25/2014 
Version 7 
05/22/2014 
Version 8 
3/4/2015 
 
 
 


 
2
 
TABLE OF CONTENTS 
 
Schema 
Eligibility Checklist 
1.0 
Introduction 
 
 
1.1  
 Non-small Cell Lung Cancer 
 
1.2 
Radiation Therapy for Stage III NSCLC 
 
1.3  
nab-Paclitaxel 
 
1.4  
Rationale 
 
 
 
 
2.0 
Objectives 
 
2.1 
Primary Objective 
 
2.2 
Secondary Objective 
 
3.0 
Patient Selection 
 
3.1 
Eligibility 
 
3.2 
Conditions for Patient Ineligibility  
 
 
4.0 
Recommended Pretreatment Evaluations 
 
4.1  
PET scan of chest at pretreatment 
 
4.2  
Post-treatment PET scan 
 
4.3 
Patient Reported Outcomes 
5.0 
Registration Procedures 
 
 
5.1  
Pre-Registration Requirements  
 
 
5.2  
Registration 
 
 
5.3  
Written Informed Consent 
 
 
5.4  
Subject Data Protection 
 
6.0 
Radiation Therapy 
 
6.1 
Dose Specifications 
 
6.2 
Technical Factors 
  
6.3 
Localization, Simulation, and Immobilization 
  
6.4 
Treatment Planning/Target Volumes 
  
6.5 
Critical Structures 
  
6.6 
Documentation Requirements 
  
6.7 
Compliance Criteria  
 
6.8 
R.T. Quality Assurance Review 
 
6.9 
Radiation Adverse Events 
 
6.10 
Functional Imaging 
 
6.11 
Radiation Adverse Event Reporting 
 
7.0 
Drug Therapy 
 
 
7.1  
Treatment Plan 
 
 
7.2  
nab-Paclitaxel 
 
 
7.3  
Paclitaxel 
 
 
7.4  
Carboplatin 
 
 
7.5  
Dose Modifications 
 
 
7.6  
Duration of Treatment 
 
 
7.7  
Procedures In the Case of Pregnancy 
8.0 
Other Therapy 
 
 
8.1  
Prohibited Therapies 
 
 
8.2  
Supportive Therapy 
9.0 
Safety Reporting 
 
9.1 
Definitions and Reporting 


 
3
 
9.2 
Audits and Inspections 
 
10.0 
Patient Assessments 
 
 
10.1 
Study Parameters  
 
 
10.2 
Post-treatment Follow up 
 
 
10.3 
Prospective Health-Related Quality of Life (HRQOL) Analysis 
 
 
10.4 
Response Assessment (RECIST Criteria) 
 
11.0 
Tissue/Specimen Submission 
11.1 
Specimen Collection  
 
12.0 
Data Management 
12.1 
Data Collection 
12.2 
Summary of Data Submission 
 
 
12.3 
Data Safety Monitoring Board 
13.0 
Statistical Considerations 
 
 
13.1 
Study Design and Primary Endpoint 
 
13.2 
Sample Size Justification 
 
 
13.3  
Initial Toxicity and Compliance Phase  
 
 
13.4 
Patient Accrual 
 
 
13.5 
Fatal Treatment-Related Toxicity 
 
 
13.6 
Interim Analyses of Accrual and Toxicity Data 
 
 
13.7 
Analysis for Reporting Initial Treatment Results 
 
 
13.8 
Analysis for Reporting Long-Term Results 
 
 
13.9 
Health-Related Quality of Life (HRQOL) and Health Utility Analysis 
References 
 
Appendix A 
Zubrod Performance Scale 
Appendix B 
New York Heart Association Cardiac Classification 
 
 
 
 
 
 


 
4
SCHEMA 
 
A RANDOMIZED PHASE I/II STUDY OF NAB-PACLITAXEL, OR PACLITAXEL, PLUS CARBOPLATIN WITH 
CONCURRENT RADIATION THERAPY FOLLOWED BY CONSOLIDATION IN PATIENTS WITH FAVORABLE 
PROGNOSIS INOPERABLE STAGE IIIA/B NON-SMALL CELL LUNG CANCER (NSCLC) 
 
Phase 1 (Feasibility Testing) 
 
 
  
 
 
         Concurrent 
 
 
 
 
 
     Consolidation  
 
 
 
 
 
 
 
 
Phase 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Sections 6.0 and 7.0 for details. 
 
* 
Premedication (before each cycle of paclitaxel) 
• 
Dexamethasone 
20 mg PO on the evening prior to and morning of paclitaxel  
infusion, or IV 30 minutes prior to paclitaxel 
• 
Diphenhydramine 50 mg IV (or equivalent) 30 minutes prior to paclitaxel 
• 
Cimetidine 
300 mg IV (or equivalent, ranitidine 50 mg or famotidine 20 mg) 
30 minutes prior to paclitaxel 
 
** 
Dose of Carboplatin using Calvert Formula = AUC x (CrCl + 25): 
 
*** Based on Phase I data, 40 mg/m2 of Nab-Paclitaxel will be given during concurrent Phase. 
 
Patient Population  (See Section 3.0 for Eligibility) 
Histologically or cytologically documented NSCLC; Patients must be M0. Patients with T1-T2 with N2 or T3N1-2 are eligible, if 
inoperable.  Patients with T4 with any N or any T with N2 or N3 disease are eligible if unresectable. 
 
Required Sample Size:  6 total during the Phase 1 (Feasibility Testing) 
 
  92 during the Phase 2 (46 in Arm A, 46 in Arm B): total patient accrual is 98.  
 
 
 
R
E 
G 
I 
S 
T 
E 
R 
R
A
N
D
O
M
I
Z
E
nab-Paclitaxel 100 mg/m2 IV/30min, on days 
1,8,15 (of a 21 day cycle) x2 cycles 
Carboplatin AUC **6 IV/30 min, on day 1 (of a 
21 day cycle) x2 cycles 
ARM B 
nab-Paclitaxel 40 mg/m2 IV/30min/wk x6 
wks *** 
Carboplatin AUC **2 IV/30 min/wk x6 wks 
XRT 6000 cGy 
ARM A 
Paclitaxel 50 mg/m2 IV/1h/wk* x6 wks 
Carboplatin AUC **2 IV/30 min/wk x6 wks 
XRT 6000 cGy 
Paclitaxel 200 mg/m2 IV/3h*, q3 wks x2 cycles 
Carboplatin AUC **6 IV/30 min, q3 wks x2 
cycles 
nab-Paclitaxel 50 mg/m2 IV/30min/wk x6 
wks 
Carboplatin AUC **2 IV/30 min/wk x6wks 
XRT 6000 cGy  
nab-Paclitaxel 100 mg/m2 IV/30min, on days 
1,8,15 (of a 21 day cycle) x2 cycles 
Carboplatin AUC **6 IV/30 min, on day 1 (of a 
21 day cycle) x2 cycles 


 
5
Institution #    
 
 
 
Patient Initials   
 
 
          Patient #  
 
 
 
 
ELIGIBILITY CHECKLIST 
(page 1 of 2) 
 
 
(Y) 
1. 
Does the patient have histologically or cytologically documented NSCLC? 
 
 
(N) 
2. 
Has the tumor been totally resected? 
 
 
(Y) 
3. 
Is the patient stage IIIA/B with no evidence of metastasis (M0)? 
 
 
 (Y) 
4.  
Is disease measurable, as defined in Section 10.4? 
 
 
(Y) 
5. 
Is the patient ≥ 18 years of age? 
 
 
(Y) 
6. 
Is the Zubrod performance status 0-1? 
 
 
(Y) 
7. 
Are the pre-treatment laboratory values within the parameter of eligibility per section 3.1.5? 
 
 
(Y) 
8. 
Is the FEV1 ≥ 1200 cc or ≥ 50% predicted? 
 
 
 
(N) 
9. 
Has the patient had weight loss > 10% over the past 3 months? 
 
 
 
(Y) 
10. 
Has the patient recovered from exploratory thoracotomy? 
 
 
(Y) 
11. 
Were required pretreatment evaluations administered as specified in Section 3.1.11? 
 
 
(N) 
12. 
Has the patient had prior systemic chemotherapy, targeted therapy and/or thoracic/neck 
radiotherapy for any reason and/or surgical resection of present cancer? 
 
 
(N) 
13. 
Does the patient have a > grade 1 neuropathy? 
 
 
 (N) 
14. 
Is there evidence of other malignancy within the past two years other than those stated in Section 
3.2.7? 
 
 
 (N) 
15. 
If female, is the patient pregnant or nursing? 
 
 
 (Y) 
16. 
Is the patient (male or female) willing and able to practice effective contraception throughout the 
study and for four weeks after completion of treatment? 
 
 
 (Y/N) 17. 
Is there evidence of pleural effusion on CT scan? 
 
 
 (Y) 
 
If yes, is the pleural effusion transudate, cytologically negative, and non-bloody; or determined to 
be too small to tap? 
 
 
 
  
 
 
 
 
 
 
 
 
(Continued on next page) 
 
 


 
6
Institution #    
 
 
 
Patient Initials   
 
 
         Patient #  
 
 
 
 
ELIGIBILITY CHECKLIST 
(page 2 of 2) 
 
The following questions will be asked at Study Registration: 
 
 
 
 
1. 
Name of institutional person registering this case? 
 
 
 
(Y) 
2. 
Has the Eligibility Checklist (above) been completed? 
 
 
 
(Y) 
3. 
Is the patient eligible for this study? 
 
 
  
4. 
Date the study-specific Consent Form was signed? (must be prior to study entry) 
 
         
    
5.  
Patient’s Initials (First Middle Last)  (If no middle initial, use hyphen) 
  
 
  
6. 
Name of Verifying Physician 
 
 
  
7. 
Patient’s ID Number 
 
 
  
8. 
Date of Birth 
 
 
          9.    
 Ethnic Category (Hispanic or Latino; Not Hispanic or Latino; African American; Unknown)  
 
 
  
10. 
Race 
 
 
  
11. 
Gender 
 
 
  
12. 
Smoking History 
 
 
  
 
____Never,  
____Quit:____Yrs ago, ____yr Smoking Hx,    ____Still Smoking 
 
 
  
13. 
Treatment Start Date 
 
 
  
14. 
Name of Medical Oncologist 
 
 
(Y/N) 15.   
Tissue/Blood kept for current study? 
 
 
  
 
 
  
 
 
 
______________  (Y/N) 16. 
Tissue/Blood kept for cancer research? 
 
 
(Y/N) 17. 
Tissue/Blood kept for medical research? 
 
 
(Y/N) 18. 
Allow contact for future research? 
 
_______________(Y/N)  19.    Was a PET scan performed on this patient?  
 
____________(NA/Y/N)  20.    Was the PET scan used in staging? 
 
____________(NA/Y/N)  21.    Was the PET scan used in treatment planning for radiation therapy? 
 
 
Completed by __________________________  
 
 
Date __________________________________ 
 
 
 
 
 


 
7
 
 
1.0 INTRODUCTION 
 
1.1  
Non-small Cell Lung Cancer 
 
1.1.1 
 Background on Non-small Cell Lung Cancer (NSCLC) Therapy 
   
  
Lung cancer is the second most common cancer diagnosed for both sexes in the 
United States, second to prostate cancer for men and breast cancer for women.  
Approximately 226,160 new cases are estimated for 2012, accounting for about 
14% of cancer diagnoses  It is the leading cause of cancer deaths in both men 
and women, with approximately 160,340 deaths estimated for 2012.1  
 
 
Upon initial presentation, less than one-half of patients will have surgically 
resectable lung cancer with the potential for cure.  Approximately one-quarter of 
patients will present with locally advanced disease involving either the ipsilateral 
mediastinal or subcarinal lymph nodes (American Joint Committee on Cancer 
[AJCC] Tl-3 N2 M0, Stage IIIA) or contralateral mediastinal, hilar or ipsilateral or 
contralateral scalene or supraclavicular nodes (AJCC Tl-2 N3 M0, Stage IIIB) 
without evidence of extrathoracic metastases.  A smaller number of patients will 
have a centrally located primary tumor involving mediastinal structures (AJCC T4 
Nx M0, Stage IIIB).  These patients are generally not considered candidates for 
surgical resection.  
 
    
Since the 1970's, a number of investigators sought to improve the survival results 
of stage III NSCLC patients by combining chemotherapy with thoracic RT. There 
now have been four randomized trials published that demonstrate a statistically 
significant survival advantage of a cisplatin-containing regimen with thoracic RT 
over thoracic RT alone.2-6  
 
Two of these trials, CALGB 8433 and RTOG 88-08, used two cycles of pre-RT full 
dose cisplatin and vinblastine.2,4 One alternated chemotherapy with RT and the 
other delivered low dose daily and weekly single agent cisplatin during thoracic 
RT.6 Based on somewhat incomplete analyses of patterns of tumor failure 
location, it appears that sequential chemoradiation reduces or delays the 
development of extra-thoracic metastases, while low dose concurrent cisplatin 
appeared to improve the control rate of intra-thoracic tumor, i.e., acted as a 
potentiator of the radiation effect.  The goal of many investigators in recent years 
has been to take advantage of both the benefits of full dose chemotherapy and 
the sensitizing effects of concurrent chemoradiation. 
 
RTOG 94-10 was a three-arm phase III trial that compared: 1) an established 
sequential chemoradiation regimen of vinblastine and cisplatin followed by once-
daily RT to a dose of 60Gy on Day 50, 2) concurrent chemoradiation regimen in 
which once-daily RT to a dose of 60Gy (with cisplatin/vinblastine) or 3) concurrent 
chemoradiation regimen in which twice-daily RT to a dose of 69.6Gy (with 
cisplatin/etoposide). Median survival times were 14.6 months for the sequential 
arm and 17 and 15.6 months for the concurrent arms with once-daily and twice-
daily RT, respectively.  5-year overall survival was 10% for Arm 1, 16% for Arm 2 
and 13% for Arm 3 (P=0.046).7 
 
The West Japan Lung Cancer Group compared sequential to concurrent 
chemoradiation using mitomycin, vindesine, and cisplatin, (MVC) chemotherapy 
among 320 patients with stage III NSCLC and demonstrated a survival advantage 


 
8
favoring the concurrent arm, with median survival times of 16.5 versus 13.3 
months, respectively (P=0.047).8  
 
1.1.2 
Paclitaxel, Carboplatin, and RT in NSCLC 
 
Paclitaxel acts as a mitotic inhibitor, blocking cells in G2 and M phases of the cell 
cycle. The inhibition is unique in that the drug enhances the rate and yield of 
microtubular assembly and prevents microtubular depolymerization.9,10 It is well 
known that cells in the G2 and M phase of the cell cycle are particularly sensitive 
to radiation.11 Tishler et al. showed that 24-hour treatment with 10 nM paclitaxel 
resulted in a radiosensitivity enhancement in a radio-resistant astrocytoma cell 
line.12 The enhanced level of cell kill was consistent with the greater 
radiosensitivity of G2 /M cells.  A radiation sensitizing effect of paclitaxel was also 
observed with only one hour of treatment with 300 nM Taxol‚ in human leukemia 
cell line (HL-60) and human lung cancer cell line (Calu-3).13  
 
Carboplatin also can be used as a radiation sensitizer.  The mechanism of 
radiation sensitization with carboplatin is different from that of paclitaxel.  
Carboplatin potentially interferes with repair of sublethal radiation injury while 
paclitaxel recruits cells in the radiosensitive G2/M phase. Laboratory data have 
suggested a possible synergistic relationship of paclitaxel and carboplatin.14  
 
