Conditions: Lung Cancer
Keywords: stage IIIA non-small cell lung cancer stage IIIB non-small cell lung cancer adenocarcinoma of the lung
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 70
Healthy volunteers: no

Brief summary:
RATIONALE: Vaccines may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vaccine therapy together with bevacizumab after chemotherapy and radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying the side effects of giving BLP25 liposome vaccine together with bevacizumab after chemotherapy and radiation therapy in treating patients with newly diagnosed stage IIIA or stage IIIB non-small cell lung cancer that cannot be removed by surgery.

Detailed description:
OBJECTIVES:

Primary

* To determine the safety of BLP25 liposome vaccine (tecemotide) and bevacizumab after definitive chemoradiotherapy and consolidation chemotherapy in patients with newly diagnosed, unresectable stage IIIA or IIIB nonsquamous cell non-small cell lung cancer.

Secondary

* To evaluate the overall survival and progression-free in patients treated with this regimen.
* To evaluate the toxicity of this regimen in these patients.

OUTLINE: This is a multicenter study.

Step 1:

* Chemoradiotherapy: Patients receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 15-30 minutes once a week for 6 weeks. Patients also undergo concurrent definitive radiotherapy 5 days a week for 6½ weeks. Patients with complete response (CR), partial response (PR), or stable disease (SD) proceed to consolidation chemotherapy.
* Consolidation chemotherapy: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with CR, PR, or SD proceed to maintenance therapy.

Step 2:

* Maintenance therapy: Patients receive a single dose of cyclophosphamide IV over 15-30 minutes 3 days before the first dose of bevacizumab and BLP25 liposome vaccine. Patients then receive bevacizumab IV over 30-90 minutes on day 1 and BLP25 liposome vaccine subcutaneously on days 1, 8, and 15 of courses 1 and 2 and on day 1 of every other course beginning in course 4. Treatment repeats every 21 days for up to 34 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 5 years.

Arms:
arm 1: Concomitant Chemoradiotherapy: Patients (pts) receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 15-30 minutes weekly for 6 weeks. Pts also receive radiotherapy 5 days a week for 6½ weeks. Pts with CR, PR, or SD proceed to consolidation chemotherapy.

Consolidation chemotherapy: Pts receive paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for 2 courses in the absence of disease progression (PD) or unacceptable toxicity. Pts with CR, PR, or SD proceed to maintenance therapy.

Maintenance therapy: Pts receive a single dose of cyclophosphamide IV over 15-30 minutes 3 days before the first dose of bevacizumab and tecemotide. Pts then receive bevacizumab IV over 30-90 minutes on day 1 and tecemotide subcutaneously on days 1, 8, and 15 of courses 1 and 2 and on day 1 of every other course beginning in course 4. Treatment repeats every 21 days for up to 34 courses in the absence of PD or unacceptable toxicity.

Interventions: intervention 1: bevacizumab intervention 2: Tecemotide intervention 3: carboplatin intervention 4: cyclophosphamide intervention 5: paclitaxel intervention 6: radiotherapy
Intervention descriptions: intervention 1: IV intervention 2: None intervention 3: IV intervention 4: IV intervention 5: IV intervention 6: radiotherapy is given 5 days a week for 6½ weeks during concomitant chemoradiotherapy

Protocol document:
Prot_SAP_000.pdf: 
E6508 
 
1 
A Phase II Study of L-BLP25 and Bevacizumab in 
Unresectable Stage IIIA and IIIB Non-Squamous Non-
Small Cell Lung Cancer after Definitive Chemoradiation 
 
STUDY CHAIR: 
Jyoti D. Patel, M.D. 
 
STUDY CO-CHAIR: 
David P. Carbone, M.D., Ph.D. 
 
LABORATORY CO-CHAIRS: 
David P. Carbone, M.D., Ph.D. 
 
 
Lisa Butterfield, Ph.D. 
 
RADIATION ONCOLOGY CO-CHAIR: 
Henry Wagner, Jr., M.D. 
 
STUDY STATISTICIAN: 
Ju-Whei Lee, Ph.D. 
Rev. 1/12 
THORACIC COMMITTEE CHAIR: 
Suresh Ramalingam, M.D. 
Version Date:  December 8, 2014 
NCI Update Date:  April 29, 2013 
 
Bevacizumab (NSC 704865, IND # 14510) 
Tecemotide (NSC 744225, IND # 14510) 
 
STUDY PARTICIPANTS 
ACTIVATION DATE 
US Sites Only 
December 22, 2010 
 
 
PRE-ACTIVATION DATE 
November 10, 2010 
 
 
 
 
Addendum #1 – Incorporated Prior to Activation 
Addendum #2 – Incorporated Prior to Activation 
Addendum #3 – Incorporated Prior to Activation 
Update #1 – Incorporated Prior to Activation 
Addendum #4 – 8/11 
Addendum #5 – 12/11 
Addendum #6 – 12/11 
 
Addendum #7 – 1/12 
 
Update #2 – 2/12 
Addendum # 8 – 10/12 
Update #3 – 4/13 
Addendum # 9 – 10/13  
Addendum #10 – 5/14 
 
Addendum #11 – 8/14 
 
Addendum #12 – 1/15 
 
Rev. 8/11 
Rev. 1/12, 4/13 
Rev. 5/14 
Rev. 1/15 


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Version Date: December 8, 2014 
 
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Table of Contents 
Schema ...................................................................................................................... 5 
1. Introduction ........................................................................................................ 6 
1.1 Treatment of Unresectable Stage IIIA and IIIB NSCLC .............................. 6 
1.2 Tecemotide immunotherapy .................................................................... 7 
1.3 Bevacizumab ........................................................................................... 11 
1.4 Bevacizumab and Tumor Vaccine Development .................................... 19 
1.5 Summary ................................................................................................. 22 
2. Objectives ......................................................................................................... 23 
2.1 Primary Objective .................................................................................... 23 
2.2 Secondary Objective ............................................................................... 23 
2.3 Laboratory Endpoints .............................................................................. 23 
3. Selection of Patients ......................................................................................... 24 
3.1 Step 1 – Registration ............................................................................... 24 
3.2 Step 2 – Registration ............................................................................... 30 
4. Registration Procedures.................................................................................... 31 
4.1 Step 1 – Registration ............................................................................... 33 
4.2 Step 2 – Registration ............................................................................... 34 
5. Treatment Plan ................................................................................................. 36 
5.1 Step 1 - Concomitant Chemoradiation ................................................... 36 
5.2 Step 1 – Consolidation Chemotherapy (Cycles 1 & 2)............................. 47 
5.3 Step 2 – Maintenance Therapy (Cycles 1, 2, 3,…for up to 34 cycles) ...... 47 
5.4 Adverse Event Reporting Requirements ................................................. 48 
5.5 Comprehensive Adverse Events and Potential Risks List (CAEPR) .......... 58 
5.6 Dose Modifications ................................................................................. 63 
5.7 Duration of Therapy ................................................................................ 73 
5.8 Duration of Follow-up ............................................................................. 73 
5.9 Supportive Therapy ................................................................................. 73 
6. Measurement of Effect ..................................................................................... 74 
6.1 Antitumor Effect – Solid Tumors ............................................................. 74 
7. Study Parameters .............................................................................................. 82 
7.1 Therapeutic Parameters.......................................................................... 82 
7.2 Biological Sample Submissions ............................................................... 84 
8. Drug Formulation and Procurement ................................................................. 85 
8.1 Paclitaxel ................................................................................................. 85 
8.2 Carboplatin .............................................................................................. 88 
8.3 Bevacizumab ........................................................................................... 90 
8.4 Tecemotide ............................................................................................. 94 
8.5 Cyclophosphamide ................................................................................ 100 
9. Statistical Considerations ................................................................................ 104 
9.1 Objectives .............................................................................................. 104 


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9.2 Accrual Rate .......................................................................................... 104 
9.3 Primary Objective .................................................................................. 105 
9.4 Secondary Objectives ............................................................................ 106 
9.5 Laboratory Endpoints ............................................................................ 106 
9.6 Safety Monitoring ................................................................................. 107 
9.7 Gender and Ethnicity ............................................................................ 107 
10. Correlative Studies .......................................................................................... 108 
10.1 Sample Submissions .............................................................................. 108 
10.2 Fraction of Immature Myeloid Cells (ImCs) .......................................... 112 
10.3 Anti-Muc1 Antibody Titer ..................................................................... 112 
10.4 VEGF, ICAM-1 and Other Analyte Levels ............................................... 112 
10.5 Treg Assessments .................................................................................. 112 
10.6 Cellular Immune Response against Muc-1 ............................................ 113 
10.7 Banking .................................................................................................. 113 
10.8 Sample Inventory Submission Guidelines ............................................. 113 
10.9 Lab Data Transfer Guidelines ................................................................ 113 
11. Records to Be Kept .......................................................................................... 114 
11.1 Records Retention ................................................................................. 114 
11.2 ECOG-ACRIN Radiation Oncology Quality Assurance Materials ........... 114 
12. Patient Consent and Peer Judgment .............................................................. 115 
13. References ...................................................................................................... 115 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Update #3] .................................................................. 121 
Appendix II  Pathology Submission Guidelines ..................................................... 122 
Appendix III  Patient Thank You Letter .................................................................. 127 
Appendix IV  Calculation of Carboplatin Dose ....................................................... 128 
Appendix V ECOG-ACRIN Checklist for Submission of Radiation Oncology Quality 
Assurance Materials ........................................................................................ 129 
Appendix VI  E6508 Bevacizumab Drug Request Form ......................................... 130 
Appendix VII  E6508 Peripheral Blood Collection and Shipping Kit Order Form ... 131 
Appendix VIII  E6508 Specimen Shipment Notification Form ............................... 132 
Appendix IX  E6508 Tecemotide Initial Shipment Request and Receipt Form ...... 133 
Appendix X  E6508 Tecemotide Shipment Request and Receipt Form for Resupply135 
Appendix XI  E6508 Contingency Imaging Guideline Manual ............................... 137 
Appendix XII  E6508 Needles & Syringes Shipment Request and Receipt Form ... 150 
 


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NCI Update Date: April 29, 2013 
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STUDY CHAIR 
Jyoti D. Patel, M.D. 
Northwestern University 
676 N. St. Clair, Suite 850 
Chicago, IL 60611 
Phone: 312-695-4549 
Fax: 312-695-4530 
Email: jd-patel@northwestern.edu  
STUDY CO-CHAIR 
David P. Carbone, M.D., Ph.D. 
Vanderbilt University 
685 Preston Research Bldg 
2220 Pierce Avenue 
Nashville TN 37232-6838 
Phone: 615-936-3321 
Fax: 615-936-3322 
Email: d.carbone@vanderbilt.edu 
RADIATION ONCOLOGY CO-CHAIR 
Henry Wagner, Jr, MD 
Penn State Cancer Institute 
H063, 500 University Drive 
Hershey, PA 17033-0850 
Phone: 717-531-1523 
Fax: 717-531-5737 
Email: hwagner@psu.edu 
STUDY CHAIR LIAISON (SCL) 
Therese Zumdahl, MS, PA 
Northwestern University 
676 North St. Clair, Suite 850 
Chicago, IL 60611-2998 
Phone: 312-695-6772 
Fax: 312-695-6189 
E-mail: therese.zumdahl@nmff.org 
 
 
 


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Schema 
Concomitant 
Chemoradiation1
Paclitaxel:
45 mg/m2 IV 
over 1 hour, 
once per week 
for 6 weeks
Carboplatin:
AUC 2 IV 
15-30 min 
infusion, once 
per week for 6 
weeks  
(immediately 
following 
paclitaxel)
Definitive 
radiation 
(6600 cGy) at 
2.0 Gy/fraction, 
5 days a  week 
(Mon-Fri) for 
6.5 weeks
R
E
G
I
S
T
E
R
E
V
A
L
U
A
T   
E4,5
Discontinue 
protocol 
treatment
Consolidation 
Chemotherapy2:
Paclitaxel: 
225 mg/m2 IV over 
3 hours Day 1 
Carboplatin:
AUC 6 IV 15-30 
min infusion 
(immediately 
following 
paclitaxel) Day 1 
For 2 21-day 
cycles
Maintenance Therapy
Cyclophosphamide: 300 mg/m2 (600 mg 
maximum) IV over 15-30 minutes, 3 days 
prior to day 1 of cycle 1 only.
Bevacizumab3: 15 mg/kg IV Day 1 of 
each cycle
Tecemotide immunotherapy: 806 mcg 
subcutaneously:  
Days 1, 8 & 15 of cycles 1 & 2
Day 1 of cycles 4, 6, 8, … (every other 
cycle) until disease progression or 
unacceptable toxicity for a maximum of 
34 21-day cycles.
Unresectable 
Stage IIIA 
and IIIB 
non-
squamous 
NSCLC
1.
Please refer to section 5.1.1 for Concomitant Chemoradiation pre-medication specifics.
2.
Please refer to section 5.2.1 for Consolidation Chemotherapy pre-medication specifics.
3.
Please refer to section 8.3.9 for bevacizumab infusion specifics.
4.
A rest period has been built-in between completion of Concomitant Chemoradiation and initiation of Consolidation Chemotherapy for the resolution of any RT-related toxicities; patient must start Consolidation Chemotherapy within 4 
weeks of completing Concomitant Chemoradiation or patient will discontinue protocol therapy.
5.
This is a radiologic evaluation.
6.
Patient must register to Step 2 within 28 days of completing Consolidation Chemotherapy.
PD
1 Cycle = 21 days
Accrual Goal = 88 patients
Cycles 1-34
PD
CR
PR
SD
STEP 1
Weeks 1-7
Cycles 1 and 2
CR
PR
SD
Discontinue 
protocol 
treatment
E
V
A
L
U
A
T
 E5
R
E
G
I
S
T
E
 R6
STEP 2
Rev. 12/11
Rev. 12/11, 1/12, 4/13
Rev. 10/13
 
Rev. 4/14, 1/15 


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1. 
Introduction 
Lung cancer continues to be the leading cause of cancer related death in both men and 
women in the United States [1].  Non-small cell lung cancer (NSCLC) accounts for 80% of 
lung cancer cases and approximately 40% of NSCLC patients present with stages IIIA and 
IIIB disease. Thoracic radiation therapy has been the traditional treatment for patients with 
unresectable stages IIIA and IIIB NSCLC.  Although radiation therapy provides effective 
symptom relief and contributes to locoregional tumor control, 5-year survival rates with 
radiation alone are disappointing [2,3].  The combination of radiation therapy with 
chemotherapy has demonstrated superiority over radiation alone [4,5,6,7]. Subsequent 
locally advanced NSCLC trials compared induction chemotherapy followed by radiation 
with concomitant chemoradiotherapy and found that the concurrent approach provides 
superior outcome in patients with performance status of 0 or 1 [8,9].    
1.1 
Treatment of Unresectable Stage IIIA and IIIB NSCLC 
Several large trials demonstrated that the use of chemotherapy regimens that 
could be given at full doses during radiation, to allow for the systemic therapy of 
micrometastatic disease while contributing to locoregional control through a 
radiation enhancing effect, could lead to encouraging survival [8,10,20]. A 
regimen utilized in two phase II studies conducted by the Southwest Oncology 
Group (SWOG), consisting of two cycles of concurrent cisplatin (50 mg/m2 on 
days 1,8,29, and 36) plus etoposide (50 mg/m2 on days 1 to 5 and 29 to 33) with 
concurrent once daily radiation therapy to approximately 60 Gy, has been 
followed by two additional cycles of either cisplatin plus etoposide or docetaxel. 
The efficacy of this regimen with cisplatin plus etoposide consolidation was 
shown in a multicenter phase II trial of 50 patients with pathologically confirmed 
stage IIIB disease [10]. With an average follow-up of 52 months, the three and 
five year survival rates were 17% and 15%, respectively. Treatment was 
complicated by grade 4 neutropenia in 32% and grade 3 or 4 esophagitis in 12% 
and 8% of patients, respectively. Even better results have been attained with 
docetaxel consolidation [11]. 
Newer chemotherapy agents such as paclitaxel have been successfully 
integrated in thoracic radiation in combined modality programs.  Pilot studies that 
evaluated weekly regimens of paclitaxel and carboplatin with thoracic radiation 
for patients with locally advanced NSCLC provided encouraging safety, efficacy 
and tolerability results.  Belani et al conducted a phase II randomized three arm 
study to determine the optimal schedule sequence of paclitaxel and carboplatin 
when administered in combination with thoracic radiation therapy.  The LAMP 
(Locally Advanced Multimodality Protocol) was a three-arm randomized phase II 
study that compared induction chemotherapy with consolidation chemotherapy 
for locally advanced NSCLC along with concurrent radiosensitizing 
chemotherapy with thoracic radiation [12].  In the control arm, patients received 
two cycles of chemotherapy with carboplatin and paclitaxel followed by 63 Gy 
external beam radiotherapy (sequential). Induction therapy consisted of two 
cycles of chemotherapy with carboplatin and paclitaxel followed by concurrent 
chemoradiation with weekly carboplatin and paclitaxel.  In the consolidation arm, 
the same chemoradiation regimen was given before two cycles of consolidation 
chemotherapy.  Among patients randomized to the induction regimen, fewer than 
60% received the planned course of therapy due to toxicity, which led to the 


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closure of this arm of the study.  In the final analysis, the median survival 
duration was 16.1 months with the consolidation approach after concurrent 
chemoradiation compared with 12.5 month with sequential chemoradiation.  
These studies have led to the current acceptance of initial concomitant 
chemoradiotherapy as a preferred standard therapy.  
There is little consensus on the appropriate RT dose to use for these patients, 
and the RTOG is currently conducting a randomized trial comparing 60 Gy and 
74 Gy. The 66 Gy regimen in this trial was chosen to be in the middle of this 
range, and has been used in prior large trials with weekly Carbo/Paclitaxel by the 
CALGB [76]. Several recent RTOG trials have used doses of 63 Gy, but without 
corrections for lung density. As we require lung density corrections in E6508, its 
corrected dose of 66 Gy is about the same as an uncorrected dose of 63 Gy [77]. 
However, even with initial concomitant chemoradiotherapy and consolidation, the 
vast majority of patients with NSCLC succumb to recurrent micrometastatic 
disease.  There is a clear need for new therapeutic approaches to NSCLC and 
immunotherapy is one of several promising areas.  By exploiting the patient’s 
own immune system to control cancer growth, it may be possible to enhance the 
therapeutic index without substantially increasing toxicity.  While it is unlikely that 
boosting immunity would be sufficient to eradicate a solid tumor by itself, 
stimulating an antitumor response might be useful in the elimination or minimal 
residual disease or micrometastases following primary treatment. One such 
strategy to stimulate recognition by the immune system is vaccination.  
1.2 
Tecemotide immunotherapy 
Among all the immunotherapy approaches, there has been particular interest in 
mucin-1 (MUC1) as an immunotherapeutic target.  MUC1 is overexpressed and 
aberrantly glycosylated in NSCLC, making it an excellent target for 
immunotherapy. Tecemotide (L-BLP25) offers an innovative approach to target 
MUC1 and is designed to induce a cellular immune response that may lead to 
immune rejection of tumor tissues that express MUC1 antigen. Tecemotide is a 
liposome-based MUC1 immunotherapy composed of a synthetic 25 amino acid 
peptide derived from the tandem repeat region of MUC1, coupled with the 
adjuvant monophosphoryl lipid A. A single low dose of cyclophosphamide (300 
mg/m2 to maximum 600 mg) is given 3 days before treatment with tecemotide to 
further stimulate the immune system and overcome the immune suppression 
seen in cancer patients [13,14].  In various animal models, cyclophosphamide 
has demonstrated its ability to augment delayed-type hypersensitivity responses, 
increase antibody production, abrogate tolerance, and potentiate antitumor 
response [14,15]. 
In preclinical studies of tecemotide in mice, the observed immune response was 
characterized by a proliferative T-cell response to the MUC1 antigen and the 
production of interferon gamma, indicating a T-helper type 1 response [21].  An 
uncontrolled phase I to II trial in patients with NSCLC demonstrated that 
tecemotide produced no significant safety issues and was capable of eliciting a 
T-cell response [17]. Tecemotide has been investigated in several clinical trials in 
NSCLC in the past. Three early trials established that a dose of 800 to 1000 μg 
of tecemotide can be delivered safely with an administration schedule identical to 
the current one[80]. Furthermore, translational as well as survival data from these 
early trials encouraged conduct of a randomized controlled phase IIB trial in 
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patients with stage IIIB and IV NSCLC who had completed initial therapy without 
disease progression. This trial (EMR 63325–005) suggested a survival benefit for 
the tecemotide treated patients (hazard ratio [HR] 0.739; 95% confidence interval 
[CI], 0.509 to 1.073; p-value of 0.112) over patients treated with best supportive 
care (BSC). Further analysis showed that the majority of the benefit was 
observed in the patients with true locoregional disease, i.e., stage IIIB without 
malignant pleural effusion[22]. These patients experienced a prolongation of 
median survival from 13.3 months in the control group to 30.6 months 
(tecemotide group; HR 0.55; 95% CI 0.301–0.999)[81]. Based on this 
observation, a large phase III trial (“START”) was conducted that compared 
patients with unresectable locoregionally advanced NSCLC (i.e., stage IIIA + B) 
after completion of initial CRT, who received tecemotide to a placebo group. 
In START, overall the treatment with tecemotide resulted in a moderate survival 
benefit which was not statistically significant. Patients on tecemotide experienced 
a prolongation of survival from 22.3 to 25.6 months compared to the placebo 
patients, with an adjusted HR 0.88 (95% CI 0.75-1.03) and a p-value of 0.123 
[82]. Pre-specified subgroup analyses revealed that subjects who had received 
prior concurrent CRT (N=806) had a survival benefit from tecemotide treatment 
with a HR of 0.78 (95% CI 0.64-0.95; p-value of 0.016) and a prolongation of 
median survival from 20.6 months in the placebo group to 30.8 months in the 
tecemotide-treated patients. In contrast, for patients with sequential pretreatment 
(N=433), a beneficial effect of tecemotide on the survival time was not observed. 
Baseline characteristics for concurrently and sequentially pretreated subjects 
were comparable, and further anti-cancer therapies after disease progression 
revealed no imbalances between concurrently and sequentially pretreated 
subjects. Of note, patients with prior concurrent CRT represent 2/3 of the study 
population in START. The biological rationale for the observed difference of the 
tecemotide effect on OS in concurrently and sequentially pretreated patients is 
currently not fully understood. However, it is known that both, prior chemotherapy 
and radiotherapy, have modulating effects on the immunogenicity of tumors and 
therefore on the effect of following immunotherapies. [83,84] 
As a result of the START data, a further randomised, double blind, placebo-
controlled phase III study to provide confirmation of the effect of tecemotide 
observed in patients treated with concurrent CRT, has been initiated. This study 
is currently recruiting a target of 1002 subjects with stable disease or better 
following concomitant chemoradiotherapy for stage III NSCLC. In addition, a 
further phase III double-blind placebo-controlled study, INSPIRE, is currently 
recruiting a target of 420 subjects in Asian countries who have with stable 
disease or better following concomitant chemoradiotherapy for stage III NSCLC. 
For further details of the current investigational status, in particular, safety 
results, including ISRs, primary immunology results, and survival results, please 
refer to the current Investigators’ Brochure. 
The strategy for immunotherapy has included a single low dose of 
cyclophosphamide prior to initiation of treatment. Carcinoma-associated mucins 
can be highly immunosuppressive.  High levels of mucin in the blood have been 
correlated with poorer prognosis in cancer patients [19,23]. Bass and 
Mastrangelo have reviewed the use of low-dose cyclophosphamide with active 
specific immunotherapy in patients with advanced melanoma and other 
metastatic cancers, and outlined the basic scientific research that supports its 


ECOG-ACRIN 
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use [14]. In various animal models, cyclophosphamide demonstrated the ability 
to augment delayed-type hypersensitivity responses, increase antibody 
production, abrogate tolerance and potentiate antitumor immunity. It is believed 
that the mechanism of action of cyclophosphamide is the inhibition or reduction in 
the number of the putative suppressor T-cells and their precursors. 
1.2.1 
Tecemotide: Current Investigational Safety Data 
Most common adverse events 
Higher frequencies with risk differences ≥ 2 percentage points 
observed in the tecemotide group are noted in Table A. 
Table A: Adverse Events by Preferred Term with Risk Difference of ≥ 2% in 
Tecemotide Group (Safety Analysis Set, START Trial) 
Preferred Term 
Tecemotide Subjects N=1024 (%) 
Placebo subjects N=477 (%) 
Nausea 
140 (13.7) 
39 (8.2) 
Cough 
338 (33.0) 
133 
Chest pain 
135 (13.2) 
45 (9.4) 
Arthralgia 
108 (10.5) 
34 (7.1) 
Nasopharyngitis 
128 (12.5) 
44 (9.2) 
Myalgia 
73 (7.1) 
18 (3.8) 
Back pain 
146 (14.3) 
53 
Injection site reaction 
34 (3.3) 
2 (0.4) 
Hypertension 
50 (4.9) 
12 
Injection site pain 
49 (4.8) 
13 (2.7) 
Injection site erythema 
39 (3.8) 
8 (1.7) 
Musculoskeletal pain 
93 (9.1) 
34 
Some of the risk difference in percentage points in the adverse 
event (AE) nausea can be ascribed to the treatment with CPA as 
the risk difference in percentage points is reduced to 2.2 (8.4% vs. 
6.2%) when considering AEs occurring after first tecemotide/placebo 
dose. 
The following Grade 3 or 4 AEs occurred more frequently in the 
tecemotide group  (risk difference ≥ 0.5 percentage points): 
metastases to central nervous system (2.8% vs 1.3%), back pain 
(1.6% vs 0.6%), and pulmonary embolism (0.9% vs 0.2%). 
The following Grade 4 AEs occurred more frequently in the 
tecemotide group (risk difference ≥ 0.25 percentage points): 
metastases to central nervous system (1.0% vs 0.6%) and pulmonary 
embolism (0.6% vs 0.2%). 
Serious adverse events 
Three hundred three (29.6%) subjects in the tecemotide group and 
151 (31.7%) in the placebo group experienced a serious AE (SAE). 
Higher frequencies (risk difference ≥ 0.5 percentage points) were 
observed in the tecemotide group for the following SAEs: metastases 


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to central nervous system (3.1% in the tecemotide group vs 1.9% in 
the placebo group), pyrexia (0.8% vs 0.0%), and pulmonary embolism 
(1.0% vs 0.4%). 
Adverse events leading to death 
Forty-six (4.5%) subjects in the tecemotide group and 35 (7.3%) 
subjects in the placebo group experienced an AE leading to death. All 
but 1 of the 46 events was assessed not related to tecemotide.  AEs 
leading to death in more than 2 subjects in the tecemotide group were 
pulmonary hemorrhage (N=7, 0.7% in the tecemotide group vs N=4, 
0.8% in the placebo group), dyspnea (N=6, 0.6%, vs N=4, 0.8%), 
disease progression (N=5, 0.5% vs N=8, 1.7%), hemoptysis (N=3, 
0.3% vs N=3, 0.6%), and metastases to central nervous system (N=3, 
0.3% vs N=2, 0.4%) 
Adverse events of special interest 
The following AEs are considered AEs of special interest: ISRs, flu-
like symptoms (FLSs), and potentially immune-related diseases (for 
details regarding definitions of AEs of special interest refer to the IB). 
FLS comprise the AEs arthralgia, body temperature increased, chills, 
cold sweat, feeling cold, hyperhidrosis, feeling hot, influenza like 
illness, headache, muscle fatigue, musculoskeletal pain, myalgia, 
pyrexia, feeling of body temperature change. ISRs occurred in 176 
(17.3%) of subjects receiving tecemotide vs 56 (11.9%) of subjects in 
the placebo group; 161 (15.8%) subjects in the tecemotide group and 
47 (10.0%) subjects in the placebo group were assessed as related to 
trial treatment. There was no Grade 3 or 4 ISR. 
FLSs occurred in 391 (38.2%) subjects receiving tecemotide vs 158 
(33.1%) subjects in the placebo group; 85 (8.3%) subjects in the 
tecemotide group and 27 (5.7%) subjects in the placebo group were 
assessed as related to trial treatment. Grade 3 or 4 FLSs occurred in 
15 (1.5%) subjects in the tecemotide group vs 8 (1.7%) subjects in the 
placebo group. None of them was assessed as related to trial 
treatment. FLSs causing temporary discontinuation of trial drug 
occurred in 11 (1.1%) subjects vs 5 (1.0%) subjects. FLSs causing 
permanent discontinuation of trial drug occurred in 12 (1.2%) subjects 
vs 4 (0.8%) subjects. 
A similar frequency and severity of potentially immune-related disease 
events occurred in subjects treated with tecemotide and placebo in 
the START trial. The following Grade 3 or 4 potentially immune-
related diseases in START were reported in subjects receiving 
tecemotide: adrenal insufficiency, Guillain-Barré syndrome, 
autoimmune thrombocytopenia (Grade 4, reported as 
thrombocytopenia). 
In addition, the following potentially immune-related SAEs were 
observed in tecemotide trials other than START: encephalitis (EMR 
63325-008), rheumatoid arthritis, Sjogren’s syndrome (both in EMR 
63325-012), hypothyroidism, autoimmune thyroiditis and 


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thrombocytopenia (all in EMR 63325-009). The SAEs from trials EMR 
63325-009 and -012 are still blinded. 
After the administration of a single low dose of CPA (300 mg/m²) the 
most frequent AEs (any grade) observed before the first tecemotide 
injection were nausea (7.2% in the tecemotide group vs 2.7% in the 
placebo group), vomiting (2.7% vs 0.4%), and fatigue (2.3% vs 0.6%). 
There were no clinically relevant findings with regard to laboratory, 
electrocardiogram (ECG), or vital signs data in the START trial. 
Overall, tecemotide is well tolerated in the clinical trials and shows a 
favorable safety profile. 
The START data confirm the safety profile of tecemotide seen in the 
early tecemotide trials. 
1.3 
Bevacizumab 
1.3.1 
Bevacizumab Background 
The growth of solid tumors is dependent on angiogenesis to nourish 
the tumor (24,25).  Blood vessel density in tumors correlates with 
survival (26). The discovery in the 1980s of vascular endothelial 
growth factor (VEGF), a highly conserved endothelial cell specific 
mitogen essential for angiogenesis, permitted development of another 
strategy to combat cancer (27).  In vivo studies in the early 1990s 
demonstrated that antibodies against VEGF led to tumor inhibition 
(28). A murine AVF neutralizing antibody against VEGF inhibits in vivo 
growths of multiple human tumor cell lines including lung cancer 
(27,28), thus proving the role of VEGF in tumorogenesis.  Although 
other angiogenic factors have been identified, VEGF is the most 
potent and specific, with a well-defined role in normal and pathologic 
angiogenesis. VEGF stimulates proliferation of vascular endothelial 
cells and its expression is substantially increased in a majority of 
human tumors including lung cancer, when compared with the 
surrounding tumor-free tissues (30).  A correlation has been noted 
between the degree of tumor vascularization and the level of VEGF 
mRNA expression and in virtually all specimens examined, VEGF 
mRNA is expressed in tumor cells but not endothelial cells, while 
mRNAs for the two VEGF receptors, Flt-1 and KDR, are upregulated 
in endothelial cells associated with the tumor (30). A humanized 
version of the murine antibody to VEGF, known as rhuMab-VEGF 
(bevacizumab) has undergone extensive testing and is now FDA 
approved for the treatment of metastatic colorectal cancer. 
Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that 
binds all biologically active isoforms of human vascular endothelial 
growth factor (VEGF, or VEGF-A) with high affinity (kd = 1.1 nM) (29). 
The antibody consists of a human IgG1 framework and the antigen-
binding complementarity-determining regions from the murine anti-
VEGF MAb A.4.6.1 [Bevacizumab Investigators Brochure, 2008; 
(28,29)].   
Neutralization of VEGF by A.4.6.1 or bevacizumab has been shown to 
inhibit the VEGF-induced proliferation of human endothelial cells in 


