Randomized Phase III Study of Maintenance Therapy With Bevacizumab, Pemetrexed, or a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and Bevacizumab for Advanced Non-Squamous NSCLC
Phase: PHASE3
Conditions: Lung Cancer
Sponsor: ECOG-ACRIN Cancer Research Group

E5508 
 
1 
Randomized Phase III Study of Maintenance Therapy with 
Bevacizumab, Pemetrexed, or a Combination of Bevacizumab 
and Pemetrexed Following Carboplatin, Paclitaxel and 
Bevacizumab for Advanced Non-Squamous NSCLC 
 
STUDY CHAIR: 
Suresh S. Ramalingam, M.D. 
 
STUDY CO-CHAIR: 
Chandra P. Belani, M.D. 
 
STUDY STATISTICIAN: 
Suzanne Dahlberg, Ph.D. 
 
DEVELOPMENTAL THERAPEUTICS CO-CHAIR: 
Jill Kolesar, Pharm.D. 
Rev. 7/12 
THORACIC COMMITTEE CHAIR: 
Suresh S. Ramalingam, M.D. 
 
LABORATORY CO-CHAIRS: 
David Carbone, M.D. 
 
 
Heinz-Joseph Lenz, M.D. 
Rev. 11/13 
CALGB CO-CHAIR: 
Thomas Stinchcombe, M.D. 
Rev. Add13 
DEVELOPMENTAL THERAPEUTICS 
COMMITTEE CHAIR: 
 
Keith Flaherty 
Version Date:  October 12, 2018 
NCI Update Date: December 8, 2014 
Commercial Agents: paclitaxel, carboplatin, pemetrexed, and bevacizumab 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology 
 
August 12, 2010 
NRG / NRG Oncology Foundation, Inc 
 
 
SWOG / SWOG 
 
Addendum #1 – Incorporated Prior to Activation 
 
 
Addendum #2 – Incorporated Prior to Activation 
Addendum #3 – Incorporated Prior to Activation 
NOTE: 
As of 11/17, all protocol changes will 
be noted by addendum number. 
Please reference the activation memo 
for the addendum activation date. 
 
Addendum #4 – Incorporated Prior to Activation 
Addendum #5 – 1/11 
Addendum #6 – 12/11 
Addendum #7 – 7/12 
 
 
Addendum #8 – 11/13 
 
 
Addendum #9 – 5/14 
 
 
Addendum #10 – 8/14 
 
 
 
Update #1 – 12/14 
 
 
 
Addendum #11 – 7/15 
 
 
 
Addendum #12 – 11/16 
 
 
 
Addendum #13 
 
Rev. 11/13 
Rev. 5/14 
Rev. 8/14 

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Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 Non-Small Cell Lung Cancer ...................................................................... 7 
1.2 Role of Maintenance Therapy ................................................................... 7 
1.3 Bevacizumab ............................................................................................. 8 
1.4 Pemetrexed ............................................................................................... 9 
1.5 Maintenance Therapy with Pemetrexed ................................................ 10 
1.6 Laboratory Research Studies .................................................................. 10 
1.7 Hypothesis for Study ............................................................................... 11 
1.8 Rationale for Selected Approach and Trial Design .................................. 11 
2. Objectives ......................................................................................................... 12 
2.1 Primary Objective .................................................................................... 12 
2.2 Secondary Objectives .............................................................................. 12 
3. Selection of Patients ......................................................................................... 13 
3.1 Step 1: ..................................................................................................... 13 
3.2 Step 2: ..................................................................................................... 16 
4. Registration Procedures.................................................................................... 18 
4.1 Step 1: Registration to Arm I ................................................................... 21 
4.2 Step 2: Randomization to Arm A, Arm B or Arm C .................................. 22 
5. Treatment Plan ................................................................................................. 24 
5.1 Administration Schedule ......................................................................... 24 
5.2 Adverse Event Reporting Requirements ................................................. 28 
5.3 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Bevacizumab (rhuMAb VEGF, NSC 704865) ............................................ 33 
5.4 Dose Modifications ................................................................................. 39 
5.5 Supportive Care ....................................................................................... 51 
5.6 Duration of Therapy ................................................................................ 52 
5.7 Duration of Follow-up ............................................................................. 52 
6. Measurement of Effect ..................................................................................... 53 
6.1 Antitumor Effect – Solid Tumors ............................................................. 53 
7. Study Parameters .............................................................................................. 61 
7.1 Therapeutic Parameters.......................................................................... 61 
7.2 Biological Sample Submissions ............................................................... 62 
8. Drug Formulation and Procurement ................................................................. 63 
8.1 Paclitaxel ................................................................................................. 63 
8.2 Carboplatin .............................................................................................. 65 
8.3 Bevacizumab ........................................................................................... 67 
8.4 Pemetrexed Disodium Heptahydrate (Alimta) ....................................... 71 
9. Statistical Considerations .................................................................................. 75 
9.1 The details of the design are given below. ............................................. 75 