A number of phase I-II single arm trials have been performed evaluating paclitaxel 
and paclitaxel/carboplatin concurrent with radiation. Many of these have also 
incorporated induction or consolidation full-dose paclitaxel/carboplatin.15-19  Two 
recent randomized trials evaluating this general approach have been reported.  
The LAMP trial was a randomized phase II trial for patients with unresected 
stages IIIA and IIIB NSCLC with Karnofsky performance status ≥ 70% and weight 
loss ≤ 10%.  The three arms were: 1) paclitaxel (200mg/m2)/carboplatin (AUC 6) 
followed by radiation (sequential), 2) paclitaxel(200mg/m2)/carboplatin (AUC 6) 
followed by chemoradiation with paclitaxel(45mg/m2)/carboplatin (AUC 2) (weekly) 
(induction/concurrent), 
and 
3) 
chemoradiation 
with 
paclitaxel(45mg/m2)/carboplatin (AUC 2) (weekly) followed by consolidation 
paclitaxel(200mg/m2)/carboplatin (AUC 6)  (concurrent/consolidation). Accrual to 
arm 2 was discontinued early for low feasibility in that only 46% of patients 
completed chemoradiation. Analysis showed median overall survival rates of 13, 
12.7, and 16.3 months in arms 1, 2, 3 respectively.20 
 
CALGB 39801 is a phase III randomized trial that tested induction chemotherapy 
with paclitaxel and carboplatin followed by concurrent radiation with paclitaxel/ 
carboplatin versus chemoradiation with paclitaxel/carboplatin alone.  Patients with 
unresectable stage III NSCLC were enrolled onto the study and received either 
induction therapy consisting of two cycles of paclitaxel (200 mg/m2) and 
carboplatin (AUC 6) administered every 3 weeks followed by weekly paclitaxel 
(50 mg/m2) and carboplatin (AUC 2) with RT (2.0 Gy/day for 66.0 Gy) (arm 1) or 
the same chemoradiation without induction or consolidation paclitaxel/carboplatin 
(arm 2).  Three hundred thirty-one patients were evaluable.  Response rates, 
median and two year failure-free and overall survival rates were not significantly 
different between the two arms.   Median survival was 14 and 12 months (p = .10) 
in arms 1 and 2, respectively.21  
 
Results from the LAMP trial and CALGB 39801 suggest that induction 
paclitaxel/carboplatin followed by chemoradiation has low feasibility and is not 
more effective than chemoradiation alone.  This may be related, in part, to poor 
tolerance and limited delivery of chemoradiation following chemotherapy.  
However, additional systemic chemotherapy beyond what is delivered with 


 
9
chemoradiation is theoretically important given the high rate of distant metastases 
observed in patients so treated.  Thus, using paclitaxel/carboplatin as a base 
regimen, the study proposed herein utilizes concurrent chemoradiation followed 
by consolidation with additional chemotherapy, similar to arm 3 of the LAMP trial.  
In order to further improve on the outcome of treating patients with unresectable 
NSCLC, we propose to use weekly nab-paclitaxel (Abraxane) and carboplatin with 
concurrent radiation followed by consolidaton with nab-paclitaxel (Abraxane) and 
carboplatin. 
 
1.2 
Radiation Therapy for Stage III NSCLC 
 
A significant radiation therapy trial begun more than 30 years ago (RTOG 73-01) 
established 60 Gy as the optimal standard radiation dose for locally advanced 
NSCLC.22  Based on this trial, doses from 55-66 Gy are still used in most studies.  
It is important to realize that the dose of 60 Gy was established as optimal before 
the advent of modern imaging.  The first computed tomography scanner in the 
U.S. was installed in 1973 at the Mayo Clinic.  Before the widespread use of 
computed tomography (CT), radiation planning was two-dimensional (2-D) based 
on plain X-ray.  Most of the published phase III studies to date for lung cancer 
have used 2-D treatment planning.  There have been many advances since 
RTOG 73-01 established 60 Gy as the standard of care.  These include CT-
based treatment planning, conformal radiation therapy, positron emission 
tomography (PET), and knowledge of tumor motion during radiation delivery.  
One major shift in treatment strategy was the irradiation of gross disease without 
prophylactic/elective nodal irradiation.  There were several reasons for this 
philosophy.  The dose of radiation commonly employed (60 Gy/30 fractions) was 
not enough to sterilize bulky epithelial tumors.  Simply increasing the dose 
delivered to the large volumes of the chest included when irradiating lymph 
nodes prophylactically was believed to cause unacceptable toxicity.  Additionally, 
irradiating clinically uninvolved nodal areas prophylactically did not appear 
rational when the gross tumor was infrequently controlled. 
 
The currently accepted standard of care for patients with inoperable stage III 
NSCLC is concurrent chemoradiation therapy.  The accepted standard radiation 
dose is 60-66 Gy.  Three separately run phase I dose escalation trials using 
concurrent chemoradiation therapy have demonstrated a maximum tolerated 
dose of 74 Gy (RTOG, NCCTG, and North Carolina).23-25  Current phase II data 
from these series estimate a median survival of 24 months, which is higher than 
the expected median survival time for the RTOG 94-10 control arm (17 months).  
However, results of an early analysis of RTOG 06-17, a randomized phase III 
trial examining whether treatment with a higher radiation dose (74 Gy) improves 
overall survival compared with the current standard dose (60 Gy) (scheduled to 
take place upon 90 participant deaths being reported) demonstrated that the 
higher dose of radiation did not improve overall survival, at which time the two 
high-dose radiation therapy arms were closed to further participant enrollment.  It 
was also reported that there was no significant difference in treatment-related 
toxicity between the high-dose and standard radiation treatment arms.  
Therefore, the current standard dose of 60Gy will be used in this regimen. 
 
1.3 
Nab-Paclitaxel 
 
 
Paclitaxel and docetaxel are highly hydrophobic, and have to be delivered in 
synthetic vehicles. For paclitaxel, the vehicle is polyoxyethylated castor oil 
(Cremophor EL) and ethanol, and for docetaxel, the vehicle is polysorbate 80 
and ethanol. These vehicles are both biologically and pharmacologically active. 
They are known to cause hypersensitivity reactions characterized by dyspnea, 


 
10
flushing, angioedema, rash and generalized urticaria. It requires premedication 
with moderate to high doses of corticosteroids and antihistamines. (Cremophor 
EL) also contributes to peripheral neurotoxicity caused by paclitaxel 
administration. These vehicles also alter the pharmacokinetics by drug 
entrapment, leading to decreased drug clearance, decreased volume of 
distribution, and nonlinear pharmacokinetics.  
 
Nab-Paclitaxel (Abraxane) is a novel, solvent-free, albumin-bound, 130 nm 
particle form of paclitaxel designed to avoid the problems caused by the solvent 
used in (Cremophor EL) based paclitaxel.26 Nab-Paclitaxel (Abraxane) can be 
administrated intravenously over 30 minutes without premedication. A higher 
concentration of intratumor paclitaxel can be achieved with Nab-Paclitaxel 
(Abraxane) due to the utilization of albumin receptor-mediated endothelial 
transport, thus leading to increased antitumor activity.27 
 
Nab-Paclitaxel (Abraxane) has been tested extensively in metastatic breast 
cancer. A phase III study randomized 460 patients to receive Nab-Paclitaxel 
(Abraxane) 260 mg/m2 or CrEL-paclitaxel 175 mg/m2 every 3 weeks.28 Nab-
Paclitaxel (Abraxane) demonstrated significantly higher response rate compared 
with CrEL-paclitaxel (33% versus 19%, p=0.001) and significantly longer time to 
tumor progression (23.0 weeks versus 16.9 weeks, p=0.006). Although higher 
dose was given, the incidence of grade 4 neutropenia was significantly lower for 
Nab-Paclitaxel 
(Abraxane) 
compared 
with 
CrEL-paclitaxel 
and 
febrile 
neutropenia was uncommon. Grade 3 sensory neuropathy was more common in 
the Nab-Paclitaxel (Abraxane) arm than in the CrEL-paclitaxel arm (10% versus 
2%), but was easily managed and improved rapidly. Based on the results of this 
study, Nab-Paclitaxel (Abraxane) is approved by the U.S. Food and Drug 
Administration (FDA) for the treatment of breast cancer after failure of 
combination chemotherapy for metastatic disease or relapse within 6 months of 
adjuvant chemotherapy.  
 
Randomized study comparing Nab-Paclitaxel (Abraxane) to docetaxel in 
metastatic breast cancer has completed.29 In this study, patients were 
randomized into four arms: Nab-Paclitaxel (Abraxane) 300 mg/m2 every 3 weeks, 
Nab-Paclitaxel (Abraxane) 100 mg/m2 weekly for 3 out of 4 weeks, Nab-
Paclitaxel (Abraxane)150 mg/m2 weekly for 3 out of 4 weeks, or docetaxel 100 
mg/m2 every 3 weeks.  Report of interim analysis showed that the response rate 
of both weekly Nab-Paclitaxel (Abraxane) schedules were significantly better 
than 3-weekly Nab-Paclitaxel (Abraxane) and docetaxel and the progression-free 
survival was significantly better for Nab-Paclitaxel (Abraxane) regardless of 
schedule. All doses of Nab-Paclitaxel (Abraxane) were better tolerated than 
docetaxel. The difference between Nab-Paclitaxel (Abraxane) and docetaxel 
toxicity was most striking in the incidence of neutropenia: grade 3-4 neutropenia 
occurred in 95% of docetaxel patients compared with only 22% of those on Nab-
Paclitaxel (Abraxane) arms. 
 
Nab-Paclitaxel (Abraxane) is also active in head and neck cancer.30 In a phase 
I/II study, 31 patients with advanced head and neck cancer were treated with 
Nab-Paclitaxel (Abraxane) by intraarterial administration. The maximal tolerance 
dose (MTD) was determined to be 270 mg/m2. Of 29 patients with assessable 
diseases, 3 had complete response and 19 partial responses, with a total 
response rate of 76% (10% complete response and 66% partial response). No 
human trials using Nab-Paclitaxel (Abraxane) with radiation have been reported; 
however, preclinical data has also shown that Nab-Paclitaxel (Abraxane) has 
tumor radiosensitizing effects, while not increasing normal tissue sensitivity.  A 


 
11
dose of 90 mg/m2 (150% of the MTD of paclitaxel) demonstrated no treatment 
related animal toxicity, and tumor progression was significantly delayed.31   
 
Nab-Paclitaxel (Abraxane) has also demonstrated activity in NSCLC.32-37  Green 
et. al. evaluated Nab-Paclitaxel (Abraxane) 260mg/m2 in 43 patient who had not 
previously received therapy for advanced NSCLC.33  The overall response rate of 
16% and median time to progression (TTP) of 6 months were comparable with 
reports of phase II trials of single agent paclitaxel but without the need for 
premedication.  The median OS was 11 months and 1-year survival rate was 
45%.  Virtually identical results were seen in a phase I/II trial at a dose of 
125mg/m2 on days 1, 8 and 15 of a 28-day cycle conducted by Rizvi et al.36  
Stinchcombe and colleagues have evaluated Nab-Paclitaxel (Abraxane) in 
combination with carboplatin in advance solid tumors, including NSCLC, and 
found that the combination demonstrates level of activity comparable with 
paclitaxel/carboplatin, with less toxicity.37  The study enrolled 41 patients and 
evaluated escalating doses of Nab-Paclitaxel (Abraxane) with 3 different 
schedules of drug administration (weekly for 3 out of 4 weeks, on days 1 and 8 
every 21 days, and on days 1 every 21 days) in combination with a fixed dose of 
carboplatin area under the curve (AUC) of 6.  The primary toxicity of the 
combination was myelosuppression.  The maximum tolerated dose (MTD) for 
Nab-Paclitaxel (Abraxane) were 100 mg/m2, 125 mg/m2 and 300 mg/m2 for the 
weekly, days 1 and 8, and every 21-day schedules respectively.  Allerton et al 
also evaluated weekly Nab-Paclitaxel (Abraxane) 100mg/m2 combined with 
carboplatin AUC of 6 in 56 patients.32  They compared the toxicity and outcomes 
with a similar regimen of carboplatin/paclitaxel and found a comparable level of 
benefit with less neurotoxicity (0% vs 5%).  A large phase I/II study by Hawkins et 
al evaluated 4 cohorts of patients with previously untreated NSCLC.34  Nab-
Paclitaxel (Abraxane) was administered to cohorts of 25 patients at doses of 225 
mg/m2, 260 mg/m2, 300 mg/m2 and 340 mg/m2 in combination with carboplatin 
AUC of 6.  The response rate was 27% overall, without a clear dose response.  
More recently, initial results of a randomized phase III trial of Nab-Paclitaxel 
(Abraxane) and carboplatin compared with paclitaxel and carboplatin as first-line 
therapy in advanced NSCLC were presented.38 Patients received carboplatin 
AUC of 6 every 3 weeks and either Nab-Paclitaxel (Abraxane) at 100 mg/m2 
every week or paclitaxel 200 mg/m2 every 3 weeks.  The primary endpoint of 
overall response rate was met with a rate of 33% for the Nab-Paclitaxel 
(Abraxane) group verus 25% for the paclitaxel group.  Additionally, Nab-
Paclitaxel (Abraxane) was well tolerated with significantly improved safety profile 
compared to paclitaxel, with decreased rates of neutropenia, neuropathy, 
myalgia and arthralgias. 
 
In an attempt to further decrease rates of adverse effects, Paik et al has shown 
that infusion of 125 mg/m2 of Nab-Paclitaxel (Abraxane) over 2 hours (compared 
to the standard 30 minutes) on days 1, 8, and 15 of a 28-day cycle for the 
treatment of advanced NSCLC lead to decreased rates of peripheral neuropathy 
and neutropenia with similar rates of median overall survival of 11 months.39 
 
1.4 
Rationale 
 
Unresectable and/or metastatic NSCLC is a cancer with few successful 
therapeutic options.  Since taxanes have been widely used in treating locally 
advanced 
non-small 
cell 
lung 
cancer, 
Nab-Paclitaxel 
(Abraxane) 
has 
demonstrated activity in non-small cell lung cancer and has better side effect 
profile as compared to Cremophor EL-based paclitaxel and docetaxel as 
demonstrated in the breast cancer trials and phase I/II NSCLC trials, and 
potentially better antitumor activity, it is of interest to further explore the use of 


 
12
Nab-Paclitaxel (Abraxane) in concurrent chemoradiotherapy for treating non-
small cell lung cancer.  
 
The investigators at the Vanderbilt University just completed a Phase I trial 
evaluating weekly nab-paclitaxel/carboplatin with concurrent radiation therapy 
(66 Gy) in patients with unresectable stage III NSCLC.40 In that trial, eleven 
patients were enrolled. Ten patients were treated at 2 dose levels of nab-
paclitaxel, 40mg/m2 (6 pts) and 60mg/m2 (4 pts). One patient signed consent and 
then withdrew. Six patients were treated at 40mg/m2 with no dose limiting 
toxicities (DLT). Four patients were treated at 60mg/m2 with 2 DLT of radiation 
dermatitis and esophagitis. During concurrent treatment, Grade 2 toxicities were 
fatigue, dehydration, nausea, dysphagia, esophagitis, mucositis, hypoxia, 
neutropenia, anemia, and thrombocytopenia, and Grade 3 toxicities were 
neutropenia, mucositis, esophagitis, and dermatitis. No grade 4 toxicities were 
seen during concurrent treatment. Ten patients were evaluable for response with 
9 partial responses and 1 stable disease. Based on these results, the 
investigators recommended a Phase II dose of weekly nab-paclitaxel to be 
40mg/m2. However we will explore 50 mg/m2 of nab-paclitaxel as a lead in dose 
during the initial phase. 
 
We propose this phase I/II study to use weekly Nab-Paclitaxel (Abraxane) and 
carboplatin with concurrent radiation in local-regionally advanced lung cancer. 
There are no published human studies combining Nab-Paclitaxel (Abraxane) with 
radiation.  We will first confirm the tolerated dose (TD) of concurrent Nab-
Paclitaxel (Abraxane) at 50mg/m2, and then will begin enrolling patients into the 
phase II component using either Nab-Paclitaxel (Abraxane) at the TD with 
carboplatin concurrent with daily radiation or paclitaxel with with carboplatin 
concurrent with daily radiation. 
 