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vitro, and decrease microvessel density and interstitial pressure in 
tumor xenografts in vivo. In patients, preliminary results from a 
neoadjuvant trial in rectal cancer demonstrated a decrease in blood 
perfusion/permeability and interstitial fluid pressure in tumors after 
one dose of bevacizumab (31). 
The first phase I study of bevacizumab found no dose-limiting 
toxicities at weekly doses up to 10 mg/kg and various regimens 
including 10 mg/kg every other week and 15 mg/kg every 3 weeks 
have now been utilized (32). The estimated half-life of bevacizumab is 
approximately 21 days (range 11-50 days). The predicted time to 
reach steady state was 100 days. The volume of distribution is 
consistent with limited extravascular distribution. Another phase I trial 
evaluated bevacizumab in combination with chemotherapy and found 
that the pharmacokinetics of neither chemotherapeutic agents nor the 
pharmacology of bevacizumab were altered with these combinations 
(33).  Bevacizumab has been studied in at least 3500 patients in a 
number of phase I, II, and III clinical trials. These clinical trials have 
included patients with a number of tumor types, including colorectal, 
breast, lung, and renal carcinoma. 
The maximum tolerated dose (MTD) of bevacizumab has not been 
determined; however, the dose level of 20 mg/kg was associated with 
severe headaches (34). The dose schedule of either 10 mg/kg or 15 
mg/kg q3w is used in most phase II or III trials with only a few 
exceptions (e.g., the pivotal phase III trial in colorectal cancer, in 
which bevacizumab was given at 5 mg/kg q2w). 
In a large phase III study (AVF2107g) in patients with metastatic 
colorectal cancer, the addition of bevacizumab to irinotecan/5-
fluorouracil/leucovorin (IFL) chemotherapy resulted in a clinically and 
statistically significant increase in duration of survival, with a hazard 
ratio of death of 0.660 (median survival 15.6 vs. 20.3 months; p < 
0.0001) (35). Similar increases were seen in progression-free survival 
(6.2 vs. 10.6 months; p < 0.0001), overall response rate (35% vs. 
45%; p < 0.0029), and duration of response (7.1 vs. 10.4 months;  
p < 0.0014) for the combination arm versus the chemotherapy only 
arm (35). 
Based on the survival advantage demonstrated in AVF2107g, 
bevacizumab was designated for priority review and was approved on 
26 February 2004 in the United States for first-line treatment in 
combination with IV 5-FU−based chemotherapy for subjects with 
metastatic colorectal cancer.  
The role of bevacizumab in the treatment of NSCLC has been under 
active investigation.  The lung cancer specific phase II trial was a 
three arm, multi-institutional study in which patients with advanced 
NSCLC were randomized to carboplatin (AUC = 6) and paclitaxel (200 
mg/m2) every 3 weeks for 6 cycles or the same chemotherapy 
regimen plus a low (7.5 mg/kg) or high (15 mg/kg) dose of 
bevacizumab also given every 3 weeks (36). After completion of the 6 
cycles of chemotherapy, patients with stable disease, or a partial or 


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complete response, who were on a bevacizumab arm, continued to 
receive bevacizumab for up to one year. Patients in the control arm 
were allowed to crossover to bevacizumab upon evidence of tumor 
progression. The trial closed in August 1999 after enrollment of 99 
subjects. In general, patient characteristics were comparable across 
the treatment arms, although there were more patients with squamous 
histology and stage IV disease in the low-dose bevacizumab arm 
compared to the remaining arms. The mean age of the participants 
was 62 years; 61% were male; 93% were ECOG PS 0 or 1; 80% had 
non-squamous histology; and 85% had recurrent or stage IV disease. 
The results comparing the high dose bevacizumab to the control arm 
revealed improved response rate (31.5% versus 18.8%), longer 
median time to progression (7.4 versus 4.2 months) and a survival 
benefit (17.7 versus 14.9 months) on the arm containing bevacizumab 
(36).  Notably, the exceptional survival results observed in the control 
arm may be explained in part by the crossover to bevacizumab. 
Nineteen (59%) patients in the control arm received at least one dose 
of bevacizumab as crossover therapy (15 mg/kg every other week). 
Although there were no objective responses to bevacizumab in the 
crossover population, five (26%) patients had stable disease for at 
least 6 months after changing to bevacizumab. One-year survival was 
47.4% following cross-over. Significant bleeding, with major 
hemoptysis, occurred in 6 patients on the phase II NSCLC trial, 
leading to death in 4. This event was associated with squamous cell 
histology. Patients with squamous cell histology have been excluded 
from all subsequent NSCLC trials with bevacizumab. 
Subsequently, ECOG conducted a randomized phase III trial (ECOG 
E4599) looking at the addition of bevacizumab to carboplatin and 
paclitaxel for advanced NSCLC.  This trial, with 878 patients, has 
been completed and was presented in 2005 (37).  Because of the 
bleeding risk, patients with squamous cell histology, on 
anticoagulation, with hemoptysis, or brain metastases were excluded.  
Patients were randomized to receive paclitaxel 200 mg/m2 plus 
carboplatin (AUC = 6) (PC) on day 1 every 3 weeks or 
paclitaxel/carboplatin plus bevacizumab (PCB) 15 mg/kg on day 1 
every 3 weeks.  Patients on PCB continued bevacizumab after 
completion of the 6 cycles of chemotherapy until progressive disease 
or intolerable toxicity.  The response rate was 10% versus 27% (p < 
0.0001), progression-free survival 4.5 months versus 6.4 months (p < 
0.0001) and median survival 10.2 months versus 12.5 months (p = 
0.0075), all favoring PCB.  Both regimens were well tolerated with 
selected toxicities: (PC versus PCB): grade 4/5 neutropenia (16.4% 
versus 24%, p=.006), grade 3/4 thrombosis/embolism (3% versus 
3.8%, NS); grade 3 or higher hypertension (0.7% versus 6.0%, p 
<.001) and grade 3 or higher hemorrhage (0.7% versus 4.5%, p 
<.001).  Four patients (1%) on the PCB arm experienced CNS 
hemorrhage, versus none on the PC alone arm.  There were 10 
treatment-related deaths (arm PC: 2; arm PCB: 8); 5 due to 
hemoptysis, all on PCB, 3 due to gastrointestinal bleeding (2 on PCB 
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As mentioned earlier, this is the first time a third drug added to the 
current standard two-drug regimen has shown an improvement in 
survival in advanced NSCLC patients. 
Results of a Randomized Phase III Trial of Paclitaxel Plus 
Carboplatin +/-Bevacizumab in Patients with Advanced 
Nonsquamous Non-Small Cell Lung Cancer  
 
PC 
PCB 
p value 
Number of patients 
431 
424 
 
Overall response rate (%) 
10 
27 
<0.0001 
Median Survival (months) 
10.2 
12.5 
0.007 
1-year Survival (%) 
44 
52 
 
2-year Survival (%) 
17 
22 
 
Median TTP (months) 
4.5 
6.4 
<0.0001 
Grade 4 neutropenia (%) 
16.4 
24 
0.006 
Grade 3-4 hemorrhage (%) 
0.7 
4.5 
<0.001 
Grade 3-4 hypertension (%) 
0.7 
6 
<0.001 
PC: paclitaxel/carboplatin  PCB: paclitaxel/carboplatin/bevacizumab 
Because of promising activity in patients with metastatic non-
squamous NSCLC, efforts have been underway to incorporate 
bevacizumab into therapy for locally advanced disease. When given 
with radiation, important safety signals have emerged. In one study 
combining concurrent irinotecan, carboplatin, bevacizumab and 
radiation followed by maintenance bevacizumab for limited-stage 
small-cell lung cancer two of 29 patients developed a 
tracheoesophageal fistula (one event was fatal) (Spigel, personal 
communication). A third patient suffered upper aerodigestive tract 
hemorrhage and death of unknown cause in which a 
tracheoesophageal fistula was suspected but not confirmed. All of the 
adverse events occurred during the bevacizumab maintenance 
phase. The rate of tracheoesophageal fistula in patients with small-
cell lung cancer is estimated to be less than 1%, far lower than the 
nearly 7% seen in the study.  After those cases, studies of concurrent 
radiation and bevacizumab were held nationally.  Six cases of 
tracheoesophageal fistula have been reported in other lung and 
esophageal cancer studies, using bevacizumab and either 
chemotherapy alone or with concurrent radiation. Therefore, all trials 
utilizing concurrent mediastinal radiation and bevacizumab are closely 
monitored.  
One such trial, by Socinski and colleagues is a phase I/II trial that 
incorporates bevacizumab and erlotinib with induction and concurrent 
carboplatin/paclitaxel and 74Gy of thoracic radiotherapy in stage III 
NSCLC [79].  In interim analysis, 20 patients had been accrued to the 
study.  Patients with squamous cell histology are eligible for the study. 
In the initial cohorts, all patients received induction 
carboplatin/paclitaxel/bevacizumab and then concurrent weekly 
carboplatin/paclitaxel and every 14 days bevacizumab without 
excessive toxicity. In the third cohort of the study (n=5), there was 1 


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grade 3 pulmonary hemorrhage requiring bevacizumab termination, 1 
grade 3 interstitial pneumonitis and 2 grade 3 esophagitis with 4 of 5 
patients receiving the target dose of 74 Gy.  Overall 33% of patients 
had grade 3 esophagitis. One grade 5 late hemorrhage occurred in a 
squamous patient.  The authors concluded that incorporation of 
bevacizumab and erlotinib to concurrent chemoradiation was feasible, 
and phase II accrual continues. 
Another trial by the Southwest Oncology Group is investigating 
bevacizumab with concurrent chemoradiation built upon 
cisplatin/etoposide. Thus far, untoward toxicity has not been noted. 
1.3.2 
Safety 
In the phase I and II clinical trials, four potential bevacizumab-
associated safety signals were identified: hypertension, proteinuria, 
thromboembolic events, and hemorrhage. Completed phase II and 
phase III studies of bevacizumab have further defined the safety 
profile of this agent in patients with metastatic malignancies. Also 
during the phase III trials, three new possible bevacizumab-
associated safety signals were identified: congestive heart failure 
(CHF) in patients who had been exposed to anthracyclines, 
gastrointestinal perforations, and wound healing complications.   
Based on clinical trials with bevacizumab as monotherapy or in 
combination with chemotherapy, the most common adverse events of 
any severity include asthenia, pain, headache, hypertension, diarrhea, 
stomatitis, constipation, epistaxis, dyspnea, dermatitis and proteinuria.  
The most common grade 3-4 adverse events were asthenia, pain, 
hypertension, diarrhea and leukopenia.  The most serious AEs include 
life-threatening or fatal hemorrhage, arterial thromboembolic events, 
gastrointestinal perforation and wound dehiscence; these events were 
uncommon but occurred at an increased frequency compared to 
placebo or chemotherapy controls in randomized studies.    
Infusion-Related Reactions:  Infusion reactions with bevacizumab 
were uncommon (< 3%) and rarely severe (0.2%).  Infusion reactions 
may include rash, urticaria, fever, rigors, hypertension, hypotension, 
wheezing, or hypoxia.  Currently, there is no adequate information on 
the safety of retreatment with bevacizumab in patients who have 
experienced severe infusion-related reactions.  
Hypertension: Hypertension is common in patients treated with 
bevacizumab, with an incidence of 20-30% across trials.  Initiation or 
increase of anti-hypertensive medications may be required, but in 
most cases, blood pressure (BP) can be controlled with routine oral 
drugs.  However, incidents of hypertensive crisis with encephalopathy 
or cardiovascular sequelae have been rarely reported.  BP should be 
closely monitored during bevacizumab therapy and the goal of BP 
control should be consistent with general medical practice.  
Bevacizumab therapy should be suspended in the event of 
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Proteinuria: Proteinuria has been seen in all bevacizumab studies to 
date, ranging in severity from an asymptomatic increase in urine 
protein (incidence of about 20%) to rare instances of nephrotic 
syndrome (0.5% incidence).  Pathologic findings on renal biopsies in 
two patients showed proliferative glomerulonephritis.  NCI-CTCAE 
grade 3 proteinuria (> 3.5gm/24 hour urine) is uncommon, but the risk 
may be higher in patients with advanced RCC.  In the phase 2 
randomized study in RCC, 24-hour urine was collected in a subset of 
patients enrolled, and grade 3 proteinuria was found in 4 patients in 
the 10 mg/kg-arm (n=37), 2 patients in the 3mg/kg arm (n=35) and 
none in the placebo arm (n=38).  The safety of continuing 
bevacizumab in patients with moderate or severe proteinuria has not 
been adequately tested.   
Hemorrhage: The incidence of hemorrhage is increased with 
bevacizumab therapy.  Epistaxis is common, occurring in 20-40% of 
patients, but it is generally mild and rarely requires medical 
intervention.  Life-threatening and fatal hemorrhagic events have been 
observed in bevacizumab studies and included pulmonary 
hemorrhage, CNS bleeding and gastrointestinal (GI) bleeding.  In a 
phase 2 study in non-small cell lung cancer, 6 cases of life-
threatening hemoptysis or hematemesis were reported among 66 
patients treated with bevacizumab and chemotherapy; 4 of these 
events were fatal (Novotny et al., 2001).  In the pivotal phase 3 trial in 
advanced colorectal cancer, the rate of GI hemorrhage (all grades) 
was 24% in the IFL/bevacizumab arm compared to 6% in the IFL arm; 
grade 3-4 hemorrhage was 3.1% for IFL/bevacizumab and 2.5% for 
IFL.  Serious GI hemorrhage has also been observed in clinical trials 
with bevacizumab in patients with pancreatic cancer or varices treated 
with bevacizumab.  
Arterial Thromboembolic Events:  The risk of arterial thromboembolic 
events is increased with bevacizumab therapy, and such events 
included cerebral infarction, transient ischemic attack (TIA), 
myocardial infarction and other peripheral or visceral arterial 
thrombosis.  In the pivotal trial in CRC (AVF2107), the incidence of 
arterial thromboembolic events was 1% in the IFL/placebo arm 
compared to 3% in the IFL/ bevacizumab arm.  A pooled analysis of 
five randomized studies showed a two-fold increase in these events 
(4.4% vs 1.9%).  Certain baseline characteristics, such as age and 
prior arterial ischemic events, appear to confer additional risk 
(Schilling et al, ASCO 2005).  In patients > 65 years treated with 
bevacizumab and chemotherapy, the rate of arterial thromboembolic 
events was approximately 8.5%.  
Gastrointestinal Perforation/Fistula: GI perforations/fistula were rare 
but occurred at an increased rate in bevacizumab-containing 
therapies.  The majority of such events required surgical intervention 
and some were associated with a fatal outcome.  In the pivotal phase 
3 trial in CRC (AVF2107), the incidence of bowel perforation was 2% 
in patients receiving IFL/bevacizumab and 4% in patients receiving 5-
FU/bevacizumab compared to 0.3% in patients receiving IFL alone.  


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GI perforation has also been reported in patients with 
gastric/esophageal cancer, pancreatic cancer, ovarian cancer or 
comorbid GI conditions such as diverticulitis and gastric ulcer.  GI 
perforation should be included in the differential diagnosis of patients 
on bevacizumab therapy presenting with abdominal pain or 
rectal/abdominal abscess. 
Wound Healing Complications:  Bevacizumab delays wound healing 
in rabbits and it may also compromise or delay wound healing in 
humans. Bowel anastomotic dehiscence and skin wound dehiscence 
have been reported in clinical trials with bevacizumab.  The 
appropriate interval between surgery and initiation of bevacizumab 
required to avoid the risk of impaired wound healing has not been 
determined.  However, all clinical trials with bevacizumab have 
required a minimum of 28 days from prior major surgery; experience 
in the pivotal trial in advanced CRC suggests that initiation of 
bevacizumab 29-50 days following surgery should be associated with 
a very low incidence of wound dehiscence.  The optimal interval 
between termination of bevacizumab and subsequent elective surgery 
has not been determined either.  In the pivotal study in CRC, 40 
patients on the IFL/bevacizumab arm and 25 patients on the 
ILF/placebo arm underwent major surgery while on study; among 
them, significant post-operative bleeding or wound healing 
complications occurred in 4 of the 40 patients from the 
IFL/bevacizumab arm and none of the 25 patients from the IFL alone 
arm.  Decisions on the timing of elective surgery should take into 
consideration the half-life of bevacizumab (average 21 days, with a 
range of 11-50 days). 
Congestive Heart Failure:  The risk of left ventricular dysfunction may 
be increased in patients with prior or concurrent anthracycline 
treatment.  In phase 3 controlled clinical trials in metastatic breast 
cancer (AVF 2119g) in which all patients had received prior 
anthracyclines, congestive heart failure (CHF) or cardiomyopathy 
were reported in 7 patients (3%) in the bevacizumab/capecitabine arm 
compared to 2 (1%) in the capecitabine-only arm.  No increase in 
CHF was observed in CRC trials with bevacizumab in combination 
with IFL or 5-FU.   
Venous Thrombosis:  Venous thromboembolic events reported in 
bevacizumab trials included lower extremity deep vein thrombosis 
(DVT), pulmonary embolism and rarely, mesenteric or portal vein 
thrombosis.  In the pivotal phase 3 trial of IFL + bevacizumab (given 
at 5 mg/kg q2w), the overall incidences of G3-4 venous 
thromboembolic events were comparable in the two arms (15.1 vs 
13.6%).    
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or 
similar leukoencephalopathy syndrome: RPLS or clinical syndromes 
related to vasogenic edema of the white matter have been rarely 
reported in association with bevacizumab therapy (<1%).   Clinical 
presentations are variable and may include altered mental status, 
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was present in most (though not all) patients on bevacizumab who 
developed RPLS.  MRI scans are key to diagnosis and typically 
demonstrate vasogenic edema (hyperintensity in T2 and FLAIR 
images and hypointensity in T1 images) predominantly in the white 
matter of the posterior parietal and occipital lobes; less frequently, the 
anterior distributions and the gray matter may also be involved.  RPLS 
should be in the differential diagnosis in patients presenting with 
unexplained mental status change, visual disturbance, seizure or 
other CNS findings.  RPLS is potentially reversible, but timely 
correction of the underlying causes, including control of BP and 
interruption of the offending drug, is important in order to prevent 
progression to irreversible tissue damage. 
Tracheoesophageal (TE) Fistula: In a phase II trial of concurrent 
chemoradiation and bevacizumab in limited SCLC (concurrent 
irinotecan, carboplatin, radiotherapy, and bevacizumab, followed by 
maintenance bevacizumab), among the first 25 patients enrolled, 
there have been two confirmed cases of tracheoesophageal (TE) 
fistula (one fatal) and a third case of fatal upper aerodigestive tract 
hemorrhage, with TE fistula suspected but not confirmed.  All three 
events occurred during the bevacizumab maintenance phase (1.5 to 4 
months after completion of concurrent bevacizumab and 
chemoradiation).  The TE fistula rate in this trial was higher than 
expected with chemoradiation alone.  While pulmonary fistula 
(including TE fistula) has also been observed in advanced NSCLC or 
SCLC patients  receiving bevacizumab and chemotherapy (without 
radiation), the incidence was extremely low (<< 1%), and the 
relationships to treatment vs. tumor in those cases were unclear.  
Experience is limited for bevacizumab administered sequentially after 
chemoradiation for either NSCLC or SCLC; in a study for 
chemoradiation followed by bevacizumab in SCLC, one of the 60 
patients enrolled developed TE fistula. 
Neutropenia: When combined with chemotherapy, bevacizumab 
increased the risk of neutropenia compared to chemotherapy alone. In 
a phase 3 trial with IFL +/- bevacizumab in colorectal cancer, grade 3-
4 neutropenia was 21% in the bevacizumab + IFL arm vs. 14% in the 
IFL arm (grade 4 neutropenia was 3% vs. 2%). In a phase 3 trial with 
carboplatin and paclitaxel +/- bevacizumab is NSCLC, the 
bevacizumab-containing arm was associated with an increased rate of 
grade 4 neutropenia (27% vs. 17%), febrile neutropenia (5.4% vs. 
1.8%), and an increased rate of infection with neutropenia (4.4% vs. 
2.0%) with three fatal cases in the bevacizumab + chemotherapy arm 
vs. none in the chemotherapy control arm. 
Fertility and Pregnancy:  Clinical data are lacking regarding the 
immediate or long-term effect of bevacizumab on fertility and 
pregnancy.  However, bevacizumab is known to be teratogenic and 
detrimental to fetal development in animal models.  In addition, 
bevacizumab may alter corpus luteum development and endometrial 
proliferation, thereby having a negative effect on fertility.  As an IgG1, 
it may also be secreted in human milk.  Therefore, fertile men and 


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women on bevacizumab studies must use adequate contraceptive 
measures and women should avoid breast feeding.  The duration of 
such precautions after discontinuation of bevacizumab should take 
into consideration the half-life of the agent (average 21 days, with a 
range of 11 to 50 days). 
Immunogenicity:  As a therapeutic protein, there is a potential for 
immunogenicity with bevacizumab.  With the currently available assay 
with limited sensitivity, high titer human anti-bevacizumab antibodies 
have not been detected in approximately 500 patients treated with 
bevacizumab. 
1.4 
Bevacizumab and Tumor Vaccine Development 
Tumor vaccine development is hampered by impaired immune responses in 
patients with cancer and evasion of an effective host immunologic response. 
Inadequate function of dendritic cells is one mechanism of tumor escape from 
immune system control and may compromise the efficacy of cancer 
immunotherapy.  Vascular endothelial growth factor (VEGF), produced by most 
tumors, not only plays an important role in tumor angiogenesis, but can also 
inhibit the maturation of dendritic cells from hematopoietic progenitors.  
Vascular Endothelial Growth Factor (VEGF), a pro-angiogenic factor produced by 
most human solid tumors has profound effects on hematopoiesis, specifically 
inhibition of dendritic cell (DC) differentiation and diversion of progenitors to other 
myeloid lineages [39-42].  Blockade of VEGF reverses this effect in both animals 
and humans and significantly improves the efficacy of immunotherapy in animal 
models [43]. We now have data that VEGF also affects other mechanisms of 
immune resistance. Contributing to immunosuppression are inhibition of T-cell 
differentiation along with rapid thymic involution and diversion of lymphocytes 
toward B-cell differentiation and dramatic expansion of immunosuppressive 
immature myeloid cells (ImCs).  ImCs directly inhibit T-cell responses and we 
have demonstrated that treatment with retinoids may differentiate these cells and 
restore the immune response.  
In this trial, the clinical impact of VEGF blockade in combination with 
immunotherapy will be tested in a phase II trial that combines the tecemotide 
immunotherapy with the anti-VEGF antibody (bevacizumab) in stage III non-
squamous NSCLC. 
1.4.1 
VEGF Receptors of Hematopoietic Cells  
VEGF, a homodimeric protein, is recognized as a key factor in normal 
and abnormal vasculogenesis regulating multiple biological responses 
in endothelial cells including cell proliferation, migration survival, and 
production of vasoactive mediators.  VEGF binds two specific 
receptors, VEGFR1/Flt1, and VEGFR2/KDR/Flk1, which belong to the 
receptor tyrosine kinase superfamily [reviewed in 44-49].  VEGF is 
produced by almost all tumor cells [50] and is found in the serum of 
cancer patients [51].  High concentrations of VEGF were found in 
tissues even when serum concentrations were relatively low [52].   
The essential role of VEGF and VEGF receptors in hematopoiesis is 
underscored by the fact that knockouts of VEGF or either of its 
receptors are embryonic lethal and have defects in hematopoietic cell 
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development [53-55].  Functional experiments indicated that 
megakaryocytic and erythroid precursors release significant amount of 
VEGF, particularly and low O2 level, whereas exogenous VEGF or 
PlGF, a VEGFR1 specific ligand, markedly potentiate megakaryocyte 
maturation [56].  Recently, Gerber et al. [57], using conditional tissue 
specific targeting of VEGF gene, demonstrated that VEGF knockout 
HSCs lack repopulation potential.  He has also made an important 
observation that VEGF regulates HSC survival by an internal (private) 
autocrine loop mechanism and reported essential role of signaling via 
VEGFR1 thus identifying a novel intracellular function of this receptor.  
Studies of the VEGF effects on colony formation using in vitro and in 
vivo clonogenic assays revealed the role of VEGF in lineage 
redistribution with substantial shift toward formation of myeloid, mixed, 
and erythroid colonies (CFU-GM, CFU-GEMM, and CFU-E and BFU-
E, respectively) from lineage committed progenitors.  At the same 
time, VEGF showed inhibition of colony formation from less mature 
pluripotent progenitors and stem cells [39,58].  
We have shown that VEGF dependence persists in post-natal bone 
marrow differentiation [59,60], and that acquired pathologic levels of 
VEGF may have profound effects on lymphoid as well as myeloid 
lineage cells.  Preliminary data to be shown below identify VEGFR1 
as the primary mediator of inhibitory effect of VEGF on DC 
development. 
1.4.2 
Mechanisms of Immunosuppression in Cancer 
Tumor-associated immune defects are observed in all immune organs 
and cell lineages, including DCs [59,61], thymus and T-cells [62-67].  
We, along with other groups, have demonstrated that defective DC 
differentiation caused by tumor-derived factors contributes to 
immunosuppression in tumor-bearing hosts [68-71].  In 1996, one of 
these factors was reported to be VEGF by demonstrating that anti-
VEGF antibodies block the negative effect of tumor cell supernatants 
on DC maturation and restore antigen-presenting function [59].  In 
vivo studies confirmed these results.  Exposure of mice to VEGF at 
concentrations similar to those observed in advanced stage cancer 
patients not only reproduces tumor effects on DC maturation, but also 
induces profound thymic atrophy accompanied by a dramatic 
reduction in CD4+/CD8+ thymocytes [72].   
1.4.3 
Anti-VEGF Therapy in Enhancing Tumor Vaccine Efficacy 
In addition to improving our basic understanding of the process, 
knowledge of the specific mechanisms of immunosuppression may 
lead to therapeutic strategies aimed at enhancing the therapeutic 
efficacy of tumor vaccines (referred to as immunotherapies in this 
protocol).  To investigate the potential role of anti-VEGF therapy in 
enhancing such efficacy, the novel combination of anti-VEGF 
antibodies with tumor vaccine immunotherapy in two tumor mouse 
models [43] was studied.  Anti-VEGF antibodies in such combination 
doubled the effect of immunotherapy alone and led to a 3 to 4-fold 
reduction in average tumor growth after one month as well as curing a 
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subset of the animals.  Clinical data has since revealed an essentially 
complete restoration of normal DC maturation and function defects in 
lung cancer patients receiving anti-VEGF antibody treatment [61]. In 
this application, we propose a human clinical trial combining anti-
VEGF (bevacizumab) with tecemotide, a recently-reported defined 
antigen, MUC1 lipopeptide based immunotherapy for human lung 
cancer that did not lead to an overall survival advantage but 
suggested favorable survival results in a predefined subset of stage III 
lung cancer patients after concurrent chemoradiation therapy. Our 
results showed regression of pre-established tumors with significant 
levels of specific anti-tumor cytotoxic T-lymphocytes and 
accumulation of dendritic cells at the site of tumor consistent with a 
mechanism of improving tumor antigen presentation [73]. 
1.4.4 
Inhibition of DC Function in Intact Animals by VEGF Infusion 
In vivo infusion of recombinant VEGF with implanted osmotic pumps 
reproduces the observed DC dysfunction in mice.  Continuous VEGF 
infusion resulting in serum VEGF concentrations of 120 to 160 pg/ml 
(close to the median level observed in patients with cancer), resulted 
in a dramatic inhibition of DC development and functional activity 
associated with an increase in the production of B cells and immature 
Gr-1+ myeloid cells.  Infusion of VEGF was associated with inhibition 
of NFκB activation in bone marrow HPCs [39]. 
1.4.5 
Improvement of DC Function and Anti-Tumor Immunity by Anti-VEGF 
Antibody Treatment 
Blockade of VEGF signaling by specific antibodies can effectively 
reverse inhibition of DC and LC maturation and improve specific 
immune responses.  Two s.c. mouse tumor models were used: D459 
cells, expressing mutant human p53 and MethA sarcoma with point 
mutations in the endogenous murine p53 gene.  Therapy with anti-
mouse VEGF antibody (10 µg IP twice a week over 4 weeks) was 
initiated when tumors became palpable.  Treatment of established 
tumors with anti-VEGF antibody alone did not affect the rate of tumor 
growth. However, anti-VEGF antibody significantly improved the 
number and function of lymph node and spleen DCs in these tumor-
bearing animals [43].  Similar results were obtained in respect to LC in 
D459 cells model. 
A novel combination of anti-angiogenic and immunotherapy was 
subsequently investigated based on the dual role of VEGF.  Tumor-
bearing mice were immunized with DCs pulsed with the 
corresponding mutation-specific p53 peptides, together with injections 
of anti-VEGF antibody.  Therapy with peptide-pulsed DCs alone 
resulted in considerable slowing of tumor growth but only during the 
period of treatment, and tumor growth resumed after the end of the 
therapy.  Combined treatment with peptide-pulsed DCs and anti-
VEGF antibody resulted in a prolonged and much more pronounced 
anti-tumor effect and 60% cures, the only cures ever observed with 
peptide-pulsed DC in this tumor model.  This effect was associated 
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group of mice [43].  Substantial improvement of DC function was also 
observed in human patients with lung cancer receiving therapy with 
anti-VEGF antibody [43]. 
1.5 
Summary 
Bevacizumab has recently been shown to improve survival in metastatic non-
squamous NSCLC in combination with paclitaxel and carboplatin [37]. It is thus 
reasonable to postulate that bevacizumab may improve survival in addition to 
standard therapy for patients with locally advanced, and potentially curable, non-
squamous NSCLC. Patients with stage IIIB locoregional disease who received 
tecemotide seemed to derive most benefit in the phase IIB trial and the 
subpopulation of patients with stage III disease who received concomitant 
chemoradiotherapy seemed to benefit most in the phase III study START; a 
similar strategy of immunizing patients with locally advanced disease after 
chemoradiation is being studied.  This phase II study will assess the impact of 
tecemotide in the setting of bevacizumab immune modulation. 
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2. 
Objectives 
2.1 
Primary Objective 
The primary objective is to determine the safety of combination therapy with 
chemoradiation, followed by consolidation, finally followed by tecemotide and 
bevacizumab for patients with non-squamous, locally advanced NSCLC. 
2.2 
Secondary Objective 
The secondary objectives are to evaluate overall survival, toxicity, and 
progression-free survival for patients treated with tecemotide plus bevacizumab 
in addition to chemoradiation and consolidation therapy. 
2.3 
Laboratory Endpoints 
The laboratory endpoints of this study will attempt to 
2.3.1 
Determine the fraction of circulating dendritic cells and immature 
myeloid cells before, during, and after maintenance treatment. 
2.3.2 
Determine the ability of dendritic cells to induce an allogenic mixed 
lymphocyte reaction in vivo. 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. This checklist must be photocopied, completed and 
maintained in each patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG-ACRIN Patient No. 
 