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9.2 Interim and Final Analyses ...................................................................... 75 
9.3 Secondary endpoints............................................................................... 77 
9.4 Gender and Ethnicity .............................................................................. 78 
9.5 Study Monitoring .................................................................................... 78 
10. Correlative Studies ............................................................................................ 79 
10.1 Samples Submissions .............................................................................. 79 
10.2 Genotyping Studies ................................................................................. 83 
10.3 Population Pharmacokinetics of Bevacizumab and Pemetrexed to 
Predict Toxicity and Response ................................................................ 87 
10.4 Banking .................................................................................................... 88 
10.5 Sample Inventory Submission Guidelines ............................................... 88 
10.6 Lab Data Transfer Guidelines .................................................................. 88 
11. Records to Be Kept ............................................................................................ 89 
11.1 Records Retention ................................................................................... 89 
12. Patient Consent and Peer Judgment ................................................................ 89 
13. References ........................................................................................................ 89 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Addendum 8] ................................................................ 94 
Appendix II  ECOG Performance Status ................................................................... 95 
Appendix III  Pathology Submission Guidelines ...................................................... 96 
Appendix IV  Patient Thank You Letter .................................................................. 101 
Appendix V  E5508 Shipment Notification Form ................................................... 102 
Appendix VI  Cockcroft and Gault Formula ........................................................... 103 
Appendix VII  Medication Diary for Folic Acid ....................................................... 104 
Appendix VIII  Docetaxel Treatment Plan .............................................................. 106 
 

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NCI Update Date: December 8, 2014 
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STUDY CHAIR 
STUDY CO-CHAIR 
Suresh Ramalingam, MD 
Associate Professor of Hematology-
Oncology  
Chief of Thoracic Medical Oncology  
Emory University School of Medicine  
Winship Cancer Institute  
1365 Clifton Road NE, Room C-3090  
Atlanta, GA 30322  
Phone: 404-778-5378  
Fax: 404-778-5520  
Email: suresh.ramalingam@emory.edu 
  
Chandra P. Belani, MD 
Miriam Beckner Professor of Medicine 
Penn State Hershey Medical Center  
Deputy Director 
Penn State Hershey Cancer Institute 
500 University Drive, HQ72 
Hershey, PA 17033 
Phone: 717-531-1078 
Fax: 717-531-0002 
Email: cbelani@psu.edu 
 
 
CALGB CO-CHAIR 
STUDY CHAIR LIAISON (SCL) 
Thomas Stinchcombe, MD 
University of North Carolina at Chapel Hill 
170 Manning Drive 
POB 3rd Floor 
Chapel Hill, NC 27599-7305  
Phone: 919-966-9268  
Fax: 919-966-6735 
Email: thomas_stinchcombe@med.unc.edu 
Renea Stinson, CRC 
Emory University School of Medicine  
Winship Cancer Institute  
1365 Clifton Road NE, 3rd Floor  
Atlanta, GA 30322  
Phone: 404-778-4576 
Fax: 404-778-4326 
Email: renea.stinson@emoryhealthcare.org   
 
 
 
 
Rev. 1/11, 7/12 
Rev. 11/13 

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Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206  
Email -  
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
ECOG-ACRIN Operations 
Office – Boston, 
FSTRF, 900 Commonwealth 
Avenue Boston, MA 02215 
(ATTN: DATA). 
Phone # 617-632-3610 
Fax # 617-632-2990 
Data should be sent via postal 
mail (preferred), however fax is 
accepted. 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy the 
CTSU on data submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related): Contact the Study PI of the 
Coordinating Group. 
For non-clinical (i.e. questions unrelated to patient eligibility, treatment, or data submission): 
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
For detailed information on the regulatory and monitoring procedures for CTSU sites: Please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org> education and resources tab > CTSU Operations Information >CTSU Regulatory 
and Monitoring Policy 
The CTSU Public Web site is located at: http://www.ctsu.org 
 
Rev. 8/14 

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Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
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Schema 
Stratification factors:

Gender (male vs. female)

Stage (IIIB-T4Nx*/IV M1a 
vs. IV M1b vs. 
recurrent) 

Best response to first-line 
therapy (CR/PR vs. SD)

Smoking status (never vs. 
ever-smokers)
Stage IIIB-T4Nx*/IV 
M1a/IV M1b NSCLC
Recurrent Non-
squamous histology
ECOG PS 0 or 1
No prior 
chemotherapy
Adequate bone 
marrow, renal and 
hepatic parameters
No history of major 
hemoptysis
Informed consent
R
E
G
I
S
T
R
A
T
I
O
N
Paclitaxel 200 mg/m2 IV
Carboplatin AUC = 6
Bevacizumab 15 mg/kg IV
Day 1 of every cycle
CR
PR
SD
Pemetrexed 500 mg/m2 IV 
Day 1 of every cycle**
Pemetrexed 500 mg/m2 IV
Bevacizumab 15 mg/kg IV
Day 1 of every cycle**
1 cycle= 21 days
Accrual= 1495
Bevacizumab 15 mg/kg IV 
Day 1 of every cycle**
Induction
Arm I
Arm B
Arm C
Step 1:
Step 2:
Cycles 1-4:
L
O
N
G
-
T
E
R
M
 