 
 
2.0 
OBJECTIVES  
 
2.1 
Primary Objective 
 
To determine the 2-year overall survival from randomization for patients receiving 
carboplatin/paclitaxel or carboplatin/nab-paclitaxel with radiation therapy 
 
2.2 
Secondary Objectives 
 
2.2.1 
To determine the feasibility of concurrent carboplatin/nab-paclitaxel and radiation 
therapy as measured by safety and compliance.  Safety is measured by the rate 
of grade 3 or higher radiation related esophagitis or pulmonary toxicity or 
chemotherapy related grade 4 hematological or other non-hematological toxicities 
occurring within 60 days of the start of treatment; compliance is defined as the 
completion of the treatment regimen with no more than minor variations. 
 
2.2.2 
To 
determine 
the 
overall 
response 
rate 
for 
patients 
receiving 
carboplatin/paclitaxel or carboplatin/nab-paclitaxel with radiation therapy 
 
2.2.3 
To 
determine 
the 
progression-free 
survival 
for 
patients 
receiving 
carboplatin/paclitaxel or carboplatin/nab-paclitaxel with radiation therapy 
 
2.2.4 
To 
determine 
the 
median 
overall 
survival 
for 
patients 
receiving 
carboplatin/paclitaxel or carboplatin/nab-paclitaxel with radiation therapy 
 


 
13
2.2.5 
To assess quality of life (QOL) of patients receiving either nab-paclitaxel or 
paclitaxel when given with concurrent radiotherapy 
 
2.2.6 
To correlate outcomes (survival, toxicity, QOL) with biological parameters (future 
analysis under UTSW tissue bank protocol – see Section 11.0). 
 
3.0 
PATIENT SELECTION 
 
3.1 
Eligibility 
 
3.1.1 
Histologically or cytologically documented NSCLC, including squamous cell 
carcinoma, adenocarcinoma (including bronchioloalveolar carcinoma), and 
large cell anaplastic carcinoma (including giant and clear cell carcinomas) and 
poorly differentiated (not otherwise specified, NOS) non-small cell lung cancer; 
totally resected tumors are excluded. 
 
Patients must be M0;  
 
Patients with T1 or T2 disease with N2 or T3N1-2 disease (Stage IIIA) 
are eligible.  
 
Patients with T4 with any N or any T with N3 disease are eligible (Stage 
IIIB).  
 
Measurable disease is required. See Section 10.4 for RECIST definitions 
of measurable disease. 
3.1.2 
Patients with tumors adjacent to a vertebral body are eligible as long as all 
gross disease can be encompassed in the radiation boost field.  The boost 
volume must be limited to < 50% of the ipsilateral lung volume. 
3.1.3 
Patients must be ≥18 years of age 
3.1.4 
Patients with Zubrod performance status 0-1 (See Appendix A) 
3.1.5 
Adequate hematologic function defined as:  ANC ≥ 1,000/mm3, platelets ≥ 
100,000/mm3, and hemoglobin ≥ 9 g/dL (prior to transfusions); adequate 
hepatic function defined as:  total bilirubin ≤ 1.5 x upper limit of normal (ULN), 
AST/SGOT and ALT/SGPT ≤ 2.5 x ULN, adequate renal function defined as 
Creatinine clearance > 30 mL/minute (calculated by Cockcroft-Gault formula), a 
serum creatinine level ≤ 1.5 mg/dL alkaline phosphatase ≤ 2.5 x ULN, glucose 
≤ 2 x ULN 
3.1.6 
FEV1 with ≥ 1200 cc or ≥ 50% predicted 
3.1.7 
Patients with weight loss ≤ 10% over the past 3 months 
3.1.8 
Patients with a pleural effusion that is a transudate, cytologically negative and 
non-bloody are eligible if the radiation oncologists feel the tumor can still be 
encompassed within a reasonable field of radiotherapy  (See Sections 6.4 and 
6.5).  If a pleural effusion can be seen on the chest CT but is too small to tap, 
the patient is eligible. 
3.1.9 
Patients who have recovered from exploratory thoracotomy 
3.1.10 
Women of childbearing potential must have a negative serum pregnancy test 
performed within 7 days prior to registration 
3.1.11 
Pretreatment evaluations required for eligibility include:  
 
A medical history, physical examination, assessment of Zubrod 
performance status within 4 weeks prior to study entry;  
 
CBC with differential and platelet count, and laboratory profile must be 
completed within 4 weeks prior to study entry;  
 
FEV1, CT scan or MRI of the chest,  a bone scan (or PET or PET/CT), 
and a CT scan or MRI of the brain (to rule out brain metastasis) within 6 
weeks prior to study entry; 
 
Medical Oncology and Radiation Oncology consults and approval. 
3.1.12  
Patients must sign a study-specific consent form prior to study entry. 
 


 
14
3.2 
Conditions for Patient Ineligibility  
 
3.2.1 
Prior systemic chemotherapy (for lung cancer) and/or thoracic/neck 
radiotherapy for any reason and/or surgical resection of present cancer; 
3.2.2 
 Exudative, bloody, or cytologically malignant effusions; 
3.2.3 
 Prior therapy with any molecular targeted drugs (for lung cancer) 
3.2.4 
 Active pulmonary infection not responsive to conventional antibiotics; 
3.2.5 
Active cardiac disease defined as unstable angina, uncontrolled hypertension, 
myocardial infarction in the last six months (unless successfully treated with 
CABG or PTCA), uncontrolled arrhythmia, or congestive heart failure; > 3 
heart-related hospitalization in the past year. 
3.2.6 
 Patients with > grade 1 neuropathy; 
3.2.7 
 Evidence of malignancy in the past 2 years except for adequately treated basal 
cell or squamous cell skin cancer, in situ cervical cancer, or other in situ 
cancers; 
3.2.8 
 Women who are pregnant or breast feeding, as treatment involves 
unforeseeable risks to the participant, embryo, fetus, or nursing infant; women 
with a positive pregnancy test on enrollment or prior to study drug 
administration; 
3.2.9 
 Women of childbearing potential and male participants who are unwilling or 
unable to use an acceptable method of contraception throughout the study and 
for four weeks after completion of treatment or those who are using a 
prohibited contraceptive method. 
3.2.10  Patients who currently are participating in other phase III therapeutic clinical 
trials and/or who have participated in other phase III therapeutic clinical trials in 
the previous 30 days. 
3.2.11  Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or 
diastolic pressure > 90 mmHg, despite optimal medical management 
3.2.12   Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or 
3.2.13  
Active clinically serious infection > CTCAE Grade 2. 
3.2.14 
Thrombolic or embolic events such as a cerebrovascular accident including 
transient ischemic attacks within the past 6 months. 
3.2.15 
Pulmonary hemorrhage/bleeding event ≥CTCAE Grade 2 within 4 weeks of 
study registration. 
3.2.16 
Any other hemorrhage/bleeding event ≥CTCAE Grade 3 within 4 weeks of 
study registration. 
3.2.17 
Serious non-healing wound, ulcer, or bone fracture. 
3.2.18 
Evidence or history of bleeding diathesis or coagulopathy. 
3.2.19 
Major surgery, open biopsy or significant traumatic injury within 4 weeks of first 
study drug. 
3.2.20 
Known or suspected allergy to any agent given in the course of this trial.  
3.2.21    Total bilirubin  > 1.5x the upper limit of reference range (ULRR) 
3.2.22  
Creatinine clearance < 30 mL/minute (calculated by Cockcroft-Gault formula).   
3.2.23    CTCAE  V4.0 grade 3-4 electrolyte abnormalities: 
•  
Calcium < 7 mg/dl or > 12.5 mg/dl; 
•  
Glucose < 40 mg/dl or > 250 mg/dl; 
• 
 Magnesium < 0.9 mg/dl or > 3 mg/dl; 
•  
Potassium < 3 mmol/L or > 6 mmol/L; 
•  
Sodium < 130 mmol/L or > 155 mmol/L 
3.2.24    Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × 
ULRR or alkaline phosphatase (ALP) >2.5 x ULRR. 
3.2.25    Evidence of severe or uncontrolled systemic disease or any concurrent 
condition which in the Investigator’s opinion makes it undesirable for the patient 
to participate in the trial or which could jeopardize compliance with the protocol. 
3.2.26 
Any unresolved toxicity greater than CTC grade 1 from previous anti-cancer 
therapy 


 
15
 
  
3.3 
Restrictions 
 
Patients who are blood donors should not donate blood during the trial and for 3 
months following their last dose of trial treatment. 
 
 
 
4.0  
RECOMMENDED PRETREATMENT EVALUATIONS  
(In addition to required evaluations in Section 3.1.11) 
 
4.1  
PET scan of chest at pretreatment:  Highly recommended. 
 
4.2 
Post-treatment PET scan 
 
The post-treatment PET scan is also highly recommended on the same scanner 
(or, if this is not feasible, on the same model PET scanner).  The post-treatment 
PET scan will be done approximately 12-16 weeks after the completion of all 
radiotherapy/chemotherapy that the participant has received. This includes any 
adjuvant, post-radiotherapy chemotherapy. It will be done no sooner than 12 
weeks after the completion of radiotherapy in order to allow for partial resolution 
of post-treatment inflammatory effects that can cause false positive PET scan 
results. 
 
4.3 
Patient-Reported 
Outcomes: 
Trial Outcome Index 
of the 
Functional 
Assessment of Cancer Therapy-Lung (FACT-L), FACT-Taxane and EQ-5D 
 
 
 
5.0  
REGISTRATION PROCEDURES 
 
5.1  
Pre-Registration Requirements  
   
See study parameters (section 10.1) for a complete list of required pre-
registration procedures. 
 
5.2  
Registration 
The coordinating center for this trial will be UT Southwestern. Patients can be 
registered only after eligibility criteria are met and approved by UTSW. For 
patients who pass screening, a completed patient registration form, which can be 
found in your forms binder,  and a copy of the signed patient consent will need to 
be faxed with the provided cover sheet to: Radiation Oncology Clinical 
Research, UT Southwestern, fax 214-645-8913. UTSW will review the eligibility 
criteria to ensure eligibility and will fax back page 3 of the form which will contain 
signature and patient study number. If a patient is ineligible or if a waiver is 
granted, the enrolling institution will be notified of such decision which will include 
a brief explanation. Any waiver granted for patient eligibility is at the discretion of 
the principal investigator, Dr. Choy.   
5.3 
Written Informed Consent 
Provision of written Informed Consent must be obtained prior to any study-related 
procedures.  The principal investigator will ensure that the subject is given full 
and adequate oral and written information about the nature, purpose, possible 
risk and benefit of the study.  Subjects must also be notified that they are free to 
discontinue from the study at any time.  The subject should be given the 
opportunity to ask questions and allowed time to consider the information 
provided. 


 
16
The principal investigator must store the original, signed written Informed 
Consent Form.  A copy of the signed written Informed Consent Form must be 
given to the subject.  Where genetic analyses are included, special account of 
these will be made in the consent form, as it is recognized that special provisions 
need to be made to retain confidentiality of medical information.  These factors 
have been taken into account in the design of the consent form.  Consent forms 
specific for the collection of genotyping samples will be used; the format depends 
on the design of the study.  The subject’s signed and dated informed consent(s) 
must be obtained before conducting any procedure specifically for the study.  
The principal investigator(s) must store the original, signed written Informed 
Consent Form(s).  A copy of the signed written Informed Consent Form(s) must 
be given to the subject. If modifications are made according to local 
requirements, the new version has to be approved by Celgene. 
 
5.4 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act 
(HIPAA), the written Informed Consent Form must include a subject authorization 
to release medical information to Celgene and/or allow Celgene, a regulatory 
authority, or Institutional Review Board access to subject’s medical information 
that includes all hospital records relevant to the study, including subjects’ medical 
history. 
 
 
 
 
6.0  
RADIATION THERAPY [NOTE: INTENSITY MODULATED RADIOTHERAPY (IMRT) IS 
ALLOWED] 
Questions regarding Radiation Therapy should be directed to Dr. Choy, (preferably 
by email or alternatively by phone). 
 
Protocol treatment must begin within 4 weeks after patient registration to the 
trial.   
 
6.1 
Dose Specifications 
 
6.1.1  
Patients will receive treatment 5 days per week, in once daily fractions, 2 Gy per 
fraction.  The total dose will be 60 Gy in 30 fractions.  There are no field 
reductions.  All fields must be treated daily and the entire PTV must be treated 
daily.  Radiation therapy (RT) commences within 48 hours of chemotherapy.  On 
days when chemotherapy is given concurrently with RT, chemotherapy is not 
necessarily administered prior to RT. 
 
6.1.2 
Normalization of the treatment plan will cover 95% of the PTV with the 
prescription dose.   The minimum PTV dose must not fall below 95% of the 
prescription dose. All radiation doses will be calculated with inhomogeneity 
corrections that take into account the density differences within the irradiated 
volume (i.e., air in the lung and bone).  The MTD will be quoted as the PTV 
minimum target dose.    The maximum and minimum point doses (within the 
PTV) will be reported.   
 
6.1.3 
Variations of dose prescription: 
 
6.1.3.1  
No deviation:  ≥ 95% of the PTV receives the prescribed dose; ≥ 
99% of the PTV receives ≥ 93% of the prescribed dose, and no more 
than 20% of the PTV receives ≥110% of the prescribed dose. 
 
 


 
17
6.1.3.2 
Minor deviation:  Deviations of this magnitude are not desirable, but 
are acceptable.  Coverage for the dose that is equal to 93% of the 
prescribed dose falls below 99% of the PTV but not below 95% of 
this volume.  Or, between 20 and 25% of the PTV receives >110% of 
the prescribed dose. 
 
6.1.3.3 
Major deviation:  Doses in this region are not acceptable.  More than 
1 cm3 of tissue outside the PTV receives ≥ 110% of the prescribed 
dose.  Or, coverage for the dose that is equal to 93% of the 
prescribed dose falls below 95% of the PTV.    Or, > 25% of the PTV 
receives ≥ 110% of the prescribed dose. 
 
6.1.4 
Heterogeneous dose 
calculations: For the 
purposes of this 
protocol, 
superposition/convolution dose calculation algorithms demonstrate agreement 
between planned versus delivered dose.    
 
6.2 
Technical Factors  
 
6.2.1 
Beam Energy:   6 - 18 MV are to be used.  
6.2.2 
Beam Shaping:  Multi-leaf collimation (MLC) or individually-shaped custom 
blocks should be used to protect normal tissues outside of the target volume. 
 
6.3 
Localization, Simulation, and Immobilization 
 
6.3.1 
A volumetric treatment planning CT study will be required to define gross tumor 
volume (GTV), clinical target volume (CTV), and planning target volume (PTV) 
(see definitions below).  Each patient will be positioned in an immobilization 
device in the treatment position on a flat table.  Contiguous CT slices, having 3 
mm thickness through the regions harboring gross tumor and grossly enlarged 
lymph nodes and 8-10 mm thickness of the remaining regions are to be obtained 
starting from the level of the cricoid cartilage and extending inferiorly through the 
entire liver volume.  The GTV, CTV, and PTV and normal organs will be outlined 
on all appropriate CT slices. 
 
6.3.2 
A treatment planning FDG PET/CT scan (or FDG-PET alone) with the patient in 
the treatment position is encouraged for treatment planning.  In the case where 
the PET/CT is obtained in the treatment position, the CT from this study may be 
used as the planning CT scan. 
 
6.3.3 
Intravenous (IV) contrast during the planning CT is optional provided a diagnostic 
chest CT was done with contrast to delineate the major blood vessels.  If not, IV 
contrast should be given during the planning CT. If contrast is used, the densities 
can be overridden or the contrast scan must be registered to a non-contrast scan 
for planning purposes. 
 