Patient’s Initials (L, F, M) 
 
NOTE: All questions regarding eligibility should be directed to the Study Chair or Study 
Chair Liaison. 
NOTE: This study involves a Step 1 (Registration) and a Step 2 (Registration); see 
Section 4. All time frames for prestudy scan and lab values and other 
requirements will be based on the date of Step 1 Registration. 
NOTE: Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration in each step by the 
treating physician. 
3.1 
Step 1 – Registration 
3.1.1 
Patients must have newly diagnosed histologically confirmed non-
squamous non-small cell lung cancer (adeno, large cell 
undifferentiated, bronchoalveolar, and non-small cell carcinoma 
NOS). 
3.1.2 
Patients must be without significant pleural effusion and have either 
unresectable Stage IIIA disease or Stage IIIB disease (TNM staging 
system AJCC V7). 
• 
“Unresectable” Stage IIIA = Stage IIIA patients with mediastinal 
lymph node enlargement of > 1 cm but < 2.0 cm on CT scans 
must have these nodes biopsied (pathologic confirmation) to rule 
out resectability. These staging procedures are not mandatory for 
patients with obvious nodal involvement (obvious nodal 
involvement ≥ 2cm). Patients with stage IIIA must not have 
significant pleural effusion. 
• 
All patients with stage IIIB disease (without significant pleural 
effusion) will be eligible. This includes patients with metastases to 
contralateral mediastinal or supraclavicular nodes. 
• 
To be eligible patients with either unresectable Stage IIIA disease 
or Stage IIIB disease must not have significant pleural effusion. 
Patients without significant pleural effusion will constitute those in 
whom: 1) pleural effusion is seen on CT scan only (not seen on 
CXR) or 2) pleural effusion does not reaccumulate after one 
thoracentesis and is cytologically negative. 
• 
If pleural effusion is seen on CT scan, a CXR must be done. 
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• 
If pleural effusion is seen on CT scan only, and not seen 
on CXR, patient is eligible. 
• 
If pleural effusion is seen on CT scan, and seen on CXR, 
thorocentesis must be done. 
• If fluid does not reaccumulate within 1 week after 
thoracentesis, cytology must be done: 
• 
If cytologically negative, patient is eligible. 
• 
If cytologically positive, patient is not eligible. 
• 
If fluid does reaccumulate within 1 week after 
thorocentesis, patient is not eligible. 
• Does patient have either unresectable Stage IIIA disease or Stage 
IIIB disease ______ (Yes or No) 
• 
If Stage IIIA with mediastinal lymph node enlargement 
between 1 and 2.0 cm, have nodes been biopsied to rule out 
resectability?  
______ (Yes or No)    Date of biopsy: ___________________ 
• Is patient without significant pleural effusion? ______ (Yes or No) 
• 
If pleural effusion was seen on CT scan, was pleural effusion 
seen on CXR? 
______ (Yes or No) Date of CXR: __________________ 
• 
If pleural effusion was seen on CT scan and CXR after 
thorocentesis was done, did fluid reaccumulate within 1 
week?  
______ (Yes or No)  Date of thorocentesis:____________ 
• 
If, after thorocentesis was done and fluid did not 
reaccumulate within 1 week, was cytologic result 
negative? 
_____ (Yes or No)  Date of cytologic tests: _________ 
3.1.3 
Patients must have measurable or non-measurable disease, as 
defined by RECIST (see Section 6). Baseline 
measurements/evaluations of all sites of disease must be obtained 
within 4 weeks prior to registration. 
3.1.4 
Patients must not have CNS metastases. A head CT or MRI is 
required within 4 weeks prior to registration for evaluation. 
3.1.5 
Patients must have ECOG performance status of 0-1. 
3.1.6 
Patients must have no other active malignancies. 
3.1.7 
Patients must be ≥ 18 years of age. 
3.1.8 
Required bone marrow function laboratory values (obtained within 4 
weeks prior to registration): 
• 
WBC ≥ 4000/mm3 or ANC ≥ 2000/mm3 
 
WBC or ANC:_________________ Date of Test: ____________ 
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• 
Platelets ≥ 140,000/mm3 
 
Platelet count:_________________ Date of Test: ____________ 
• 
Hemoglobin ≥ 9.0 g/dL 
Hgb:____________________ Date of Test: ____________ 
3.1.9 
Required liver function laboratory values (obtained within 4 weeks 
prior to registration): 
• 
Total bilirubin ≤ 1.5 mg/dL 
 
Total Bilirubin:__________________ Date of Test: ____________  
• 
SGOT (AST) ≤ 2.5 times the Institutional upper limit of normal. 
 
SGOT (AST):___________________ Date of Test: 
____________ 
 
Institutional Upper Limit of Normal: ________________________ 
• 
SGPT (ALT) ≤ 2.5 times the Institutional upper limit of normal. 
 
SGPT (ALT):___________________ Date of Test: ____________ 
 
Institutional Upper Limit of Normal: ________________________ 
3.1.10 
Required renal function laboratory values (obtained within 4 weeks 
prior to registration): 
• 
Serum creatinine ≤ 1.5 mg/ml or calculated creatinine clearance  
≥ 45 ml/min 
 
Serum Creatinine or calculated creatinine clearance:___________  
 
Date of Test: _________ 
• 
Urine dipstick must be ≤ 0-1+.  If urine dipstick results > 1+, 24 
hour urine for protein must be obtained. Patients must have < 1g 
protein/24 hours to participate in the study. 
 
Urine protein value by urine dipstick ≤ 0 – 1+ ?  (Yes/No) ______ 
 
Date of test_________ 
 
If no, 24 hour urine for protein < 1g/24 hours?: (Yes/No)  ______ 
 
Date of test__________ 
3.1.11 
Patients may be on a stable regimen of therapeutic anticoagulation or 
may be receiving prophylactic anticoagulation of venous access 
devices, provided that coagulation studies met entry criteria. Caution 
must be exercised for patients requiring anticoagulation, including 
treatment with low dose heparin or low molecular weight heparin for 
DVT prophylaxis while on study due to an increased risk of bleeding 
with bevacizumab. 
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3.1.12 
Required Coagulation laboratory values (obtained within 4 weeks prior 
to registration): 
• 
INR ≤ 1.5, or, if patient is on therapeutic anticoagulation, INR  
≤ 3.0. 
 
INR:________________ Date of Test: ____________ 
Is patient on therapeutic anticoagulation?______ (Yes/No) 
• 
A PTT no greater than institutional upper limits of normal 
 
PTT:_______________________ Date of Test: ____________ 
Upper Limit of Normal: ___________________________ 
3.1.13 
Patients must not have had prior chemotherapy or monoclonal 
antibodies for other cancers within 5 years prior to registration. 
3.1.14 
Patients must not have had prior chemotherapy for lung cancer. 
3.1.15 
Patients must not have had prior chest radiation. 
3.1.16 
Patients must not have ongoing (lasting > 14 days) or active infection, 
ongoing (lasting > 14 days) fever within 6 months prior to registration.  
3.1.17 
Patients must not have a history of gross hemoptysis (≥ grade 2; 
defined as bright red blood of a ½ teaspoon or more) within 3 months 
prior to registration.  If a patient has hemoptysis, the source of 
hemoptysis should be confirmed; extrapulmonary hemoptysis is 
allowable, pulmonary hemoptysis is not. 
If patient has hemoptysis, has it been confirmed that the hemoptysis 
is extrapulmonary?   
______  (Yes or No)   Date of confirmation: ___________________ 
3.1.18 
Patients must not have Grade 2 or greater bleeding or any bleeding 
requiring intervention.  Patients must have no history of bleeding 
diathesis or coagulopathy. 
3.1.19 
Patients must not have any of the following: 
• 
Clinically significant cardiovascular disease 
• 
Previous myocardial infarction within 6 months prior to registration 
• 
New York Heart Association (NYHA) > class II congestive heart 
failure 
• 
Unstable angina pectoris 
• 
Serious cardiac arrhythmia requiring medication within 4 weeks of 
registration 
• 
History of stroke within 6 months prior to registration  
• 
Any prior history of hypertensive crisis or hypertensive 
encephalopathy 
• 
History of TIA within 6 months prior to registration  
______
______
______
______
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3.1.20 
Patients must not have had any of the following within 6 months prior 
to registration: grade 2 or greater peripheral vascular disease, 
abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess. 
3.1.21 
Patients must not have psychiatric illness/social situations that would 
limit compliance with study requirements. 
3.1.22 
Patients with a history of hypertension must be well-controlled  
(< 150/100) on a stable regimen of anti-hypertensive therapy. 
3.1.23 
Patients must not have had any of the following within 4 weeks prior 
to registration: a significant traumatic injury, a serious non-healing 
wound, ulcer, bone fracture, open biopsy, or major surgical procedure.   
3.1.24 
Patients must not have any anticipated major surgical procedure(s) 
during the course of the study.  
3.1.25 
Patients receiving daily treatment with aspirin (> 325 mg/day) or 
nonsteroidal anti-inflammatory agents (NSAIDS) known to inhibit 
platelet function are not eligible. Treatment with dipyridamole 
(Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and/or cilostazol 
(Pletal) is also not allowed.  
3.1.26 
Patient must not have a recognized immunodeficiency disease 
including cellular immunodeficiencies, hypogammaglobulinemia or 
dysgammaglobulinemia, or presence of hereditary or congenital 
immunodeficiencies. 
3.1.27 
Patient must not have any preexisting medical condition requiring 
chronic steroid or immunosuppressive therapy. 
3.1.28 
Patient must not have any autoimmune disease. 
3.1.29 
Patient must not have known Hepatitis B or C. 
3.1.30 
Women must not be pregnant or breast-feeding due to potential harm 
to the fetus or infant from cytotoxic chemotherapy and the unknown 
risk from bevacizumab.  It is also unknown if these agents are 
excreted into breast milk. 
All females of childbearing potential must have a blood or urine test 
within 2 weeks prior to Step 1 registration to rule out pregnancy. 
Female of child-bearing potential? _____ (Yes or No) 
Date of blood or urine test: ___________________ 
3.1.31 
Women of childbearing potential and sexually active males must 
agree to use an accepted and effective method of contraception 
(hormonal or barrier methods, abstinence) prior to study entry, during 
study treatment and for at least 6 months after completion of 
bevacizumab. 
3.1.32 
Patients who received immunotherapy (e.g. interferon, interleukins, 
GM-CSF, G-CSF) within 28 days prior to registration are not eligible 
for this study. 
3.1.33 
No prior splenectomy allowed. 
______
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3.1.34 
Patients must not have any known hypersensitivity to any component 
of bevacizumab. 
3.1.35 
Patient must not have a core biopsy or any other minor surgical 
procedure, excluding the placement of a vascular access device, ≤ 7 
days prior to registration.  
 
 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: This signature line is provided for use by institutions 
wishing to use the eligibility checklist as source 
documentation. 
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3.2 
Step 2 – Registration 
If, after completion of Consolidation Chemotherapy, patient’s disease has not 
progressed and patient has adequate renal function, patient will go on to Step 2, 
Maintenance Therapy. 
3.2.1 
Patient must not have Progressive Disease or unevaluable disease 
per RECIST criteria upon post- Consolidation Chemotherapy 
evaluation. 
Unevaluable disease? ______ (Yes or No)  
PD? ______ (Yes or No) Date of evaluation: ______________ 
3.2.2 
Required renal function laboratory values (obtained at post-
Consolidation Chemotherapy evaluation within 2 weeks prior to Step 2 
registration): 
• 
Serum creatinine ≤ 1.5 mg/ml or calculated creatinine clearance  
≥ 45 ml/min 
Serum Creatinine or calculated creatinine clearance:___________ 
Date of Test: _________ 
• 
Urine dipstick must be ≤ 0-1+.  If urine dipstick results > 1+, 24 
hour urine for protein must be obtained. Patients must have < 1g 
protein/24 hours to participate in the study. 
Urine protein value by urine dipstick ≤ 0 – 1+ ? (Yes/No) ____ 
Date of test_____ 
If no, 24 hour urine for protein < 1g/24 hours?: (Yes/No) ____ 
Date of test______ 
3.2.3 
Patient must be registered to step 2 within 28 days of completion of 
Consolidation Chemotherapy. 
Date of completion of Consolidation Chemotherapy (Cycle 2, day 21): 
________ 
3.2.4 
Patient must have met all eligibility requirements for Step 1 (Section 
3.1) to be eligible for step 2. 
Eligible for Step 1? ________ (yes or no) 
3.2.5 
Required platelets (obtained at post-Consolidation Chemotherapy 
evaluation within 2 weeks prior to Step 2 registration): 
• 
≥ 100,000/mm3 
Platelet count: ________ Date of Test: ________ 
3.2.6 
Patient must not have any autoimmune disease. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions 
wishing to use the eligibility checklist as source 
documentation. 
______
______
______
______
______
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4. 
Registration Procedures 
NOTE: This study involves a Step 1 (Registration) and a Step 2 (Registration); please 
read these instructions carefully. 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Study centers can 
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check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU members’ website by entering 
credentials at https://www.ctsu.org.  For sites under the CIRB initiative, IRB data will 
automatically load to RSS. 
Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS. 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
PHONE: 1-866-651-2878 
FAX: (215) 569-0206 
E-MAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
Required Protocol Specific Regulatory Documents 
1.  
CTSU Regulatory Transmittal Form. 
2.  
Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the sample 
informed consent document must be justified in writing by the 
investigator and approved by the IRB. 
3.  
A.  
CTSU IRB Certification Form. 
Or 
B.  
Signed HHS OMB No. 0990-0263 (replaces Form 310). 
Or 
C.  
IRB Approval Letter 
NOTE: The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
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• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To 
access OPEN, the site user must have an active CTEP-IAM account (check at < 
https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or 
participating organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria has been met within the protocol stated timeframes. All patients 
have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
NOTE: 
To receive site reimbursement for specific tests and/or bio-specimen 
submissions, completion dates must be entered in the OPEN Funding screen 
post registration. Please refer to the protocol specific funding page on the 
CTSU members’ website for additional information. Timely entry of 
completion dates is recommended as this will trigger site reimbursement. 
Further instructional information is provided on the CTSU members’ website OPEN tab 
or within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-
888-823-5923 or ctsucontact@westat.com. 
4.1 
Step 1 – Registration 
Patients must not start protocol treatment prior to registration. 
Treatment should start within 3 working days after registration. 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
4.1.2.1 
Institution and affiliate name 
4.1.2.2 
Investigator’s name 
4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials and chart number 
4.1.3.2 
Patient’s Social Security number 
4.1.3.3 
Patient demographics 
• 
Sex 
• 
Birth date (mm/yyyy) 
• 
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• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1. An eligibility worksheet has been appended to the protocol. A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.1.5 
Additional Requirements  
4.1.5.1 
Patients must provide a signed and dated, written informed 
consent form. 
4.1.5.2 
Specimens are to be submitted as indicated in Section 10. 
NOTE: ECOG-ACRIN requires that all samples submitted from 
patients participating in E6508 be entered and tracked via 
the online ECOG-ACRIN sample tracking System. See 
Section 10.1.4 
4.1.6 
Instructions for Patients Who Do Not Start Assigned Protocol 
Treatment  
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
according to the instructions in the E6508 Forms Packet. Document 
the reason for not starting protocol treatment on the Off-Treatment 
form. Also report the date and type of the first non-protocol treatment 
that the patient receives. 
4.2 
Step 2 – Registration 
Patients must not start protocol treatment prior to registration. 
Treatment should start within 8 working days after registration. 
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
4.2.2.1 
Institution and affiliate name 
4.2.2.2 
Investigator’s name 
4.2.3 
Patient Identification  
4.2.3.1 
Patient’s initials and chart number 
4.2.3.2 
Patient’s Social Security number 
4.2.3.3 
Patient demographics 
• 
Sex 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
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• 
Nine-digit ZIP code 
• 
Method of payment 
4.2.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.2. An eligibility worksheet has been appended to the protocol. A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.2.5 
Additional Requirements  
4.2.5.1 
Patients must provide a signed and dated, written informed 
consent form. 
4.2.5.2 
Specimens are to be submitted as indicated in Section 10. 
NOTE: 
ECOG-ACRIN requires that all samples submitted from 
patients participating in E6508 be entered and tracked via 
the online ECOG-ACRIN sample tracking System.  See 
Section 10.1.4 
4.2.6 
Instructions for Patients Who Do Not Start Assigned Protocol 
Treatment  
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
according to the instructions in the E6508 Forms Packet. Document 
the reason for not starting protocol treatment on the Off-Treatment 
form. Also report the date and type of the first non-protocol treatment 
that the patient receives. 
4.2.7 
Investigator’s Drug Brochure and Safety Alerts 
Bevacizumab and tecemotide are INVESTIGATIONAL AGENTS. This 
protocol is to be conducted under IND # 14510. A copy of the 
Investigator’s Drug Brochure (IDB) for both investigational agents is 
available in the Study Specific Tools section of E6508 on the ECOG 
web page (www.ecog.org).  The IDBs provide relevant and current 
scientific information about the investigational products. The IDBs 
should be submitted to your IRB/EC according to GCP regulations. 
The IDBs and any correspondence to the Institutional Review Board 
(IRB)/Ethics Committee (EC) should be kept in the E6508 regulatory 
files. 
Should any SAE report on this study qualify as a safety alert report 
requiring expedited reporting, the SAE report will be sent by the 
sponsors to regulatory authorities globally (including the FDA) and 
ECOG-ACRIN. If applicable, ECOG-ACRIN will disseminate these 
safety alert reports to all ECOG-ACRIN investigators in the bimonthly 
group mailings.  These reports should be forwarded to your IRB/EC 
within 90 days of receipt for review.  Reporting instructions are 
provided with each safety alert.  These safety alerts and any 
correspondence to your IRB/EC should be maintained in your E6508 
study files. 
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5. 
Treatment Plan 
5.1 
Step 1 - Concomitant Chemoradiation  
After initial registration, all patients will receive: 
• 
Paclitaxel 45 mg/m2 IV over 1 hour once per week for 6 weeks. 
• 
Carboplatin AUC 2 IV 15-30 minute infusion once per week for 6 weeks, 
immediately following paclitaxel.  When calculating carboplatin dose, GFR 
should not exceed 125 mL/min. See Appendix IV for additional information 
on calculation of carboplatin dose. 
• 
Definitive radiation therapy 6600 cGy at 2.0 Gy/fraction for 6.5 weeks. 
Radiation therapy will be administered daily, 5 days a week (Monday through 
Friday). 
All patients with CR, PR or SD at evaluation at end of Concomitant 
Chemoradiation may continue on to Consolidation Chemotherapy. Patients with 
progressive disease or whose response is unevaluable will discontinue protocol 
treatment. 
5.1.1 
Premedication for Concomitant Chemoradiation: 
Prior to receiving paclitaxel, all patients will receive the following 
premedication:  
• 
Dexamethasone 10 mg IV just prior to paclitaxel. 
• 
Diphenhydramine 50 mg IV 1 hour prior to paclitaxel. 
• 
Cimetidine 300 mg IV (or equivalent, ranitidine 50 mg or 
famotidine 20 mg)  
1 hour prior to paclitaxel.  
5.1.2 
Radiation Therapy 
Radiation therapy will start within a 72 hour window of the start of 
chemotherapy with weekly carboplatin/paclitaxel (day -1 to day +2). 
The intent of this protocol is to deliver a dose of 66Gy in 33 fractions 
over 6.5 weeks to all areas of known macroscopic primary tumor and 
nodal metastases while delivering a minimum dose of 50Gy to 
intervening areas of possible microscopic involvement. Within broad 
guidelines regarding definition of target volumes, treatment planning, 
and dose prescription, the choice of details of treatment technique 
(e.g. number and angles of beams used, etc.) are left to the 
determination of the treating Radiation Oncologist based on their local 
policy, expertise, and the particular circumstances pertaining to each 
patient’s unique tumor and normal tissue anatomy. Hand in hand with 
this freedom is the responsibility of the Radiation Oncologist to 
document accurately that the chosen technique provides appropriate 
coverage of the targeted volumes while adequately protecting critical 
normal tissues. This entails strict adherence to timetables for 
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for real-time review and, if indicated, modification of plans to meet 
protocol requirements. 
CT-based planning is required for this study.  Use of either 3D 
conformal planning or IMRT is allowed provided that all credentialing 
requirements as outlined below have been satisfied.  If IMRT is used, 
the institution must demonstrate that respiratory motion can be limited 
to a maximum excursion of 1.0 cm with implementation of motion 
management techniques if required.  Use of proton therapy is not 
allowed. 
NOTE: Digital submission of treatment plans is required on this 
study. 
5.1.2.1 
Credentialing 
Institutions using 3D conformal techniques must complete 
the 3D Conformal Benchmark. Those treating with IMRT 
must either complete the IMRT Questionnaire and 
Benchmark or irradiate the RPC’s head and neck phantom. 
The benchmark material is available from theIROC Rhode 
Island (QARC) at (www.QARC.org). Contact IROC 
Houston (http://rpc.mdanderson.org/rpc/) for information 
about their phantoms. 
If techniques are used to compensate for or limit 
respiratory motion, the IROC Motion Management 
Questionnaire will also be submitted. If patients are treated 
with IMRT and gating or tracking methods are used to 
compensate for respiratory motion, the Thorax-Lung 
Phantom must be irradiated with its accompanying 
reciprocating platform to simulate motion. 
NOTE: An institution will be considered credentialed for 
this study if they have successfully irradiated the 
Thorax-Lung Phantom with accompanying 
reciprocating platform using the same treatment 
modality and motion management technique to 
be used for treating patients on this study.  This is 
in lieu of the other credentialing requirements 
noted above. 
5.1.2.2 
Equipment 
Beam Energy: All patients will be treated with linear 
accelerator photon beams. The use of 
60Co or electron beams is not permitted. It 
is recommended that photon energies of 
12 MV or less be used because lack of 
electronic equilibrium at air-tumor 
interfaces with higher energies.  In 
institutions with only low (4-6MV) and high 
(15-25 MV) energy beams, the higher 
energy may be used if it provides a better 
dose distribution. Such cases should be 
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discussed with the study Radiation 
Oncology Co-Chair (Dr. Wagner). 
Geometry:  
Source-to-axis distance greater than or 
equal to 100 cm. 
Calibration: 
Teletherapy units used in this study shall 
have their calibration verified by IROC 
Houston 
5.1.2.3 
Target Volume Definitions 
The nomenclature and definitions of ICRU Reports 50 and 
62 shall be followed in this study. 
5.1.2.3.1 
GTV 
The primary tumor and radiologically 
positive lymph nodes (> 1 cm short axis OR 
SUV > 3 on PET) or nodes of any size 
pathologically positive at biopsy. This may 
result in two or more noncontiguous 
volumes (e.g. for a peripheral primary tumor 
with ipsilateral hilar and high paratracheal or 
supraclavicular nodal involvement. In cases 
of atelectasis of lung distal to an obstructing 
tumor the PET scan may be helpful in better 
defining the GTV than the planning CT. 
Careful attention should be paid to the 
outlining of the tumor and lymph nodes on 
the planning axial CT images. The lymph 
nodes should be outlined using a 
“mediastinal window” setting and any tumor 
interfacing with lung parenchyma, with the 
“lung window” setting. The direct use of 
fused CT and PET images in treatment 
planning is allowed but not required. 
5.1.2.3.2 
CTV1 
The CTV1 is defined as the GTV plus a 1 
cm margin to allow for microscopic tumor 
extension plus expansion of these volumes 
to produce a single contiguous volume for 
the primary tumor and its defined lymph 
node involvement. This represents a limited 
form of elective nodal irradiation (ENI) but 
does NOT require or allow treatment of 
additional nodal echelons that are not 
located between areas of known 
involvement. Thus treatment of the 
contralateral hilum or of the supraclavicular 
fossa(e), except incidental to irradiation of 
an upper lobe primary or for known nodal 
involvement, are not allowed. This volume 
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will be treated to a dose of 50 Gy in 25 
fractions over 5 weeks. 
5.1.2.3.3 
CTV2 
The CTV2 is defined as the GTV plus a 0.5 
to 1.0 margin. Intervening lung or 
hilar/mediastinal node-bearing regions will 
not be included to produce a contiguous 
single volume, thus CTV2 may describe two 
or more distinct volumes. This volume will 
be treated after completion of treatment of 
CTV1 to an additional 16 Gy in 8 fractions 
over 1.5 weeks. 
5.1.2.3.4 
PTV 
PTV is the CTV plus a margin to ensure that 
the prescribed dose is actually delivered to 
the CTV. This margin accounts for 
variations in treatment delivery, including 
variations in setup between treatments, 
patient motion during treatment, movement 
of the tissues that contain the CTV (e.g. 
respiration), and size variations in the tissue 
containing the CTV. A 0.5 cm margin is 
required to account for setup uncertainties 
for typical thoracic patient setups. The PTV 
is a geometric concept and will be created 
by adding 0.5 = margin for motion. If motion 
is not explicitly measured, a maximum 
margin of 1.5 cm from the CTV to PTV may 
be used (PTV=CTV + 0.5 to 1.5 cm). It is 
the treating physician’s decision what 
margin to use, depending on observed 
motion of the tumor detected by the 
fluoroscope (in general, the margin will be 
smaller for upper lung tumors and larger for 
lower lung tumors). More margin may be 
necessary in the cranio-caudad direction 
than in the other directions. Investigators 
will document how much margin (beyond 
the normal margin) was added, based on 
fluoroscopy findings, on the Motion 
Management Reporting Form. 
5.1.2.4 
Motion Management 
The use of four-dimensional radiation therapy planning is 
allowed. Estimations of tumor excursion during the 
cardiorespiratory cycle may be made by fluoroscopy as 
well.  Acceptable methods to compensate for or manage 
motion include an ITV approach, an MIP approach, 
abdominal compression, breath hold, beam gating, or 
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other technologies. Whichever technique is chosen, each 
institution will be asked to document how they intend to 
limit motion and verify this on a case by case basis.  The 
Motion Management Reporting Form will be submitted for 
each patient. 
Intensity modulated radiation therapy (IMRT) is allowed so 
long as the participating institution has satisfied the 
credentialing requirements noted above and the maximum 
tumor excursion as a result of respiratory motion can be 
limited to 1.0 cm.  An appropriate method for managing 
motion shall be utilized if required. If patients are treated 
with IMRT and gating or tracking methods are used to 
compensate for respiratory motion, the Thorax-Lung 
Phantom must be irradiated with its accompanying 
reciprocating platform to simulate motion. The NCI 
guidelines for the use of IMRT in clinical trials can be found 
at www.QARC.org. 
5.1.2.5 
Target Dose 
Prescribed Dose: 
Dose will be prescribed to an isodose line that 
encompasses the target volume and satisfies the 
uniformity requirements below. 
Dose Definition:  
Dose is to be specified in Gy to muscle. 
Tissue Heterogeneity: 
Doses delivered to patients are to be calculated with 
heterogeneity correction, i.e., correction is to be made for 
density differences in air spaces, lung, water-density or 
bony tissue. 
Approved Dose Algorithms 
Planning must be performed using an approved dose 
calculation algorithm. Approved algorithms include: 
convolution superposition, collapsed cone convolution, and 
Monte Carlo. Contact IROC Rhode Island (QARC) at 
(physics@qarc.org) for information regarding approved 
dose algorithms. 
Fractionation: 
The daily fraction size prescribed to a volume 
encompassing at least 95% of the CTV is 2.0 Gy.  All fields 
of a multiple field plan are to be treated daily, 5 days per 
week.  
Patients may not be treated with more than one fraction 
per day to ‘catch up’ after treatment breaks. A single BID 
treatment (with a 6-8 hour interval between fractions) may 
be given on the last day of treatment in order to allow 
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treatment to complete on a Friday rather than giving the 
last fraction on the following Monday.  
Dose Uniformity: 
At least 95% of CTV1 or CTV2 receives at least 95% of its 
respective prescription dose, and no more than 10% of 
CTV2 receives more than 110% of the prescription dose. 
Dose constraints for tumor and normal tissues will be the 
same whether conformal or IMRT approaches are used. 
The primary justification for using IMRT is for those cases 
where the constraints cannot be achieved using conformal 
approaches but can be achieved using IMRT, particularly 
in cases where doses to the spinal cord or esophagus 
approach tolerance. 
5.1.2.6 
Dose to Target Volumes and Organs at Risk 
Volume 
Dose/Volume Limit 
Comment 
CTV1 
50 Gy 
At least 95% of the target volume 
must receive the prescribed dose. 
CTV2 
66Gy 
At least 95% of the target volume 
must receive the prescribed dose. 
Spinal Cord 
50 Gy to any 
significant volume 
Treatment of a few voxels along the 
edge of the cord to > 50 Gy may be 
acceptable. Careful correlation of 
DVH and isodose curves is required. 
Total lung 
V20 < 35%; try to 
keep < 30% 
Exclude CTV (not PTV) in 
calculating total lung volume. 
Heart 
V45 < 67% 
V60 < 33% 
 
Brachial Plexus 
60 Gy to any point 
Unless tumor invades plexus 
Esophagus 
V55 < 67% 
V65 < 33% 
 