F
O
L
L
O
W
U
P
PD
Cycles 1 and up:
Arm A
 R
A
N
 D
O
M
I
 Z
A
T
I
O
N
Maintenance
*     Stage IIIB-T4Nx patients must have a nodule in the ipsilateral lung lobe and must not be candidates for combined chemotherapy and radiation.
**    Continue until progression or unacceptable toxicity.
 
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NCI Update Date: December 8, 2014 
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1. 
Introduction 
1.1 
Non-Small Cell Lung Cancer 
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related 
deaths in the United States (1). Approximately 215,000 new cases are diagnosed 
each year in this country. Majority of the patients present with an advanced stage 
at the time of diagnosis. For patients with a good performance status (ECOG 0 or 
1), platinum-based combination chemotherapy is the mainstay of treatment. The 
combination of a platinum compound with paclitaxel, gemcitabine, docetaxel or 
vinorelbine is considered appropriate for patients with advanced stage NSCLC. 
The ECOG-ACRIN Cancer Research Group conducted a phase III study of 
various two-drug combinations for advanced stage NSCLC and concluded that 
the efficacy was similar between the regimens (2). The 4 regimens evaluated in 
this study were cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel and 
carboplatin-paclitaxel. There were no differences in response rate or overall 
survival between the 4 regimens. The regimen of carboplatin and paclitaxel was 
chosen as the reference regimen for subsequent studies based on its favorable 
tolerability profile. The study results demonstrated that an efficacy plateau had 
been achieved with standard chemotherapeutic regimens in this setting.   
Combination chemotherapy confers a modest improvement in overall survival for 
patients with advanced stage NSCLC (3.4). Four to six cycles of chemotherapy 
are considered optimal for patients with advanced stage NSCLC. Continuation of 
chemotherapy beyond 6 cycles results in higher toxicity without any improvement 
in efficacy (5).  
In addition to evaluation of efficacy of the treatment regimens, we also intend to 
conduct correlative science studies to identify the relationship between certain 
biomarkers and outcome. The overarching goal is to identify sub-populations of 
patients who might benefit from a certain treatment regimen included in the study 
to a greater extent (positive selection) and those will not derive any benefit 
(negative selection). The study includes two main treatment phases which 
include the first line therapy and the maintenance therapy. All patients enrolled to 
the study will receive first line therapy with carboplatin, paclitaxel and 
bevacizumab. We intend to conduct studies on the baseline tumor tissue and 
peripheral blood to identify markers that will predict for both response and toxicity 
with the treatment regimen. During the maintenance therapy phase, we will 
conduct studies to evaluate the correlation with outcome for biological markers 
relevant to the specific agent that the patient received on the study. The studies 
on polymorphisms for VEGF and metabolizing enzymes for taxanes will be to 
confirm prior studies that have suggested an important role for these markers on 
outcome. The other studies will be exploratory in nature. 
1.2 
Role of Maintenance Therapy  
‘Maintenance therapy’ refers to the administration of systemic therapy following 
maximal response to front line chemotherapy, in the setting of advanced stage 
NSCLC. This is also referred to as ‘consolidation therapy’ by many physicians. 
Several recent studies have demonstrated a trend towards improved survival 
with the use of single agent therapy following maximal response to combination 
chemotherapy in the frontline setting. Most notably, in a randomized study led by 
Drs. Fidias and Schiller, the use of docetaxel as maintenance therapy versus 