6.3.4 
Optimal immobilization is critical for this protocol.  Immobilization to assure 
reproducibility of the set-up is necessary. 
 
6.3.5 
The use of four-dimensional radiation treatment planning is highly encouraged.  
Acceptable methods of accounting for tumor motion include:  design of the PTV 
to cover the excursion of the lung primary cancer and nodes during breathing 
such as an ITV approach,  a maximum intensity projection (MIP) approach, 
automatic breath-hold (i.e., Elekta ABC device) or a gating approach (e.g., Varian 
RPM system). 
  
6.4 
Treatment Planning/Target Volumes 


 
18
 
6.4.1 
Target Volumes: The definitions of volumes will be in accordance with the 1993 
ICRU Report #62  
 
6.4.1.1 Definition of the GTV:  The primary tumor and clinically positive lymph 
nodes seen either on the planning CT (> 1 cm short axis diameter) or 
pretreatment PET scan (SUV > 3) will constitute the GTV.  This 
volume(s) may be disjointed.  In the event of a collapsed lobe or lung 
segment, the use of PET to distinguish tumor from fluid/atelectasis is 
encouraged. The ITV includes the envelope that encompasses the tumor 
motion for a complete respiratory cycle.   
 
6.4.1.2 Definition of the CTV:  The CTV is defined to be the GTV plus a 0.5 cm 
to 1 cm margin as appropriate to account for microscopic tumor 
extension. If an ITV approach is used then the ITV plus 0.5 cm to 1 cm is 
added to the ITV to form the CTV.  Elective treatment of the mediastinum 
and supraclavicular fossae will not be done. 
 
6.4.1.3 Definition of the PTV:   
Non-ITV approach:   
There are two components to the PTV expansion if the ITV approach is 
not used.  The first is a margin to account for motion (IM margin) which 
should be at least 1 cm in the inferior-superior direction, and 0.5 cm in 
the axial plane.  An additional 0.5 – 1.0 cm margin should be added to 
account for setup uncertainty (SU margin).  If the ITV approach is NOT 
used then the total PTV includes the CTV plus a total margin of 1.5 to 2.0 
cm to the superior-inferior dimensions and 1.0 to 1.5 cm in the axial 
plane. If daily imaging is used to align vertebrae on a daily basis we 
recommend using the smaller of these margins.   
ITV approach:  
If the ITV approach is used, then the PTV margin should account for 
setup uncertainties and may be individualized but should not be less 
than 1.0 cm.  If daily imaging is used to align the vertebral bodies, then 
the margins for setup margins may be reduced to 0.5 cm.   
For institutions not using 4DCT, the use of fluoroscopy to determine the 
margin for motion in the inferior superior direction is encouraged.   
For institutions with gating technology, the use of respiratory gating is 
encouraged.  
 
6.4.1.4 Normal anatomy to be identified:  The normal anatomy to be outlined on 
each CT image will include the lungs (right and left done separately), 
heart, skin, esophagus and spinal cord.  The heart should be contoured 
from its base to apex, beginning at the CT slice where the ascending 
aorta originates.  The esophagus should be contoured from the bottom of 
the cricoid to the gastroesophageal junction.  The skin and spinal cord 
should be contoured on each CT slice. 
 
6.4.2 
Treatment Planning: 
 
6.4.2.1 3D Conformal Therapy   The PTV is to be treated with any combination 
of coplanar or noncoplanar 3-dimensional conformal fields shaped to 
deliver the specified dose while restricting the dose to the normal tissues.  
Field arrangements will be determined by 3D planning to produce the 
optimal conformal plan in accordance with volume definitions.  The 
treatment plan used for each patient will be based on an analysis of the 


 
19
volumetric dose including DVH analyses of the PTV and critical normal 
structures.  Each field is to be treated daily. 
 
6.4.2.2 Intensity Modulated Radiation Therapy (IMRT): IMRT is allowed for intra-
thoracic IMRT treatments.  
  
6.5 
Critical Structures 
Normal tissue constraints shall be prioritized in the following order for treatment 
planning:  1=spinal cord, 2=lungs, 3=esophagus, 4=brachial plexus, and 5=heart. 
 
6.5.1 
Spinal Cord:  The spinal cord dose limitation is the highest priority dose 
constraint and thus must be met irrespective of other constraints.  Total “direct” 
dose to the spinal cord must not exceed 48 Gy, and total dose must not exceed 
50.5 Gy (counting scatter dose).  
 
6.5.2 
Lungs:  The dose-volume constraint to the lungs is the second highest priority 
and must be met, except if it conflicts with the cord dose constraints.  The volume 
of both lungs that receive more than 20 Gy (the V20) should not exceed 37% of 
the total.  Alternatively, the mean lung dose should optimally be ≤ 20 Gy.  (By 
total lung volume we mean the total lung minus the CTV).   
 
6.5.2.1 If either of these constraints is exceeded, several solutions can be 
entertained. 
First, one might increase the weighting of AP/PA treatments by one and 
reduce the obliques.  This can be done as long as the cord dose (above), 
which takes precedence, is not exceeded.  
Second, one can reduce the CTV to the minimum range suggested 
above.  
Third, one can try to reduce the PTV by using respiratory gating 
techniques.  
If after all attempts to decrease the V20 to below 37%, the V20 value still 
exceeds this limit, the patient should be treated to the dose specified 
 
6.5.3 
Esophagus:  The mean dose to the esophagus is optimally kept below 34 
Gy.41,42 This is not an absolute requirement, but is strongly recommended unless 
other, more critical constraints force the situation.  The V60 (% volume of 
esophagus exceeding 60 Gy) should be calculated for each patient. 
 
6.5.4 
Brachial Plexus:  Brachial plexus doses should be kept <66 Gy. 
 
6.5.5 
Heart:  The following limits are recommended:  60 Gy to <1/3, 45 Gy to <2/3, and 
40 Gy to <100% of the heart.  
 
6.5.6 
Skin:  Care should be taken to minimize the volume of skin receiving the full 
dose.  No “hot spot” (except within pure tumor) should exceed 120%. 
 
6.6 
Documentation Requirements 
 
6.6.1  
Portal image of each field of 3-D radiotherapy or orthogonal images that 
localize the isocenter placement of IMRT must be obtained on the first day of 
therapy but should not be submitted. 
 
6.6.2  
Weekly verification or orthogonal images are required to be taken, but not 
submitted. This verification information also can be gathered with cone-beam 
CT or other CT devices that are present in the treatment room. 
 


 
20
6.6.3  
Isodose plans for 3-D radiotherapy and IMRT and DVHs of GTV, CTVs, and 
critical normal structures for IMRT. 
 
6.7 
Compliance Criteria    
See Section 6.1.3 for radiation dose compliance criteria. 
 
6.8 
R.T. Quality Assurance Review 
 
The Radiation Oncology Principal Investigator, Hak Choy, M.D., will perform an 
RT Quality Assurance Remote Review after complete data for the first 20 cases 
enrolled have been received at the UTSW. Dr. Choy will perform the next remote 
review after complete data for the next 20 cases enrolled have been received at 
the UTSW. The final cases will be reviewed within 3 months after this study has 
reached the target accrual or as soon as complete data for all cases enrolled 
have been received at UTSW, whichever occurs first.  
 
The Radiation Therapy Quality Assurance (RTQA) Review will be performed by 
Hak Choy, M.D. All of the materials listed below should be forwarded to: 
 
Jean Wu  
Clinical Research Manager 
Department of Radiation Oncology 
 
5641 Southwestern Medical Ave. 
Dallas, Texas 75235-8808 
 
214-648-1892 
 
Fax: 214-645-8913 
 
Jean.Wu@UTSouthwestern.edu 
 
6.9 
Radiation Therapy Adverse Events 
 
6.9.1  
Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and 
esophagitis are expected side effects of radiation therapy. Radiation induced 
myocarditis or transverse myelitis rarely occur at doses lower than 50 Gy. 
Radiographic evidence of radiation change and subsequent fibrosis of the lung 
will occur ?within lung volume receiving ≥ 20 Gy, usually within the first six 
months after initiation of treatment. It is essential to spare as much normal lung 
as possible in order to avoid symptomatic lung injury. 
 
6.9.2    Esophagitis 
Esophageal complaints are common with combined modality therapy. Esophagitis 
does not constitute a reason to interrupt or delay radiotherapy or chemotherapy 
provided oral intake is sufficient to maintain hydration. Patients should be advised 
to avoid alcoholic, acidic, or spicy foods or beverages. Viscous Xylocaine, 
Carafate, or other medications should be used for symptomatic relief. 
Occasionally, narcotics may be required. 
It is not necessary to biopsy acute esophagitis in the first 2 weeks of combined 
therapy since it is rarely due to underlying viral or fungal disease. Acute 
esophagitis may persist for 4-6 weeks.  If Grade 4 esophagitis occurs, and a 
treatment interruption is being considered, every effort should be made to limit it 
to 3 treatment days or less. Patients requiring hospitalization because of 
esophagitis may have their treatment interrupted.  In this event, please notify Dr. 
Choy. 
Esophagitis should be graded according to the CTCAE v.4.0 
 
Table 1: Esophagitis grading system 


 
21
Grade
Clinical Scenario
1
Asymptomatic pathologic, radiographic, or endoscopic findings only 
2
Symptomatic; altered eating/swallowing (e.g., altered dietary habits, oral 
supplements), IV fluids indicated  <24 hrs      
3 
Symptomatic and severely altered eating/swallowing (e.g., inadequate oral 
caloric or fluid intake), IV fluids, tube feedings, or TPN indicated >24 hrs
4 
Life-threatening consequences  
5
Death
 
Treatment should be interrupted for grade 4 or greater dysphagia or 
odynophagia. Acute esophageal toxicity, which typically can occur within two 
weeks of the initiation of treatment and manifests as dysphagia, odynophagia, 
reflux symptoms, etc. should be pharmacologically managed with the following 
approach and should be initiated at the first signs or symptoms of esophageal 
toxicity.  Recommended treatments are in Table 2. 
 
Table 2:  Suggestions for management of radiation esophagitis  
1) Ketoconazole 200 mg PO q day OR
2) Fluconazole 100 mg PO q day until the completion of radiation 
3)   Mixture of: 2% viscous lidocaine: 60 cc 
Mylanta: 30 cc 
Sucralfate (1 gm/ 10cc): 10 cc  
Take 15-30 cc of mixture PO q3-4 hrs prn. 
(Contraindications: pts on Dilantin, Cipro, Digoxin) 
4) Ranitidine 150 mg PO BID (or other H2 blocker or a proton pump inhibitor such 
as omeprazole)until the completion of radiation 
5) Grade 4 esophagitis:  hold RT + chemotherapy until grade 2 or less.  We expect 
a significant portion of patients will experience grade 3 esophagitis.  
 
6.10 
Functional Imaging  
FDG-PET functional imaging is not a required component of this protocol, but is 
strongly encouraged for cancer staging. 
6.10.1 Adverse Events 
Adverse events from FDG-PET are exceedingly rare.  If an adverse event from 
functional imaging is to occur, it would most likely be related to the intravenous 
catheter infusion site, consisting of erythema and discomfort from the IV.  An 
allergic reaction to the FDG is possible as well. 
 
6.11 
Radiation Adverse Event Reporting  
 
 
See Section 9.0 for Adverse Event Reporting. 
 
7.0  
DRUG THERAPY 
 
7.1 
Treatment Plan 
 
This is a multi-center randomized phase I/II study evaluating 60 Gy 
chemoradiation therapy with carboplatin/paclitaxel or carboplatin/nab-paclitaxel in 
patients with locally advanced NSCLC.  Nab-paclitaxel will be administered (in 
conjunction with carboplatin) to the patients at a planned dose run-in of 50 mg/m2 
during the initial feasibility testing phase followed by 50 mg/m2 during the phase II 
stage intravenously in a weekly manner if no more than 1 dose limiting toxicities 
(DLT) are observed.  If more than 1 DLTs are observed in the phase I stage, then 
a dose level of 40 mg/m2 will be used in the phase II stage.  During the 
consolidation phase, a 100mg/m2 weekly dose of nab-paclitaxel (in conjunction 
with carboplatin) will be administered.  


 
22
 
 
Phase 1 (Feasibility Testing): Nab-paclitaxel dose during the concurrent phase 
(in conjunction with weekly carboplatin AUC=2) 
 
Level   
Dose 
 
 
# of patients 
1 
  
50 mg/m2  
 
initially 3, then if there are < or = 
1 DLT increase to 6  
-1 
  
40 mg/m2 
(continue to phase 2 using dose level 1 if < or = 1 DLT total out of the 6 
patients; if > 1 DLT, use dose level -1 in phase 2 stage) 
 
This study will utilize the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 for grading of all adverse events. A copy of the CTCAE v4.0 
can be downloaded from the CTEP home page (http://ctep.info.nih.gov).  A DLT 
will be considered if it is deemed to be definitely or probably related to treatment. 
 
We define dose-limiting toxicity (DLT) as: 
 
 
• 
Any > grade 4 hematologic toxicity that lasted > 7 days 
• 
Any > grade 3 other non-hematologic toxicity that lasted > 7 days 
(excluding esophagitis, nausea, vomiting, and alopecia) 
• 
Grade 3 or 4 febrile neutropenia 
 
Based on the Phase I stage, 40mg/m2 of nab-paclitaxel will be administered 
during the concurrent chemoradiation phase. 
 
7.1.1     Concurrent Chemoradiation (Weeks 1-6)  
During the concurrent phase of treatment patients will receive paclitaxel 
50 mg/m² over 60 minutes and carboplatin AUC=2 over 30 minutes administered 
weekly for 6 weeks (6doses) or will receive nab-paclitaxel 40 mg/m2 based on 
phase I stage over 30 minutes and carboplatin AUC=2 over 30 minutes 
administered weekly for 6 weeks (6doses).  Weekly administration of nab-
paclitaxel or paclitaxel with carboplatin will be considered as one cycle for a total 
of 6 cycles administered.  Patients need to be pre-medicated prior to paclitaxel 
infusion (see section 7.3.4). 
7.1.2 
Consolidation Therapy (Weeks 10-16) 
 
 
Beginning on week 10 (3 weeks post concurrent therapy), paclitaxel will be 
administered at 200 mg/m² over 3 hours and carboplatin at AUC=6 IV over 30 
minutes or nab-paclitaxel will be administered at 100 mg/m² over 30 minutes and 
carboplatin at AUC=6 IV over 30 minutes. Paclitaxel and carboplatin will be 
delivered every 3 weeks for 2 cycles or nab-paclitaxel will be delivered on days 1, 
8 and 15 (of a 21 day cycle) and carboplatin will be delivered on day 1 (of a 21 
day cycle) for 2 cycles. Patients need to be pre-medicated prior to paclitaxel 
infusion (see section 7.3.4).  
 
7.2 
Nab-Paclitaxel (ABI-007, Abraxane, albumin-bound paclitaxel) 
 
7.2.1 
Description: NAB-PACLITAXEL (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. NAB-PACLITAXEL (ABRAXANE) is supplied as a 


 
23
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. NAB-
PACLITAXEL (ABRAXANE) is free of solvents.   The active agent in NAB-
PACLITAXEL (ABRAXANE) is paclitaxel.  
 
7.2.2 
Potential Risks of NAB-PACLITAXEL (ABRAXANE) Toxicities  
 
Myelosuppression, nausea and vomiting, diarrhea, mucositis, infections, 
hypotension, abnormal ECG changes, cough, dyspnea, edema, sensory 
neuropathy, bilirubin/liver enzyme elevations, allergic reactions, alopecia, 
asthenia, arthralgia, and myalgia. During post marketing surveillance, rare cases 
of severe hypersensitivity reactions have occurred.  