Liver 
V35 < 50% 
 
Dose Volume Histograms (DVH):  DVHs for the composite 
plan shall be provided for all of the target volumes and 
organs at risk listed above. When using IMRT, a DVH shall 
also be submitted for a category of tissue called 
“unspecified tissue.” This is defined as tissue contained 
within the skin, but which is not otherwise identified by 
containment within any other structure. 
5.1.2.7 
Treatment Planning 
All planning for both the initial and boost volumes should 
be completed before the patient is registered on protocol. 
This will ensure that the dose/volume constraints (SEE 
SECTION 5.1.2.4) can be met. The registration form will 
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indicate confirmation by the responsible Radiation 
Oncologist that these criteria are met. 
Patients must be positioned in a stable and consistent 
manner during simulation and treatment. This will typically 
require immobilization either in a custom device (e.g. Alpha 
Cradle or VacLoc) or with the use of a T-bar or other 
device to position the arms above the head.  
CT simulation is REQUIRED and will be performed on a 
flat table using the aforementioned immobilization device 
to maintain the patient in treatment position.  Contiguous 
slices will be obtained from the top of the thyroid cartilage 
superiorly to the insertion of the diaphragm inferiorly. Slice 
thickness should be 2-5 mm through the volume of known 
primary and nodal tumor and may be 8-10 mm throughout 
the remainder of the scanned volume. The administration 
of intravenous contrast during CT simulation is suggested, 
since it allows a better definition of the involved lymph 
nodes, albeit with some perturbation of dose calculations.  
If 4D CT is not utilized, it is highly desirable (but not 
mandatory) that the planned treatment beams be 
simulated using a fluoroscopic simulator to obtain an 
estimate of the degree of respiratory motion and its impact 
on the adequacy of treatment margins. In facilities without 
such capabilities pre-ports on the treatment machine 
should be obtained with the patient breathing quietly. 
5.1.2.8 
Treatment Technique 
The use of direct posterior spinal cord blocks is not 
permissible.  
Compensating Filter or Wedges.  In the case of a large 
sloping contour, such as usually encountered when 
treating upper lobe tumors in large patients, wedges or 
compensating filters are recommended. The maximum in 
homogeneity acceptable without compensation will be 
10%. A wedge may also be used as a 2-dimensional tissue 
compensator. If necessary, appropriate reduction in field 
size must be done to avoid excessive irradiation to critical 
structures. While some ‘field within a field’ compensation 
will be allowed formal IMRT is not permitted on this study. 
The irradiated target must be defined by individually 
shaped ports with secondary blocking, using custom-made 
Cerrobend blocks (5HVL), or multi-leaf collimator (MLC) 
devices.  
Both coplanar and non-coplanar beam arrangements may 
be used so long as the plans and verification of their 
implementation are adequately documented. 
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5.1.2.9 
Dose modification for toxicity 
In general, radiation therapy should not be interrupted for 
bothersome but non-life-threatening acute toxicities which 
can be managed symptomatically. The primary criterion for 
a decision to interrupt treatment should be the clinical 
status of the patient rather than numerical laboratory 
values. Most acute toxicities should be managed with 
vigorous supportive care including pain management, 
nutritional support, and consideration of prophylactic 
antibiotics, rather than by treatment interruptions. 
An interruption of one day only is allowed for non-treatment 
related issues such as travel problems, inability to get to 
the center (bad weather) or national holidays.  For 
treatment related toxicities such as acute mucositis, an 
interruption of up to 3 days is permitted. Total number of 
elapsed days should be carefully reported.  The reason for 
any interruption shall be documented in the treatment chart 
and reported to IROC Rhode Island (QARC). 
If more than three treatment days interruption is required, 
resumption of the treatment is at the discretion of the 
treating radiation oncologist. The radiation oncology chair 
should be called if there are any issues regarding dose 
and further treatment. 
Any interruption > 3 days or discontinuation of radiation 
requires notification to IROC Rhode Island (QARC) (please 
see Appendix V). 
NOTE:  If patient cannot complete radiation therapy, 
patient will discontinue protocol treatment. 
• 
Radiation therapy should not be interrupted 
for hematologic toxicity or for fever so long as 
the patient is physiologically stable (e.g. 
febrile neutropenia without cardiorespiratory 
distress) 
• 
Radiation therapy should not be interrupted 
for acute esophagitis which can be managed 
by provision of adequate pain control and 
fluid/caloric administration by enteral or 
parenteral methods. 
• 
Reversible 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 for 2 Gy/Fx. Radiation pneumonitis and 
subsequent fibrosis of the lung will occur in 
100% of all patients receiving 40 Gy 
equivalent (conventional fractionation) to the 
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lung, usually within the first six months after 
initiation of treatment. It is therefore essential 
to spare all normal lung possible. 
• 
Acute esophagitis will be graded according to 
the NCI Common Toxicity Criteria for Adverse 
Events (CTCAE) version 4.0 (dysphagia-
esophageal related to radiation) on a weekly 
basis and subsequently for 3 weeks after 
completion of radiotherapy.  
The NCI Common Toxicity Criteria for 
Adverse Events (CTCAE) version 4.0 is 
located on the CTEP website 
(http://ctep.cancer.gov). See Section 5.4 for 
Adverse Event Reporting. 
5.1.2.10 
Radiation Adverse Event Reporting 
All acute and late adverse events from radiation therapy 
will be reported and scored for severity using the CTEP 
version 4.0 of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE). The CTCAE version 4.0 located 
on the CTEP website at (http://ctep.cancer.gov). See 
Section 5.4 for Adverse Event Reporting. 
5.1.2.11 
QA Documentation 
Required Benchmarks:  See Section 5.1.2.1 for required 
benchmarks. 
Digital Submission: Submission of treatment plans in 
digital format (either DICOM RT or RTOG format) is 
required. Digital data must include CT scans, structures, 
plan and dose files. Submission may be either by SFTP or 
CD. Instructions for data submission are on the IROC 
Rhode Island (QARC) Web site at www.qarc.org. Any 
items on the list below that are not part of the digital 
submission may be submitted as screen captures along 
with the digital data. 
Within three days of the start of radiotherapy, the 
following data for on-treatment review shall be 
submitted: 
Treatment Planning System Output 
• 
RT treatment plan including CT, structures, dose, and 
plan files.  These items are included in the digital plan. 
• 
Dose volume histograms (DVH) of all target volumes 
and required critical structures.  When using IMRT, a 
DVH shall be submitted for a category of tissue called 
“unspecified tissue.”  This is defined as tissue 
contained within the skin, but which is not otherwise 
identified by containment within any other structure.  
DVH’s are included in the digital plan. 
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• 
Digitally reconstructed radiographs (DRR) for each 
treatment field.  Please include two sets, one with and 
one without overlays of the target volumes and organs 
at risk. When using IMRT, orthogonal setup images are 
sufficient. 
• 
Treatment planning system summary report that 
includes the monitor unit calculations, beam 
parameters, calculation algorithm, and volume of 
interest dose statistics. 
Supportive Data 
• 
Copies of the E6508 On-Study Form and the E6508 
Baseline Data Form 
• 
Copy of the baseline diagnostic CT scan of the chest 
with and without contrast as well as copies of any other 
imaging studies (i.e. PET scan) used to define the 
target volumes. Copies of the radiology reports must 
be included.  Submission of Diagnostic Imaging data in 
digital format is required. Digital files must be in 
DICOM format. These files can be submitted via sFTP 
or burned to a CD. Multiple studies for the same patient 
may be submitted on one CD; however, please submit 
only one patient per CD. 
• 
Prescription Sheet for Entire Treatment  
Forms 
• 
Copy of Appendix V “ECOG-ACRIN Checklist for 
Submission of Radiation Oncology Quality Assurance 
Materials.” 
• 
RT-1 Dosimetry Summary Form 
• 
Motion Management Reporting Form 
Within one week of the completion of radiotherapy, the 
following data shall be submitted for all patients: 
• A copy of the patient’s radiotherapy record including 
prescription, and the daily and cumulative doses to all 
required areas and reference points. 
• Documentation listed above showing any modifications 
from original submission. 
• Copy of Appendix V “ECOG-ACRIN Checklist for 
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Any of the above data that is not submitted digitally may be 
forwarded to: 
IROC Rhode Island (QARC) 
640 George Washington Highway 
Suite 201, Building B 
Lincoln, RI 02865-4207 
Phone 401-753-7600 
FAX 401-753-7601 
Questions regarding the dose calculations or 
documentation should be directed to: 
Protocol Dosimetrist 
IROC Rhode Island 
640 George Washington Highway 
Suite 201, Building B 
Lincoln, RI 02865-4207 
Phone 401-753-7600 
FAX 401-753-7601 
Questions regarding the radiotherapy section of this 
protocol should be directed to: 
Henry Wagner Jr., MD 
Director, Division of Radiation Oncology 
Penn State Cancer Institute 
H063, 500 University Drive 
Hershey, PA 17033 
Phone 717-531-1523 
FAX 717-531-0882 
Email hwagner@psu.edu 
5.1.2.12 
Definitions of Deviations in Protocol Performance: 
Prescription Dose: 
Minor Deviation: The dose to the prescription point differs 
from that in the protocol by between 6% and 10% 
Major Deviation: The dose to the prescription point differs 
from that in the protocol by more than 10% 
Dose Uniformity: 
Minor Deviation: Less than 95% of the CTV1 or CTV2 
receives less than 95% of its respective prescription dose 
or more than 10% of CTV2 receives more than 110% of 
the prescription dose. 
Major Deviation: Less than 90% of the CTV1 or CTV2 
receives less than 90% of its respective prescription dose 
or more than 10% of CTV2 receives more than 120% of 
the prescription dose. 
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Minor Deviation: Margins less than specified or fields 
excessively large as deemed by the study. 
Major Deviation: Transection of tumor (GTV) or potentially 
tumor bearing area (CTV) (i.e. geographic miss of any part 
of the GTV), or GTV not included within the 95% isodose 
volume. 
5.2 
Step 1 – Consolidation Chemotherapy (Cycles 1 & 2)  
1 Cycle = 21 days. 
Consolidation chemotherapy will be administered for 2 cycles. 
NOTE: Consolidation Chemotherapy will begin after the resolution of all RT-
related toxicities. Patient must start Consolidation Chemotherapy within 
4 weeks of completing Concomitant Chemoradiation or the patient’s 
protocol treatment will be discontinued. 
Consolidation Chemotherapy: 
• 
Paclitaxel 225 mg/m2 IV over 3 hours on day 1. 
• 
Carboplatin AUC 6 IV 15-30 minute infusion on day 1, immediately following 
paclitaxel. When calculating carboplatin dose, GFR should not exceed 125 
mL/min. See Appendix IV for additional information on calculation of 
carboplatin dose. 
All patients with CR, PR, or SD at evaluation at end of Consolidation 
Chemotherapy may be registered to Step 2 (Maintenance Therapy). Patients with 
progressive disease or whose response is unevaluable will discontinue protocol 
treatment.   
5.2.1 
Premedication for Consolidation: 
Prior to receiving paclitaxel, all patients will receive the following 
premedication: 
• 
Dexamethasone 20 mg PO 12 and 6 hours prior to paclitaxel 
infusion. Patients may be treated with 20 mg IV 1 hour prior to 
paclitaxel if they did not take oral dexamethasone. 
• 
Diphenhydramine 50 mg IV 1 hour prior to paclitaxel. 
• 
Cimetidine 300 mg IV (or equivalent, ranitidine 50 mg or 
famotidine 20 mg) 1 hour prior to paclitaxel. 
5.3 
Step 2 – Maintenance Therapy (Cycles 1, 2, 3,…for up to 34 cycles) 
1 Cycle = 21 days. 
Maintenance therapy will continue for a maximum of 34 cycles or until PD or 
unacceptable toxicity. 
NOTE: Patients must be registered to Maintenance Therapy (Step 2) within 28 
days of completing Consolidation Chemotherapy (Step 1). 
5.3.1 
Patients on Step 2 Will Receive the Following:  
• 
Cyclophosphamide 300 mg/m2 (600 mg maximum) IV over 15-30 
minutes – 3 days prior to day 1 of Cycle 1 only. 
Rev. 12/11 
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• 
Bevacizumab 15 mg/kg IV on day 1 of each cycle. 
A urine dipstick should be performed at baseline then prior to every 
other course of bevacizumab. Treatment may proceed if dipstick 
result is 0 –1+. If the result of urine protein dipstick is > 1+, 24 hour 
urine for protein must be obtained. 
For a 2+ dipstick, treatment with bevacizumab may be administered, 
but 24 hour urine must be performed prior to the next cycle and the 
result must be < 2g protein/24 hours for the subsequent cycle to be 
given. 
For ≥ 3+ dipstick, bevacizumab should be held and a 24 hour urine 
collection must be preformed. Bevacizumab treatment may be 
resumed when protein is < 2g/24 hours. 
NOTE: Initial bevacizumab infusion (cycle 1) will be administered 
over a minimum of 90 minutes. If no adverse reactions 
occur, the second dose should be administered over a 
minimum of 60 minutes. Again, if no adverse reactions 
occur, the third and subsequent doses should be 
administered over a minimum of 30 minutes. Infusions 
should be run in via a volumetric infusion device. Do NOT 
administer as an IV push of bolus. If infusion-related adverse 
reactions occur, subsequent infusions should be 
administered over the shortest period that is well tolerated, 
but never less than 30 minutes. 
• 
Tecemotide Immunotherapy 806 mcg subcutaneously: 
• 
Days 1, 8, & 15 of cycles 1 & 2 
 
then 
• 
Day 1 of cycles 4, 6, 8, … (every other cycle) 
5.4 
Adverse Event Reporting Requirements 
5.4.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents. 
• 
Routine reporting:  Adverse events are reported in a routine 
manner at scheduled times during a trial (please refer to the 
E6508 Forms Packet for the list of forms with directions and 
timeframes for routine adverse event reporting). 
• 
Expedited reporting:  In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
5.4.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
Rev. 8/11, 1/12, 4/13 
Rev. 8/11 
5/14 


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considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
Unlikely 
The AE is doubtfully related to treatment 
Possible 
The AE may be related to treatment 
Probable 
The AE is likely related to treatment 
Definite 
The AE is clearly related to treatment 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List):  An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND.  Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.   
• 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term 
• 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred 
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). 
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions. 
• 
A congenital anomaly/birth defect. 
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a serious adverse event when it may jeopardize 
the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 


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5.4.3 
Reporting procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). The CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) for Arm A and B 
and 
• 
the FDA (1-800-332-1088) form Arm A 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to  
• 
the FDA (800-332-0178) for Arm A in the same timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457 
5.4.4 
Determination of reporting requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
• 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
• 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E6508 and outline 
the specific expedited adverse event reporting requirements for 
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5.4.5 
Steps to determine if an adverse event is to be reported in an 
expedited manner for Step 1 (Arm A) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Identify the type and grade of the 
event using CTCAE v4.0 
Determine if the event is related to the 
protocol treatment (attribution) 
With this information, review the chart in 
Section 5.4.6 to determine if event is 
reportable via CTEP-AERS 
Refer to footnote b in Section 5.4.6 
to determine if the event meets the 
protocol specific reporting 
requirements for this study. If so, 
report the event via CTEP-AERS 
Is the event 
reportable? 
No 
Yes 
Report the 
event via 
CTEP-AERS 
Determine the expectedness of the 
event.  An unexpected event is defined 
as one where the type of severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol. 
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5.4.6 
Expedited Reporting Requirements for Arm A on protocol E6508 
Commercial Agents: Carboplatin and Paclitaxel 
Expedited reporting requirements for adverse events experienced by patients on arms with commercial agents 
only 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or 
Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE:  Any 
death that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or 
definitely to the treatment must be reported within 7 calendar days of learning of the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS within 7 calendar 
days of learning of the event.  For instructions on how to specifically report these events via 
CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com  or 301-897-
7497.  This will need to be discussed on a case-by-case basis. 
 


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5.4.7 
Steps to determine if an adverse event is to be reported in an 
expedited manner for Step 2 (Arm B) 
5.4.7.1 
Guidelines for adverse events OCCURRING WITHIN 30 
DAYS of the last administration of the investigational 
agent(s). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the table 
below in Section 5.4.8  
Yes 
No 
Identify the type and 
grade of the event using 
CTCAE v4.0 
Determine if the patient 
was hospitalized for ≥ 24 
hours for the event 
With this information, 
review the chart in 
Section 5.4.8 to 
determine if event is 
reportable via  
CTEP-AERS
Refer to Section 5.4.9 to 
determine if the event meets 
the protocol specific reporting 
requirements for this study. If 
so, report the event via 
CTEP-AERS 
Refer to Section 5.4.9 to determine 
if the event meets the protocol 
specific reporting requirements for 
this study. If so, report the event via 
CTEP-AERS 
Is the event 
reportable? 
No 
Yes 
Refer to Section 5.4.9 to determine if the 
event meets the criteria as an exception to 
reporting on this protocol. If it does not, 
report the event via CTEP-AERS. 
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5.4.7.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.4.8, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 3, 4 and Grade 5 AEs 
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported via CTEP-AERS even if the patient 
is off study 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation 
of hospitalization 
• 
[Deleted in Addendum #5] 
5.4.8 
Expedited Reporting Requirements for Step 2 (Arm B) on protocol 
E6508 
Investigational Agents: Bevacizumab and tecemotide immunotherapy 
Commercial Agents: Cyclophosphamide 
When an investigational agent(s) is used in combination with a 
commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events follow the 
guidelines for investigational agents.   
Phase I and Early Phase 2 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1 
NOTE: Footnote 1 instructs how to report serious adverse 
events that occur more than 30 days after the last 
administration of investigational agent/intervention. 
 
Rev. 12/11 
Rev. 12/11 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 Timeframes 
Resulting in Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in Hospitalization ≥ 24 
hrs 
Not required 
Expedited AE reporting timelines are defined as: 
• “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
• “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 


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5.4.9 
Additional instructions, requirements and exceptions for Step 2 (Arm 
B) on protocol E6508 
Additional Instructions: 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or birth 
defect events via CTEP-AERS, please contact the AEMD Help Desk at 
aemd@tech-res.com  or 301-897-7497. This will need to be discussed on 
a case by case basis. 
E6508 specific expedited reporting requirements: 
• 
All occurrences of grade 4-5 hemorrhage, esophagitis, fistula, 
encephalitis infection, or hepatic failure that is possibly, 
probably, or definitely related to treatment must be reported via 
CTEP-AERS within the time frames outlined in the chart above. 
• 
All occurrences of grade 3-5 thrombocytopenia, regardless of 
attribution or expectedness, must be reported via CTEP-AERS 
within the time frames outlined in the chart above. 
• 
All occurrences of grade 3-5 elevation of transaminase, 
regardless of attribution or expectedness, must be reported via 
CTEP-AERS within the time frames outlined in the chart above. 
• 
All occurrences of a newly diagnosed autoimmune disease, 
regardless of attribution or expectedness, must be reported via 
CTEP-AERS within the time frames outlined in the chart above. 
NOTE: 
Please refer to Section 5.6.5 for guidelines on 
treatment discontinuation following any of the events 
listed above. 
5.4.10 
Other recipients of adverse event reports and supplemental data 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and pharmaceutical company, if applicable. 
The drug supporter is obliged to forward reported AEs to the FDA. A 
drug supporter representative may call a site for additional or 
supplemental information regarding a serious adverse event.  Any 
additional written AE information requested by the drug supporter 
MUST be submitted to BOTH ECOG-ACRIN and the drug supporter. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.4.11 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN: 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine 


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reporting as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Submit a copy of the pathology report to ECOG-ACRIN 
confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol).  
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
and NCI/CTEP. 
NOTE: The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even if 
ECOG-ACRIN was not the patient's most recent trial. 
NOTE: Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should be 
submitted via CTEP-AERS or by the Second Primary Form 


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5.5 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
The Comprehensive Adverse Events and Potential Risks List (CAEPR) provides 
a thorough and detailed list of reported and/or potential adverse events 
associated with the agent below. They are developed and continuously 
monitored by the CTEP Investigational Drug Branch (IDB).  Frequency is 
provided based on 3540 patients. 
Below is the CAEPR for bevacizumab (rhuMAb VEGF, NSC 704865). 
Version 2.3, August 1, 20131 
 
Adverse Events with Possible 
Relationship to Bevacizumab (rhuMAb VEGF) 
(CTCAE 4.0 Term) 
[n= 3540] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
 
Blood and lymphatic system disorders 
- Other (renal thrombotic 
microangiopathy) 
 
Febrile neutropenia 
 
CARDIAC DISORDERS 
 
 
Acute coronary syndrome2 
 
Cardiac disorders - Other 
(supraventricular arrhythmias)3 
 
 
 
Heart failure 
 
 
Left ventricular systolic dysfunction 
 
 
Myocardial infarction2 
 
 
Ventricular arrhythmia 
 
 
Ventricular fibrillation 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
Colitis 
 
 
Constipation 
 
 
Diarrhea 
 
 
Dyspepsia 
 
 
 
Gastrointestinal fistula4 
 
Gastrointestinal hemorrhage5 
 
 
 Gastrointestinal obstruction6 
 
 
 
Gastrointestinal perforation7 
 
 
Gastrointestinal ulcer8 
 
Ileus 
 
 
Mucositis oral 
 
 
Nausea 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Fatigue 
 
 
Infusion related reaction 
 
 
Non-cardiac chest pain 
 
 
Pain 
 
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IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
 
 
 
Anaphylaxis 
INFECTIONS AND INFESTATIONS 
 
Infection9 
 
 
 
Infections and infestations - Other 
(necrotizing fasciitis) 
 
Infections and infestations - Other 
(peri-rectal abscess) 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Injury, poisoning and procedural 
complications – Other (anastomotic 
leak)10 
 
Wound complication 
 
 
Wound dehiscence 
 
INVESTIGATIONS 
 
Alanine aminotransferase increased 
 
 
Alkaline phosphatase increased 
 
 
Aspartate aminotransferase increased  
 
Blood bilirubin increased 
 
 
Cardiac troponin I increased 
 
Neutrophil count decreased 
 
 
 
Platelet count decreased 
 
 
Weight loss 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Dehydration 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Musculoskeletal and connective tissue 
disorder -  Other (bone metaphyseal 
dysplasia)11 
 
 
Myalgia 
 
 
Osteonecrosis of jaw12 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
 
 
Intracranial hemorrhage 
 
 
Ischemia cerebrovascular2 
 
Peripheral sensory neuropathy13 
 
 
 
Reversible posterior 
leukoencephalopathy syndrome 
 
Syncope 
 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
 
Hematuria 
 
 
Proteinuria 
 
 
 
Renal and urinary disorders - Other 
(Nephrotic Syndrome) 
 
 
Urinary fistula 


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REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
Reproductive system and breast 
disorders - Other (ovarian failure)14  
 
 
 
Vaginal fistula 
 
Vaginal hemorrhage 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Allergic rhinitis 
 
 
 
Bronchopleural fistula 
 
 
Bronchopulmonary hemorrhage 
 
Cough 
 
 
Dyspnea 
 
 
Epistaxis 
 
 
Hoarseness 
 
 
 
Respiratory, thoracic and mediastinal 
disorders - Other (nasal-septal 
perforation) 
 
 
Respiratory, thoracic and mediastinal 
disorders - Other (tracheo-esophageal 
fistula) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Pruritus 
 
 
Rash maculo-papular 
 
 
Urticaria 
 
VASCULAR DISORDERS 
Hypertension 
 
 
 
Thromboembolic event 
 
 
 
Vascular disorders - Other (arterial 
thromboembolic event)2,15 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and 
in patients with a history of diabetes. 
3 Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation and atrial flutter. 
4 Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Gastric fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL 
DISORDERS SOC. 
5 Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-
abdominal hemorrhage, Oral hemorrhage, Rectal hemorrhage, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
6 Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and 
other sites under the GASTROINTESTINAL DISORDERS SOC. 
7 Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Jejunal perforation, Rectal perforation, Small intestinal perforation, and 
other sites under the GASTROINTESTINAL DISORDERS SOC. 
8 Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites 
under the GASTROINTESTINAL DISORDERS SOC. 
9 Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 


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10 Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large 
intestinal anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; 
Vaginal anastomotic leak 
11 Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
12 Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with 
bevacizumab treatment, the majority of whom had received prior or concomitant treatment with i.v. 
bisphosphonates. 
13 Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab 
and chemotherapy compared to chemotherapy alone.  
14 Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone 
(FSH) elevation (≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus 
mFOLFOX compared to mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, 
resumption of menses and an FSH level <30 mIU/mL was demonstrated in 22% (7/32) of these 
women.  Long term effects of bevacizumab exposure on fertility are unknown. 
15 Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart 
attack and stroke. 
Also reported on bevacizumab (rhuMAb VEGF) trials but with the relationship to 
bevacizumab (rhuMAb VEGF) still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (idiopathic thrombocytopenia purpura); Bone marrow hypocellular; Disseminated 
intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; 
Cardiac arrest; Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular 
dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic 
membrane perforation); Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye 
disorders - Other (blindness); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - 
Other (corneal epithelial defect); Eye disorders - Other (floaters); Eye disorders - Other 
(ischemic CRVO); Eye disorders - Other (macular pucker); Eye disorders - Other (transient 
increased IOP > or =30 mm Hg); Eye disorders - Other (vitreous hemorrhage); Eye pain; 
Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; Retinal tear; Retinopathy; 
Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Chelitis; Colonic stenosis; Dry mouth; 
Dysphagia; Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal 
disorders - Other (peritonitis); Oral pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal 
stenosis;Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema 
face; Edema limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; 
Injection site reaction; Localized edema; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; 
Hepatic failure; Hepatic necrosis 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (aseptic meningitis) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; 
Dermatitis radiation; Fracture 


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INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic 
hormone abnormal; CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing 
capacity decreased; Electrocardiogram QT corrected interval prolonged; Forced expiratory 
volume decreased; GGT increased; INR increased; Lipase increased; Lymphocyte count 
decreased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone 
pain; Chest wall pain; Fibrosis deep connective tissue; Generalized muscle weakness; Head 
soft tissue necrosis; Joint effusion; Muscle weakness lower limb; Muscle weakness upper limb; 
Musculoskeletal and connective tissue disorder - Other (aseptic necrotic bone); Musculoskeletal 
and connective tissue disorder - Other (myasthenia gravis); Musculoskeletal and connective 
tissue disorder - Other (polymyalgia rheumatica); Neck pain; Pain in extremity; Pelvic soft tissue 
necrosis; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; 
Cerebrospinal fluid leakage; Cognitive disturbance; Depressed level of consciousness; 
Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Facial nerve 
disorder; Hydrocephalus; Leukoencephalopathy; Memory impairment; Nervous system 
disorders - Other (increased intracranial pressure); Paresthesia; Peripheral motor neuropathy; 
Pyramidal tract syndrome; Seizure; Somnolence; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido 
decreased; Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis 
noninfective; Renal and urinary disorders - Other (dysuria); Renal and urinary disorders - Other 
(ureterolithiasis); Renal hemorrhage; Urinary frequency; Urinary incontinence; Urinary retention; 
Urinary tract obstruction; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; 
Irregular menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Pulmonary 
hypertension; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (dry 
nares); Respiratory, thoracic and mediastinal disorders - Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail 
loss; Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; Rash 
acneiform; Skin and subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin and 
subcutaneous tissue disorders - Other (skin breakdown/ decubitus ulcer); Skin 
hyperpigmentation; Skin induration; Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; 
Vasculitis  
NOTE: 
Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or 
the combination may result in events never previously associated with either agent. 
 