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standard second line therapy (use as maintenance therapy versus salvage 
therapy upon progression) was studied following initial chemotherapy with 
carboplatin and gemcitabine (6). The study enrolled 562 patients, and 307 were 
randomized to early versus delayed docetaxel. There was a statistically 
significant improvement in median progression-free survival (6.5 vs. 2.8 months, 
P < 0.0001) and a trend towards improved survival (11.9 vs. 9.1 months, p 
=0.071) with the earlier use of docetaxel before progression. Early docetaxel was 
tolerated well and was associated with a higher objective response rate. Notably, 
approximately 40% of the patients randomized to the delayed docetaxel did not 
receive therapy due to various reasons including disease progression and patient 
unwillingness to receive therapy. Other randomized studies have also suggested 
survival benefit for maintenance therapy with various agents including 
gemcitabine, paclitaxel, erlotinib and gefitinib (7,9).  Taken together, these data 
provide strong support for further evaluation of maintenance therapy for patients 
with advanced stage NSCLC. The use of novel agents such as molecularly 
targeted agents and well tolerated cytotoxic agents have made maintenance 
therapy feasible without any major increase in toxicity. 
1.3 
Bevacizumab 
The efforts to improve the outcome for advanced stage NSCLC so far have 
revolved around the addition of molecularly targeted agents to combination 
chemotherapy. Bevacizumab is the first targeted agent to be approved by the 
FDA for use in combination with chemotherapy for advanced stage NSCLC. It is 
a monoclonal antibody against the vascular endothelial growth factor (VEGF). 
Under physiological situations, VEGF is the rate-limiting step for new blood 
vessel formation and also plays a major role in tumor-related angiogenesis. 
Blockade of VEGF results in regression of tumor and improved outcomes in a 
variety of solid tumor model systems. Though bevacizumab does not possess 
potent single-agent activity, it enhances the efficacy of chemotherapy. In the 
United States, bevacizumab is approved for use in combination with 
chemotherapy for the treatment of metastatic breast, colon and non-squamous 
NSCLC.  
The efficacy of bevacizumab in NSCLC was proven by a phase III study 
conducted by ECOG (ECOG 4599) (10). This study randomized patients with 
advanced nonsquamous NSCLC to treatment with carboplatin and paclitaxel with 
or without bevacizumab. Patients with predominant squamous cell histology, 
brain metastasis, major hemoptysis (defined as ½ tsp or more per event) and 
those on therapeutic doses of anti-coagulation were excluded. The treatment 
consisted of carboplatin and paclitaxel alone or in combination with bevacizumab 
(15 mg/Kg Q 3 weeks). Following 6 cycles of therapy, patients on the 
experimental arm with either stable disease or response were continued on 
bevacizumab as monotherapy for maintenance. Cross over of patients from the 
control to the experimental arm was not permitted. The primary endpoint of the 
study was to determine whether the overall survival for the experimental arm is 
superior to chemotherapy alone. A total of 878 patients were enrolled to the 
study. With the exception of a slightly higher representation of females in the 
bevacizumab arm, the baseline patient characteristics were evenly distributed 
between the two treatment groups. The median duration of follow-up was 19 
months. The median number of cycles of treatment was 5 for the chemotherapy 
group and 7 for the bevacizumab-chemotherapy regimen. Fifty-three percent of 

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the patients in the bevacizumab arm received it as monotherapy for 
maintenance.  
There was a statistically significant improvement in survival for patients treated 
with bevacizumab-chemotherapy combination compared to chemotherapy alone 
(12.3 months vs. 10.3 months, hazard ratio for death 0.79, P= 0.003). The 
median progression-free survival also favored the experimental arm (6.2 months 
vs. 4.5 months, HR 0.66, P< 0.001). The objective response rate among the 773 
patients with measurable disease was higher for the bevacizumab-chemotherapy 
treated group (35% vs. 15%, P < 0.001).  There was no correlation between the 
baseline VEGF level and overall survival for the 166 patients whose blood 
samples were collected (11).  
The addition of bevacizumab to chemotherapy was also associated with a higher 
incidence of adverse events. Grade 3/4 neutropenia, hypertension, proteinuria 
and hemorrhage occurred more commonly for patients treated with the 
experimental regimen. There were 15 treatment-related deaths in the 
bevacizumab group compared to 2 with chemotherapy alone. Of the 15 deaths in 
the experimental arm, pulmonary hemorrhage and neutropenic sepsis lead to 5 
deaths each. Among patients who received bevacizumab monotherapy, 
hypertension, proteinuria and fatigue were the most common grade 3/4 adverse 
events.  
The positive results of this study led to the adoption of carboplatin, paclitaxel and 
bevacizumab as the new ECOG-ACRIN reference regimen for advanced stage 
non-squamous NSCLC. Consistent with the study design, bevacizumab is now 
used in routine practice until progression of disease for first-line treatment of 
advanced NSCLC. Recently, the results of another phase III study that evaluated 
cisplatin and gemcitabine with or without the addition of bevacizumab was 
reported (12). The study met its primary endpoint of improvement in median PFS 
with the addition of bevaciuzmab, though the overall survival was not improved. 
Bevacizumab is now being studied in the use of earlier stages of NSCLC such as 
with adjuvant chemotherapy and in combination with chemoradiation for stage III 
disease. Other strategies to block angiogenesis such as with the use of VEGF 
receptor tyrosine kinase inhibitors are also under investigation. 
1.4 
Pemetrexed 
The FDA has approved the use of pemetrexed in combination with cisplatin for 
patients with locally advanced or metastatic NSCLC other than predominantly 
squamous cell histology. 
Pemetrexed, a multi-targeted antifolate compound, has recently been approved 
for the treatment of non-squamous NSCLC. It exerts anti-cancer effects by 
inhibition of thymidylate synthase (TS), dihydrofolate reductase (DHFR) and 
glycinamide ribonucleotide formyl transferase (GARFT). The main adverse 
events associated with pemetrexed include myelosuppresison, diarrhea and skin 
rash. Interestingly, the toxicity profile is much improved with the administration of 
vitamin B12 and folic acid.  
The efficacy of pemetrexed in NSCLC was first established by a phase III study 
conducted for second line therapy (13). Pemetrexed was directly compared to 
docetaxel for patients who progressed with platinum-based chemotherapy. The 
study met its primary endpoint of non-inferiority in overall survival for 
pemetrexed. In particular, the incidence of neutropenia, hospitalizations and most 