 
24
Table 3: Frequency
a 
of Important Treatment Emergent Adverse Events in 
the Randomized Study on an Q3W Schedule  
Percent of Patients  
 
NAB-PACLITAXEL 
(ABRAXANE) 
260/30min
b
  
(n=229) 
 
Paclitaxel Injection 
175/3h
c,d 
 
(n=225) 
Bone Marrow  
Neutropenia  
< 2.0 x 10
9
/L  
< 0.5 x 10
9
/L 
80  
9  
82  
22  
Thrombocytopenia  
< 100 x 10
9
/L  
< 50 x 10
9
/L  
2  
<1  
3  
<1  
Anemia  
< 11 g/dL  
< 8 g/dL  
33  
1  
25  
<1  
Infections  
24  
20  
Febrile Neutropenia  
2  
1  
Bleeding  
2  
2  
Hypersensitivity Reaction
e 
 
All  
4  
12  
Severe
f 
0  
2  
Cardiovascular  
Vital Sign Changes
g 
 
Bradycardia  
<1  
<1  
Hypotension  
5  
5  
Severe Cardiovascular 
Events
f
 
3  
4  
Abnormal ECG  
All patients  
60  
52  
Patients with Normal 
Baseline  
35  
30  
Respiratory  
Cough  
7  
6  
Dyspnea  
12  
9  
Sensory Neuropathy  
Any Symptoms  
71  
56  
Severe Symptoms
f
 
10  
2  
Myalgia / Arthralgia  
Any Symptoms  
44  
49  
Severe Symptoms
f
 
8  
4  
 


 
25
Table 3 (continued): Frequency
a 
of Important Treatment Emergent Adverse 
Events in the Randomized Study on an Every-3-Weeks Schedule 
Percent of Patients  
 
NAB-PACLITAXEL 
(ABRAXANE)
®
 
260/30min
b
  
(n=229)  
 
Paclitaxel 
Injection 
175/3h
c,d 
 
(n=225)  
Asthenia  
Any Symptoms  
47  
39  
Severe Symptoms
f
 
8  
3  
Fluid Retention/Edema  
Any Symptoms  
10  
8  
Severe Symptoms
f
 
0  
<1  
Gastrointestinal  
Nausea  
Any symptoms  
30  
22  
Severe symptoms
f
 
3  
<1  
Vomiting  
Any symptoms  
18  
10  
Severe Symptoms
f
 
4  
1  
Diarrhea  
Any Symptoms  
27  
15  
Severe Symptoms
f
 
<1  
1  
Mucositis  
Any Symptoms  
7  
6  
Severe Symptoms
f
 
<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 
NAB-PACLITAXEL (ABRAXANE) dose in mg/m
2
/duration in minutes  
c 
paclitaxel injection dose in mg/m
2
/duration in hours  
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.  
 
7.2.3 
Nab-Paclitaxel (Abraxane) Premedication 


 
26
Patients do not require premedication prior to NAB-PACLITAXEL (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,43 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 NAB-
PACLITAXEL (ABRAXANE). 
 
7.2.4 
Study Medication Administration 
 
Nab-paclitaxel will be administered over 30 minutes for both the concurrent and 
consolidative phases.  
  
NOTE: For NAB Paclitaxel (ABRAXANE) the use of inline filters is not 
recommended because the reconstituted solution may clog the filter.   
 
7.2.5 
Dose Modifications/Reductions 
Administration of Study Drug to Patients with Abnormal Hematologic Function 
NAB-PACLITAXEL (ABRAXANE) dosing should not be administered at the start 
of each cycle (day 1 of q weekly cycle during the concurrent phase and day 1 of 
a 21 day cycle during the consolidation phase) until the absolute neutrophil count 
returns to ≥1.0 x 109 cells/L and the platelet count returns to >75 x 109 cells/L.  
For patients receiving weekly NAB-PACLITAXEL (ABRAXANE) for a 21 day 
cycle, for each subsequent dose of NAB-PACLITAXEL (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.  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 (21 days).   
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. 
Sensory Neuropathy 
NAB-PACLITAXEL (ABRAXANE) should be withheld in patients who experience 
≥ Grade 3 sensory neuropathy.  Treatment may be resumed at the next lower 
dose level (see Table 5) in subsequent cycles after the sensory 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 


 
27
experience Grade 4 sensory neuropathy, study drug should be withheld, and 
treatment resumed at a reduction of 2 dose levels (Dose Level -1; see Table 5) in 
subsequent cycles after the sensory neuropathy improves to ≤ Grade 1.  Note: 
the investigator may elect to dose modify for Grade 3 sensory neuropathy. 
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 NAB-
PACLITAXEL (ABRAXANE) should not be re-challenged.  It is not recommended 
to administer NAB-PACLITAXEL (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 5). 
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 may be administered at the 
discretion of the investigator, consistent with institutional guidelines.  
 
7.2.6 
Packaging, Labeling, and Storage of Study Drug 
Availability 
NAB-PACLITAXEL (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.  
  
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 NAB-PACLITAXEL (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 NAB-PACLITAXEL (ABRAXANE) should be used immediately, but 
may be refrigerated at 2ºC to 8ºC (36ºF to 46ºF) for a maximum of 8 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 8 hours.  


 
28
Study Medication Administration 
NAB-PACLITAXEL (ABRAXANE) is injected into a vein [intravenous (I.V.) 
infusion] over 30 minutes.  The use of an in-line filter is not recommended.  
Reconstitution and use of NAB-PACLITAXEL (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 NAB-PACLITAXEL (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.   
• 
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 NAB-PACLITAXEL (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. Draw up the calculated dosing volume of the 


 
29
reconstituted NAB-PACLITAXEL (ABRAXANE) suspension into a syringe and 
administer via a syringe pump or inject the dose into an emptysterile, standard 
PVC IV bag using an injection port if the dose volume is large enough to 
infuse the entire dose through a standard infusion pump.  If a standard PVC IV 
bag is used, 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 NAB-PACLITAXEL 
(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.  
7.2.7 
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 
Fax: 908-673-2779 
Email: npowers@celgene.com 
 
 
• 
Drug Distribution 
NAB-PACLITAXEL (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 NAB-PACLITAXEL 
(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 
 
• 
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 


 
30
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. 
 
7.3  
Paclitaxel 
 
7.3.1 
Formulation: Paclitaxel is a poorly soluble plant product from the pacific yew, 
Taxus brevifolia. Improved solubility requires a mixed solvent system with 
further dilutions of either 0.9% sodium chloride or 5% dextrose in water.  Vials 
will be labeled with shelf life.  All solutions of paclitaxel exhibit a slight haziness 
directly proportional to the concentration of drug and the time elapsed after 
preparation, although when prepared as described above, solutions of 
paclitaxel (0.3-1.2 mg/ml) are physically and chemically stable for 27 hours. 
 
7.3.2 
 Preparation: A sterile solution concentrate, 6 mg/ml in 5 ml vials (30 mg/vial) in 
polyoxyethylated castor oil (Cremophor EL) 50% and dehydrated alcohol, USP, 
50%.  The contents of the vial must be diluted just prior to clinical use.  
Paclitaxel for injection must be diluted before administration with 5% dextrose 
USP, 0.9% sodium chloride USP, or 5% dextrose in Ringer’s injection to a final 
concentration of 0.3 to 1.2 milligrams/milliliter.  This solution is stable for 27 
hours under ambient temperature (25 degrees Celsius) and room lighting (Prod 
Info Taxol, 1997). Use 5% polyolefin containers due to leaching of 
diethylhexphthalate (DEHP) plasticizer from polyvinyl chloride (PVC) bags and 
intravenous tubing by the Cremophor vehicle in which paclitaxel is solubilized.  
Each bag/bottle should be prepared immediately before administration.  NOTE: 
Formation of a small number of fibers in solution has been observed after 
preparation of paclitaxel (NOTE: acceptable limits established by the USP 
Particular Matter Test for LVP’s). Therefore, in-line filtration is necessary for 
administration of paclitaxel solutions. In-line filtration should be accomplished 
by incorporating a hydrophilic, microporous filter of pore size not greater than 
0.22 microns (e.g.: Millex-GV Millipore Products) into the IV fluid pathway distal 
to the infusion pump. Although particulate formation does not indicate loss of 
drug potency, solutions exhibiting excessive particulate matter formation 
should not be used. 
 
7.3.3 
Administration: Paclitaxel will be administered as a 60 minute IV infusion for 
the concurrent phase and as a 3 hours IV infusion for the consolidation phase 
using non-PVC tubing and connectors, such as the IV administration sets 
(polyethylene or polyolefin) that are used to infuse parenteral nitroglycerin 
and/or fat emulsion.  A 0.22 micron filter must be placed on the distal end of 
the infusion line.  Nothing else is to be infused through the line where paclitaxel 
is being administered.   
 


 
31
7.3.4 
Patients will receive prophylactic antiallergy premedication prior to paclitaxel 
administration as follows: 
Dexamethasone:  20 mg IV approximately 30 minutes prior to paclitaxel 
Diphenhydramine:  50 mg IV x 1 dose 30 min prior to paclitaxel 
Ranitidine:  50 mg IV x 1 dose 30 minutes prior to paclitaxel 
 
The premedication schedule can be altered at the discretion of the treating 
physician after the first paclitaxel dose. 
 
7.3.4 
 Storage: Paclitaxel vials should be stored between 2°- 25°C (36°-77°F). 
 
7.3.5 
 Adverse Effects: 
 Hematologic:  Myelosuppression 
 Gastrointestinal: Nausea and vomiting; diarrhea, stomatitis, mucositis, 
pharyngitis, 
typhlitis, 
ischemic 
colitis, 
neutropenic 
enterocolitis, 
increased liver function tests (SGOT, SGPT, bilirubin, alkaline 
phosphatase); hepatic failure, hepatic necrosis 
 Heart: Arrhythmias, heart block, ventricular tachycardia, myocardial infarction 
(MI), 
bradycardia, 
atrial 
arrhythmia, 
hypotension, 
hypertension, 
lightheadedness 
 Neurological: Sensory (taste), peripheral neuropathy, seizures, mood swings, 
hepatic encephalopathy, encephalopathy, sensation of flashing lights; 
blurred vision, scintillating scotoma 
 Allergy: Anaphylactoid and urticarial reactions (acute); Stevens-Johnson 
Syndrome; flushing, rash, pruritus 
 Other: Alopecia, fatigue, arthralgia, myopathy, myalgia, infiltration (erythema, 
induration, tenderness, rarely ulceration); radiation recall reaction. 
 
7.3.6 
 Supply:  Paclitaxel is commercially available. 
 
7.4  
Carboplatin 
 
7.4.1 
 Formulation: Carboplatin is supplied as a sterile lyophilized powder available in 
a single-dose vial containing 50 mg, 150 mg, and 450 mg of carboplatin for 
administration by intravenous infusion.  Each vial contains equal parts by 
weight of carboplatin and mannitol. 
7.4.2 
 Preparation: Immediately before use, the content of each vial must be 
reconstituted with either sterile water for injection, USP, 5% dextrose in water, 
or 0.9% sodium chloride injection, USP, according to the following schedule: 
 
Vial Strength 
Diluent Volume 
 
50 mg 
5 ml 
 
150 mg 
15 ml 
 
450 mg 
45 ml 
   
 These dilutions all produce a carboplatin concentration of 10 mg/ml.  When 
prepared as directed, Paraplatin solutions are stable for eight hours at room 
temperature; since no antibacterial preservative is contained in the formulation, 
it is recommended that Paraplatin solutions be discarded eight hours after 
dilution. 
 
7.4.3 
 Administration: Carboplatin will be administered after paclitaxel/nab-paclitaxel 
as an IV infusion over 30 minutes.  The dose will be calculated based on the 
patient’s actual body weight at each treatment visit and the AUC (area under 
curve) dosing. 
 


 
32
   
 The dose of carboplatin is calculated (in mg, not mg/m2) as follows, using the 
modified Calvert formula based on creatinine clearance: 
  
   
 AUC dose = Target AUC* x (creatinine clearance + 25) 
  
   
 The *Target AUC for carboplatin treatment is AUC=2 (concurrent therapy) or 
AUC=6 (consolidation therapy). 
  
   
 The creatinine clearance used to calculate the carboplatin dose will be 
estimated, based on serum creatinine, using the Cockroft-Gault formula (In the 
Calvert Formula to calculate AUC based dosing using the Cockcroft Gault 
equation to calculate CrCI, the CrCI should not exceed 125mL/min): 
 
 
 
   
Table 4 
   
 For males: 
 
CrCl (mL/min) =  
(140-age) x (weight in kg) 
72 x serum creatinine in mg/dL 
 
For females: 
 
CrCl (mL/min) =  
 
0.85 x 
 
(140-age) x (weight in kg) 
72 x serum creatinine in mg/dL 
 
7.4.4 
 Storage: Unopened vials of Paraplatin are stable for the life indicated on the 
package when stored at controlled room temperature and protected from light. 
 
7.4.5 
Adverse Events: 
 Hematologic:  Myelosuppression 
 Gastrointestinal: 
Nausea 
and 
vomiting; 
hepatic 
toxicity; 
electrolyte 
imbalance; hypomagnesemia; hypercalcemia  
 Neurological: Peripheral neuropathy, ocular changes 
 Other: Ototoxicity, myalgia, fatigue, allergic reaction  
 
7.4.6 
 Supply: Carboplatin is commercially available. 
 
7.5  
Dose Modifications 
 
7.5.1 
 Dose Levels: Patients will be treated at the following dose levels: 
Table 5: 


 
33
Dose Levels of Paclitaxel and Carboplatin 
 
Starting Dose 
 
Dose Level -1 
 
Dose Level -2 
 
Concurrent Therapya 
Paclitaxel 
50 mg/m2 
NA 
NA 
Nab-
Paclitaxel 
50 mg/m2 
40 mg/m2 
NA 
Carboplatin 
AUC=2 
NA 
NA 
Consolidation Therapyb 
Paclitaxel 
200 mg/m2 
150 mg/m2 
NA 
Nab-
Paclitaxel 
100 mg/m2 
80 mg/m2 
NA 
Carboplatin 
AUC=6 
AUC=4.5 
NA 
a For concurrent therapy, paclitaxel and carboplatin doses will not be adjusted.   
b  For consolidation therapy, dose reductions of paclitaxel, nab-paclitaxel and 
carboplatin below the -1 dose level will not be allowed. 
 
7.5.2 
 Dose Modifications During Concurrent Therapy 
 
7.5.2.1 Paclitaxel/nab-Paclitaxel/Carboplatin Dose Modifications for Hematologic Toxicity 
 Table 6: 
Toxicity 
NCI CTCAE Grade 
(CTCAE v4.0) 
Paclitaxel Dose
At Start of 
Subsequent Cycles  
of Therapy a 
Nab-Paclitaxel Dose 
at Start of 
Subsequent Cycles 
of Therapy a 
Carboplatin Dose at 
Start of Subsequent 
Cycles of Therapy a 
Neutropenia
 
1 (1500-1999/mm3)
Maintain dose level
Maintain dose level
Maintain dose level
2 (1000-1499/mm3) 
Maintain dose level 
Maintain dose level 
Maintain dose level 
3 (500-999/mm3) 
Hold therapyb 
Hold therapy b
Hold therapy b
4 (< 500/mm3) 
Hold therapyb
Hold therapy b
Hold therapy b
Neutropenic fever
Hold therapyb 
Hold therapyb 
Hold therapyb 
Thrombocytopenia
1 (< LLN-75,000/mm3) Maintain dose level 
Maintain dose level 
Maintain dose level 
2 (50,000- 
74,999/mm3) 
Hold therapy b 
Hold therapy b 
Hold therapy b 
3 (25,000- 
49,999/mm3) 
Hold therapyb 
Hold therapy b 
Hold therapy b 
4 (< 25,000/mm3) 
Hold therapy b 
Hold therapy b 
Hold therapy b 
 
 
 
aDose levels are relative to the starting dose in the previous cycle. For concurrent 
therapy, paclitaxel and carboplatin doses will not be adjusted. 
 
b Repeat lab work weekly and resume chemotherapy based on this table. 
 