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5.6 
Dose Modifications 
All toxicities should be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE can be downloaded from the CTEP 
website (http://ctep.cancer.gov). 
NOTE: If treatment is held for the maximum allotted time, and patient is not 
able to resume, patient will discontinue protocol treatment. 
5.6.1 
Step 1 - Concomitant Chemoradiation  
Dose modifications for paclitaxel and carboplatin will be made for the 
following treatment related toxicities.  
NOTE: If chemotherapy is held during the concomitant 
chemoradiation portion of treatment, these doses are 
skipped and should not be made up. 
NOTE: If dose reduced more than 2 times, patient will discontinue 
protocol treatment. 
5.6.1.1 
Hematologic Toxicity  
If chemotherapy is to be held due to hematologic toxicity, 
that week’s dose of chemotherapy should be omitted, then 
obtain CBC and platelet counts weekly until the counts 
reach the lower limits for treatment as outlined. 
The treatment schedule will then proceed in the usual 
sequence.  Treatment may be withheld for up to 2 weeks. 
No dose reductions are made for anemia.  Patients should 
be supported per the treating physician’s discretion. 
5.6.1.1.1 
Absolute Neutrophil Count  
ANC Day of Treatment 
Paclitaxel and Carboplatin 
≥ 1,000/mm3 
No change, treat full dose 
< 1,000/mm3 
Skip dose* 
* If ANC is < 1,000/mm3 chemo should be skipped. 
Repeat counts weekly until the ANC has recovered to 
≥ 1,000/mm3. If treatment is skipped for more than 2 
weeks the patient’s protocol treatment will be 
discontinued. 
Platelets 
Platelets Day of Treatment 
Paclitaxel and Carboplatin 
> 100,000/mm3 
No change, treat full dose 
< 100,000/mm3 
Skip dose* 
* If platelets are < 100,000/mm3 chemo should be skipped. 
Repeat counts weekly until the platelets have recovered to 
≥ 100,000/mm3. If treatment is skipped for more than 2 
weeks the patient’s protocol treatment will be discontinued. 
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5.6.1.2 
Gastrointestinal Toxicity 
Nausea and/or vomiting should be controlled with 
adequate antiemetics.  If grade 3 nausea or grade 3 or 4 
vomiting occurs in spite of antiemetics, chemotherapy 
should be held until the event recovers to grade 1 or less. 
Once the event has improved, paclitaxel and carboplatin 
should be reduced 25%.  If there is a second instance of a 
grade 3 or 4, doses should be reduced by another 25%. 
These are permanent dose reductions. If nausea/vomiting 
doesn’t improve to a grade 1 or less within 2 weeks, the 
patient’s protocol treatment will be discontinued.  
If, on a day chemotherapy is to be administered, the 
patient has grade 2 or greater mucositis, the treatment with 
paclitaxel and carboplatin should be withheld until the 
mucositis has completely resolved. Once the event has 
resolved, chemotherapy should resume. If treatment is 
held for > 2 weeks, protocol treatment will be discontinued.  
5.6.1.3 
Peripheral Neuropathy 
Patients who develop grade 3 or 4 neuropathy should have 
the paclitaxel and carboplatin withheld until the neuropathy 
improves to a grade 1 or less.  Treatment should then be 
resumed with paclitaxel given at 50% dose.  This is a 
permanent reduction.  No dose modifications will be made 
in the carboplatin for neuropathy.  If the neuropathy does 
not improve to grade 1 or less within 2 weeks, the patient’s 
protocol treatment will be discontinued. 
5.6.1.4 
Hemoptysis 
(Bleeding will be graded according to the CTCAE version 
4.0, which can be found using the link located at the start 
of Section 5.6). 
Patients who develop gross hemoptysis (defined as bright 
red blood of a ½ teaspoon or more) during chemoradiation 
will come off of study. If a patient has hemoptysis, the 
source of hemoptysis should be confirmed (pulmonary vs 
extrapulmonary). 
Hemoptysis: > Grade 1, patient’s protocol treatment will be 
discontinued. For Grade 1, patients should be evaluated to 
determine the source of on treatment hemoptysis.  If no 
source is found, and resolves within 1 week, patient may 
continue treatment per protocol. 
5.6.1.5 
Other Toxicity 
For any grade 3 or 4 treatment related toxicity not 
mentioned above (see exceptions below), the treatment 
with paclitaxel and carboplatin should be withheld until the 
toxicity recovers to ≤ grade 1. Treatment may be withheld 
for up to 2 weeks. The treatment should be resumed at 


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50% dose for paclitaxel and carboplatin. This is a 
permanent dose reduction. 
Exceptions - If a patient experiences a grade 3 or 4 of the 
following  toxicities that is thought to be related to 
treatment, paclitaxel and carboplatin should be held until 
the toxicity recovers to ≤ grade 1, but a dose reduction is 
NOT required: acidosis, alkalosis, hyperglycemia, 
hyperkalemia, hypokalemia, hypermagnesemia, 
hypomagnesemia hypernatremia and hyponatremia. 
Treatment may be withheld for up to 2 weeks.  
Additionally if a patient experiences grade 3 or 4 fatigue 
thought to be related to treatment, neither a hold in 
treatment or a dose reduction is required. 
5.6.2 
Step 1 – Consolidation Chemotherapy 
Dose modifications for paclitaxel and carboplatin will be made for the 
following treatment related toxicities.  
NOTE: 
If dose reduced more than 2 times, patient will discontinue 
protocol treatment. 
5.6.2.1 
Hematologic Toxicity 
In the event that dose adjustments are needed for both 
ANC and platelets, patients are to receive the lower dose.  
This is a permanent dose reduction. 
If chemotherapy is to be held due to hematologic toxicity, 
CBC and platelet counts should be obtained weekly until 
the counts reach the lower limits for treatment as outlined. 
The treatment schedule will then proceed in the usual 
sequence. Treatment may be held for up to 2 weeks. 
No dose reductions are made for anemia. Patients should 
be supported per the treating physician’s discretion. 
5.6.2.1.1 
Absolute Neutrophil Count  
Reduce doses only for febrile neutropenia 
or if ANC ≤ 1,000 for > 7 days.  
ANC (ANC must be ≥ 1500/mm3 on day 1.) 
Nadir ANC of Last Course 
(Consolidation Chemotherapy) 
% of Paclitaxel & Carboplatin 
Day of Treatment ANC 
< 1500 
≥ 1500 
Febrile neutropenia 
(regardless of duration) 
0 
50% 
> 1000 or ≤ 1000 for ≤ 7 days 
0 
100% 
500-1000 for > 7 days 
0 
75% 
< 500 for > 7 days 
0 
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Platelets 
(Platelet count must be ≥ 100,000/mm3 on 
day 1.) 
Nadir of Last Course 
(Consolidation Chemotherapy) 
% of Paclitaxel & Carboplatin 
Day of Treatment Platelets 
< 100,000 
≥ 100,000 
> 75,000 
0 
100% 
50,000-75,000 
0 
75% 
< 50,000 
0 
50% 
5.6.2.2 
Gastrointestinal Toxicity 
Nausea and/or vomiting should be controlled with 
adequate antiemetics.  If grade 3 nausea or grade 3 or 4 
vomiting occurs in spite of antiemetics, chemotherapy 
should be held until the event recovers to grade 1 or less. 
Once the event has improved, paclitaxel and carboplatin 
should be reduced 25%.  If there is a second instance of a 
grade 3 or 4, doses should be reduced by another 25%. 
These are permanent dose reductions. If nausea/vomiting 
doesn’t improve to a grade 1 or less within 2 weeks, 
protocol treatment should be discontinued.  
If, on day 1 of any treatment cycle, the patient has grade 2 
or greater mucositis, paclitaxel and carboplatin should be 
held until the mucositis has completely resolved.  If acute 
grade 3 or 4 mucositis occurs at any time, paclitaxel and 
carboplatin should be held until event has completely 
resolved, then reduced 25% for the next course. This is a 
permanent dose reduction. If treatment is held for greater 
than 2 weeks, protocol treatment will be discontinued. 
5.6.2.3 
Peripheral Neuropathy 
Patients who develop grade 3 or 4 neuropathy should have 
the paclitaxel and carboplatin delayed until the neuropathy 
improves to a grade 1 or less. Treatment should then be 
resumed with paclitaxel given at 50% dose. This is a 
permanent reduction.  No dose modifications will be made 
in the carboplatin for neuropathy.  If the neuropathy does 
not improve to grade 1 or less within 2 weeks, the patient’s 
protocol treatment will be discontinued. 
5.6.2.4 
Hemoptysis 
(Bleeding will be graded according to the CTCAE version 
4.0, which can be found using the link located at the start 
of Section 5.6). 
Patients who develop gross hemoptysis (defined as bright 
red blood of a ½ teaspoon or more) during chemotherapy 
will come off of study.  If a patient has hemoptysis, the 


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source of hemoptysis should be confirmed (pulmonary vs 
extrapulmonary). 
Hemoptysis: > Grade 1, patient’s protocol treatment will be 
discontinued. For Grade 1, patients should be evaluated to 
determine the source of hemoptysis.  If no source is found, 
and resolves within 1 week, patient may continue 
treatment per protocol. 
5.6.2.5 
Other Toxicity 
For any grade 3 or 4 treatment related toxicity not 
mentioned above (see exceptions below), the treatment 
with paclitaxel and carboplatin should be withheld until the 
toxicity recovers to ≤ grade 1. Treatment may be withheld 
for up to 2 weeks. The treatment should be resumed at 
50% dose for paclitaxel and carboplatin. This is a 
permanent dose reduction. 
Exceptions - If a patient experiences a grade 3 or 4 of the 
following  toxicities that is thought to be related to 
treatment, paclitaxel and carboplatin should be held until 
the toxicity recovers to ≤ grade 1, but a dose reduction is 
NOT required: acidosis, alkalosis, hyperglycemia, 
hyperkalemia, hypokalemia, hypermagnesemia, 
hypomagnesemia hypernatremia and hyponatremia. 
Treatment may be withheld for up to 2 weeks.  
Additionally if a patient experiences grade 3 or 4 fatigue 
thought to be related to treatment, neither a hold in 
treatment or a dose reduction is required. 
5.6.3 
Paclitaxel: Hypersensitivity Reactions (Concomitant Chemoradiation 
and Consolidation Chemotherapy) 
NOTE: Patients who had a mild to moderate hypersensitivity 
reaction have been successfully rechallenged, but careful 
attention to prophylaxis and bedside monitoring of vital signs 
is recommended. 
• 
Mild symptoms: Complete paclitaxel infusion.  Supervise at 
bedside. No treatment required. 
• 
Moderate symptoms: Stop paclitaxel infusion. Give intravenous 
diphenhydramine 25-50 mg and intravenous dexamethasone 10 
mg.  Resume paclitaxel infusion after recovery of symptoms at a 
low rate, 20 ml/hour for 15 minutes, then 40ml/hour for 15 
minutes, then, if no further symptoms recur, continue the 
paclitaxel infusion. If symptoms have not fully resolved within 2 
hours, patient will discontinue protocol treatment. 
• 
Severe life-threatening symptoms: Stop paclitaxel infusion.  Give 
intravenous diphenhydramine and dexamethasone as above. Add 
epinephrine or bronchodilators if indicated.  Protocol therapy will 
be discontinued. 


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5.6.4 
Step 2 - Maintenace Therapy - Dose Modifications – Bevacizumab 
NOTE: There will be no dose reduction for bevacizumab.  Treatment 
should be interrupted or discontinued for certain adverse 
events, as described below. If bevacizumab must be held 
temporarily due to toxicity, tecemotide treatment should be 
administered as scheduled. If bevacizumab must be 
permanently discontinued, tecemotide should also be 
discontinued. 
NOTE: Missed doses of bevacizumab will not be made up. 
NOTE: If tecemotide must be held temporarily due to toxicity, 
bevacizumab should still be administered as scheduled. If 
tecemotide must be permanently discontinued, discontinue 
bevacizumab. 
5.6.4.1 
Please see Section 5.6.4.2 – Treatment Modification for 
Bevacizumab-Related Adverse Events for the following 
adverse events: 
• 
Allergic reactions, or Acute infusional reactions/ 
cytokine release syndrome  
• 
Arterial Thrombosis 
• 
Venous Thrombosis 
• 
Hypertension 
• 
Proteinuria 
• 
Hemorrhage 
• 
Wound dehiscence requiring medical or surgical 
intervention 
• 
GI perforation, GI leak or fistula 
• 
Other clinically significant AEs attributable to 
bevacizumab 
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5.6.4.2 
Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE version 
4.0 Grade 
Action to be Taken 
Allergic reactions, or acute 
infusional reactions/cytokine release 
syndrome 
Grade 1-3 
If infusion-related or allergic reactions occur, premeds (Benadryl 25-50 mg; dexamethasone 10-
20 mg) should be given with the next dose, and infusion time may not be reduced for the 
subsequent infusion.  Follow the guidelines in the Section 8.3.9 for bevacizumab 
administration.  
For patients with Grade 3 reactions, bevacizumab infusion should be stopped and not 
restarted on the same day.  At the physicians’ discretion, bevacizumab may be reinstituted with 
premeds and at a rate of 90 +/- 15 min.  If bevacizumab is re-instituted, the patient should 
be closely monitored for a duration comparable to or longer than the duration of the 
previous reactions. 
 
Grade 4 
Discontinue protocol treatment 
Arterial Thrombosis 
 
 
• Myocardial infarction, acute coronary 
syndrome 
• Ischemia cerebrovascular 
• Any peripheral or visceral arterial 
ischemia/thrombosis 
Grades 2-4 
Discontinue protocol treatment 
Venous Thrombosis 
 
 
NOTE: Patient may be on a stable 
regimen of therapeutic 
anticoagulation or may be 
receiving prophylactic 
anticoagulation of venous 
access devices, provided 
patient's prothrombin time/INR 
≤ 3.0. 
Caution must be exercised for patients 
requiring anticoagulation, including 
treatment with low dose heparin or low 
molecular weight heparin for DVT 
prophylaxis while on study due to an 
increased risk of bleeding with 
bevacizumab. 
Grade 3 or 4 
Treatment may continue with bevacizumab during initiation and continuation of therapeutic 
anticoagulation. Caution must be exercised as anticoagulation is initiated due to an increased 
risk of bleeding with bevacizumab. 


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Hypertension 
(Treat with anti-hypertensive medication 
as needed.  The goal of BP control 
should be consistent with general 
medical practice.) 
Controlled BP 
Continue bevacizumab 
Persistent or 
symptomatic HTN 
Hold bevacizumab.  If treatment is delayed for > 4 weeks due to uncontrolled hypertension, 
discontinue protocol treatment. 
Grade 4 
Discontinue protocol treatment 
Proteinuria 
Proteinuria should be monitored by 
urine dipstick prior to every other dose 
of bevacizumab.  If urine dipstick is > 1+ 
then 24 hour urine for protein must be 
obtained. 
Urine Dipstick  
≤ 1+ 
Continue bevacizumab 
Urine Dipstick 2+ 
May administer bevacizumab, 24 hour urine must be obtained prior to next cycle and 
proteinuria must be < 2g/24 hours before subsequent cycle can be given. If therapy is held for > 
2 months due to proteinuria, discontinue protocol treatment. 
Urine Dipstick  
≥ 3+ 
Hold bevacizumab and obtain 24 hour urine for protein.  Bevacizumab may be resumed when 
proteinuria is < 2g/24 hours. If therapy is held for > 2 months due to proteinuria, discontinue 
protocol treatment. 
Permanently discontinue protocol treatment for nephrotic syndrome. 
Hemorrhage 
Non-pulmonary or 
Non-CNS 
Hemorrhage 
Grades 1/2 
• 
No dose modifications necessary 
 
Grade 3 
• 
Patients who are receiving full-dose anticoagulation will be discontinued from protocol 
treatment 
• 
For patients not on full-dose anticoagulation, hold bevacizumab until ALL of the following 
criteria are met: 
- 
The bleeding has resolved and Hgb is stable 
- 
There is no bleeding diathesis that would increase the risk of therapy 
- 
There is no anatomic or pathologic condition that significantly increases the risk of 
hemorrhage recurrence 
• 
Patients who experience recurrence of Grade 3 hemorrhage should discontinue protocol 
treatment 
 
Grade 4 
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Pulmonary or 
CNS Hemorrhage 
Grade 1 
• 
Patients who are receiving full-dose anticoagulation will be discontinued from protocol 
treatment 
• 
For patients not on full-dose anticoagulation, hold bevacizumab until ALL of the following 
criteria are met: 
- The bleeding has resolved and Hgb is stable 
- There is no bleeding diathesis that would increase the risk of therapy 
- There is no anatomic or pathologic condition that significantly increases the risk of 
hemorrhage recurrence 
 
Grades 2-4 
Discontinue protocol treatment 
Reversible Posterior 
Leukoencephalopathy Syndrome 
(RPLS) 
 
Bevacizumab should be held in patients with symptoms/signs suggestive of RPLS, pending 
work-up and management, including MRI and control of blood pressure. Protocol treatment 
should be discontinued upon diagnosis of RPLS.   
If treatment delay is > 4 weeks due to toxicity, discontinue protocol treatment. 
Protocol treatment will be discontinued upon diagnosis of RPLS. 
Wound dehiscence requiring medical 
or surgical intervention 
 
Discontinue protocol treatment 
GI perforation, GI leak or fistula 
 
Discontinue protocol treatment 
Congestive Heart Failure 
Grade 3 
Hold bevacizumab until resolution to ≤ Grade 1 
Grade 4 
Discontinue protocol treatment 
Bowel Obstruction 
Grade 1 
Continue patient on study for partial obstruction NOT requiring medical intervention 
 
Grade 2 
Hold bevacizumab for partial obstruction requiring medical intervention. Patients may restart 
upon complete resolution 
 
Grade 3/4 
Hold bevacizumab for complete obstruction. If surgery is necessary, discontinue protocol 
treatment. 
Other clinically significant AEs 
attributable to bevacizumab (except 
controlled nausea/vomiting) 
Grade 3 
• 
Hold bevacizumab until symptoms resolve to ≤ Grade 1 
• 
If treatment delay is > 3-4 weeks due to toxicity, discontinue protocol treatment 
Grade 4 
• 
Discontinue protocol treatment 
• 
Upon consultation with the study chair, resumption of protocol treatment may be 
considered if a patient is benefiting from therapy and the grade 4 toxicity is transient, has 
recovered to ≤ grade 1 and unlikely to recur with re-treatment. 
 
 


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5.6.5 
Dose Modifications – tecemotide 
NOTE: If bevacizumab must be held temporarily due to toxicity,  
tecemotide treatment should be administered as scheduled. 
If bevacizumab must be permanently discontinued, also 
discontinue tecemotide. 
There will be no dose reduction for tecemotide. Treatment should be 
interrupted or discontinued due to certain adverse events, as 
described below. Missed doses of tecemotide will not be made up. 
Event 
CTCAE V. 4.0 Grade 
Action to be taken 
Injection site 
reaction 
Grade 4 
• Discontinue protocol treatment. 
Chills (rigors) 
Grade 3 
• Discontinue protocol treatment. 
Platelet count 
decrease 
(thrombocytopenia) 
Grade 1 
<140,000/mm³-75,000/mm³ 
• If Grade 1 thrombocytopenia and documented 
decrease in platelets by > 40,000/mm³, proceed 
with tecemotide dose, but begin monitoring 
platelet count every 2 weeks until toxicity 
completely resolves. 
Grade 2* 
< 75,000/mm³- 50,000/mm³ 
• Hold tecemotide until resolution to ≤ Grade 1**, 
with monitoring of platelet count every 2 weeks 
until toxicity completely resolves. 
• Evaluation by a hematologist should be obtained. 
≥ Grade 3* 
< 50,000/mm³ 
• Discontinue all protocol treatment. 
• Evaluation by a hematologist should be obtained. 
ALT/AST increase* 
(elevation of 
transaminases)  
 
And/or 
 
Blood bilirubin 
increase 
Grade 2  
Blood bilirubin increase 
• Hold tecemotide until resolution to ≤ Grade 1**. 
• Repeat tests (at least AST, ALT, ALP, INR, and 
total bilirubin) within 2-3 days. 
• Then repeat tests (at least ALP, INR, total 
bilirubin) weekly. 
Grade 2 – Asymptomatic 
ALT/AST increase 
• Hold tecemotideuntil resolution to ≤ Grade 1**. 
• Repeat tests (at least AST, ALT, ALP, INR, and 
total bilirubin) within 2-3 days. 
• Then repeat tests (at least ALP, INR, total 
bilirubin) weekly. 
Grade 2 – 
Asymptomatic 
ALT/AST 
increase 
WITH Grade 2 
blood bilirubin 
increase 
• Discontinue protocol treatment. 
WITH Grade 2 
INR increase 
• Discontinue protocol treatment. 
Grade 2 – Symptomatic 
ALT/AST increase 
• Discontinue protocol treatment. 
≥ Grade 3 ALT/AST increase 
• Discontinue protocol treatment. 
*  Evaluation for the etiology of these abnormalities should be performed. If etiology of the above 
laboratory abnormalities is not apparent from the initial evaluation, a hepatologist consult should be 
obtained. 
** If event has not improved to ≤ grade 1 within 9 weeks (3 cycles), discontinue protocol treatment. 
Rev. 1/15 
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5.6.5.1 
Autoimmune Disease 
In the case of a newly diagnosed, pathologically confirmed 
autoimmune disease, discontinue protocol treatment and 
continue monitoring the patient with respect to these 
abnormalities. 
5.6.5.2 
Encephalitis 
If a patient presents with symptoms suspicious of 
encephalitis or other neuroinflammatory conditions, an 
expert neurological opinion must be obtained. Discontinue 
protocol treatment immediately upon diagnosis of 
encephalitis or other neuroinflammatory conditions and 
continue to monitor the patient with respect to this 
condition and any emergent symptoms or diseases 
deemed to be related. The neurologist should initiate 
appropriate imaging as described in the Contingency 
Imaging Guideline Manual (See Appendix XI), viral 
serology, and cerebrospinal fluid (CSF) investigations 
according to best practice. 
In case of suspected encephalitis or other 
neuroinflammatory conditions, a CSF sample for further 
diagnostic evaluation should be collected and stored 
frozen at -80°C at the site. 
5.7 
Duration of Therapy 
5.7.1 
Patients will discontinue study treatment for progressive disease at 
any time. 
5.7.2 
Patients will discontinue study treatment due to excessive toxicity. 
5.7.3 
Patients will discontinue study treatment anytime he or she withdraws 
consent to participate in the study. 
5.8 
Duration of Follow-up 
Patients will be followed for response until progression and for survival until 
death up to a maximum of 5 years from study entry.  Follow-up after patient 
discontinues protocol therapy: every 3 months for patients < 2 years from study 
entry, and every 6 months if patient is 2-5 years from study entry. No specific 
requirements if patient is > 5 years from entry. 
5.9 
Supportive Therapy 
5.9.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.9.2 
G-CSF should only be used if there is persistent neutropenia or 
persistent delay despite dose reductions in the previous course.  If G-
CSF is used it must be used in accordance with the American Society 
of Clinical Oncology (ASCO) guidelines as published in the Journal of 
Clinical Oncology. 
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6. 
Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response post 
completion of the concomitant chemoradiation, post completion of the 
consolidation chemotherapy, and then every 9 weeks. 
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before registration. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers.  
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for response.  
These patients will have their response classified according to the 
definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but 
do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target lesion assessment.  The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 


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with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: Tumor lesions that are situated in a previously irradiated 
area (prior to study entry) are considered measurable if there 
is incontrovertible evidence of interval progression since 
completion of prior radiation, documented on relevant 
imaging. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as malignant 
lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected.   
A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum.  The baseline 


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sum of the diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up. 
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers.  All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm 
in diameter as assessed using calipers (e.g., skin nodules).  In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up 
must be the same as was used at baseline and the lesions should be 
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measured/assessed on the same pulse sequence.  It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases.  
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next.  If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor 
has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 


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FDG-PET 
While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning 
to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following 
algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at 
follow-up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be 
the date of the initial abnormal FDG-PET scan).  If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
NOTE: A ‘positive’ FDG-PET scan lesion means one which is 
FDG avid with an uptake greater than twice that of the 
surrounding tissue on the attenuation corrected image. 
6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progression, See Section 
6.1.4.3). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 


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sum diameters while on study. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 6 weeks. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 
“increase” in the size of one or more on-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on 
the basis of change in non-target disease in the face of SD 
or PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
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A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) increases in size to ≥ 15 mm in the short axis, or; 
b) there is new pathological confirmation that it is disease 
(regardless of size). 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the 
achievement of measurement criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Best 
Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not 
evaluated 
No 
PR 
SD 
Non-PD***/not 
evaluated 
No 
SD 
Documented at least 
once ≥ 6 wks. from 
study entry 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be 
representative of overall disease status change, not single lesion increase. Please refer 
to the Evaluation of Non-Target Lesions – Progressive Disease section for further 
explanation. 
NOTE: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment. 


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For Patients with Only Non-Measurable Disease (i.e., Non-
Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for 
assessment of efficacy in some trials so to assign this category 
when no lesions can be measured is not advised 
6.1.4.5 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 6 weeks. 


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7. 
Study Parameters 
7.1 
Therapeutic Parameters 
1. Any scans or x-rays used to document measurable or non-measurable disease must be done within 4 weeks 
prior to Step 1 Registration. 
2. Prestudy CBC (with differential and platelet count) and all required prestudy chemistries, as outlined in Section 3, 
must be done within 4 weeks prior to Step 1 Registration. Labs required for eligibility purposes for Step 2 must be 
done within 2 weeks prior to Step 2 Registration  
Rev. 1/15 
 
 
Step 1 
Step 2 
Follow-
Up9 
Baseline 
Concomitant 
Chemoradiation 
Prior to 
Consolidation 
Chemotherapy 
Consolidation 
Chemotherapy Prior to Step 2 
(Maintenance 
Therapy) 
Maintenance Therapy (up to 34 cycles) 
Cyclophosphamide & tecemotide + Bevacizumab 
Once per week for 
6 Weeks 
C1 
C2 
C17 
C2 
C3 C413 C514 C68, 15 
C7 & 
beyond 
History and 
Physical (BP)19 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
Repeat schedule testing for  
cycles 4-6  
(see footnotes 13, 14, 15) 
X 
Weight 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
Toxicity 
Assessment 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  X12 
CBC1, CMP2 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
  X12 
PT(INR), PTT 
  X10 
 
 
 
 
X 
 
 
X 
 
 
X 
  X12 
Urine dipstick 
for protein3 
X 
 
 
 
 
X 
 
 
X 
 X16 
 X16 
  X16 
  X12 
Esophagitis 
evaluation 
 
 
X 
X 
 
X 
X 
X 
X 
 X18 
 X18 
  X18 
 
Chest CT4 
X 
 
X 
 
 
X 
 
 
   X17 
 
 
  X17 
  X11 
Pregnancy 
test5 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Brain MRI/CT 
 X6 
 
 
 
 
 
 
 
 
 
 
 
 
1. CBC’s (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct, that are required for protocol treatment, 
must be done < 24 hours prior to the treatment cycle. 
2. CMP including total bilirubin, ALT, AST, alkaline phosphatase, albumin and serum creatinine must be done < 24 hours prior to the 
treatment cycle. 
3. 24 hour urine for protein is required for patients with dipstick > 1+. See Section 5.6.4.2, proteinuria section, for details regarding 24 hour 
urine collection. 


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4. Consistency in using the same type of scan for tumor measurements is required.  
5. Serum or urine pregnancy test within 2 weeks prior to registration on Step 1 and Step 2. 
6. Brain MRI/CT within 4 weeks prior to registration, and if needed, to confirm a diagnosis of RPLS 
7. Cyclophosphamide will be administered 3 days prior to day 1 of Step 2 Cycle 1 only. 
8. For patients continuing on treatment beyond cycle 6, follow a repeating test schedule as outlined in cycles 4 through 6, for up to 34 cycles.  
9. Follow-up after patient discontinues protocol therapy: every 3 months for patients < 2 years from study entry, and every 6 months if patient 
is 2-5 years from study entry. No specific requirements if patient is > 5 years from entry. 
10. Obtained within 4 weeks prior to registration. 
11. All patients, including those who discontinue protocol therapy early, will be followed for response until progression. 
12. Required only if needed to follow persistent adverse reaction possibly related to treatment. 
13. Tests to be done on cycle 4, cycle 7, cycle 10,…repeating this schedule until protocol treatment discontinuation. 
14. Tests to be done on cycle 5, cycle 8, cycle 11,…repeating this schedule until protocol treatment discontinuation. 
15. Tests to be done on cycle 6, cycle 9, cycle 12,…repeating this schedule until protocol treatment discontinuation. 
16. The urine dipstick for protein is to be done every OTHER cycle of bevacizumab (i.e. prior to initiation of maintenance therapy, Cy 3, Cy 5, 
Cy 7, Cy 9, ect…) 
17. Scan to be done at the end of this cycle, but prior to next cycle. 
18. Esophagitis evaluation does not need to be repeated beyond Cycle 6. 
19. To include neurologic assessment. Neurologic assessment may be performed by advanced practice nurse, physician assistant, radiation 
oncologist, medical oncologist or neurologist. 
 
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7.2 
Biological Sample Submissions  
Samples for correlative studies are to be submitted as outlined in Section 10. 
Collection and submission of samples is to be limited to those patients who have 
given written consent to participate in the correlative studies or banking. 
NOTE: ECOG-ACRIN requires that all samples submitted from patients 
participating in E6508 be entered and tracked via the online ECOG-
ACRIN Sample Tracking System.  See Section 10.1.4. 
 
Maintenance Therapy 
Prior to start of 
Maintenance therapy 
q 3 cycles, prior 
to treatment 
(cycle 4,7,10,…) 
Discontinuation of 
Protocol 
Treatment5 
Peripheral Blood, no anticoagulant 
(e.g. red top)2,3 
X 
X 
X 
Peripheral Blood, ACD tube1,3 
X 
X 
X 
Peripheral Blood, heparin tubes2,3 
X 
X 
X 
Diagnostic or surgical tumor tissue4 
X 
X 
1 
Samples are to be submitted day of collection to the Shanker Laboratory, Meharry Medical 
College.  
2 
Samples are to be submitted day of collection to the IMCPL, University of Pittsburgh 
Cancer Institute 
3 
To order kits for the collection and shipment of samples, fax the E6508 Kit Request, 
Appendix VII, to the UPCI-IMCPL at (412) 623-6625. 
4 
Submit original diagnostic or surgical block within one month following registration from 
patients who consent to allow banking of samples for future research. Specimens from any 
additional biopsies are also requested. 
5 
Upon completion of protocol therapy or progression. 
Rev. 8/11 
Rev. 10/12 


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8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
8.1 
Paclitaxel  
8.1.1 
Other Names  
Taxol, NSC #673089 
8.1.2 
Classification  
Antimicrotubule agent 
8.1.3 
Mode of Action  
Promotes microtuble assembly and stabilizes tubulin polymers by 
preventing their depolarization, resulting in the formation of extremely 
stable and nonfunctional microtubules, and consequently inhibition of 
many cell functions. 
8.1.4 
Storage and Stability  
Freezing does not adversely affect the product. Solutions diluted to a 
concentration of 0.3 to 1.2 mg/mL in normal saline, 5% dextrose and 
normal saline, or 5% dextrose in Ringer’s solution are stable for up to 
27 hours when stored at room temperature in normal light. 
8.1.5 
Dose Specifics  
• 
Concomitant chemoradiation: 45 mg/m2 IV over 1 hour weekly for 
6 weeks. 
• 
Consolidation chemotherapy (cycles 1 – 2): 225 mg/m2 IV over 3 
hours on day 1. 
8.1.6 
Preparation  
The concentrated solution must be diluted prior to use in normal 
saline, 5% dextrose, 5% dextrose and normal saline, or 5% dextrose 
in Ringer’s solution to a concentration of 0.3 –1.2 mg/mL. Solutions 
exhibit a slight haze, common to all products containing non-ionic 
surfactants.  Glass, polypropylene, or polyolefin containers and non-
PVC-containing (nitroglycerin) infusions sets should be used. A small 
number of fibers have been observed after dilution. Therefore, a 
hydrophilic 0.22 micron in – line filter should be used. Analyses of 
solutions filtered through IVEX-2 and IVEX-HP 0.2 micron filters 
showed no appreciable loss of potency. 
8.1.7 
Route of Administration  
Intravenous infusion over 3 hours (1 hour for concomitant 
administration). 
8.1.8 
Incompatibilities  
Avoid the use of PVC bags and infusion sets due to leaching of DEHP 
(plasticizer).  Prior administration of cisplatin may increase 


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myelosuppression because of reduced clearance of paclitaxel. 
Ketoconazole, verapamil, diltiazem, quinidine, dexamethasone, 
teniposide, etoposide, vincristine, and cyclosporine may inhibit 
paclitaxel metabolism, based on in vitro data. 
8.1.9 
Availability  
Paclitaxel is commercially available. A concentrated solution of 
6mg/ml in polyoxyethylated castor oil (Cremophor EL) 50% and 
dehydrated alcohol 50% in commercially available in 5, 16.7, and 50 
mL vials. 
8.1.10 
Side Effects  
1. Hematologic:  Myelosuppression (neutropenia, leukopenia, 
thrombocytopenia, anemia. 
2. Hypersensitivity:  Thought to be caused by the Cremophor 
vehicle.  Minor symptoms include hypotension, flushing, chest 
pain, abdominal or extremity pain, skin reactions, pruritus, 
dyspnea, and with bronchospasm, generalized urticaria, and 
angioedema.  The majority (53%) of the reported reactions 
occurred within 2-3 minutes of initiation of treatment and 78% 
occurred within the first 10 minutes.  Reactions usually occurred 
with the first and second doses.   
3. Cardiovascular:  Atrial arrhythmia (sinus bradycardia [usually 
transient and asymptomatic], sinus tachycardia, and premature 
beats); significant events include syncope, hypotension, other 
rhythm abnormalities (including ventricular tachycardia, bigeminy, 
and complete heart block requiring pacemaker placement), and 
myocardial infraction.  Hypertension (possibly related to 
concomitant medication – Dexamethasone) may also occur.   
4. Neurologic:  Sensory (taste changes); peripheral neuropathy; 
arthralgia and myalgia (dose-related, more common when colony-
stimulating factors are also administered); seizures; mood 
alterations; neuro encephalopathy; hepatic encephalopathy; motor 
neuropathy; and autonomic neuropathy (paralytic ileus and 
symptomatic hypotension).   
5. Dermatologic:  Alopecia (universal, complete and often sudden, 
between days 14-21); injection site reactions (erythema, 
induration, tenderness, skin discoloration); infiltration (phlebitis, 
cellulitis, ulceration, and necrosis, rare); radiation recall; and rash. 
6. Gastrointestinal:  Nausea, vomiting, diarrhea, stomatitis, 
mucositis, pharyngitis, typhlitis (neutropenic enterocolitis), 
ischemic colitis, and pancreatitis. 
7. Hepatic:  Increased AST, ALT, bilirubin alkaline phosphatase; 
hepatic failure, and hepatic necrosis.   
8. Other:  Fatigue, headache, light-headedness, myopathy, elevated 
serum creatinine, elevated serum triglycerides, and visual 
abnormalities (sensation of flashing lights, blurred vision). 