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other toxicities were less with pemetrexed. Subsequently, it was studied in 
combination with cisplatin for first line therapy of advanced stage NSCLC. In this 
trial, cisplatin-pemtrexed was compared to the combination of cisplatin-
gemcitabine (14). The study met its primary endpoint of non-inferiority in overall 
survival.The median survival was identical at 10.3 months for patients on both 
arms of the study. Moreover, there was a significant reduction in neutropenia, 
thrombocytopenia and anemia with cisplatin-pemetrexed. Furthermore, in a pre-
planned subset analysis, patients with adenocarcinoma and large cell histology 
experienced a superior median survival with cisplatin-pemetrexed (hazard ratio of 
0.84 and 0.67 respectively, P < 0.001). The median survival for adenocarcinoma 
histology was 12.6 months with pemetrexed compared to 10.9 months with 
cisplatin-gemcitabine. This has led to the approval of cisplatin-pemetrexed for the 
treatment of non-squamous NSCLC in the United States and Europe. The 
superior efficacy of pemetrexed in patients with non-squamous NCSLC has also 
resulted in a label change in the second line setting. It is now not indicated for the 
treatment of patients with squamous cell NSCLC. The favorable tolerability profile 
and the ability to administer pemetrexed for extended number of cycles lend itself 
for evaluation as maintenance or consolidation therapy.  
1.5 
Maintenance Therapy with Pemetrexed 
Recently, the positive results of a phase III study that compared maintenance 
pemetrexed to placebo were reported. Advanced NSCLC patients who achieved 
stable disease or objective response with 4 cycles of platinum-based therapy 
were randomized to receive pemetrexed (500 mg/m2 every 3 weeks) or placebo 
(15). The primary endpoint was progression-free survival. The preliminary results 
of the study demonstrated a significant improvement in median PFS (4 m vs. 
1.97 m, P < 0.0001) and a strong trend towards improved survival (13.3 m vs. 
10.1 m, P=0.06). The final survival data will be available in 2009. In particular, in 
patients with non-squamous histology, the median survival was improved by 5 
months (14.4 m vs. 9.4 m, P = 0.005) with pemetrexed. Based on this 
observation, even if the final results of this study fails to meet statistical 
significance for survival with pemetrexed in the overall patient population, the 
observed superiority in survival for non-squamous histology would provide 
adequate grounds for testing in a prospective randomized phase III study.  
Though the exact reasons behind the histology-based efficacy of pemetrexed are 
not known, the higher prevalence of MTAP (methylthioadenosine phosphorylase) 
deletions and lower TS expression in non-squamous histology, primarily 
adenocarcinoma may confer increased sensitivity to pemetrexed. Based on this, 
pemetrexed has now emerged as an option for maintenance therapy in patients 
with advanced stage non-squamous NSCLC following 4 cycles of combination 
chemotherapy. Furthermore, pemetrexed is well tolerated, allowing optimal 
maintenance therapy to be given for an extended duration without cumulative 
toxicity. Whether optimal maintenance therapy should include continuation of an 
agent the patient has already been exposed to or introduction of a 
mechanistically distinct agent from those utilized upfront remains an open 
question which will be addressed in this study.  
1.6 
Laboratory Research Studies 
In addition to evaluation of efficacy of the treatment regimens, we also intend to 
conduct correlative science studies to identify the relationship between certain 
biomarkers and outcome. The overarching goal is to identify sub-populations of 