7.5.2.2  
If paclitaxel, nab-paclitaxel and/or carboplatin doses must be withheld for 
greater than two consecutive  weeks, the drug(s) will be held permanently for 
the duration of concurrent therapy. 


 
34
 
7.5.2.3  Paclitaxel/nab-Paclitaxel/Carboplatin Dose Modifications for Non-Hematologic 
Toxicity During Concurrent Therapy 
Table 7: 
Worst Toxicity
NCI CTCAE Grade  
(CTCAE v4.0) a, c 
Paclitaxel Dose
At Start of 
Subsequent Cycles  
Of Therapyb 
Nab-Paclitaxel Dose
At Start of 
Subsequent Cycles  
of Therapyb 
Carboplatin Dose
At Start of 
Subsequent Cycles  
of Therapyb 
Neuropathy 
≤ Grade 1 
Maintain dose level 
Maintain dose level 
Maintain dose level 
Grade 2 
Hold therapy until 
Grade ≤ 1; restart at 
full dosed
Hold therapy until 
Grade ≤ 1; restart at full 
dosed
Maintain dose level 
Grade 3 
Discontinue therapy 
Discontinue therapy 
Maintain dose level 
Other non-hematologic 
toxicities  
Grade 4 
Hold treatment until  
≤ Grade 2  
Hold treatment until  
≤ Grade 2  
Hold treatment until  
≤ Grade 2  
 
a  For ≤ CTCAE Grade 2 non-hematologic toxicity not described above, excluding 
neuropathy, maintain dose level of all study. For neuropathy, follow the guidelines listed 
above. 
 b  Dose levels are relative to the starting dose in the previous cycle. For concurrent 
therapy, paclitaxel and carboplatin doses will not be adjusted. 
 c Radiation therapy should continue to be delivered for ≤ Grade 3 non-hematologic 
toxicities in or outside the radiation treatment field.  RT should be held for all Grade 4 non-
hematologic toxicity in or outside the treatment field and resumed only when toxicity is ≤ 
Grade 2. 
 
d  See Section 7.5.2.5 for further neuropathy details. 
 
7.5.2.4 
Carboplatin Dose Modifications for Renal Toxicity 
A > 25% change in the renal function, based on weekly calculated creatinine 
clearance, will warrant a recalculation of the carboplatin dose. 
 
7.5.2.5  
Paclitaxel/nab-paclitaxel Dose Modifications for Neuropathy 
   
 
If paclitaxel/nab-paclitaxel doses must be withheld for greater than two 
consecutive weeks, the drug will be held permanently for the duration of 
concurrent therapy (see Section 7.5.2.2). 
 
7.5.2.6 
If there is a decline in Zubrod performance status to ≥ 2 for greater than 2 
weeks while under treatment, radiotherapy should be held with no further 
chemotherapy administered.  Re-evaluate patient after one week for 
resumption of radiotherapy.  
 
7.5.2.7 
Paclitaxel/Nab-paclitaxel/Carboplatin/RT Dose Modifications for In RT Field, 
Non-Hematologic Toxicity During Concurrent Therapy. 
Formatted: BMS Table Note, Do not check
spelling or grammar
Deleted: a
Formatted: BMS Table Note, Do not check
spelling or grammar
Deleted: a
Formatted: BMS Table Note, Do not check
spelling or grammar
Deleted: b


 
35
 
Table 8:  
Treatment Modification for In-field Non-Hematologic Toxicity 
In-field 
CTCAE
Toxicity 
Grade
XRT
Paclitaxel
Nab-
Paclitaxel 
Carboplatin
Esophagus/pharynx 
(on day of XRT) 
4 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Hold 
treatment 
until ≤ Grade 
2
Esophagus/pharynx 
(on day of chemo) 
3 
No change or 
hold ≤ 5 days 
 
Hold treatment 
until ≤ Grade 2 
 
Hold treatment 
until ≤ Grade 2 
 
Hold 
treatment 
until ≤ Grade 
2
Esophagus/pharynx 
(on day of chemo)
2 
No change
No change
No change
No change
Pulmonary 
4 
Discontinue
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Hold 
treatment 
until ≤ Grade 
2 
Pulmonary 
3 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Hold 
treatment 
until ≤ Grade 
2
Skin
4 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Hold 
treatment 
until ≤ Grade 
2 
Skin
3 
No change
No change
No change
No change
 
7.5.2.8 
For infield esophagitis, see the table 8 in section 7.5.2.7. and table 2 in 
Section 6.9.2 for treatment recommendations. Re-evaluate patient weekly. 
 
7.5.2.9 
For dermatitis or other in-field radiotherapy-related toxicity, see the table 8 in 
section 7.5.2.7. On day of chemotherapy administration during any treatment 
week, omit paclitaxel/nab-paclitaxel and carboplatin until toxicity resolves to 
grade ≤ 2 as detailed in table 8. 
 
7.5.2.10 
Radiotherapy should be interrupted for Grade 4 toxicity, including Grade 4 
esophagitis or pulmonary toxicity and resumed according to the table 8 in 
Section 7.5.2.7. If treatment is interrupted for > 2 weeks, protocol treatment 
should be discontinued. Follow up and data collection will continue as 
specified in the protocol. Further treatment off protocol is at the discretion of 
the treating physician. If the patient experiences esophagitis so that IV fluid 
support is needed, insertion of a feeding tube should be considered. 
 
7.5.3 
 Dose Modifications During Consolidation Therapy 
 
7.5.3.1   
Paclitaxel/Nab-paclitaxel/Carboplatin Dose Modifications for Hematologic 
Toxicity 


 
36
 
Table 9: 
Toxicity
NCI CTCAE Grade 
(CTCAE v4.0) 
Paclitaxel Dose
At Start of Subsequent 
Cycles  
of Therapy a, c 
Nab-Paclitaxel Dose at 
Start of Subsequent 
Cycles of Therapy a, c 
Carboplatin Dose at Start 
of Subsequent Cycles of 
Therapy a, c 
Neutropenia 
 
 
1 (1500-1999/mm³) 
 
Maintain dose level 
 
Maintain dose level 
 
Maintain dose level 
2 (1000-1499/mm3) 
. Maintain dose level if fully 
recovered in 1 week. If not, 
decrease by 1 dose level 
when ≥ 1,000 mm3 
. Maintain dose level if fully 
recovered in 1 week. If not, 
decrease by 1 dose level 
when ≥ 1,000 mm3 
. Maintain dose level if fully 
recovered in 1 week. If not, 
decrease by 1 dose level 
when ≥ 1,000 mm3 
3 (500-999/mm3) 
Hold therapyb. Maintain dose 
level if fully recovered in 1 
week. If not, decrease by 1 
dose level when ≥ 1,000 mm3
Hold therapyb. Maintain 
dose level if fully recovered 
in 1 week. If not, decrease 
by 1 dose level when ≥ 
1,000 mm3 
Hold therapyb. Maintain 
dose level if fully recovered 
in 1 week. If not, decrease 
by 1 dose level when ≥ 
1,000 mm3 
4 (< 500/mm3) 
Hold therapyb and decrease 
by 1 dose level when ≥ 1,000 
mm3 
Hold therapyb and decrease 
by 1 dose level when ≥ 
1,000 mm3 
Hold therapyb and decrease 
by 1 dose level when ≥ 
1,000 mm3 
Neutropenic fever 
Hold therapyb and decrease 
by 1 dose level when ≥ 1,000 
mm3 
Hold therapyb and decrease 
by 1 dose level when ≥ 
1,000 mm3 
Hold therapyb and decrease 
by 1 dose level when ≥ 
1,000 mm3 
Thrombocytopenia 
 
1 (≥ 75,000/mm3) 
Maintain dose level 
Maintain dose level 
Maintain dose level 
2 (50,000 - 74,999/  
    mm3) 
Hold therapyb. Maintain dose 
level if fully recovered in 1 
week. If not, decrease by 1 
dose level when ≥ 75,000 
mm3 
Hold therapyb. Maintain 
dose level if fully recovered 
in 1 week. If not, decrease 
by 1 dose level when ≥ 
75,000 mm3 
Hold therapyb. Maintain 
dose level if fully recovered 
in 1 week. If not, decrease 
by 1 dose level when ≥ 
75,000 mm3 
3 (25,000- 49,999/  
    mm3) 
Hold therapyb. Maintain dose 
level if fully recovered in 1 
week. If not, decrease by 1 
dose level when ≥ 75,000 
mm3 
Hold therapyb. Maintain 
dose level if fully recovered 
in 1 week. If not, decrease 
by 1 dose level when ≥ 
75,000 mm3 
Hold therapyb. Maintain 
dose level if fully recovered 
in 1 week. If not, decrease 
by 1 dose level when ≥ 
75,000 mm3 
4 (< 25,000/mm3) 
Hold therapyb and decrease 
by 1 dose level when ≥ 
75,000 mm3 
Hold therapyb and decrease 
by 1 dose level when ≥ 
75,000 mm3 
Hold therapyb and decrease 
by 1 dose level when ≥ 
75,000 mm3 
 
 
 
a Dose levels are relative to the worst toxicities in the previous cycle. For 
consolidation therapy, dose reductions of paclitaxel/nab-paclitaxel and carboplatin 
below the –1 dose level will not be allowed. 
b Repeat lab work weekly and resume chemotherapy based on this table. 
c Dose delays greater than 2 weeks will warrant discontinuation of chemotherapy for 
the consolidation cycles. 
 
7.5.3.2  
Paclitaxel/Nab-paclitaxel/Carboplatin Dose Modifications for Non-Hematologic 
Toxicity During Consolidation Therapy 


 
37
 
Table 10: 
Worst Toxicity
NCI CTCAE Grade 
(CTCAE v4.0) 
 a 
Paclitaxel Dose
At Start of Subsequent 
Cycles of Therapy b  
Nab-Paclitaxel Dose
At Start of 
Subsequent Cycles  
of Therapy b  
Carboplatin Dose
At Start of 
Subsequent Cycles  
of Therapy b 
Neuropathy 
≤ Grade 1 
Maintain dose level 
Maintain dose level 
Maintain dose level 
Grade 2 
Hold therapy until Grade 
≤ 1; restart at full dose 
Hold therapy until 
Grade ≤ 1; restart at full 
dose 
Maintain dose level 
≥ Grade 3 
Discontinue therapy 
Hold therapy until 
Grade ≤ 1 then resume 
at next lowest dose 
level 
Maintain dose level 
Other non-
hematologic  
toxicities 
≥ Grade 3 
Hold treatment until ≤  
Grade 2  
Hold treatment until ≤  
Grade ≤ 1 then resume 
at next lowest dose 
level  
Hold treatment until ≤  
Grade 2 
 
a For ≤ CTCAE Grade 2 non-hematologic toxicity not described above, excluding 
neuropathy, maintain dose level of all study drugs. For neuropathy, follow the guidelines 
above. 
b Dose levels are relative to the worst toxicities in the previous cycle. Dose reductions of 
nab-paclitaxel below the -1 dose level will not be allowed. For concurrent therapy, 
paclitaxel and carboplatin doses will not be adjusted. 
 
When a chemotherapy dose reduction is required during the consolidation 
course of therapy, re-escalation of the chemotherapy dose will not be 
allowed for subsequent doses during that specific course. 
 
7.5.3.3  
Carboplatin Dose Modifications for Renal Toxicity 
A > 25% change in the renal function, based on weekly calculated creatinine 
clearance for the concurrent phase and every 3 weeks calculated creatinine 
clearance for the consolidation phase prior to chemo infusion, will warrant a 
recalculation of the carboplatin dose. 
 
7.5.3.4  
Paclitaxel/nab-paclitaxel Dose Modifications for Neuropathy 
If paclitaxel/nab-paclitaxel doses must be withheld for greater than two 
consecutive weeks, the drug will be held permanently for the duration of 
concurrent therapy. 
 
 
7.6  
Duration of Treatment 
 
7.6.1 
 Discontinuation from Protocol Treatment: Study therapy MUST be immediately 
discontinued for the following reasons: 
 Withdrawal of consent (patient’s decision to withdraw for any reason); 
 Any clinical adverse event, laboratory abnormality, or intercurrent illness that, 
in the opinion of the Investigator, indicates that continued treatment with all 
study therapy is not in the best interest of the patient; 
 Pregnancy; 


 
38
 Progressive disease (Further treatment will be at the discretion of the treating 
physician). 
 
The reason(s) for discontinuation from protocol treatment should be 
documented in the patient’s medical record and Case Report Form (CRF).  All 
patients should be followed as specified in Sections 10.2. 
 
7.6.2 
 Treatment Compliance: Trained medical personnel will administer study 
therapy.  Treatment compliance will be monitored by drug accountability, as 
well as recording treatment administration in the patient’s medical record and 
Case Report Forms.  
 
7.6.3 
 Modality Review: The Medical Oncology Co-Chair, David Gerber, M.D., will 
perform a Chemotherapy Assurance Review of all patients who receive or are 
to receive chemotherapy in this trial.  The goal of the review is to evaluate 
protocol compliance.  The scoring mechanism is: per protocol; variation 
acceptable; deviation unacceptable; not evaluable for chemotherapy review, or, 
incomplete chemotherapy.  A report is sent to each institution once per year to 
notify the institution about compliance for each case reviewed in that year.  
7.7 
Procedures in Case of Pregnancy 
 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion 
that the investigational product under study may have interfered with the 
effectiveness of a contraceptive medication.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject 
was discontinued from the study.  Should pregnancy occur during a subject’s trial 
participation, the subject will immediately be discontinued from the trial and 
followed-up per protocol. 
 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous 
miscarriages should also be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs.  All outcomes of pregnancy 
must be followed-up, documented and reported to Celgene.  The site will 
complete and forward to Celgene their site-specific pregnancy form. The 
following information must be reported to Celgene. 
 
 
8.0  
OTHER THERAPY 
 
8.1 
Prohibited Therapies 
 
 
Patients should not receive any other anti-cancer drugs while receiving 
paclitaxel, carboplatin, or nab-paclitaxel, including hormonal and immunotherapy 
agents.  Treatment with hormones or other chemotherapeutic agents will result in 
the patient’s removal from the study.  Exceptions are steroids administered for 
acute symptom management, adrenal failure, septic shock, or as antiemetics; or 
hormones administered for non-disease related conditions (e.g., insulin for 
diabetes). Colony stimulating factors (i.e., G-CSF, GM-CSF, etc.) should not be 
administered.  In case of myelotoxicity, dose reductions will be made. In addition, 
treatment with amifostine is not allowed during radiation or within 3 months of 
completion of radiation therapy 
 
8.2 
Supportive Therapy 
 


 
39
Patients should receive full supportive care (except for colony stimulating factors) 
including transfusions of blood and blood products, antibiotics, antiemetics, etc., 
when appropriate.  Electrolytes should be maintained within the normal range 
using supplements if necessary.  The use of erythropoietin (i.e., Epogen®, 
Procrit®) is permitted. Sucralfate slurries may provide symptomatic relief of 
mucositis and esophagitis.  Post-treatment pneumonitis attributed to radiation 
should be treated with prednisone after excluding microbial causes. 
 
9.0  
SAFETY REPORTING 
 
 
 
9.1  
Definitions and Reporting:   
The definitions of Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
given below.  It is of the utmost importance that all staff involved in the study be 
familiar with the content of this section.  The principal investigator is responsible 
for ensuring this. 
 