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8.1.11 
Nursing/Patient Implications  
1.  Paclitaxel Premedication: 
• 
Weeks 1-6 (concomitant):  
Prior to receiving paclitaxel, all patients will receive the following 
premedication:  
o Diphenhydramine 50 mg IV 1 hour prior to paclitaxel 
o Cimetidine 300 mg IV (or equivalent, ranitidine 50 mg or 
famotidine 20 mg) 1 hour prior to paclitaxel infusion.  
o Dexamethasone 10 mg IV just prior to paclitaxel. 
• 
Cycles 1 & 2 (consolidation):  
Prior to receiving paclitaxel, all patients will receive the following 
premedication:  
o Dexamethasone 20 mg PO 12 and 6 hours prior to paclitaxel 
infusion. Patients may be treated with 20 mg IV 1 hour prior to 
paclitaxel infusion if they did not take oral dexamethasone. 
o Diphenhydramine 50 mg IV 1 hour prior to paclitaxel 
o Cimetidine 300 mg IV (or equivalent, ranitidine 50 mg or 
famotidine 20 mg) 1 hour prior to paclitaxel infusion. 
2. Monitor CBC and platelet count prior to drug administration. 
3. Symptom management of expected nausea, vomiting, and 
stomatitis. 
4. Monitor for and evaluate abdominal pain occurring after paclitaxel 
administration (especially in severely neutropenic patients and in 
those receiving G-CSF) due to the risk of ischemic and 
neutropenic enterocolitis. 
5. Advise patients of possible hair loss. 
6. Cardiac Monitoring for assessment of arrhythmias in patients with 
serious conduction abnormalities. 
7. Monitor liver function tests. 
8. Advise patient of possible arthralgias and myalgia which may 
occur several days after treatment.  Monitor for symptoms of 
peripheral neuropathy.   
9. Monitor for signs and symptoms of hypersensitivity reactions.  
Insure that the recommended premedications have been given.  
Premedications (diphenhydramine, steroids, and H2 blocker) 
appear to reduce the incidence and severity of hypersensitivity 
reactions but do not provide complete protection.  Emergency 
agents (diphenhydramine and epinephrine) should be available.   
10. Evaluate IV site regularly for signs of infiltration.  It is not known if 
paclitaxel is a vesicant; however, the CremophorsEL vehicle for 
this drug can cause tissue damage. 
11. In-line filtration with a 0.22-micron filter should be used. 


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8.1.12 
References  
R Rowinsky EK, Casenave LA, Donehower RC.  Taxol:  A novel 
investigational microtubule agent.  J Natl Cancer Inst 1990: 82:1247-
1259. 
Gregory RE, DeLisa AF.  Paclitaxel:  A new antineoplastic agent for 
refractory ovarian cancer.  Clin Pharm 1993; 12:401-415. 
Rowinsky EK, Elisenhauer EA, Chaudry V, et al.  Clinical toxicities 
encountered with paclitaxel.  Semin Oncology 1993; 20:1-15. 
Walker FE.  Paclitaxel:  Side effects and patient education issues.  
Semin Oncology Nurs 1993; 9 (suppl 2):6-10. 
Taxol (paclitaxel) package insert, July 2000. 
8.2 
Carboplatin 
8.2.1 
Other Names 
CBDCA, Paraplatin, JM-8, NSC 241240. 
8.2.2 
Classification 
Second generation tetravalent organic platinum compound. 
8.2.3 
Mode of Action  
Like cisplatin, carboplatin produces predominantly interstrand DNA 
crosslinks rather than DNA-protein crosslinks. Cell-cycle nonspecific. 
8.2.4 
Storage and Stability  
Unopened vials should be stored at controlled room temperature 15° - 
30°C (59° - 86°F). Protect unopened vials from light. Solutions for 
infusion should be discarded 8 hours after preparation. 
8.2.5 
Dose Specifics  
• 
Concomitant chemoradiation: Carboplatin AUC 2 IV 15-30 minute 
infusion once per week for 6 weeks, immediately following 
paclitaxel, during radiotherapy.  See Appendix IV for calculation of 
carboplatin dose. 
• 
Consolidation chemotherapy (cycles 1 – 2): Carboplatin AUC 6 IV 
15-30 minute infusion on day 1, immediately following paclitaxel. 
See Appendix IV for calculation of carboplatin dose. 
NOTE: GFR should not exceed 125 mL/min. Using the Calvert 
formula: Carboplatin dose (mg) = AUC x (GFR + 25):  
Maximum carboplatin dose during Concomitant Chemoradiation is 2 x 
(125+25), or 300 mg. 
Maximum carboplatin dose during Consolidation Chemotherapy is 6 x 
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8.2.6 
Preparation  
Add 5, 15, or 45 mL sterile water, normal saline, or 5% dextrose to the 
50, 150, or 450 mg vial, respectively. The resulting solution contains 
10 mg/mL. The desired dose is further diluted, usually in 5% dextrose. 
8.2.7 
Route of Administration 
Intravenous infusion over 15-30 minutes.  
8.2.8 
Incompatibilities  
General: Needles or intravenous administration sets containing 
aluminum parts that may come in contact with PARAPLATIN should 
not be used for the preparation or administration of the drug. 
Aluminum can react with carboplatin causing precipitate formation and 
loss of potency.  
8.2.9 
Compatibilities  
Carboplatin is not sensitive to light. Carboplatin is compatible with 
standard PVC administration sets and intravenous solution bags. 
8.2.10 
Availability 
Commercially available in 50, 150, and 450 mg vials. 
8.2.11 
Side Effects 
1. Hematologic: Thrombocytopenia, neutropenia, leukopenia, more 
pronounced in patients with compromised renal function and 
heavily pretreated patients; may be cumulative.  
2. Gastrointestinal: Nausea and vomiting (less severe than with 
cisplatin), treatable with moderate doses of antiemetics.  
3. Dermatologic: Rash, urticaria.  
4. Hepatic: Abnormal liver function tests, usually reversible with 
standard doses.  
5. Neurologic: Rarely peripheral neuropathy.  
6. Renal: Elevations in serum creatinine, BUN; electrolyte loss (Na, 
Mg, K, Ca).  
7. Other: Pain, asthenia.  
8.2.12 
Nursing/Patient Implications 
Monitor CBC and platelet count; nadir occurs at approximately day 21 
with recovery by day 28-30.  Premedicate with antiemetics - evaluate 
effectiveness.   Monitor fluid status - maintain adequate hydration.  
Assess skin/mucous membranes.  Assess for signs of peripheral 
neuropathy - coordination, sensory loss. 
8.2.13 
References  
Calvert AH, et al. Carboplatin dosage: Prospective evaluation of a 
simple formula based on renal function. J Clin Oncol 1989; 7:1748-
1756. 


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Woloschuk DMM, Pruemer JM, Cluxton RJ. Carboplatin: A new 
cisplatin analog. 
Drug Intell Clin Pharm 1988; 22:843-849. 
Christian MC.  Carboplatin. Principles and Practice of Oncology, PPO 
Updates 1989; 3(11):1-16. 
Paraplatin (carboplatin) package insert, February 2000.  
8.3 
Bevacizumab  
8.3.1 
Other Names  
NSC 704865, RhuMAb VEGF, Recombinant Humanized Monoclonal 
Bevacizumab Antibody 
8.3.2 
Trade Name 
For further details and molecule characterization, see the updated 
bevacizumab Investigator Brochure. 
8.3.3 
Drug Availability 
Bevacizumab (IND# 14510) is being provided by Genentech and 
distributed by UVI, Inc. 400 mg vials are available for this protocol.   
Each 400 mg glass vial contains bevacizumab with phosphate, 
trehalose, polysorbate 20 and Sterile Water for Injection, USP.  
Quantities should be ordered in multiples of 2 as drug is 
packaged 2 vials/pack.  An initial order per patient should be 
enough for 3 cycles. 
Drug Orders: 
Initial Orders: Following submission of the required regulatory 
documents and patient registration to step 2, a supply of 
Bevacizumab may be ordered from UVI, Inc. Institutions must email a 
completed E6508 Bevacizumab Drug Request Form (Appendix VI) to 
the ECOG-ACRIN Drug Team at 900.drugorder@jimmy.harvard.edu.  
Orders may also be sent by fax to: ATTN: ECOG-ACRIN Drug Team 
at (617) 632-2063.  No starter supplies are available. 
Institutions should allow 2 business days for receipt of the 
bevacizumab from the date the drug request is received by the 
ECOG-ACRIN Drug Team. Shipments will be made from UVI, Inc. 
Monday through Thursday for delivery onsite Tuesday through Friday.  
There will be no weekend or holiday delivery of drugs. 
Reorders: Institutions should reorder drug once it has been 
determined the patient will proceed to the next cycle.  Institutions 
should keep in mind that shipments take 2 business days from the 
date the drug request is received by the ECOG-ACRIN Drug Team. 
Reorders using the E6508 Bevacizumab Drug Request Form 
(Appendix VI) should be emailed to 
900.drugorder@jimmy.harvard.edu or faxed to the ECOG-ACRIN 
Operations Office - Boston, Attn: Drug Team at 617-632-2063.  Once 
approved by ECOG-ACRIN, the request will be faxed to UVI, Inc. for 


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shipment within 2 business days. Shipments will be made from UVI, 
Inc. on Monday through Thursday for delivery onsite Tuesday through 
Friday. Quantities should be ordered in multiples of 2 as drug is 
packaged 2 vials/pack. There will be no weekend or holiday 
delivery of drugs. 
Drug Inventory Records: 
Investigational Product Records at Investigational Site(s):It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried and disposed. Records or 
logs must comply with applicable regulations and guidelines. 
Drug Destruction and Return: 
All partially or unused drugs may be destroyed at the site according to 
the institution's policy for drug destruction once all patients have 
completed treatment.  Please maintain appropriate records of the 
disposal, including dates and quantities. 
8.3.4 
Classification 
Antiangiogenesis agent; recombinant humanized monoclonal antibody 
Bevacizumab is a recombinant humanized anti-VEGF monoclonal 
antibody, consisting of 93% human and 7% murine amino acid 
sequences.  The agent is composed of human IgG framework and 
murine antigen-binding complementarity-determining regions. 
8.3.5 
Action  
Monoclonal antibody which neutralizes Vascular Endothelial Growth 
Factor (VEGF, also known as Vascular Permeability Factor, or VPF).  
VEGF is a 45,000 Dalton glycoprotein, which is a major regulator of 
angiogenesis, in response to trauma immune stimulation. Many 
human tumors have been shown to have increase VEGF gene 
expression, when compared to normal surrounding tissues. 
Bevacizumab has been shown to inhibit in vivo growth of a variety of 
human tumors, providing proof of preclinical efficacy and the role of 
VEGF in oncogenesis. 
8.3.6 
Dose Form 
Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid 
ready for parenteral administration in two vial sizes: 
• 
Each 400 mg (25 mg/mL - 4 mL fill) glass vial contains 
bevacizumab with phosphate, trehalose, polysorbate 20 and 
Sterile Water for Injection, USP. 
8.3.7 
Storage/Stability 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, 
sterile liquid concentrate for solution for intravenous (IV) infusion.  
Bevacizumab may be supplied in 5-cc (100-mg), 20-cc (400-mg), and 
50-cc (1000-mg) glass vials containing 4 mL, 16 mL, or 40 mL of 


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bevacizumab, respectively (all at 25 mg/mL).  Vials contain 
bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile 
Water for Injection (SWFI), USP.  Vials contain no preservative and 
are suitable for single use only. 
Upon receipt of the study drug, vials are to be refrigerated at 2°C–8°C 
(36°F–46°F) and should remain refrigerated until just prior to use.  DO 
NOT FREEZE.  DO NOT SHAKE. 
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE 
USE ONLY.  Vials used for 1 subject may not be used for any other 
subject.  Once study drug has been added to a bag of sterile saline, 
the solution must be administered within 8 hours. Vials must be 
protected from light. 
8.3.8 
Drug Preparation  
Vials contain no preservatives and are intended for single use only. 
Place the calculated dose in 100 mL of 0.9% Sodium Chloride for 
Injection. 
8.3.9 
Dose/Administration 
Beginning on Cycle 1 of Step 2, bevacizumab 15 mg/kg IV on day 1. 
The subject’s actual weight at screening should be used to calculate 
the bevacizumab dose.  If a subject’s weight changes by > 10% 
during the course of the study, the bevacizumab dose should be 
recalculated (see Section 8.3.8 for preparation guidelines). 
Initial dose should be infused over 90 minutes. If no adverse reactions 
occur, the second dose should be administered over 60 minutes. 
Again, if no adverse reactions occur, the third and subsequent doses 
should be administered over a minimum of 30 minutes. If infusion-
related adverse reactions occur, subsequent infusions should be 
administered over the shortest period that is well-tolerated, but never 
less than 30 minutes. Infusions should be run in via a volumetric 
infusion device. Do NOT administer as an IV push of bolus. 
To ensure complete delivery of bevacizumab, the IV infusion line must 
be flushed with 0.9% sodium chloride. The following are two 
recommended methods for flushing the bevacizumab IV infusion line: 
1. When the bevacizumab infusion is complete, an additional 50 mL 
of 0.9% sodium chloride for injection should be added to the 
bevacizumab infusion bag. The infusion should continue until a 
volume equal to that of the volume contained in the tubing has 
been administered. 
2. Replace the empty bevacizumab infusion bag with a 50 mL bag of 
0.9% sodium chloride for injection and infuse a volume equal to 
the volume contained in the tubing.  
NOTE: The flush is not included in the total recommended 
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8.3.10 
Kinetics 
Estimated half-life of bevacizumab is approximately 21 days (range 
11-50 days). 
The clearance of bevacizumab was higher in males and in patients 
with a higher tumor burden.  
8.3.11 
Drug Interactions 
Bevacizumab may increase the concentration of SN38 (the active 
metabolite of irinotecan) by as much as 33%.  This may potentially 
increase the incidence of irinotecan-induced side effects such as 
diarrhea and leucopenia. 
8.3.12 
Side Effects 
Refer to CAEPR in Section 5.5. 
8.3.13 
Nursing/Patient Implications 
• 
Monitor CBC and platelets. For patients on warfarin for venous 
access prophylaxis, routine PT monitoring. 
• 
Monitor patient closely during infusion, for infusion related events 
and for bleeding.  
• 
Monitor blood pressure prior to each dose to assess for 
development of hypertension. 
• 
Instruct patient to monitor and report signs/symptoms of: bleeding 
(nose bleeds, blood in sputum), wound healing problems, 
abdominal pain, thromboembolic problems (chest or leg pain, 
dyspnea, vision changes, severe headache, cough, swelling).  
• 
A urine dipstick should be performed at baseline then prior to 
every other course of bevacizumab. Treatment may proceed if 
dipstick result is 0-1+. If the result of urine protein dipstick is > 1+, 
24 hour urine for protein must be obtained.  At baseline for both 
steps 1 and step 2, patients must have < 1 g protein/24 hrs to 
participate in the study. 
During treatment:  
For a 2+ dipstick, treatment with Bevacizumab may be administered, 
but 24 hour urine must be performed prior to the next cycle and the 
results must be < 2g protein/24 hours for subsequent cycle to be 
given. 
For ≥ 3+ dipstick, Bevacizumab should be held and a 24 hour urine 
collection must be performed.  Bevacizumab treatment may be 
resumed when protein is < 2g/24 hours. 
• 
Treat pain, arthralgias, etc. with acetaminophen, or other pain 
relief strategies that do not interfere with the clotting cascade. 
• 
In patients with bleeding, hemostasis evaluation should be 
performed as clinically indicated.   
• 
Patients who have an ongoing bevacizumab-related Grade 4 or 
serious adverse event at the time of discontinuation from study 
treatment will continue to be followed (see Section 5.8). 
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8.3.14 
References 
Bevacizumab Investigators Brochure, Genentech, October 2005. 
Personal Communication, Genentech, May, 2000.  
Textbook of Immunopharmacology, Third edition; 1994; pp. 262, 263, 
Blackwell Scientific publications. 
Gary Mead, (570) 457-9201, June 1, 2000 
8.4 
Tecemotide 
8.4.1 
Other Names 
L-BLP25. Previously known by the non-approved name of STIMUVAX 
8.4.2 
Classification 
Tecemotide is a liposome-based MUC1 vaccine. 
8.4.3 
Mode of Action 
Tecemotide is designed to induce principally a cellular immune 
response that may lead to immune rejection of tumor tissues that 
express MUC1 antigen.  This cellular response may be characterized 
by the proliferation of Helper (CD4-positive) T-cells in response to 
peptide along with production of gamma interferon and the possible 
generation of cytotoxic T-lymphocytes (CTL) capable of directly killing 
MUC1 expressing tumors. 
The BLP25 lipopeptide provides the antigenic specificity for the T-cell 
response, while the monophosphoryl lipid A serves as a non-specific 
adjuvant to induce cellular immune responses. The delivery system is 
designed to facilitate uptake by antigen presenting cells such that the 
lipopeptide is delivered into the intracellular space. This intracellular 
delivery of the peptide leads to presentation via class I MHC 
molecules. This is expected to elicit an antigen specific cellular 
immune response mediated by T-lymphocytes and should include a 
cytotoxic T-cell response. 
Some subjects may generate a humoral response, but this is not 
expected since the vaccine was designed to generate TH1 responses. 
8.4.4 
Storage and Stability 
Store unreconstituted vials of tecemotide in a secure place at 2°C to 
8°C. DO NOT FREEZE. 
After reconstitution, the product is intended for immediate use. If not 
used immediately, storage times should be no longer than 8 hours at 
25°C or lower. DO NOT FREEZE. 
Once the solution has been drawn into the syringe, it must be 
administered to the patient within 20 minutes. 
The contents of the vial are sterile, nonpyrogenic, and do not contain 
bacteriostatic preservatives. The vaccine contains synthetic and non-
infectious biologic components. Any spills that occur should be 
Rev. 1/15 
Rev. 8/11 
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cleaned up using the facility’s standard cleanup procedures for 
biologic products.  
Discard any unused portion of the solution in biohazard waste 
disposal with final disposal by accepted local and national standards 
of incineration. 
8.4.5 
Dose Specifics 
Beginning on Cycle 1 of Step 2, tecemotide 806 mcg injected 
subcutaneously: 
• 
Days 1, 8 & 15 of cycles 1 & 2 
then 
• 
Day 1 of cycles 4, 6, 8, … (every other cycle) 
The 806 mcg dose of tecemotide will consist of four subcutaneous 
injections each containing one-fourth of the total dose (four vials 
required for an 806 mcg dose).  Each treatment will consist of four 0.5 
mL subcutaneous injections each containing one-fourth of the total 
dose (2.0 mL). 
8.4.6 
Preparation 
tecemotide is supplied as a lyophilized powder. Prior to 
administration, the powder must be reconstituted with Sodium 
Chloride Injection, 0.9 %.  
For all preparation and administration steps of tecemotide, a 1 mL 
syringe equipped with a 27G, ½ inch needle is required. Needles and 
syringes will be provided by EMD Serono. The following needles and 
syringes must be used: 
• 
Syringes: BD PlastipakTM 1ml - Becton Dickinson REF 300013  
• 
Needles: BD MicrolanceTM  27G 1/2" - Becton Dickinson REF 
300635 
To obtain the required syringes and needles please complete the 
E6508 Needles and Syringes Request Form in Appendix XII and 
send electronically to the ECOG-ACRIN Drug Team at 
900.drugorder@jimmy.harvard.edu. Requests may also be faxed to: 
ATTN: ECOG-ACRIN Drug Team at (617) 632-2063.  Please allow a 
minimum of 5 business days for delivery. 
Note that the dose administered to subjects in clinical and nonclinical 
studies is consistently expressed as the mass of BLP25 lipopeptide. 
One vial of the product provides drug material for the preparation of a 
201.5 mcg tecemotide (i.e. BLP25 lipopeptide) injection aliquot. The 
total treatment dose, consisting of 806 mcg tecemotide, will be 
prepared from four vials of the product. 
The preparation of each treatment dose must be accomplished by the 
procedures outlined below,  Steps 1 to 7 must occur within the 
pharmacy, while steps 8 to 10 must be performed by the physician (or 
Rev. 8/11, 1/12, 4/13 
Rev. 8/11, 1/12, 4/13 
Rev. 8/11 
Rev. 8/11 
Rev. 8/11, 1/12 
Rev. 8/11, 1/12, 4/13 
Rev. 1/12 
Rev. 1/12 
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other designated person) immediately prior to administration of the 
solution to the patient. 
NOTE: 
The solution must not be filtered at any time during the 
preparation or administration of the product since this will 
result in the removal of the active components of the 
solution. 
Subsequent preparation steps must occur within the pharmacy using 
aseptic techniques: 
1. Remove four vials of the lyophilized product from the medication 
box stored at 2-8oC.  Allow each vial to come to room temperature 
for a minimum of five minutes and not more than two hours before 
proceeding. 
2. Remove the flip-top cap from the aluminum crimp seal to expose 
the stopper on each vial, and then swab the stopper with alcohol. 
3. Use one 1 mL syringes equipped with a 27G, ½ inch needle to 
create a negative pressure in each vial by withdrawing 0.60 mL of 
atmosphere from within the vial.  Use a new needle and syringe 
for each vial to prevent a dull needle from coring the stopper. 
4. Reconstitute the contents of each vial by injecting 0.60 mL of 
Sodium Chloride Injection, 0.9% stored at room temperature.  
Again, use a new needle and syringe for each vial. 
5. Swirl each vial, invert it and then draw the contents of the vial in 
and out of the syringe six times to reconstitute the lyophilized 
material.  After reconstitution, the vial contents should form a milky 
suspension free of visible particles.  Do not use the product if 
visibly opaque particles, discoloration or foreign particulates are 
observed. 
6. Label the reconstituted vials with the date and time of 
reconstitution and patient identification.  The product is intended 
for immediate use. If not used immediately, in-use storage times 
should not be longer than 8 hours at 25oC or lower due to absence 
of antimicrobial preservatives. The solution must not be frozen. 
7. Provide the following items to the physician (or other designated 
person) responsible for administration of the injection to the 
patient: Four vials of reconstituted tecemotide, four 1mL syringes 
and four 27G, ½ inch needles.  
Subsequent preparation steps must be performed by the 
physician (or other designated person) responsible for 
administration of tecemotide to the patient: 
8. Immediately prior to administration of the injection to the patient, 
swirl the four vials of reconstituted product to resuspend all 
components. 
9. Withdraw 0.50 mL of the solution into a 1 mL syringe equipped 
with a 27G, ½ inch needle.  Repeat this step with the remaining 
three vials, using a new syringe and needle per each withdrawal.  
Once the solution has been drawn up into the syringe, it must be 
administered to the patient within 20 minutes. 
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10. Per each treatment, four 0.50 mL injections will be administered to 
the patients by subcutaneous application at four different 
anatomical sites. 
NOTE: In the event of spillage of the investigational product please 
use your standard hospital cleaning procedure for biological 
materials. The IP is not a biohazardous product. 
8.4.7 
Route of Administration 
At each  tecemotide dosing the content from four vials (tecemotide) is 
to be injected subcutaneously at four different anatomical sites. To 
prepare one injection of tecemotide, 0.5 mL of the reconstituted 
vaccine is withdrawn from the vial and administered to the patient. 
This step is repeated with the remaining three vials. The total volume 
that is injected at each vaccination is thus 2.0 mL. The total dose 
administered at each vaccination to the subject is 806 µg tecemotide 
(as measured by lipopeptide mass) and has a total dose volume of 
2.0 mL provided in four vials (0.5 mL per vial = 201.5 µg BLP25 
lipopeptide). 
Please note: Patient should be monitored for one hour after receipt of 
injection to insure that they do not experience an allergic reaction. 
tecemotide, upon reconstitution with sterile sodium chloride, 0.9% 
injection, USP, should be used immediately. In use storage time 
should not be longer than 8 hours at 25°C or lower. 
Any spills that occur should be cleaned up by using the institution’s 
standard cleanup procedures for biological products. Discard any 
unused portion of the solution in biohazard waste disposal with final 
disposal by accepted local and national standards. 
8.4.8 
Compatibilities 
The physical and chemical nature of the components of tecemotide, 
the small amounts injected into the patients, and the suspected 
mechanism of action of the liposomal formulation present challenges 
to the pharmacokinetic and product metabolism studies in humans.  
These studies have not been conducted to date. 
8.4.9 
Availability 
Tecemotide is an investigational agent (IND# 14510) being provided 
by Merck KGaA and distributed by Fisher Clinical Services Allentown. 
Drug Orders: 
Initial Orders: Following submission of the required regulatory 
documents and patient registration to step 2, a supply of tecemotide 
may be ordered. Institutions must email a completed E6508 
Tecemotide Initial Shipment Request and Receipt Form (Appendix IX) 
to the ECOG-ACRIN Drug Team at 
900.drugorder@jimmy.harvard.edu. Orders may also be sent by fax 
to: ATTN: ECOG-ACRIN Drug Team at (617) 632-2063. Delivery will 
be conducted by Fisher Clinical Services Allentown. No starter 
supplies are available. 
Rev. 8/11 
Rev. 8/11, 1/12 
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Tecemotide is packaged as 4 vials/box.  An initial shipment of 6 boxes 
for each new patient is suggested. Institutions should allow 5 business 
days for receipt of the tecemotide study medication from the date the 
drug request is received by the ECOG-ACRIN Drug Team. Shipments 
will be made from Fisher Clinical Services Allentown Monday through 
Thursday for delivery onsite Tuesday through Friday.  There will be 
no weekend or holiday delivery of drugs. 
Reorders: Institutions should reorder drug once it has been 
determined the patient will proceed to cycles 4,6,8, …(every other 
cycle).  Tecemotide is given only on day 1 of cycles 4,6,8.. up to a 
total of 34 cycles.  It is suggested that institutions should reorder drug 
only if it is determined the patient will proceed to the next cycles.   
Institutions should keep in mind that shipments take 5-6 business 
days from the date the drug request is received by the ECOG-ACRIN 
Drug Team. Reorders using the E6508 Tecemotide Shipment 
Request and Receipt Form for Resupply (Appendix X) should be 
emailed to 900.drugorder@jimmy.harvard.edu or faxed to the ECOG-
ACRIN-ACRIN Operations Office - Boston, Attn: Drug Team at 617-
632-2063.  Once approved by ECOG-ACRIN, the request will be 
faxed to Fisher Clinical Services Allentown. for shipment within 5 
business days. Shipments will be made from Fisher Clinical Services 
Allentown. on Monday through Thursday for delivery onsite Tuesday 
through Friday. Quantities (boxes of 4 vials) should be ordered in 
multiples of 2. There will be no weekend or holiday delivery of 
drugs. 
Receipt Of Drug Shipment 
Study drug shipments will include a Q-tag temperature monitor and 
forms that will need to be completed and returned to Fisher Clinical 
Service. The pharmacist/study personnel responsible for the clinical 
study product will need to indicate the condition of the shipment by 
completing both the “Shipment Request and Receipt Form” and the 
Confirmation of Certificate for Use at Site (CCUS) and return both 
forms to Fisher Allentown by fax at 1-610-871-8590.    A scan, copy or 
photograph should be taken and stored with the original documents in 
the pharmacy file.  The Q-tag monitored can then be disposed, it does 
not need to be returned to Fisher Allentown. 
For additional information on the requirements for the receipt of the 
BLP25 vaccine and the Q-tag monitor please see the Study Specific 
Tools section of E6508 on the ECOG web site: www.ecog.org. 
Drug Inventory Records: 
Investigational Product Records at Investigational Site(s): It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried and disposed. Records or 
logs must comply with applicable regulations and guidelines. 
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Drug Destruction and Return: 
All partially or unused drugs may be destroyed at the site according to 
the institution's policy for drug destruction once all patients have 
completed treatment.  Please maintain appropriate records of the 
disposal, including dates and quantities. 
8.4.10 
Side Effects 
During treatment with tecemotide, the investigator should anticipate 
the following potential adverse events:  
• 
Flu-like symptoms 
• 
Malaise 
• 
Headache 
• 
Arthralgia and/or myalgia 
• 
Fatigue 
• 
Local injection site reactions 
• 
Rash 
Special attention should be directed towards possible liver toxicity or 
neurological toxicity.  
Injection site induration, nodule formation, erythema and pain have 
been noted in the majority of patients in earlier studies.  These 
reactions have been predominantly grade 1 reactions.  Injection site 
inflammation, bruising, pruritus, and burning have also been noted, 
and these similarly have been grade 1 reactions. 
Tecemotide must not be administered to women who are pregnant or 
to patients with an autoimmune disease. Tecemotide is not 
recommended in patients with immunodeficiency diseases. 
8.4.11 
Nursing/Patient Implications 
• 
As with any type of injection, epinephrine, antihistamine, and 
hydrocortisone should be available for immediate parenteral use 
in the event of an anaphylactic reaction. 
• 
Inform patient about potential symptoms related to: 
 Thrombocytopenia: symptoms such as frequent bruising, 
epistaxis, or petechiae. 
 Neurological disorders: symptoms such as double vision, loss 
of memory, personality changes, impairment of speech, or 
limb weakness. 
 Hepatic dysfunction: symptoms such as jaundice, yellow 
sclerae, concomitant itching, light colored stools, or dark urine. 
• 
Before each injection the previous treatment sites should be 
inspected and any findings documented in source data and on the 
applicable case report forms (CRFs). 
• 
The subject must be observed for 1 hour post injection 
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8.4.12 
References 
L-BLP25 (Tecemotide) MUC1 Antigen-Specific Cancer 
Immunotherapy Investigator’s Brochure, 17 October 2013 
8.5 
Cyclophosphamide 
NOTE:  Please refer to the commercial package insert for more information. 
8.5.1 
Other Names 
Cytoxan, Neosar, CTX, CPM 
8.5.2 
Classification 
Cyclophosphamide is a prodrug biotransformed to active alkylating 
metabolites by a mixed function microsomal oxidase system. 
8.5.3 
Mode of Action 
Cyclophosphamide metabolites are thought to disrupt cell division 
primarily by cross-linking DNA strands.  Cyclophosphamide is 
considered cell cycle phase non-specific. 
8.5.4 
Storage and Stability 
Tablets and injectable powder are stored at room temperature 25°C 
(77°F).  The temperature is not to exceed 30°C (90 F°).  
Reconstituted parenteral solutions are stable for 24 hours at room 
temperature for 6-14 days if refrigerated. 
8.5.5 
Dose Specifics 
Cycle 1 of Step 2 only - Cyclophosphamide 300 mg/m2 (600 mg 
maximum) IV over 15-30 minutes; administered 72 hours prior to day 
1 of cycle 1. 
8.5.6 
Preparation 
Dissolve the 100 mg, 200 mg, 500 mg, 1 g, and 2 g vials in 5, 10, 25, 
50, and 100 mL of sterile water, respectively, resulting in a solution of 
20 mg/mL.  Shake vials vigorously and warm slightly in lukewarm 
water to facilitate dissolution.  The lyophilized form is more easily 
solubilized. 
Reconstituituted solutions may be further diluted in D5W, D5W/NS, 
D5W/Ringer’s Injection, Lactated Ringer’s Injection, and ½ NS. 
8.5.7 
Administration 
IV infusion, in 250 mL NS over 15-30 minutes. 
8.5.8 
Compatibilities 
Numerous compatibility studies have been published.  For specific 
details refer to handbook on injectable drugs by Lawrence A. Trissel. 
8.5.9 
Availability 
Cyclophosphamide is commercially available for parenteral injection 
as 100 mg, 200 mg, 500 mg, 1 g, and 2 g vials. 
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8.5.10 
Side Effects 
Side effects vary significantly based on the specific dose and duration 
of cyclophosphamide.  
8.5.10.1 
Incidence More Frequent (> 5%) 
1. Anemia, leukopenia (usually asymptomatic; less 
frequently fever and/or chills)  
2. Thrombocytopenia (usually asymptomatic; less 
frequently unusual bleeding or bruising; black tarry 
stools; blood in urine or stools; pinpoint red spots on 
skin).  Nadir counts usually occur 7 to 12 days after 
administration and recovery usually compete by day 17 
to 21. 
3. Alopecia 
4. Anorexia, nausea and vomiting 
5. Gonadal suppression (azoospermia, missed menstrual 
periods) resulting in infertility.  Return of normal 
gonadal function and fertility occurs with time in many 
younger men and women. 
6. Hemorrhagic cystitis 
8.5.10.2 
Incidence Less Frequent (1-5%) 
1. Stomatitis 
8.5.10.3 
Incidence Rare (1%) 
1. Anaphylaxis (tachycardia, shortness of breath, 
wheezing, tightness in throat) 
2. Flushing or redness of face 
3. Diarrhea 
4. Skin rash 
5. Pneumonitis or interstitial pulmonary fibrosis\ 
6. Syndrome of inappropriate antidiuretic hormone (siadh) 
7. Chemical phlebitis (redness, swelling or pain at site of 
injection) 
8. Secondary malignancies 
9. Blurred vision, cardiac toxicity presenting as congestive 
heart failure 
10. Hemorrhagic mycodarditis 
11. Cardiac necrosis 
12. Pericarditis (seen with high dose regimens used with 
bone marrow transplantation) 