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Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
11 
patients who might benefit from a certain treatment regimen included in the study 
to a greater extent (positive selection) and those will not derive any benefit 
(negative selection). The study includes two main treatment phases which 
include the first line therapy and the maintenance therapy. All patients enrolled to 
the study will receive first line therapy with carboplatin, paclitaxel and 
bevacizumab. We intend to conduct studies on the baseline tumor tissue and 
peripheral blood to identify markers that will predict for both response and toxicity 
with the treatment regimen. During the maintenance therapy phase, we will 
conduct studies to evaluate the correlation with outcome for biological markers 
relevant to the specific agent that the patient received on the study. The studies 
on polymorphisms for VEGF and metabolizing enzymes for taxanes will be to 
confirm prior studies that have suggested an important role for these markers on 
outcome. The other studies will be exploratory in nature. 
1.7 
Hypothesis for Study 
We hypothesize that the use of an optimal maintenance therapy regimen will 
result in improved survival for patients with advanced stage NSCLC. An efficacy 
plateau has been achieved with combination chemotherapy in advanced stage 
NSCLC. Several targeted agents evaluated in combination with chemotherapy 
have failed to confer survival advantage with the exception of bevacizumab and 
cetuximab. On the other hand, several recent studies that have examined the 
role of maintenance therapy after maximal response to combination 
chemotherapy have demonstrated a trend towards improved survival, particularly 
for patients with non-squamous cell carcinoma receiving pemetrexed where it is 
clinically meaningful. Therefore, we propose to conduct a phase III study to 
compare maintenance therapy with bevacizumab, pemetrexed or both following 4 
cycles of carboplatin, paclitaxel and bevacizumab in patients with advanced 
stage non-squamous NSCLC. 
1.8 
Rationale for Selected Approach and Trial Design 
The proposed randomized trial will compare the efficacy of bevacizumab 
vs.pemetrexed vs. the combination of pemetrexed and bevacizumab after 4 
cycles of carboplatin, paclitaxel and bevacizumab for patients with advanced 
stage non-squamous non-small cell lung cancer. Bevacizumab is now routinely 
used for the treatment of advanced stage NSCLC, in combination with 
chemotherapy for 4-6 cycles and as monotherapy until progression thereafter. As 
outlined above, pemetrexed is the first agent to demonstrate superiority in this 
setting, especially in patients with nonsquamous histology, analogous to those 
who are bevacizumab eligible (median survival: 14.4 vs. 9.4 was preliminary, 
P=0.005). The rationale for evaluation of the combination of pemetrexed and 
bevacizumab stems from a phase II study by Patel et al (16) where the 
combination was deemed safe in the maintenance setting. Advanced non-
squamous NSCLC patients were treated with the combination of carboplatin, 
pemetrexed and bevacizumab followed by maintenance therapy with pemetrexed 
and bevacizumab. The preliminary results of the study demonstrated a robust 
median PFS of 9 months and an overall survival of 13.5 months. The 
bevacizumab-pemetrexed maintenance therapy was tolerated well without major 
toxicity. 

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2. 
Objectives 
2.1 
Primary Objective 
To compare the overall survival associated with maintenance therapy with 
bevacizumab, pemetrexed or the combination in patients with advanced stage 
NSCLC 
2.2 
Secondary Objectives 
2.2.1 
To determine the response rate in the three treatment arms 
2.2.2 
To evaluate the progression-free survival 
2.2.3 
To define the toxicity associated with each regimen 
2.2.4 
To conduct correlative science studies that will help to select 
predictive bio-markers with a primary focus on the following: 
2.2.4.1 
To determine the frequency of polymorphisms in VEGF 
3578 AA,  1154 AA, ABCB1 G2677TT/AA and ERCC-118 
TT in patients with NSCLC receiving paclitaxel, carboplatin 
and bevacizumab therapy and determine the association 
between genotypes and response rate. 
2.2.4.2 
To determine the association between bevacizumab and 
pemetrexed population pharmacokinetics and patient 
specific covariates with bevacizumab or pemetrexed 
toxicity. 
2.2.4.3 
To determine the frequency of TSER*3 polymorphisms in 
NSCLC and the association between TSER 
polymorphisms and benefit from pemetrexed. 
2.2.4.4 
To evaluate TS and ERCC1 expression by RT-PCR and 
MTAP mutations as a predictor of pemetrexed  response  
2.2.4.5 
To evaluate polymorphisms within CYPs 2C8, 3A4, 3A5 
and/or the UGT1A1 collectively or monogenically as 
markers for variation in efficacious and/or toxic response of 
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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. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
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) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Step 1: 
3.1.1 
Cytological or histological confirmation of non-small cell lung cancer. 
3.1.2 
Predominant non-squamous histology (patients with NSCLC NOS are 
eligible). Mixed tumors will be categorized by the predominant cell 
type. If small cell elements are present the patient is ineligible. 
3.1.3 
Stage IV disease (includes M1a, M1b stages or recurrent disease) 
(according to the 7th edition of the TNM classification system). 
Patients with T4NX disease (stage III B) with nodule in ipsilateral lung 
lobe are eligible if they are not candidates for combined 
chemotherapy and radiation. 
3.1.4 
No prior malignancy within the last 3 years with the exception of 
superficial melanoma, basal cell carcinoma or carcinoma in situ. 
3.1.5 
No prior systemic chemotherapy for advanced stage lung cancer. 
3.1.6 
Prior adjuvant chemotherapy is allowed if at least 12 months have 
elapsed since the prior chemotherapy administration and registration. 
Prior adjuvant chemotherapy? (Yes/No)______ 
≥ 12 months since prior chemotherapy administration? 
(Yes/No)______ 
3.1.7 
At least 2 weeks must have elapsed between completion of prior 
radiotherapy and registration. 
≥ 2 weeks since completion of prior radiotherapy? (Yes/No)______ 
3.1.8 
Prior use of paclitaxel, pemetrexed or bevacizumab is not allowed. 
Prior use of carboplatin is allowed if it was given as part of adjuvant 
chemotherapy. 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
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3.1.9 
Age ≥ 18 years. 
3.1.10 
Patients with brain metastasis must have received local therapy to the 
brain and have no evidence of progression in the brain for at least 2 
weeks from the time of completion of local therapy, prior to 
registration. 
3.1.11 
No major hemoptysis within 4 weeks prior to registration (defined as 
bright red blood of half tea-spoon or more). 
3.1.12 
Patients must have acceptable bone marrow, renal and hepatic 
function within 2 weeks of registration as defined below: 
 