9.1.1  
Adverse Event 
An Adverse Event (AE) is the development of an undesirable medical condition 
or the deterioration of a pre-existing medical condition following or during 
exposure to a pharmaceutical product, whether or not considered causally 
related to the product.  An undesirable medical condition can be symptoms (e.g., 
nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, ECG).  In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
Any detrimental change in a patient’s condition subsequent to them entering the 
study and during the follow-up period should be considered an AE.  When there 
is a deterioration in the condition for which the study treatment is being used, 
there may be uncertainty as to whether this is lack of efficacy or an AE.  In such 
cases, unless the reporting physician considers that study treatment contributed 
to the deterioration or local regulations state to the contrary, the deterioration 
should be considered a lack of efficacy.  Signs and symptoms of disease 
progression are therefore not considered AEs. 
The development of a new cancer should be regarded as an AE.  New cancers 
are those that are not the primary reason for administration of study treatment 
and have been identified after inclusion of the patient into the clinical study. 
 
9.1.2 
Serious Adverse Event 
A Serious Adverse Event (SAE) is an AE occurring during any study phase (e.g., 
run-in, treatment, washout, and follow-up), and at any dose of the investigational 
product, comparator or placebo, that fulfills one or more of the following criteria: 
-Results in death 
-Is immediately life-threatening 
-Requires inpatient hospitalization or prolongation of existing hospitalization 
-Results in persistent or significant disability or incapacity 
-Is a congenital abnormality or birth defect 
-Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above. 
 
The investigator or his team should report Local Adverse Event (Occurring to a 
subject enrolled on a protocol under the UT Southwestern IRB jurisdiction) that 
are Not Serious but Unexpected (in terms of nature, severity or frequency) and 
Definitely, Probably or Possibly related within 10 working days.  


 
40
The investigator or his team will report all local Serious Adverse Events that are 
reportable to the IRB regardless of whether they are expected or related to 
research participation within 24 hours of discovery of the event.  
 
 
     All local SAEs are required to be reported to the DSMC. 
 
Celgene will be communicating all non-local adverse events to the investigator or 
his research team. The investigator or his team will in turn report within 10 
working days non-Local Serious Adverse Event  (Occurring in the same multi-site 
study as is conducted by the PI at UT Southwestern but at a different site),  that 
is unexpected (in terms of nature, severity or frequency) and definitely, Probably 
or Possibly related  and serious or otherwise places subjects or others at a 
greater risk of harm (including physical, psychological, economic or social harm) 
than was previously known or recognized. 
 
Any event or hospitalization that is unequivocally due to progression of 
disease, as determined by the investigator, must not be reported to the 
sponsor (Celgene) as an SAE, however should be communicated to 
Celgene. 
 
The causality of SAEs (their relationship to all study treatment) will be assessed 
by the investigator(s) and communicated to Celgene. 
 
 
All non-serious adverse events will be reported to Celgene at the conclusion of 
the study.  
 
9.1.3 
Reporting of Serious Adverse Events 
 
UTSW IRB: SAEs will be collected from the time consent is given, throughout the 
treatment period, and until subject’s participation in the trial has ended or participants 
death.    
Celgene; Investigators and other site personnel must inform the FDA, via a 
MedWatch form, of any serious or unexpected adverse events that occur in 
accordance with the reporting obligations of 21 CFR 312.32, and will concurrently 
forward all such reports to Celgene.    A copy of the MedWatch report must be 
faxed to Celgene at the time the event is reported to the FDA.  It is the 
responsibility of the investigator to compile all necessary information and ensure 
that the FDA receives a report according to the FDA reporting requirement 
timelines and to ensure that these reports are also submitted to Celgene at the 
same time.  
 
* A cover page  from Celgene should accompany the MedWatch form indicating 
the following: 
 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and Celgene reference number 


 
41
* Investigative site must also indicate, either in the SAE report or the cover page, 
the causality of events in relation to all study medications and if the SAE is 
related to disease progression, as determined by the principal investigator. 
 
If a non-serious AE becomes serious, this and other relevant follow-up 
information must also be provided to Celgene and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA need 
to be reported to Celgene preferably using the MedDRA coding language for 
serious adverse events.  This information should be reported on a monthly basis 
and under no circumstance less frequently than quarterly 
 
All SAEs have to be reported to Celgene, whether or not considered causally 
related to the investigational product.  All SAEs will be documented.  The 
investigator is responsible for informing the IRB and/or the Regulatory Authority 
of the SAE as per local requirements. 
 
Non-serious adverse events will be collected from the time consent is given, 
throughout the treatment period and up to and including the 30 day follow-up 
period.   After withdrawal from treatment, subjects must be followed-up for all 
existing and new AEs for 30 calendar days after the last dose of trial drug and/or 
until event resolution.  All new AEs occurring during that period must be recorded 
(if SAEs they must be reported to the FDA and Celgene per Section 3.6.1.3).  All 
study-related toxicities/ SAEs must be followed until resolution, unless in the 
Investigator’s opinion, the condition is unlikely to resolve due to the patient’s 
underlying disease. 
 
All serious adverse events must be reported to the UT Southwestern 
TELEPHONE LINE: (214) 633-1753 within 24 hours of the investigator’s 
awareness of the occurrence of the event.  All safety reports shall be faxed to 
(214) 645-8913 or e-mail to the attention of the project manager. 
 
9.1.4 
The principal investigator will respond promptly to any query from UT 
Southwestern regarding adverse event reports. 
 
9.2 
Audits and Inspections 
Authorized representatives of Celgene, a regulatory authority, an Independent 
Ethics Committee (IEC) or an Institutional Review Board (IRB) may visit the 
center to perform audits or inspections, including source data verification.  The 
purpose of an Celgene audit or inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately 
reported according to the protocol, Good Clinical Practice (GCP), guidelines of 
the International Conference on Harmonization (ICH), and any applicable 
regulatory requirements.  The investigator should contact Celgene immediately if 
contacted by a regulatory agency about an inspection at his or her centre. 
 


 
42
 
10.0 
PATIENT ASSESSMENTS 
 
10.1 
Study Parameters  
 
Table 11: 
Procedure
Pre-
Treatment 
 
During
Protocol
Therapy 
End of 
Concurrent 
Therapy 
End of 
all 
Protocol 
Therapy
Post Treatment 
Follow-up 
(See Section 
10.2) 
Medical History
Xa 
 
 
X 
X 
Physical Examination, 
Zubrod performance 
status, concomitant 
medications 
 
Xa 
 
Xc 
 
X 
 
X 
 
X 
RT and Med Onc Consults
Xi 
 
 
 
 
Vital Signs
Xa 
Xc 
 
X 
X 
Height and Weight and 
BSA 
Xa 
Xc, d 
Xd 
Xd 
Xd 
FEV1
Xb 
 
 
 
X j
Toxicity 
Assessment/Adverse 
Events 
 
 
X 
 
X 
 
X 
 
X 
Quality of Life 
Assessments 
X 
 
X 
 
Xo 
CBC with differential 
platelet count 
 
Xa 
 
Xc 
 
X 
 
X 
 
Xe 
Bilirubin,  alk. Phos., 
glucose, sodium, 
potassium, calcium, 
magnesium, BUN, 
albumin, total bilirubin, 
AST, ALT, total protein  
 
Xa 
 
Xc 
 
X 
 
X 
 
Xe 
Serum creatinine
Xa 
Xc 
X 
X 
Xe 
Amylase, Lipase
Xa 
 
X 
X 
 
Pregnancy Test (serum)
Xg
Tissue Assessment
Xh 
 
 
 
 
Serum samples for 
correlative studies 
Xh 
 
 
 
 
CT Scan or MRI of Chest 
OR PET, PET/CT 
 
Xb,m 
 
 
 
Xn
 
Xf 
CT Scan or MRI of Brain
Xb,m 
 
 
 
Xe 
PET, PET/CT or Bone 
scan 
Xk
 
 
Xk 
 
a. Within 4 weeks prior to study entry; 
b. Within 6 weeks prior to study entry; 
c. Weekly during concurrent, q3 weeks during consolidation prior to chemo infusion 
(paclitaxel/carboplatin arm or nab-paclitaxel/carboplatin arm) 
d. Assess weight only; recalculate the BSA if there has been > 10% weight loss/gain; 
e. At relapse; 
f. 
Recommended every 6 months for 2 years, then annually; 
g. For women of childbearing potential; within 7 days prior to registration 
h. See 11.0 TISSUE/SPECIMEN SUBMISSION 


 
43
i. 
Approval to proceed must be received prior to initiation of study treatment. 
j. 
At 6 months after completion of consolidation therapy, then at 1 year 
k. Highly recommended at pretreatment and at 12-16 weeks after completion of therapy, but 
not required. Refer to section 4.0 
m. Perform CT scan or MRI at a minimum of 1 cm slice thickness to include the lung apices 
through the adrenals.  It is recommended that a consistent evaluation (CT or MRI) be 
used throughout the study. 
n. 
Within Six weeks on completion of consolidation treatment. 
o. 
On 3, 12 and 24 months follow up. 
 
10.2 
Post-treatment Follow-up 
 
    
 A follow-up evaluation will be performed approximately 30 days following 
completion of all protocol treatment.  In addition, all patients will be followed for a 
minimum of 30 days after the last dose of study therapy or every 4 weeks until 
all study drug related toxicities have resolved, returned to baseline, or are 
deemed irreversible, whichever is longer.  Thereafter, patients will be seen for 
follow up every 3 months following protocol treatments for 2 years, every 6 
months for years 3 and 4, then annually for life. 
 
 10.3 
Prospective Health-Related Quality of Life (HRQOL) Analysis 
 
Note: Patients must be offered the opportunity to participate in the correlative 
components of the study. If the patient consents to participate in the quality of life 
component of the study, sites are required to administer the baseline 
assessments prior to the start of protocol treatment. Sites are not permitted to 
delete the quality of life component from the protocol or sample consent. 
 
The study design is to prospectively analyze the QOL among patients with stage 
III 
NSCLC 
randomized 
between 
paclitaxel/carboplatin 
versus 
nab-
paclitaxel/carboplatin with concurrent radiotherapy followed by consolidation 
chemotherapy. The primary normal tissue toxicities in patients receiving 
chemoradiation for lung cancer are esophagitis and pneumonitis. Prior studies 
have demonstrated that the most sensitive and clinically meaningful method for 
accurately capturing the normal tissue toxicities is via patients reported outcomes 
(PROs), such as HRQOL.  
 
In this randomized trial, we plan to assess the FACT-L, FACT-Taxane and the 
EQ-5D in all arms at 5 specific time points to minimize patient burden: baseline 
(pretreatment), at the end of chemoradiation (week 7), at the first follow-up (3 
months), and at 12 months and 24 months from baseline.  
 
In order to analyze the difference in QOL between all arms, we plan to use a 
brief, validated instrument that is user friendly and has clinical relevance (the 
Lung Cancer Subscale of the FACT-TOI (the FACT-L)). FACT-TOI is a measure 
that sums the functional well being (FWB), physical well being (PWB), and the 
lung cancer subscale (LCS) of the Functional Assessment of Cancer Therapy - 
Lung (FACT-L) QOL instrument, which has been extensively used for measuring 
QOL in patients with lung cancer.44 In a review of the literature reported that the 
FACT-L scale has been used in more than 5,000 patients and has been found to 
be sensitive to changes in performance status and treatment response.45 FACT 
has been translated into 26 languages and is available free of charge to 
institutions with the completion of an agreement to share data, accessible at 
http://www.facit.org/translation/licensure.aspx. The full FACT-L questionnaire can 
be completed in less than 10 minutes.46 This instrument has not only been shown 
to be prognostic for survival, but also sensitive to changes in QOL on serial 


 
44
evaluations throughout treatment.45 Importantly, the FACT-TOI has been 
associated with clinically meaningful changes in patients with lung cancer.47 The 
lung cancer sub-scale (LCS) consists of 9 items, involving lung cancer specific 
symptoms. All items are rated on a 5 item (point) Likert Scale, from 0 (not at all) 
to 4 (very much). It has been determined that a 3-point difference on the FACT-G 
subscales is associated with a meaningful difference in clinical and subjective 
indicators.47 Thus, a difference of 3 LCS points will be considered clinically 
significant. As the LCS focuses on lung cancer symptoms, this will be used for 
the primary endpoint; however, the more general subscales of physical and 
functional well-being (on the brief FACT-TOI) will also be collected.  In addition, 
we will utilize the FACT-Taxane instrument to ascertain for differences in 
neuropathic symptoms and overall effect on well being. 
 
In order to analyze the potential benefits of nab-paclitaxel (in terms of survival, 
decreased toxicity), a quality-adjusted survival analysis can be performed. The 
EQ-5D is a method for obtaining valuations of health-related QOL which also can 
be used for quality-adjusted survival and cost-utility analyses.48-51 It is a two-part 
questionnaire that takes approximately 5 minutes to complete.52 The first part of 
the EQ-5D consists of five items addressing five dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension can be 
graded on three levels: 1-no problems, 2-moderate problems, and 3-extreme 
problems. Health states are defined by the combination of the response levels for 
each of the five dimensions, generating 243 health states to which 
unconsciousness and death are added.53 The second part of the EQ-5D is a 
visual analogue scale (VAS) valuing current health state, measured on a 20-cm 
10-point-interval scale. Worst imaginable health state is scored as 0 at the 
bottom of the scale, and best imaginable health state is scored as 100 at the top. 
Both the five-item index score and the VAS score are transformed into a utility 
score between 0-“worst health state” and 1-“best health state.” Either the index 
score or the VAS score can be used in the quality-adjusted survival analysis, or 
the cost-utility equation can be entered, depending on the health state(s) of 
interest.54 
 
Although developed in Europe, the EQ-5D has been used in the United States 
and Canada.48-51 The EQ-5D web site, http://www.euroqol.org/, lists multiple 
languages in which the instrument has been validated. There have been few 
studies published reporting on the incorporation of the EQ-5D into the evaluation 
of patients with NSCLC. Trippoli et. al. used the EQ-5D in the evaluation of 95 
patients with NSCLC treated at 15 Italian hospitals.55 The mean utility score was 
0.58 in the self-classifier version and 0.58 in the VAS version. Both the self-
classifier version and the VAS version showed statistically significant correlation 
with each of the eight domains of the Short Form-36 (SF-36). 
 
The patients will be given the FACT-L, FACT-Taxane and EQ5D instruments to 
be completed in the clinic at specified visits. A research assistant will be available 
to answer any questions that the patients have and review the questionnaire for 
completeness. If the questionnaires are not complete, patients will be asked if 
they left out answering the question by mistake or because they did not wish to 
answer the question. If the former, patient will be asked to answer those 
questions; if the latter, patients would not be asked anything further. If a patient 
does not come in to clinic (and/or if requested), the questionnaires will be mailed 
to the patient. If the questionnaires have not been received in two weeks after the 
due date, another set will be sent to the patients, reminding them to complete the 
questionnaire. If the patient prefers, he or she will be interviewed by the research 
assistant over the telephone at that time.  Reminder notices will be routinely sent 
to the clinical research associates whose institutions are accruing to the trial that 


 
45
the HRQOL instruments need to be distributed to the patients at the prescribed 
time frames. 
 
10.4 
Response Assessment (RECIST Criteria) 
 
10.4.1  Measurement of Response 
Response will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee.56  See http://ctep.info.nih.gov/guidelines/recist.html for further 
details. 
  
Only patients with measurable disease at baseline should be included in 
protocols where objective tumor response is the primary endpoint.  
 
 Measurable disease - the presence of at least one measurable lesion; if the 
measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology.  
 
 Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter (LD)  ≥ 20 mm using conventional 
techniques or ≥ 10 mm with spiral CT scan. 
 
 Non-measurable lesions - all other lesions, including small lesions (longest 
diameter < 20 mm with conventional techniques or < 10 mm with spiral CT 
scan), 
i.e., 
bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not 
confirmed and followed by imaging techniques 
 
Table 12: Response Criteria: 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 LD of target lesions, 
taking as reference the baseline sum LD 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new 
lesions 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started 
 
10.4.2 
Target lesion assessment guidelines 
The longest diameter (LD) for the target lesion (or lesions) will be calculated 
from the treatment planning CT scan using pulmonary and/or mediastinal 
windowing and reported as the baseline LD. The baseline LD will be used as a 
reference by which to characterize the objective tumor. 
 