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8.5.11 
Drug Interactions 
8.5.11.1 
Digoxin 
Several studies conducted in lymphoma patients receiving 
combination chemotherapy including cyclophosphamide 
revealed a 20–50% reduction in digoxin absorption when 
digoxin tablets were administered.  When digoxin capsules 
were administered no significant decrease in digoxin 
absorption occurred.  To avoid decreased serum digoxin 
levels the use of digoxin in liquid form (liquid or capsules 
containing liquid digoxin) instead of tablets is 
recommended. 
8.5.11.2 
Pentostatin 
Two case reports describe fatal cardiac toxicity in patients 
receiving CTX  6.4 g/m² over 4 days and pentostatin 4 
mg/m² over 4 hours on day 3.  Until additional data from 
clinical trials demonstrate the safety of concurrent use of 
these drugs concurrent administration is not 
recommended. 
8.5.11.3 
Succinylcholine 
Cyclophosphamide may prolong the effects of 
succinylcholine by irreversibly inhibiting the enzyme 
pseudocholinesterase.  Limited clinical observations and in 
vitro  studies suggest that prolonged apnea might result 
when  succinylcholine is administered to some patients 
also receiving cyclophosphamide. Management options 
include avoiding concurrent therapy or if concurrent 
therapy can not be avoided, to monitor for prolonged 
succinylcholine effect in patients receiving both drugs. If 
cyclophosphamide has been administered within 10 days 
of succinylcholine, extreme caution should be used after 
succinylcholine administration.  The anesthesiologist 
should be informed of the potential for succinylcholine-
induced apnea and appropriate precautions and 
monitoring should be implemented. 
8.5.11.4 
Trastuzumab 
In early clinical trials the concurrent administration of 
cyclophosphamide and trastuzumab increased the 
incidence and severity of cardiac dysfunction.  Until 
additional data from clinical trials demonstrate the safety of 
concurrent use of these drugs concurrent administration is 
not recommended. 


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8.5.12 
Nursing/Patient Implications 
1. Monitor CBC, platelet count.  Advise patients of increased risk of 
infection with absolute neutrophil count less than 500 cells/mm³ 
and increased risk of bleeding with platelet counts less than 
20,000 cells/ mm³.  Advise patients to call the clinic if they develop 
a fever above 101°F or notice any easy bruising,  petechiae 
(pinpoint red spots on skin), or prolonged bleeding. 
2. Advise patient of possible alopecia. Instruct how to obtain wig, 
hairpiece, etc. 
3. Assess hydration and fluid balance.  Patients receiving larger doses 
should force fluids up to 2 liters above normal intake for 72 hours 
after administration.  Instruct patients to void more frequently to 
minimize occurrence of hemorrhagic cystitis.   
4. Premedicate with antiemetics. 
5. Observe for possible phlebitis at injection site. 
6. Administer antiemetics as indicated. 
8.5.13 
References 
1. American Hospital Formulary Service 99 – Drug Information; 832-
837. 
2. Cytoxan Package Insert, Princeton, NJ: Mead Johnson Oncology 
Products 1998; July Micromedex Inc. Vol. 101; 1999. 
3. USPDI Volume 1 1999; 1128-1134. 
4. Trissel L.A, Handbook on injectable drugs (8th Ed), Bethesda, MD: 
American Society of Hospital Pharmacists, 1994, Pp. 287-295. 
5. Cazin B, Gorin NC, Laporte JP. Cardiac complications after bone 
marrow transplantation: A report of a series of 63 consecutive 
transplants. Cancer 1986; 57:2061-2069. 
6. Gryn et. al. Pentostatin increases the acute toxicity of high dose 
cyclophosphamide. Bone Marrow Transplantation 1993; 12:217-
220. 
7. Pedersen-Bjergaard J, Ersboll J, Sorenson HM. Risk of acute 
nonlymphocytic leukemia and preleukemia in patients treated with 
cyclophosphamide for Non-Hodgkin’s lymphoma. Ann Intern Med 
1985; 103:195-200. 
8. Stillwell TJ, Benson RJ. Cyclophosphamide-induced hemorrhagic 
cyctitis: A review of 100 patients. Cancer 1988; 61:451-457. 
9. Zucchero FJ, Ed. Evaluation of drug interactions. St. Louis: 
Professional Drug Systems, 1997; 2/35, 12/21. 
10. Hansten Pd, Ed. Drug interactions analysis and management. 
Applied Therapeutics, Inc., Vancouver, WA 1998; 185-186. 
11. Trastuzumab Package Insert, South San Francisco, CA  
Genentech, Inc. 1998; September.


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9. 
Statistical Considerations 
9.1 
Objectives   
The primary objective of this phase II study is to determine the safety of 
combination therapy with concurrent chemoradiation, followed by consolidation 
chemotherapy, finally followed by tecemotide + bevacizumab for patients with 
stage III non-squamous, locally advanced non-small cell lung cancer (NSCLC). 
Secondary endpoints include progression-free survival, overall survival, and 
toxicity. In addition, the determination of fraction of circulating immature dendritic 
cells and the relationship between the fraction of circulating dendritic cells and an 
allogenic mixed lymphocyte reaction (allo-MLR) response will be explored.   
9.2 
Accrual Rate 
A two-stage design will be used for this study, mainly for the maintenance 
therapy. As reflected by E3598, the accrual of patients with unresectable Stage 
IIIA and IIIB NSCLC was originally anticipated to be 6 patients per month. Since 
only non-squamous NSCLC patients can enter into this study and only about 
65% of patients on E3598 are non-squamous, this led to the estimation of the 
accrual rate of 4 patients per month for this study. Based on E2597, it was 
conservatively estimated that approximately 60% of patients would proceed to 
the maintenance therapy. 
Based on these expectations, it was planned that, after 18 patients enroll onto 
the study (about 11 patients projected proceeding to the maintenance therapy 
and 10 actually receiving treatment), the study would be suspended for 18 weeks 
for toxicity evaluations. (Per protocol, patients receive chemoradiation for 6 
weeks then consolidation chemotherapy for 2 cycles, and maintenance therapy 
can be up to 34 cycles. 1 cycle = 21 days)  If ≤ 1 grade 4-5 hemorrhagic, 
esophageal, fistula, platelet count decrease (thrombocytopenia), encephalitis 
infection, or hepatic failure events are reported during the treatment of 
tecemotide + bevacizumab amongst the first stage 10 treated patients, the study 
would reactivate and accrual to 55 patients. (It was projected that 22 out of 37 
patients accrued on the second stage would proceed to the maintenance step 
and 20 would actually receive treatment). It was estimated that the first stage 
accrual would take approximately 4.5 months and additional 9.5 months for the 
second stage accrual, making the study accrual (including the suspension time) 
approximately 18 months. 
Step 2 stage 1 safety evaluation was performed twice, the first one in 2012 after 
18 patients enrolled into this study (per the study plan) and the second in August 
2013. In the first safety evaluation, only 8 patients received maintenance 
treatment and no targeted adverse event was observed. After a teleconference 
with NCI, E6508 was allowed to continue accrual, under the condition that step 2 
toxicity data of the additional two new patients needed to be closely monitored. In 
the second safety evaluation, only 9 patients’ step 2 toxicity data are available 
(each for at least 2 cycles). Since none of them have experienced any targeted 
grade 4-5 adverse event, Stage 1 safety rule (i.e., If ≤ 1 grade 4-5 targeted 
adverse events are reported during the treatment of BLP25 + bevacizumab 
amongst the first stage 10 treated patients, the study will continue accrual to 
Stage 2) is not violated and we can proceed to the second stage accrual. 
Rev. 4/13 
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At the second safety evaluation, the percent of patients who have been enrolled 
into Step 2 (with stable disease, partial response, or complete response at the 
end of concurrent chemoradiation followed by consolidation chemotherapy) is 
approximately 38% (based on the first 29 enrolled patients who started protocol 
treatment) instead of 60% as originally expected. To ensure we have enough 
patients into the maintenance treatment of this study, the accrual goal of this 
study needs to be adjusted accordingly. Per our original study plan, we need to 
accrue in total 30 eligible and treated patients in Step 2. In order to achieve this 
goal, we plan to increase the accrual goal from 55 to 88 patients, taking into 
account of 10% of ineligibility rate and the drop-out rate. Based on the actual 
accrual rate of this study so far, only 2 patients per month can be recruited into 
this study. It is thus estimated that the total accrual time will be 3.7 years (without 
considering the suspension time for stage 1 safety evaluation). Given that 41 
patients have been enrolled into this study and stage 1 safety evaluations had 
been performed, it is expected that we still need approximately 2 years to 
complete the accrual goal of 88 patients. 
9.3 
Primary Objective  
All registered patients will proceed to the maintenance therapy (tecemotide + 
bevacizumab) if a CR, PR, or SD is observed at the conclusion of both 
concomitant chemoradiation and consolidation chemotherapy.  It is known that 
tecemotideafter chemoradiation is safe. However, due to the possibility of 
esophagitis, fistula, or hemorrhage as reported in previous bevacizumab trials, 
and three suspected unexpected serious adverse reactions (thrombocytopenia, 
encephalitis infection, and hepatic failure) that were previously reported in clinical 
trials with tecemotide, the safety of this new combined regimen needs to be 
investigated. A true toxicity rate of 0.25 with clearly attributable grade 4-5 
hemorrhage, esophagitis, fistula, platelet count decrease (thrombocytopenia), 
encephalitis infection, or hepatic failure events during the treatment of tecemotide 
+ bevacizumab will be considered unacceptable for this new regimen.   
A two-stage design will be used for this study, mainly for the maintenance 
therapy. Eleven patients with a CR, PR, or SD at the conclusion of both 
chemoradiation and chemotherapy will be initially entered and monitored closely 
for all life-threatening, fatal hemorrhage, esophagitis, fistula, platelet count 
decrease (thrombocytopenia), encephalitis infection, or hepatic failure episodes, 
assuming that at least 10 will start maintenance therapy. If we observe 2 or more 
clearly attributable grade 4-5 hemorrhage, esophagitis, fistula, platelet count 
decrease (thrombocytopenia), encephalitis infection, or hepatic failure events 
during the treatment of tecemotide + bevacizumab amongst first 10 treated 
patients, the study will be terminated. Otherwise, an additional 22 patients with a 
CR, PR, or SD at the conclusion of both chemoradiation and chemotherapy will 
be entered, of whom 20 will be assumed to have maintenance therapy. If we 
observe at least 5 or more clearly attributable grade 4-5 hemorrhage, 
esophagitis, fistula, platelet count decrease (thrombocytopenia), encephalitis 
infection, or hepatic failure events during the treatment of tecemotide + 
bevacizumab amongst the total 30 treated patients, the new regimen will be 
considered unacceptable. 
Table 1 gives the characteristics of this design as a function of the true toxicity 
rate of grade 4-5 hemorrhage, esophagitis, fistula, platelet count decrease 
(thrombocytopenia), encephalitis infection, or hepatic failure events during the 


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treatment of BLP25 + bevacizumab.  This design had 8.6% probability of 
stopping early and 9.3% probability of declaring the regimen unacceptable if the 
true grade 4-5 hemorrhage, esophagitis, fistula, platelet count decrease 
(thrombocytopenia), encephalitis infection, or hepatic failure events during the 
treatment of BLP25 + bevacizumab toxicity rate is 0.05, and 93.4% probability of 
declaring the regimen unacceptable if the true toxicity rate was 0.25. 
Table 1: Operating Characteristics of the Early Stopping Procedure 
 
True Grade 4-5 Hemorrhage, 
Esophagitis, Fistula, Platelet Count 
Decrease (thrombocytopenia), 
Encephalitis Infection, or Hepatic 
Failure Events Toxicity Rate 
 
0.05 
0.10 
0.15 
0.20 
0.25 
Probability of Stopping Early ≥ 2/10 grade 4-5 
Hemorrhage, Esophagitis, Fistula, Platelet Count 
Decrease (thrombocytopenia), Encephalitis Infection, or 
Hepatic Failure Events 
0.0861 0.2639 0.4557 0.6242 0.7560 
Probability of the New Regimen Unacceptable  (≥ 5/30 
grade 4-5 Hemorrhage, Esophagitis, Fistula, Platelet 
Count Decrease (thrombocytopenia), Encephalitis 
Infection, or Hepatic Failure Events 
0.0927 0.3305 0.6116 0.8219 0.9344 
9.4 
Secondary Objectives  
Secondary endpoints include progression-free survival (PFS), overall survival 
(OS), and toxicity. 
9.4.1 
Overall Survival 
Overall survival will be determined as the time from the registration 
onto the study until death from any cause. Cases with incomplete 
follow-up will be censored at date last known alive. Overall survival 
will be estimated on all treated eligible patients using the Kaplan-
Meier method. 
9.4.2 
Progression-Free Survival 
Progression-free survival is defined as the time from registration onto 
the study to disease progression or death from any cause, whichever 
comes first. Patients with incomplete follow-up will be censored at 
time of last disease assessment. Progression-free survival will be 
estimated on all treated eligible patients using the Kaplan-Meier 
method. 
9.4.3 
Toxicity 
All treated patients will be evaluated. 
9.5 
Laboratory Endpoints  
The correlative analyses of this study will be exploratory in nature and primarily 
descriptive due to the small sample size. The fraction of circulating dendritic cells 
and immature myeloid cells before, during, and after treatment will be 
summarized with 90% confidence interval. Exploratory longitudinal analyses of 


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these cells over time (prior to start of maintenance therapy, once every 3 cycles 
during the maintenance therapy, for maximum of 34 cycles) and correlation with 
allogenic mixed lymphocyte reaction will be conducted. 
9.6 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Reports of these analyses are sent to the ECOG-ACRIN Principal 
Investigator or Senior Investigator at the participating institutions. Patients will be 
closely monitored for any evidence of treatment emergent toxicities of a serious 
or unexpected nature to determine if there is a reasonable suspected relationship 
to the treatment regimen. Expedited reporting of certain adverse events is 
required, as described in Section 5.4. 
9.7 
Gender and Ethnicity 
Based on previous data from E3598, the anticipated accrual in subgroups 
defined by gender, ethnicity, and race of the 88 patients is as follows: 
 
Ethnic Category  
Gender  
 
Females 
Males 
Total 
Hispanic or Latino  
1 
1 
2 
Not Hispanic or Latino  
32 
54 
86 
Ethnic Category: Total of all subjects  
33 
55 
86 
Racial Category  
American Indian or Alaskan Native  
0 
0 
0 
Asian  
1 
1 
2 
Black or African American  
3 
5 
8 
Native Hawaiian or other Pacific Islander  
0 
0 
0 
White  
29 
49 
78 
Racial Category: Total of all subjects  
33 
55 
88 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
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10. 
Correlative Studies 
The samples submission outlined in Section 10.1 are to be submitted from patients who 
agree to participate in the optional correlative science projects and/or banking for future 
research. 
10.1 
Sample Submissions 
The kit for blood specimen collection and shipment is available for sites in the 
United States and Canada.  Complete the KIT ORDER FORM (Appendix VII) 
and fax to the UPCI-IMCPL at (412) 623-6625. Enclosed in the kit is a reorder 
form to be used to request follow-up kits. Please use this form when reordering 
follow-up kits.  Fax the reorder form one week prior to the collection of the follow-
up sample to 412-623-6625. 
Samples must be labeled with the protocol number, ECOG-ACRIN patient 
sequence number, date AND time of collection, and sample type. ECOG-ACRIN 
requires that all samples submitted from patients participating in this trial be 
entered and tracked via the online ECOG-ACRIN Sample Tracking System. See 
Section 10.1.4. 
Order of blood draw:  no anticoagulant (red top), citrate (blue top), heparin (green 
top). Note that the tube top colors are based on BD tubes. Tubes supplied by 
other companies may have different colored tops. 
Summary of specimen submissions: 
 
Maintenance Therapy 
Ship To: 
Prior to start 
of 
Maintenance 
therapy 
q 3 cycles, prior 
to treatment 
(cycle 
4,7,10,…) 
Discontinued 
Protocol 
Treatment2 
Submit from patients who answer “Yes” to “I agree to participate in the laboratory research studies that 
are part of this clinical trial.” 
Peripheral Blood, citrate tube 
X 
X 
X 
Shanker Lab 
(Lab #0169) 
See Section 
10.1.1 
Peripheral Blood, heparin tubes 
X 
X 
X 
IMCPL 
(Lab #0010) 
See Section 
10.1.2 
Peripheral Blood, no 
anticoagulant (e.g. red top) 
X 
X 
X 
Submit from patients who answer “Yes” to storage of specimens for future research (banking). 
Diagnostic or surgical tumor 
tissue1 
X 
X 
CBPF 
(Lab #0001) 
See Section 
10.1.3 
1 Submit within one month following registration to step 1 from patients who consent to allow banking of 
samples for future research. 
2 Upon completion of protocol therapy or progression. 
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10.1.1 
Submissions to the Shanker Laboratory  
Submit from patients who answer “Yes” to “I agree to participate in the 
laboratory research studies that are part of this clinical trial.” 
Questions about sample collection or submission are to be directed to 
Shanker’s Laboratory, Attn: Dr. Anil Shanker or Troy Pellom or Fred 
Duafalia at 617-327-6460. 
A. Sample schedule and preparation 
Peripheral blood (30mL) will be drawn into three ACD (yellow top) 
vacutainer tubes during Maintenance therapy at the time points 
indicated above. 
Mix the blood and anticoagulant immediately by gently inverting 
the tube 10 to 15 times.   
B. Shipping Guidelines 
Samples are to be shipped at ambient temperature the day of 
collection.  During warm weather ship with frozen kool pack but 
insulate samples so they do not freeze. 
Anil Shanker, PhD 
Department of Biochemistry and Cancer Biology 
Meharry Medical College  
2005 West Basic Sciences Building   
1005 Dr. DB Todd Jr, Blvd.  
Nashville, TN 37208  
phone:  615-327-6460 
Fax: 615-327-6440 
Materials are shipped overnight and must be shipped SUNDAY 
THROUGH THURSDAY only.  Do not ship samples the day before a 
Holiday.   
Include with the samples, the shipping manifest generated by the 
Sample Tracking System.   
10.1.2 
Submissions to the Immune Monitoring and Cellular Products 
Laboratory (IMCPL)  
Submit from patients who answer “Yes” to “I agree to participate in the 
laboratory research studies that are part of this clinical trial.” 
Questions are to be directed to the IMCPL at 412-624-0078. 
A. Sample Preparation 
 
At each time point draw: 
• 
Two (2) 10 mL tubes without anticoagulant (i.e., red top) 
• 
Six (6) 10 mL heparinized tubes. Invert gently 6-8 times. 
Rev. 8/11 
Rev. 10/12 
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B. Shipping Procedures 
All peripheral blood samples will be sent overnight at ambient the 
day of collection to the following address: 
Specimen Processor 
UPCI-IMCPL 
Hillman Cancer Center 
5117 Centre Avenue L1.26 
Pittsburgh, PA 15213-1862 
Tel: (412) 624-0078  
FAX: (412) 623-6625 
Ship samples in insulated boxes. Provide a cool pack during hot 
weather, packing specimens so they do not freeze. Materials are 
shipped overnight and must be shipped SUNDAY THROUGH 
THURSDAY only.  Do not ship samples the day before a Holiday.   
Schedule for shipping samples should be established prior to, or at 
the time of, the first shipment.  Please contact the IMCPL with this 
information at (412) 624-0078. 
Include with the samples, the shipping manifest generated by the 
Sample Tracking System.   
10.1.3 
Submissions to the ECOG-ACRIN CBPF (Banking samples for future 
research) 
When a patient is registered to receive protocol therapy, the 
submitting pathologist and clinical research associate should refer to 
Appendix II (Pathology Submission Guidelines). 
Submit from patients who answer “Yes” to “I agree my tissue will be 
submitted for research.” 
A. Requested materials 
1. 
Forms: 
• 
ECOG-ACRIN Generic Specimen Submission Form 
(#2981). Please identify the clinical status of the 
submitted material (i.e., pretreatment as opposed to 
remission and relapse). 
• 
Copy of the pathology and surgical reports. 
• 
Reports of immunologic studies, if performed   
2. 
Biological Material Submission:  
• 
Baseline Diagnostic or surgical tumor tissue block 
• 
Tissue block from any repeat biopsies are requested.  
NOTE: 
If a block is unavailable for submission, contact 
the ECOG-ACRIN CBPF (1-844-744-2420) to 
obtain alternative sample submission 
requirements. 
Rev. 8/11 
Rev. 8/11 
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B. Shipping Guidelines 
Tissue blocks are to be submitted at ambient temperature within 1 
month of patient registration.   Include a cool pack during warm 
weather. 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room 
G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
Include with the samples, the shipping manifest generated by the 
Sample Tracking System and the required forms and reports.   
10.1.4 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and 
tracked using the ECOG-ACRIN Sample Tracking System (STS). The 
software will allow the use of either 1) an ECOG-ACRIN user-name 
and password previously assigned (for those already using STS), or 
2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the 
samples required for this study, please access the Sample Tracking 
System software by clicking https://webapps.ecog.org/Tst.  
Important: Please note that the STS software creates pop-up 
windows, so you will need to enable pop-ups within your 
web browser while using the software.  A user manual 
and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a 
moment to familiarize yourself with the software prior to 
using the system. 
An STS generated shipping manifest should be shipped with all 
specimen submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog-acrin.tst@jimmy.harvard.edu. 
10.1.4.1 
Study Specific Notes 
Generic Specimen Submission Form (#2981) and 
Shipment Notification Form (Appendix VIII) (faxed to the 
receiving laboratory) will be required only if STS is 
unavailable at time of sample submission.  Indicate the 
appropriate on the submission form: 
• 
ECOG-ACRIN CBPF 
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• 
0009 = IMCPL 
• 
0167 = Shanker Laboratory, Meharry Medical College 
To obtain the overnight courier number, contact the CBPF 
(1-844-744-2420). Retroactively enter all specimen 
collection and shipping information when STS is available. 
10.2 
Fraction of Immature Myeloid Cells (ImCs) 
The PBMC will be analyzed by flow cytometry for the presence of DCs and ImCs, 
and the absolute numbers as well as ratios will be determined. PBMC from each 
sample will be stained immediately to evaluate the presence of ImC and DCs in 
freshly isolated cells. Additionally, a second aliquot will be cultured for 36-48 hr in 
complete culture medium (RPMI-1640 and 10% FCS). This condition allows for 
differentiation of relatively immature DCs and macrophages, and eliminates the 
possibility of detection of false-positive ImC.   
Freshly isolated and cultured mononuclear cells will be labeled with a cocktail of 
PE-conjugated antibodies against T cells, B cells, monocytes, and NK cells (anti-
CD3, CD14, CD19, CD56), APC conjugated anti-HLA-DR antibody, and FITC- 
conjugated anti-B7-2 antibody, or anti- CD40 antibody, or anti-CD83 antibody. 
This set will allow us to evaluate the presence of ImC as well as mature and 
immature DCs in the peripheral blood. In the other set we will use a combination 
of PE-conjugated Lin specific antibodies, FITC-conjugated anti-CD11c antibody, 
PERCP-conjugated anti-CD123 antibody (IL-3 receptor), and APC-conjugated 
anti-HLA-DR antibody. This set will allow us to evaluate the presence of different 
subsets of DCs (myeloid and plasmocytoid type cells). Cells will be evaluated by 
a dual laser flow cytometer FACSCalibur (BD corp). To obtain reliable data a 
minimum of 105 cells will be evaluated in each sample. The proportion and the 
total number of ImC and different populations of DCs will be calculated. In each 
individual patient, response to the therapy will be considered as significant if at 
least a 2- fold increase in the DC:ImC ratio is detected. Control parameters will 
be established in 12 healthy volunteers.  
This analysis will be performed under the direction of Dr. David Carbone. 
10.3 
Anti-Muc1 Antibody Titer 
Anti-Muc-1 antibody titer in sera will be determined using commercially available 
ELISA reagents (Muc-1-specific recombinant protein, polyclonal antibody; 
Abnova, Taiwan). Testing will be performed on batched serum from multiple time 
points before and after vaccination.  This analysis will be performed by the 
IMCPL. 
10.4 
VEGF, ICAM-1 and Other Analyte Levels 
Serum will also be tested for the level of VEGF, ICAM-1 and potentially other 
analytes by Luminex multiplex assay (Invitrogen/Biosource). This analysis will be 
performed by the IMCPL. 
10.5 
Treg Assessments 
Regulatory T cells (Treg) will be tested by flow cytometry. The CD3+/CD4+ T 
cells will be further phenotyped by CD25 and intracellular Foxp3 staining 
(ebioscience). The percentage of CD3+/CD4+ T cells which are phenotypical 
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Treg (CD25hi, intracellular FoxP3+) will be reported from cryopreserved PBMC at 
multiple time points. This analysis will be performed by the IMCPL. 
10.6 
Cellular Immune Response against Muc-1 
The cellular immune response against the Muc-1 antigen will be tested by 
polychromatic flow cytometry. Batched PBMC will be thawed and mixed with MS-
Flow (a cell line not expressing Muc-1) or MS-Muc (the same cell line transfected 
with Muc-1, both obtained from O. Finn, Pittsburgh, PA), and the cells will be 
stained for cell surface markers (CD3, CD4, CD8) and for effector molecules 
(IFNg, TNFa, CD107a, Granzyme B) to determine the identity (CD4+, CD8+ T 
cells) and their responsiveness to the Muc-1 antigen (increased effector 
molecules) which is not MHC-restricted.  This analysis will be performed by the 
IMCPL. 
10.7 
Banking 
Residuals and derivatives of the blood samples used for these studies will be 
forwarded to an ECOG-ACRIN Repository for possible use in future ECOG-
ACRIN approved studies. Tissue blocks and/or slides will be retained for future 
research. If future use is denied or withdrawn by the patient, the samples will be 
removed from consideration for use in any future study. 
Tissue blocks will be returned upon written request for purposes of patient 
management only. Be aware that the blocks may be used or processed for 
laboratory studies and thus material may not be available for return.  
10.8 
Sample Inventory Submission Guidelines  
Inventories of all samples collected, aliquoted, and used on the above mentioned 
laboratory correlative study(ies) will be submitted to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis. Inventories will be submitted 
electronically by any laboratory holding and/or using any specimens associated 
with this study.  
10.9 
Lab Data Transfer Guidelines  
The data collected on the above mentioned correlative study(ies) will be 
electronically submitted to the ECOG-ACRIN Operations Office - Boston by the 
central laboratory(ies) on a quarterly basis. The quarterly cut-off dates are March 
31, June 30, September 30 and December 31. Data is due at the ECOG-ACRIN 
Operations Office - Boston 1 week after these cut-off dates. 


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11. 
Records to Be Kept 
Please refer to the E6508 Forms Packet for the forms submission schedule and copies 
of all forms. The E6508 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office - Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
11.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study is being conducted under an IND. All records pertaining to the trial 
(including source documents) must be maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being 
studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office - Boston prior to destroying 
any source documents. 
11.2 
ECOG-ACRIN Radiation Oncology Quality Assurance Materials  
All radiotherapy quality assurance materials along with a copy of the ECOG-
ACRIN Checklist for Submission of Radiation Oncology Q.A. Materials (see 
Appendix V or www.qarc.org) should be submitted to IROC Rhode Island 
(QARC): 
IROC Rhode Island 
ATTN: ECOG-ACRIN Materials 
640 George Washington Highway 
Suite 201, Building B 
Lincoln, RI 02865-4207 
Tel: (401) 753-7600 
FAX: (401) 753-7601 
Refer to Section 5.1.2.10 of the QA Documentaion of the protocol and Appendix 
V ECOG-ACRIN Checklist for Submission of Radiation Oncology Q.A. Materials 
(see Appendix V) or www.qarc.org) for the required radiotherapy materials to be 
submitted to IROC Rhode Island (QARC). 


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12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
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A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation 
 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Update #3] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Update #3 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines. 
 