Leukocytes ≥ 3,000/mm3 
 
Leukocytes ≥ 3,000/ mm3?  (Yes/No)______ Date of Test______ 
 
Absolute neutrophil count ≥ 1,500/ mm3 
 
Absolute neutrophil count ≥ 1,500/ mm3?  
(Yes/No)_____ Date 
of Test______ 
 
Platelets ≥ 100,000/mm3 
 
Platelets ≥ 100,000/mm3? (Yes/No)______ Date of Test______ 
 
Total bilirubin ≤ institutional upper limits of normal  
 
Total bilirubin ≤ normal institutional limit? (Yes/No)____ Date of 
Test_____ 
 
AST(SGOT) and ALT(SGPT) ≤ 3 X institutional upper limit of 
normal 
 
AST(SGOT) ≤ 3 X institutional upper limit of normal? 
(Yes/No)______ 
 
Date of Test______ 
 
ALT(SGPT) ≤ 3 X institutional upper limit of normal? 
(Yes/No)_______  
 
Date of Test______ 
 
Creatinine ≤ institutional upper limits of normal. 
(or) 
Creatinine clearance ≥ 60 mL/min/1.73m2 (normalized to BSA) for 
patients with creatinine levels above institutional normal (See 
Appendix VI). 
Creatinine ≤ institutional upper limits of normal or creatinine clearance 
≥ 60ml/min/1.73m2?  
(Yes/No)______ Date of test______ 
 
Urine dipstick must be ≤ 0-1+. If urine dipstick results are > 1+, 
calculation of Urine Protein Creatinine (UPC) is required. Patients 
must have a UPC ratio < 1 to participate in the study (see Section 
8.3.13 for calculation details). 
Urine dipstick ≤ 0-1+?  
(Yes/No)______ Date of test______ 
______ 
______ 
______ 
Rev. 7/12 
______ 
Rev. 7/12 
Rev. 7/12 
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If no, UPC ratio < 1? 
(Yes/No)______ Date of test______ 
3.1.13 
Patients with uncontrolled intercurrent illness including, but not limited 
to, ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, serious cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study 
requirements are excluded. 
3.1.14 
Patients must have measurable or nonmeasurable disease as defined 
by the RECIST criteria in Section 6.1.2. Baseline measurements and 
evaluation of all sites of disease must be obtained ≤ 4 weeks prior to 
registration. 
3.1.15 
Patients with history of hypertension should be adequately controlled 
(BP < 150/100) with appropriate anti-hypertensive therapy or diet 
3.1.16 
Patients must have an ECOG Performance Status of 0 or 1 (See 
Appendix II). 
3.1.17 
No history of arterial thrombotic events or major bleed within 12 
months prior to registration 
3.1.18 
Concomitant use of therapeutic anti-coagulation is allowed. 
3.1.19 
Patients must not have had any major surgery such as thoracotomy, 
laparotomy, craniotomy, or significant traumatic injury within 6 weeks 
prior to registration. Biopsy procedures and chest tube insertion are 
not considered major surgery for the purpose of this protocol. 
3.1.20 
Patients must not have had a core biopsy within 7 days prior to 
registration. 
3.1.21 
Patients must not have significant vascular disease (e.g., aortic 
aneurysm requiring surgical repair or recent peripheral arterial 
thrombosis) within 6 months prior to registration. 
3.1.22 
Patients with clinically significant cardiovascular disease are 
excluded. 
3.1.23 
Patients must not have a history of abdominal fistula, gastrointestinal 
perforation, or intra-abdominal abscess within 6 months prior to 
registration. 
3.1.24 
No history of serious non-healing wounds. 
3.1.25 
Patients with cavitary lesions in the lungs are not eligible. 
3.1.26 
Women must not be pregnant or breast-feeding due to the lack of 
adequate safety data with the use of bevacizumab and pemetrexed in 
this group. 
All females of childbearing potential must have a blood test within 2 
weeks prior to registration to rule out pregnancy. 
Female of children bearing potential? ______  (Yes or No) 
Date of blood test: ___________________ 
______ 
______ 
______ 
______ 
Rev. 1/11 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
Rev. 7/12 
Rev. 7/12 
Rev. 7/12 
Rev. 11/13 