Local treatment effects in the vicinity of the tumor target may make 
determination of tumor dimensions difficult. For example, bronchial or 
bronchiolar damage may cause patchy consolidation around the tumor that 
over time may coalesce with the residual tumor. In cases in which it is 
indeterminate whether consolidation represents residual tumor or treatment 
effect, it should be assumed that abnormalities are residual tumor. 
 
 


 
46
11.0  
TISSUE/SPECIMEN SUBMISSION 
This study does not involve genetic analysis.  Patients will be offered the 
Radiation Oncology Tissue Procurement study which is a separate UTSW IRB 
approved study.   
 
12.0 
DATA MANAGEMENT 
 
12.1 
Data Collection 
 
All data will be collected and entered into the Case Report Form (CRF). The CRF 
must be completed legibly in ink and submitted within the timelines listed below. 
Participants are to be identified by initials, date of birth, and subject number. All 
information entered on the CRFs must also be reflected in the source documents.  
The CRFs will be faxed to (214) 648-5923 or e-mailed to Project Manager in a 
PDF format. 
 
UTSWMC Radiation Oncology Clinical Research department will review CRFs for 
completeness.  Audits will be performs for randomly selected cases to ensure the 
accuracy of CRFs. Data queries will be generated as needed for quality 
purposes.  
 
For patients enrolled at participating institutions, data will be collected and stored 
according to their institutional policies.  The data will be kept in a secure location 
in accordance with prevailing HIPAA regulations.  The investigator must maintain 
adequate and accurate records to enable the conduct of the study and 
monitoring.  The investigator must contact UTSWMC Radiation Oncology Clinical 
Research department prior to destroying any records associated with the study. 
 
 
12.2 
Summary of Data Submission  
 
 
   
 
 
  Table 13: 
 
Item 
Due 
Demographic Form  
Within 2 weeks of study entry 
Initial Evaluation Form  
Within 2 weeks of study entry 
Pathology Report 
Within 2 weeks of study entry
 
 
 
 
Preliminary Dosimetry Information:
Within 1 week of start of RT
RT Prescription (Protocol Treatment Form)  
Films (simulation and portal)  
 
Calculations 
Treatment Planning CT Scan [if done] 
 
 
 
Final Dosimetry Information:
Within 1 week of RT end
Daily Treatment Record  
 
Isodose Distribution  
 
Radiotherapy Form  
Within 1 week of RT end 
 
 
Treatment Summary Form 
At 8, 12, and 17 weeks
 
 
 
 
QOL Forms (FACT-L, FACT-Taxane, EQ-
5D) 
Within 2 weeks of study entry, at week 
8 and after 3, 12, 24 month follow up 
Follow-up Form 
Within 2 weeks of completion of each 


 
47
 
follow-up visit 
Adverse Event Form 
Within 48 hours of investigator’s 
awareness 
Autopsy Report  as Applicable 
Within 4 weeks of completion of 
autopsy
 
 
 
12.3 
Data Safety Monitoring Board 
 
Adverse events will be reviewed and discussed at the monthly UTSW 
Department of Radiation Oncology Clinical Research meetings and meeting 
minutes will be made available to participating institutions. The data quality and 
patient safety will also be monitored by the UT Southwestern Simmons Cancer 
Center Data Safety Monitoring Committee in accordance with UTSW cancer 
center guidelines and meeting minutes will be made available to participating 
institutions.  
 
13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
 Study Design and Primary Endpoint 
The primary goal of this randomized phase I/II study is to evaluate the efficacy of 
two treatment regimens involving radiation treatment for patients with inoperable 
stage III non-small cell lung cancer. Arm A includes concurrent chemotherapy 
consisting of paclitaxel and carboplatin with radiation therapy followed by 
additional consolidation chemotherapy of paclitaxel and carboplatin.  Arm B 
consists of nab-paclitaxel and carboplatin with radiation therapy followed by 
additional consolidation chemotherapy of nab-paclitaxel and carboplatin.  This 
study is not a comparative trial between these two arms; its purpose is to 
determine the efficacy and toxicity profile of each of the treatment regimens 
to guide further investigation.  Therefore the primary endpoint question of 2-
year survival rate will be analyzed in each treatment arm alone compared to 
historical controls. 
Randomization will be 1:1, with 1 patient accrued to Arm B for every 1 patient 
accrued to Arm A.  
The primary endpoint of this phase I/II study is 2-year overall survival from 
randomization.    
Based on previous regimens utilizing concomitant chemoradiation plus 
consolidation (LAMP), which derived a 2-year survival rate of 31%, the threshold 
of interest for pursuing a Phase 3 trial for these regimens will be 50%.  A 2-year 
survival of 30% or lower will be of no interest. It would be of interest for further 
investigation if the addition of nab-paclitaxel produced a 2-year survival rate of 
50% or higher.  
Because there is limited information about the toxicity of adding nab-paclitaxel to 
this chemoradiation regimen concurrently, an initial toxicity assessment and 
compliance phase will be conducted only for the Arm B treatment.   
Secondary endpoints are toxicity/feasibility (as described in previous paragraph), 
overall response rate, progression-free survival, median overall survival, and 
quality of life measurements. 
 
13.2 
Sample Size Justification 
We are planning the study with an accrual interval of 24 months, and additional 
follow-up after the accrual interval of 24 months.  Prior data indicate that the two-
year survival rate of historical treatment is around 31%. If the true two-year 
survival rate of our new treatment is 50% or higher, we will need to study 43 


 
48
patients to be able to reject the null hypothesis that the new treatment and the 
historical treatment survival curves are equal with probability (power) of 0.80.   
The two-sided Type I error probability associated with this test of this null 
hypothesis is 0.05.  This calculation was based on log-rank test assuming 
exponential survival function.  The exponential parameter (lamda) was derived 
from the expected two year survival rate.  Assuming ineligibility or lack of data 
rate of up to 5%, an additional 3 patients per arm should be accrued.  This would 
then lead to a sample size of 46 patients for each of the two arms, respectively. 
 
13.3  
Initial Toxicity and Compliance Phase  
Before randomization between the two treatment arms begins, an initial 6 patients 
will be treated with radiation treatment concurrently with weekly treatment of nab-
paclitaxel/carboplatin followed by nab-paclitaxel and carboplatin. The design is a 
simple 3-6 patient initial run-in. Three patients will be treated, if there are zero or 
one dose limiting toxicities (DLT) an additional 3 will be treated. If there are zero 
or one DLT (of the 6 patients) then the study will proceed to phase 2 at dose level 
1.  If there are more than one DLT out of the first three or out of the total six 
patients, then dose level -1 will be used in the phase II stage. Patients must be 
followed for one complete treatment cycle (concurrent and consolidation) from the 
start of treatment (including time for treatment breaks or delays) to the end of the 
consolidation phase before proceeding to the next step. 
 
If more than one of the first three patients or more than one of the total 6 patients 
experiences grade 3 or greater non-hematological toxicities or grade 4 or greater 
hematological toxicities, then the study will be temporarily suspended and re-
evaluated at a lower dose level of 40mg/m2 of nab-paclitaxel.  DLT will be defined 
as occurring whenever any one of the following are determined to be definitely or 
probably treatment related: 
• 
Any > grade 4 hematologic toxicity that lasted > 7 days 
• 
Any > grade 3 other non-hematologic toxicity that lasted > 7 days 
(excluding esophagitis, nausea, vomiting, and alopecia) 
• 
Grade 3 or 4 febrile neutropenia 
 
 
The UT Southwestern Data Safety Monitoring Committee (DSMC) will be asked 
to review the toxicity and compliance data and patient information and make 
appropriate recommendations about continuing the study. 
 
13.4 
Patient Accrual 
Initially, during the phase I portion of the study, 6 patients will be accrued. The 
eventual accrual goal during the phase II portion of the study is a total of 92 
patients, 46 in Arm #A and 46 in Arm #B.  Therefore, the overall accrual goal for 
this randomized phase I/phase II study is 98 patients.  
 
We expect that the study will accrue at the rate of 7 patients per month.  With an 
accrual rate of 7 patients per months, patient accrual should be completed within 
14 months. Allowing an initial 4 months for institutions to complete IRB 
paperwork before beginning patient accrual, it is expected that 18 months will be 
needed to complete patient accrual on this study. A minimum of 24 months of 
follow-up will be needed to test the primary study endpoint hypotheses 
 
13.4.1   Definition of an evaluable patient 
 


 
49
Any patient who enrolls on the study and begins therapy will be counted as an 
evaluable patient.  If a patient discontinues therapy or there is a modification to 
protocol therapy this will be noted as a protocol deviation and will be reported to 
the principal investigator, Dr. Choy. Patients with deviations will still be followed 
as specified in section 10.0 and no replacement subjects will be enrolled. 
  
13.5 
Fatal Treatment-Related Toxicity 
Accrual to this study will be suspended if any patient experiences a fatal 
treatment-related toxicity.  In the event that a patient has a fatal treatment-related 
toxicity at any time, the UT Southwestern data safety monitoring committee 
(DSMC) will be asked to review the data and patient information to make 
appropriate recommendations about continuing the study.   
 
 
13.6 
Interim Analyses of Accrual and Toxicity Data 
Interim reports will be prepared every 6 months until the primary endpoint 
analysis.  The usual components of this report are: 
a) The patient accrual rate with a projected completion date for the accrual 
phase; 
b) Accrual by institution; 
c) The distribution of pretreatment characteristics; 
d) The quality of submitted data with respect to timeliness, completeness, and 
accuracy; 
e) The frequency and severity of the toxicities. 
 
Copies of Interim reports will be provided to the SCC-DSMC on an ongoing basis 
during the course of the trial. 
 
The statistician will report any problems identified to the study chairs and UT 
Southwestern DSMC. 
 
 
13.7 
Analysis for Reporting Initial Treatment Results 
This analysis will be done when all the patients accrued to the study have been 
potentially followed for a minimum of 24 months.  It will include: 
a) Tabulation of all cases entered into the trial; 
b) Institutional accrual; 
c) Distribution of important prognostic baseline variables; 
d) Treatment compliance per study chair assessment. 
e) Observed results for the endpoints listed in Section 13.1. 
 
The primary objective of this study is to determine whether using Nab-paclitaxel 
(Abraxane) in concurrent radiation therapy and chemotherapy regimens will 
significantly increase the 2-year overall survival from historical 31%   
 
All eligible patients randomized will be included in the comparison and will be 
grouped by assigned treatment in the analysis. The primary hypothesis of 
treatment benefit for the primary endpoint question will be tested using the log-
rank statistic with a 2-sided significance level of 0.05. Comparison will be 
performed between the new treatment and historical controls.  Additional 
exploratory analyses of treatment effect will be performed using the Cox 
proportional hazard model with the stratification factors included as fixed 
covariates, as well as other possible modifying factors, such as age, gender, 
race, and other patient characteristics that are imbalanced between the treatment 
arms. 
 
Estimates of overall survival and progression free survival (calculated using the 
Kaplan-Meier method62) at one and two years will be calculated along with 95% 


 
50
confidence intervals.  Survival time is defined as the time beginning at 
randomization until death or last known follow-up. Progression-free survival is 
computed as the time between randomization and local or regional progression, 
distant metastases, death, or last known follow-up. 
 
Response 
(determined 
two 
months 
after 
completion 
of 
consolidation 
chemotherapy and for each additional post-treatment imaging study) is taken to 
be complete response (CR) or partial response (PR) using the Response 
Evaluation Criteria in Solid Tumors (RECIST) Committee (Section 10.4).63 
Overall response rate (ORR) will be defined as the percentage of people who 
experience a decrease in the size of treated measurable disease (this will be the 
sum of the complete and partial response rates).  Point and interval estimates of 
the proportion of patients with PR, CR, or either CR or PR, and ORR, using an 
exact 95% confidence interval will be calculated. 
 
For both the concurrent chemoradiation and the consolidation treatment periods, 
the frequency of toxicity occurrence will be tabulated by the most severe 
occurrence.  CTCAE v 4.0 will be used to assess and grade toxicities.  Results 
will be presented for each arm by attribution (definitely, probably, or possibly 
related to treatment and unlikely or unrelated to treatment). 
 
Within each treatment group, the pattern of treatment failure (local, distant, 
regional) will be summarized.  
 
 13.8 
Analysis for Reporting Long-Term Results 
This analysis, if necessary, will be done when all the patients accrued to the 
study have been potentially followed for a minimum of 36 months or when all 
patients are dead.  It will include all items found in section 13.7.  
 
13.9 
Health-Related Quality of Life (HRQOL) and Health Utility Analysis 
These HRQOL and health utility analyses will be carried out with respect to the 
use of nab-paclitaxel. We will use three instruments to measure HRQOL: FACT-
TOI, including the lung cancer subscale (LCS), FACT-Taxane and EQ-5D. 
FACT-TOI is a measure that sums the functional well being (FWB – 7 items), 
physical well being (PWB – 7), and the lung cancer subscale (LCS – 9 items) of 
the Functional Assessment of Cancer Therapy - Lung (FACT-L). Patients eligible 
for the treatment comparison will be included in the QOL analysis only if they 
have provided baseline and at least one subsequent measurement. The 
difference in the LCS, the FACT-TOI and FACT-Taxane score between the 
baseline and each follow-up evaluation will be computed for each patient. These 
differences of the means will be calculated at 3, 12 and 24 months and the point 
and interval estimates using an exact 95% confidence intervals will be presented. 
 
The primary QOL hypothesis is that patients receiving nab-paclitaxel will have 
clinically meaningfully higher QOL as measured by the LCS subscale of the 
FACT-L and FACT-Taxane instruments at 3 months post completion of 
treatment. Secondarily, this higher QOL score will be maintained at longer follow 
up as well (at twelve and 24 months from the start of treatment). Since the study 
is not powered for formal statistical testing on this, results will be tabulated and 
summarized by treatment arms for examination. 
 
Quality-adjusted survival is the sum of the products generated by multiplying a 
patient’s health utility score for each specific time period by the length of that time 
period. The quality-adjusted survival time estimates need to account for the 
presence of censoring.  Due to the induced informative censoring problem, the 
ordinary survival method (e.g., Kaplan-Meier estimator) cannot be applied in this 


 
51
case.  Accordingly, we will use the inverse-probability weighted method of Zhao 
and Tsiatis to carry out the survival time analysis.57,58 To estimate quality 
adjusted survival time, data from EQ-5D will first be translated into utility 
measures. These measures are obtained at discrete time points, so they will be 
interpolated into the time intervals between the visits. The quality-adjusted 
survival time is just an integration of the utility measures over a patient’s overall 
survival time.  The point and interval estimates of mean quality-adjusted survival 
for each arm using exact 95% confidence intervals will be calculated. 
 
We will describe the distributions of QOL data collection patterns over all 
collection points in each treatment arm. The distribution of pretreatment 
characteristics, such as performance score and treatment assignment, will be 
compared between the patients with available QOL data and the patients without 
QOL data. 
 


 
52
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Appendix A 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction 
 
1  
Restricted in physically strenuous activity but ambulatory and able to carry 
work of a light or sedentary nature. For example, 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, confined to bed or chair 50% or more of 
waking hours 
 
4  
Completely disabled. Cannot carry on self-care. Totally confined to bed 
 
5 
Death 
 
 


 
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Appendix B 
NEW YORK HEART ASSOCIATION (NYHA) CARDIAC CLASSIFICATION 
 
The NYHA classification system relates symptoms to everyday activities and the patient’s quality 
of life. 
 
Class 
Symptoms 
Class I (Mild) 
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort.  Symptoms 
of cardiac insufficiency at rest.  If any physical activity is undertaken, 
discomfort is increased.