 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
122 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation 
 
Appendix II 
 
Pathology Submission Guidelines 
 
The following items are included in Appendix II: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. List of Required Materials for E6508 
4.  ECOG-ACRIN Generic Specimen Submission Form (#2981) 
Rev. 1/15 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
123 
Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Central Biorepository and Pathology Facility: 
• 
Institutional Surgical Pathology Report 
• 
Pathology materials (see attached List of Required Material) 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
Instructions: 
1. Provide the following information with all specimens submitted: 
Patient’s name (last, first) 
Protocol number 
Protocol case number (the patient’s ECOG-ACRIN sequence number; for intergroup 
studies, include both the ECOG-ACRIN and other group’s sequence numbers) 
Patient’s hospital number 
Institution 
Affiliate (if appropriate) 
2. Complete blank areas of the pathologist’s instructional memo and forward it, along with the 
List of Required Material and the The Generic Specimen Submission Form. This may be 
used as a tool to capture information for entering information into STS. 
3. The pathologist should return the required pathology samples and surgical pathology 
reports, along with any additional information required. If any other reports are required, 
they should be obtained from the appropriate department at this time. 
4. Keep a copy of theSTS shipping manifest or Submission Form)for your records.  (The 
original should be sent to the CBPF.) 
5. Double-check that ALL required forms, reports and pathology samples are included in the 
package to the Central Biorepository and Pathology Facility. (See appropriate List of 
Required Material.)  
Pathology specimens submitted WILL NOT be processed by the  Central 
Biorepository and Pathology Facility until all necessary items are received. 
6. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate any problems in 
meeting the pathology material submission deadline of one month, contact the Pathology 
Coordinator at the ECOG-ACRIN Central Biorepository and Pathology Facility by telephone 1-
844-744-2420 or by email at eacbpf@mdanderson.org. 
Rev. 1/15 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
124 
 
LIST OF REQUIRED MATERIAL 
E6508 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB 
Non-Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation 
 
Pre-Treatment 
1. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
2. Institutional pathology report (must be included with EVERY pathology submission). 
3. Immunological studies, if performed. 
4. Requested path materials. 
• 
Original diagnostic or a surgical tumor tissue block 
• 
Tissue block from any repeat biopsies are requested 
If a block is unavailable, contact the ECOG-ACRIN CBPF, 1-844-744-2420, to obtain 
alternative submission guidelines. 
NOTE: Since blocks are being used for laboratory studies, in some cases the material 
may be depleted and, therefore, the block may not be returned. 
 
Rev. 1/15 


 
125 
MEMORANDUM 
TO:  ____________________________________  
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., 
Chair ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  __________________________________  
SUBJECT: 
Submission of Pathology Materials for E6508: A Phase II Study of L-BLP25 and 
Bevacizumab in Unresectable Stage IIIA and IIIB Non-Squamous Non-Small Cell 
Lung Cancer after Definitive Chemoradiation 
 
 
The patient named on the attached requesthas been entered onto an ECOG-ACRIN protocol by 
______________________________ (ECOG-ACRIN Investigator).  This protocol requires the 
submission of pathology materials for future laboratory studies. 
Please complete PART B of the Submission Form. Keep a copy for your records and return the 
completed Submission Form, the surgical pathology report(s), the slides and/or blocks and any 
other required material (see List of Required Material) to the Clinical Research Associate (CRA).  
The CRA will forward all required pathology material to the ECOG-ACRIN Central Biorepository 
and Pathology Facility. 
Blocks and slides submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies.  Paraffin blocks will be returned upon written request for purposes 
of patient management only. 
Please note: Since blocks are being used for laboratory studies, in some cases the material 
may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the  Central Biorepository and 
Pathology Facility at 1-844-744-2420 or email at eacbpf@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: ________________________________________  
Address: _______________________________________  
Phone: ________________________________________  
 
 
Thank you.  
Rev. 1/15 


ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3 
Page 1 of 1 
126 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system 
is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 
Courier 
Tracking Number    
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
 
Sample Type  
(fluid or fresh tissue, 
 include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or 
Sample ID 
Anatomic 
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
 
 
 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % Lymphocytes % 
 
 
 
 
Study Drug Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
9/12/14 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
127 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation 
 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can be 
downloaded from the ECOG web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN and the 
NCI to increase awareness of the importance of clinical trials and improve accrual and follow-
through. We appreciate your help in this effort. 
 
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions remain 
unanswered in cancer.  With the participation of people like you in clinical trials, we will improve 
treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. Your physician and research staff will 
maintain very close contact with you.  This will to allow your physician to provide you with the 
best care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank you 
again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
[PHYSICIAN NAME] 
Rev. 5/14 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
128 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation 
 
Appendix IV 
 
Calculation of Carboplatin Dose 
 
Carboplatin dose is based on the Calvert Formula: 
Carboplatin dose (mg): AUC x (GFR + 25). The AUC for this trial is 2.0 during 
chemoradiotherapy and 6.0 during consolidation. 
Please note: GFR should not exceed 125 mL/min.  
Maximum carboplatin dose during Concomitant Chemoradiation is 2 x (125+25), or 300 mg.  
Maximum dose during Consolidation Chemotherapy is 6 x (125+25), or 900 mg. 
The Cockroft-Gault formula for creatinine clearance: 
 
 
 
 
1. This value will substitute for GFR in the Calvert formula. When concerned about safety 
for a specific patient, use measured GFR. 
 
 
CrCL1= 
(140-patient’s age)x(pt’s weight in kg) 
(for females, multiply by 0.85) 
72 x patient’s serum creatinine 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
129 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation 
Appendix V 
ECOG-ACRIN Checklist for Submission of Radiation Oncology Quality Assurance 
Materials 
Patient:  
Protocol:  E6508 
Sequence # 
 
Send material c/o  
 
 
 
 
            For the Radiation Oncologist: 
ROC Rhode Island (QARC) 
Name 
Attention: ECOG-ACRIN Materials  
Address 
640 George Washington Highway, Suite 201 
Building B 
Lincoln, RI 02865-4207 
 
Phone:                                                Fax: 
Date Radiation Began:_________________ 
Rapid Review materials must be submitted within 3 days after the start of radiotherapy: 
DATE 
SUBMITTED
Appendix V: ECOG-ACRIN Checklist for Submission of Radiation Oncology Q. A. 
Materials 
 
E6508 On-Study Form (copy) 
 
E6508 Baseline Data Form (copy) 
 
Digital RT Treatment Plan in DicomRT or RTOG format 
 
Copies of the pre-study diagnostic CT scan of the chest with and without contrast and 
PET scan (if done) and other imaging studies used to define the target volumes with 
the reports  
 
RT-1 Dosimetry Form (available at www.qarc.org) 
 
Prescription Sheet for Entire Treatment 
 
Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of interest of dose 
statistics for the total plan   
 
DRRs/BEVs of each treatment field(3D) or orthogonal isocenter images (IMRT) 
 
Motion Management Reporting Form if IMRT used (available at www.qarc.org) 
 
Final Review materials must be submitted within 1 week of the completion of radiation: 
Appendix V: ECOG-ACRIN Checklist for Submission of Radiation Oncology Q. A. 
Materials 
 
Completed Daily Treatment Record including prescription, and the daily and cumulative   
Documentation listed above showing any modifications from original submission 
 
All materials must be labeled with the ECOG-ACRIN assigned protocol and Sequence 
number. 
Please contact study CRA by email (ecog@qarc.org), calling Tel: (401) 753-7600 or FAX: (401) 
753-7601 for clarification as necessary. Thank you for your ongoing co-operation. 
Digital treatment plan, screenshots of other RT data and diagnostic imaging may be submitted 
via sFTP or on CD. For data sent via sFTP, a notification email should be sent to 
sFTP@qarc.org with the protocol # and registration # in the subject line. Please refer to QARC 
website for instructions on sending digital data (www.QARC.org). 
Data not sent via sFTP may be sent via email to datasubmission@qarc.org with the protocol # 
and registration # in the subject line. Data may also be sent via courier. 
Rev. 10/12 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
130 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-Squamous Non-Small Cell Lung 
Cancer after Definitive Chemoradiation 
Appendix VI 
 
E6508 Bevacizumab Drug Request Form 
Requested By: 
 
 
 
 
 
 
     
     Ship To: 
Dr.: 
 
Name: 
 
Institution: 
 
Address*: 
 
Principal Investigator: 
 
 
 
Institution Contact: 
 
 
 
Phone: 
 
Fax: 
 
 
 
Pharmacist signature: 
 
*Please do not use PO Box numbers 
 
Patient Sequence 
Number(s) 
Patient Initials 
(Last, First) 
# of 400 mg vials requested* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date Drug Needed at Site by: 
 
 
 
 
 
 
 
 
 
 
 
* only 400 mg vials are available for this study 
 
Return Completed, Signed, and  
Dated form to: 
Reminder: See protocol Section 4  
 
 
for required documentation  
ECOG-ACRIN Operations Office - Boston 
that must be submitted prior  
FSTRF 
 
to registering patients to the  
900 Commonwealth Avenue  
study. 
Boston, MA 02215 
ATTN: Drug Orders 
FAX: (617) 632-2063 
Email: 900.drugorder@jimmy.harvard.edu 
Coordinating Center use only: 
Inst/Affil#: _______________________ __________ 
NCI site code: _____________________________  
Step 2 Registration:_________________________ 
IRB approval: _____________________________  
 _________________________________________  
 
Signature 
 
Date 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
131 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation 
 
Appendix VII 
 
E6508 Peripheral Blood Collection and Shipping Kit Order Form 
Special Study No. TBD 
 
NOTE: 
It is preferred that kits be requested after registration. 
DATE :   
 
To obtain the proper kit, provide the following information: 
 
E6508 ECOG-ACRIN patient case number:  _______________________ 
(This is the ECOG-ACRIN sequence number assigned to the patient at registration). 
 
 
Kit is to be shipped to: 
 
Institution Contact: 
 
Phone number for contact: 
 
Fax number for contact: 
 
E-mail for contact: 
 
Institution Address: 
 
 
 
 
 
 
 
FAX Completed form to (412) 623-6625 
 
 
Comments: 
 
 
 
 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
132 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation 
Appendix VIII 
 
E6508 Specimen Shipment Notification Form 
This form is for use in the event that the ECOG-ACRIN Sample Tracking System (STS) is not 
accessible at time of blood sample submission. Fax this form or the completed Generic 
Specimens Submission Form (#2987). 
 
DATE :   
 
Ship To: 
 Shanker Laboratory 
 
 IMCPL 
Fax To: 
      615-327-6440 
 
      412-623-6625 
 
FedEx Tracking Number: 
FedEx Tracking Number: 
Shipped by:  
Phone #:
 
Address: 
 
 
 
 
 
 
Shipments to the Laboratories 
• 
Please mark “For Immediate Delivery. Fragile”. 
• 
College and ship specimens Monday-Thursday only. Do not ship a day before a holiday. 
The Laboratory is closed on Saturday, Sunday and holidays. 
• 
Please make sure the shipments have appropriate regulatory labels provided.  
Comments: 
 
 
 
 
Rev. 10/12 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
133 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation 
Appendix IX 
 
E6508 Tecemotide Initial Shipment Request and Receipt Form 
Rev. 1/15 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
134 
E6508 Tecemotide Initial Shipment Request and Receipt Form 
Study No.: 
      
CTEP ID Code:         
 
Investigator: 
                         ECOG-ACRIN PT. Seq. #:         
To request supplies, please complete all details in the corresponding boxes  
and e-mail/fax to ECOG-ACRIN Drug Team. 
Fax No.:       
e-mail:         
S I T E 
Medication Order: 
L-BLP25, 4 vials/box 
Number of boxes: 
   
 
Delivery Address (institution, name, street, postal code, city, country) 
      
      
      
Phone No.:         
Fax No.:         
Delivery on Friday after 12 a.m. possible? 
YES 
 
NO 
 
Name of Requestor: 
      
Position: 
      
Contact (Phone/e-mail): 
      
Date / Signature 
 
ECOG-
ACRIN 
Drug 
Team 
I herewith confirm to have all ethics and regulatory approvals in place for this site! 
Inst./Aff: 
Completed by: 
IRB Approval Date: 
Date: 
Fisher 
Batch No.: 
Kit Range: 
Shipment No.: 
The time between receipt of shipment request and delivery of 
medication will be about 5 working days. Exceptions may exist. 
S I T E 
Acknowledgement of Receipt 
(please complete and fax to Fisher: +610-871-0775) 
Arrival Date: 
 
 
Arrival Time:  
Temperature monitor confirmation: 
Please indicate reading for each individual temperature monitor: 
 
Monitor No. 
 
 
Monitor No. 
 
 
 
 
 
OK 
 
Alarm 
 
 
 
OK 
 
Alarm 
 
The delivered medication is suitable for use if the shipment was complete, in good condition and the 
temperature monitor shows OK. If the shipment was not complete or damaged and / or the temperature 
monitor recorded an alarm the medication has to be stored at proper conditions and quarantined until 
assessment. 
Was the delivery COMPLETE AND IN GOOD CONDITION? 
YES 
 
NO 
 
If no, please explain below: 
Comments: 
Date / Signature 
Name: 
 
Position: 
 
E6508 tecemotide Initial Shipment Request and Receipt Form Version 1.6 
Rev. 8/11, 
1/12, 2/12, 
4/13, 11/14 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
135 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation 
Appendix X 
 
E6508 Tecemotide Shipment Request and Receipt Form for Resupply 
 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
136 
E6508 Tecemotide Shipment Request and Receipt Form for Resupply 
Study No.: 
      
CTEP ID Code:         
  
Investigator: 
                    ECOG-ACRIN PT. Seq. #:         
To request supplies, please complete all details in the corresponding boxes  
and e-mail/fax to ECOG-ACRIN Drug Team. 
Fax No.:       
e-mail:         
S I T E 
Medication Order: 
Tecemotide, 4 vials/box 
Please estimate the demand for a three month treatment period, based on the number of patients, dosage 
and treatment line. 
Number of boxes: 
   
 
Delivery Address (institution, name, street, postal code, city, country) 
      
      
      
Phone No.:         
Fax No.:         
Delivery on Friday after 12 a.m. possible? 
YES 
 
NO 
 
Name of Requestor: 
      
Position: 
      
Contact (Phone/e-mail): 
      
Date / Signature 
 
ECOG
-
ACRIN 
Drug 
Team 
Inst./Aff: 
Completed by: 
IRB Approval Date: 
Date: 
Fisher 
Batch No.: 
Kit Range: 
Shipment No.: 
The time between receipt of shipment request and delivery of 
medication will be about 5 working days. Exceptions may exist. 
 
S I T E 
Acknowledgement of Receipt 
(please complete and fax to Fisher: +610-871-0775) 
Arrival Date: 
 
 
Arrival Time:  
 
Temperature monitor confirmation: 
Please indicate reading for each individual temperature monitor: 
 
Monitor No. 
 
Monitor No. 
 
Monitor No. 
 
 
 
 
 
 
 
OK 
 
Alarm 
 
 
OK 
 
Alarm 
 
 
OK 
 
Alarm 
 
 
The delivered medication is suitable for use if the shipment was complete, in good condition and the 
temperature monitor shows OK. If the shipment was not complete or damaged and / or the temperature 
monitor recorded an alarm the medication has to be stored at proper conditions and quarantined until 
assessment. 
Was the delivery COMPLETE AND IN GOOD CONDITION? 
YES 
  NO 
 
If no, please explain below: 
Comments: Affix label with monitor No. 
Date / Signature 
Name: 
Position: 
 
E6508 Tecemotide Shipment Request and Receipt Form for Resupply Version 1.7 
Rev. 8/11, 
1/12, 2/12, 
4/13, 11/14 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
137 
A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small C9ell Lung Cancer after Definitive Chemoradiation 
Appendix XI 
 
E6508 Contingency Imaging Guideline Manual 
Protocol Identifier E6508 NCT00828009  
IND # 14510 
 
 This document is intended to provide clear 
guidance to imaging departments, whether 
or not they are participating in the E6508 
NCT00828009 study, in the event that any 
subject enrolled in that study develops signs 
suggestive of encephalitis or 
neuroinflammatory disorder. It details the 
exact imaging that is required by the 
authorities and explains how to arrange 
image transfer and whom to contact. 
 
  Confidential 
 
The information contained within this document 
is considered confidential information. Further 
dissemination of this material is strictly limited to 
independent sites which are being asked to 
acquire and submit data on an emergency basis.  
 
Document Approval: ECOG-ACRIN Cancer Research Group 
The signature below indicates that this document is accepted and approved for 
implementation. 
Document title: 
Contingency Imaging Guideline Manual 
Document version: 
Final_v1.0_18-Oct-2010 
Identifier: 
E6508 NCT00828009 
 
 
Approval 
 
 
 
 
 
Date 
 
Rev. 8/11 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
138 
Table of Contents 
Abbreviations and Acronyms 
1 
Overview 
1.1 
Background 
1.2 
Clinical Occurrence 
1.3 
Image Submission 
2 
MRI Acquisition 
2.1 
Scan Parameters 
3 
Reporting Suspected Occurrences 
4 
Imaging Data Transmittal Forms 
4.1 
Instructions 
4.2 
Sample Imaging DTF 
5 
Image Data Archiving and Submission 
5.1 
Archiving Instructions 
5.2 
Data Shipping Checklist 
6 
Document Revision History 
6.1 
Final_v1.0_18-Oct-2010 
Appendix A: Protocol Synopsis 
Appendix B: Data Transmittal Form 
Tables 
Table 1: MRI Parameters 
Table 2: Study Team Contact Information 
Table 3: DTF Field Instructions 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
139 
Abbreviations and Acronyms 
CD 
compact disc 
DTF   
Data Transmittal  Form                            
DVD 
digital video disc 
FOV 
field of view 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IMI 
ICON Medical Imaging 
mm 
millimeter 
MOD 
magneto optical disk 
MRI  
magnetic resonance imaging 
MRS 
magnetic resonance spectroscopy  
NA 
not applicable 
PACS 
Picture Archiving and Communication System 
 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
140 
1. 
Overview  
1.1 
Background 
The purpose of this document is to provide guidance to investigators and imaging 
professionals when a subject who has received BLP liposome vaccine 
(tecemotide) in the ECOG-ACRIN-sponsored E6508 NCT00828009 study 
develops symptoms or signs that raise a clinical suspicion of encephalitis or of a 
neuroinflammatory disorder. In such a situation, it will be important to ensure that 
appropriate imaging is undertaken and that certain, specific modalities are used 
to ensure consistency in information recommended by regulatory and other 
authorities. It is appreciated that such a situation may arise and/or a subject may 
have to be imaged at a site that is not involved in such a study, and which will not 
be familiar with the investigational agent. 
Notes: These particular magnetic resonance imaging (MRI) sequences have 
been specifically recommended by a regulatory authority, and this document has 
been produced for that reason. This study is not sponsored by EMD Serono Inc., 
but there is a regulatory obligation upon EMD Serono to provide these images for 
any subject exposed to tecemotide in such circumstance, hence the contact 
details and other instructions pertaining to this study. Questions other than those 
concerning this specific situation should always be directed to the Principal 
Investigator in the first instance. 
The first part of this document describes the clinical situation in which adherence 
to this Contingency Imaging Guideline Manual becomes appropriate; the second 
part describes image acquisition parameters; and the third part contains 
supplementary information, including contact details and how to initiate image 
preparation and transfer.  
Any site that is not able to perform these investigations should make 
arrangements to have them undertaken at a nearby facility. In the eventuality that 
the acquisition or transmission of these images according to these guidelines 
continues to present an insuperable problem due to clinical, technical, or other 
constraints, the site should discuss with the Principal Investigator and they are 
asked to contact ICON Medical Imaging (IMI – See Table 2), who will discuss the 
issue with ECOG-ACRIN Cancer Research Group and EMD Serono Inc., and 
they will jointly recommend the most appropriate way to proceed. 
1.2 
Clinical Occurrence 
This Contingency Imaging Guideline Manual will come into effect when any study 
subject who has definitely received tecemotide in the ECOG-ACRIN 6508 
NCT00828009 study develops any signs or symptoms which raise a clinical 
suspicion of encephalitis or a neuroinflammatory disorder and which are not 
explained by new metastatic disease or other obvious clinical cause. Such signs 
may include, but are not limited to, photophobia, sudden dementia, personality 
and behavioral changes, epileptiform seizures, and/or dysphasia.  
1.3 
Image Submission 
1.3.1 Acquire and submit MRI according to the parameters detailed in Table 1: 
MRI Parameters. 
1.3.2 Subject identifiers must be used for all image submissions to IMI; do not 
submit images or digital media which contain subject names. 
Rev. 1/15 


ECOG-ACRIN 
E6508 
Cancer Research Group 
Version Date: December 8, 2014 
 
NCI Update Date: April 29, 2013 
141 
 
2. 
MRI Acquisition  
2.1 
Scan Parameters 
2.1.1 Acquire and submit brain MRI according to the parameters below. If MRI 
contrast is contraindicated according to the site’s normal clinical 
protocols, brain MRI should be performed without MRI contrast. 
2.1.2 Anatomical coverage required:  Whole brain (from foramen magnum to 
vertex). 
2.1.3 If repeat imaging is required, please note that consistent scan parameters 
(spacing, thickness, FOV [field of view], etc.) must be used for all 
assessments. Include any notes concerning alternate imaging or 
parameter variation from the protocol in the “Comments” field of the 
Imaging Data Transmittal Form (DTF). 
2.1.4 The parameters in Table 1 are guidelines provided by EMD Serono Inc,. 
Sites should optimize parameters according to the scanner being used to 
acquire assessments. In the event that a site is not able to perform these 
acquisitions as documented, or has other concerns, please contact IMI as 
soon as possible, and the available options will be discussed. 


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Table 1: MRI Parameters 
Anatomical Coverage: 
Whole brain (from foramen magnum to vertex) 
 
Plane 
TR 
(ms) 
TE 
(ms) 
TI 
(ms) 
B Value 
FOV 
Slice 
Thickness 
(mm) 
Slice 
Gap 
(mm) 
Image Matrix 
Contrast 
T1 
Axial 
500-600 
10 - 20 
NA 
NA 
22-25 
≤ 5 
≤ 1 
≥ 256 x 192 
No 
T2 
Axial 
3000-5000 
80-100 
NA 
NA 
22-25 
≤ 5 
≤ 1 
≥ 256 x 192 
No 
FLAIR 
Axial 
8000-10000 
120-
135 
2100-
2400 
NA 
22-25 
≤ 5 
≤ 1 
≥ 256 x 192 
No 
FLAIR† 
Coronal 
8000-10000 
120-
135 
2100-
2400 
NA 
22-25 
≤ 5 
≤ 1 
≥ 256 x 192 
No 
T2 Star 
Axial 
400-800 
10-25 
NA 
NA 
22-25 
≤ 5 
≤ 1 
≥ 256 x 192 
No 
DWI 
Axial 
> 4500 
< 120 
NA 
0, 1000 
22-25 
≤ 5 
≤ 1 
≥ 128 x 128 
No 
T1+ 
Axial 
500-600 
10-20 
NA 
NA 
22-25 
≤ 5 
≤ 1 
≥ 256 x 192 
Yes 
3D+ 
Axial 
6-15 
2-7 
NA 
NA 
22-25 
≤ 1.5 
0 
≥ 256 x 192 
Yes 
MRS† 
Axial 
1500 
135 
NA 
NA 
22-25 
≤ 8 
0 
NA 
NA 
† Coronal FLAIR and MRS (Magnetic Resonance Spectroscopy) optional 
 
 


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3. 
Reporting Suspected Occurrences 
When a site suspects that a subject meets the criteria for suspected encephalitis or other 
neuroinflammatory disorder and images have been acquired using the parameters 
specified in this manual, the site is requested to contact IMI immediately following image 
acquisition using the contact information provided in Table 2. IMI will contact the site 
within 48 hours and will provide detailed instructions for the preparation and submission 
of imaging. The site is also encouraged to contact IMI before acquiring images if 
clarification or additional information is required. For all other matters, the site is 
instructed to contact the recruiting investigator, who will then liase with the designated 
monitoring staff/organization as appropriate. 
Table 2: Study Team Contact Information 
Team Member 
Project Role 
Phone/Email 
Heather 
Gallagher 
(IMI) 
Manager  
(Image collection 
oversight/coordination.) 
Phone: +1 267.482.6688 
Fax: +1 267.482.6301 
Email: Heather.Gallagher@iconplc.com 
Carol Venter 
(IMI) 
Project Assistant  
Phone: +1 267.482.6375 
Fax: +1 267.482.6301 
Email: Carol.Venter@iconplc.com 
Jyoti Patel, MD 
ECOG-ACRIN E6508  
Study Chair 
Phone: 312-695-4549 
Email: jd-patel@northwestern.edu 
S Peter Eggleton 
(EMD Serono) 
Contingency Imaging 
Responsible Physician 
Phone +44 7909 535269 
Fax +44 1444 243761 
Email: peter.eggleton@merckserono.net 
EMD Serono will ensure that any site that acquires/submits images as outlined in this 
Contingency Imaging Guideline Manual for any appropriate subject with suspected 
encephalitis or other neuroinflammatory disorder does not suffer financial loss as a 
result. IMI will provide the site with contact information accordingly. 
4. 
Imaging Data Transmittal Forms 
Imaging DTFs are required for all contingency image data submissions and 
resubmissions of contingency image data.  
NOTE: 
Subject identifiers must be used for all image submissions to IMI; do not 
submit images or digital media which contain subject names. 
4.1 
Instructions 
4.1.1 Ensure that all of the fields of the DTF are completed.  
4.1.2 If any fields do not apply, enter “NA” for Not Applicable. Do not leave 
blank. 
 


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4.1.3 If you have questions about completing the form, refer to the sample DTF, 
send email, or call an IMI team member at +1 267.482.6300 for 
assistance Monday – Friday, 8:00 am – 5:00 pm Eastern Time (USA). If 
you need to speak with someone directly, and your site is located in a 
time zone where your hours of operation do not overlap those of IMI, 
send an email to set up a phone meeting to take place during a mutually 
agreeable time.  
4.1.4 If, upon receipt of archival media, IMI finds problems that interfere with 
viewing the images, IMI will ask you to resubmit the data. 
Table 3: DTF Field Instructions 
General Information 
Subject Identifier 
Record the subject identifier in the field provided. 
Subject Initials 
If permitted by the regulatory agency within your country, record subject’s first, 
middle, and last initials. If subject does not have a middle initial, indicate by filling 
box with a dash (e.g., A–C). Note: If not using this field, do not enter “NA” as this 
may be mistaken for subject initials. Instead, cross field out with a single line, then 
initial and date. 
Scan Date 
Record the date that images were acquired in alphanumeric format as follows: 
ddMmmyyyy (eg, 01Jan2010). 
DTF Submission 
Check box to indicate the images are submission or resubmission data (NOTE: 
The Resubmission check box should only be used when resubmission has been 
requested). 
Principal 
Investigator 
Record name of Principal Investigator. 
Image Data 
Modality 
Check the appropriate box to indicate the modality of the images being submitted 
(this is anticipated to be MRI). 
Anatomy  
Check boxes to for all that apply (ie Brain or other). 
Comments 
Record reasons for any protocol deviation, or system or subject items of interest. 
Note: Do Not record any subject identifying information. 
Archive Media 
Check the box that indicates the method used to send images to IMI. If you check 
“Other,” record the transfer method used. If film is sent, note the number of films 
included. 
Completed By 
Printed name of person completing the DTF. 
Date 
Record date that DTF was completed in alphanumeric format as follows: 
ddMmmyyyy (eg, 01Jan2010). 
 


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4.2 
Sample Imaging DTF 
 
 


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5. 
Image Data Archiving and Submission 
5.1 
Archiving Instructions 
5.1.1 Complete the DTF carefully while scanning. The DTF is treated as a 
source document and can be audited by regulatory authorities.  
5.1.2 Archive all studies twice, immediately after image acquisition.  
• 
Keep 1 copy at your site in a dedicated location per International 
Conference on Harmonisation (ICH) guidelines on Good Clinical 
Practice (GCP) or your local requirements, whichever are a higher 
standard.  
• 
Ship the second copy to IMI.  
5.1.3 Archive imaging to digital media immediately from the system that you are 
using to acquire the images (before saving to PACS [Picture Archiving 
and Communication System]). Digital media includes CD (compact disc), 
DVD (digital video disc), MOD (magneto optical disk), or other electronic 
transfer media.  
• 
Tape/CD/DVD: IMI keeps these media as source documentation per 
regulations. 
• 
MOD: Rotate 2 MODs between your site and IMI. Archive subjects to 
1 MOD and, at the end of the week, ship the MOD to IMI. Then begin 
archiving to second MOD. IMI will ship each MOD back to your site.  
o Do not delete data on MOD; continue to add new subjects, filling 
up 1 side of the MOD before starting the other.  
o A complete series should be on 1 side only (do not split series 
between 2 sides).  
o IMI will keep MODs at the end of the study as source 
documentation per regulations. 
o Send scans immediately after image acquisition. 
• 
Ensure that all digital media and images being submitted to IMI 
contain only subject identifiers and not actual subject names. 
• 
Send the top white page of DTF to IMI. Make and keep a photocopy 
of the DTF at your site; it is the Investigator’s copy (per regulations). 
5.2 
Data Shipping Checklist 
 
Completed, signed, and dated DTF. 
 
Site Radiologist Report (if not immediately, available, please submit as 
soon as possible via fax). 
 
Ship by Courier  
For sites within the United States (US), send by FedEx to IMI. FedEx US 
air bills will be provided upon request. Additional FedEx Shipping supplies 
may be obtained by calling 1.800.GoFedEx (1.800.463.3339) or by 
visiting the website at www.fedex.com. 
NOTE: 
IMI recommends using a padded shipping envelope whenever 
possible. 


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Correct Address:  
 
ICON Medical Imaging  
2800 Kelly Road 
Suite 200 
Warrington, PA 18976 USA 
Tel. +1 267.482.6300 
Fax +1 267.482.6301 
 
6. 
Document Revision History 
6.1 
Final_v1.0_18-Oct-2010 
This document will be the first approved version; if revisions are required at a 
later date, the amended version will detail history of changes. 
Appendix A: Protocol Synopsis 
Study Title 
A Phase II Study of L-BLP25 and Bevacizumab in 
Unresectable Stage IIIA and IIIB Non-Squamous Non-
Small Cell Lung Cancer after Definitive Chemoradiation 
Study Number 
E6508 
NCT00828009 
Sponsor 
ECOG-ACRIN Cancer Research Group 
Study Phase 
Phase II 
Study Center/Countries 
US Sites Only 
 


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Appendix B: Data Transmittal Form 
The following page contains a copy of the Data Transmittal Form (DTF) that will be used when submitting image data to IMI. IMI will 
provide you with electronic DTFs upon request using the contact information provided in this Contingency Imaging Guideline Manual. 


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A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-
Squamous Non-Small C9ell Lung Cancer after Definitive Chemoradiation 
Appendix XII 
 
E6508 Needles & Syringes Shipment Request and Receipt Form 
 
Rev. 1/12, 2/12