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3.1.27 
Both fertile men and women must agree either to abstain from sexual 
intercourse or to use adequate contraceptive measures during study 
treatment and for at least 6 months after completion of the study 
drugs.  
3.1.28 
Patients with HIV disease who are taking anti-retroviral therapy are 
excluded since there are no safety data with the concomitant use of 
chemotherapy and anti-retroviral agents. 
3.2 
Step 2: 
3.2.1 
Patient must have an overall response per RECIST criteria (see 
Section 6.1.4) of stable or better after 4 cycles of induction therapy on 
step 1. 
NOTE:  
If patient discontinues Induction treatment early due to 
toxicities, but has received a minimum of 3 complete 
cycles of induction therapy and has an overall response 
per RECIST criteria of stable or better, they may be 
evaluated for step 2. 
3.2.2 
Patient must have an ECOG performance status of 0 or 1 (See 
Appendix II). 
3.2.3 
Patients must be registered to Step 2 within 6 weeks of the last day of 
chemotherapy administration on Step 1. 
3.2.4 
Patients must have acceptable bone marrow, renal and hepatic 
function within 2 weeks of registration as defined below: 
 
Leukocytes ≥ 3,000/mm3 
 
Leukocytes ≥ 3,000/ mm3? 
 
(Yes/No)______ Date of Test______ 
 
Absolute neutrophil count ≥ 1,500/mm3 
 
Absolute neutrophil count ≥ 1,500/mm3? (Yes/No)______  
 
Date of Test_____ 
 
Platelets ≥ 100,000/mm3 
 
Platelets ≥ 100,000/mm3? (Yes/No)______ 
 
Date of Test______ 
 
Total bilirubin ≤ institutional upper limit of normal 
 
Total bilirubin ≤ normal institutional limit?  
 
(Yes/No)____ Date of Test_____ 
 
AST(SGOT) and ALT(SGPT) ≤ 3 X institutional upper limit of 
normal 
 
AST(SGOT) ≤ 3 X institutional upper limit of normal? 
 
(Yes/No)_______  
 
Date of Test_____ 
______ 
______ 
______ 
______ 
______ 
Rev. 1/11 
Rev. 1/11 
______ 
Rev. 7/12 
Rev. 7/12 
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ALT(SGPT) ≤ 3 X institutional upper limit of normal? 
 
(Yes/No)_______  
 
Date of Test____ 
 
Creatinine ≤ institutional upper limits of normal. 
 
(or) 
 
Creatinine clearance ≥ 60 mL/min/1.73m2 (normalized to BSA) for 
patients with creatinine levels above institutional normal. 
 
Creatinine ≤ institutional upper limits of normal or creatinine 
clearance ≥ 60ml/min/1.73m2?  
 
(Yes/No)______ Date of test______ 
 
Urine dipstick must be ≤ 0-1+. If urine dipstick results are > 1+, 
calculation of Urine Protein Creatinine (UPC) is required. Patients 
must have a UPC ratio < 3.5 to participate in the study (see 
Section 8.3.13 for calculation details). 
Urine dipstick ≤ 0-1+?  
(Yes/No)______ Date of test______ 
If no, UPC ratio < 3.5? 
(Yes/No)______ Date of test______ 
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4. 
Registration Procedures 
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 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU member web site by entering credentials 
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at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically 
load to RSS.  
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU 
Regulatory Office for initial, continuing or amendment review.  This information will be 
provided to the CTSU Regulatory Office from the CIRB at the time the site’s Signatory 
Institution accepts the CIRB approval.  The Signatory site may be contacted by the 
CTSU Regulatory Office or asked to complete information verifying the participating 
institutions on the study.  Other site registration requirements (i.e., laboratory 
certifications, protocol-specific training certifications, or modality credentialing) must be 
submitted to the CTSU Regulatory Office or compliance communicated per protocol 
instructions. 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the E5508 protocol page located on the 
CTSU members’ website.   
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Click on the ECOG-ACRIN link to expand, then select trial protocol E5508 
 
Click on the Site Registration Documents link 
Requirements for E5508 site registration: 
 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the 
NCI CIRB) 
Requirements For E5508 Site Registration: 
 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the 
NCI CIRB) 
Submitting Regulatory Documents 
Before an ECOG-ACRIN Institution may enter patients, protocol specific 
regulatory documents must be submitted to the CTSU Regulatory Office at the 
following address:   
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. 
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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 
username and password 
 
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: 
Patients must not start protocol treatment prior to registration. 
Treatment should start within seven working days after registration. 
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 ECOG-ACRIN 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 
at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following:  
 
All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool 
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 
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.  
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
The following information will be requested: 
4.1 
Step 1: Registration to Arm I 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
 
Institution and affiliate name (Institutional CTEP ID) 
 
Investigator’s name (NCI number) 
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) 
 
Race 
 
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 checklist has been appended to the protocol.  A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office – Boston. 
4.1.5 
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 E5508 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. 
4.1.6 
Additional Requirements 
4.1.6.1 
Patients must provide a signed and dated, written informed 
consent form. 

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4.1.6.2 
Specimens are to be submitted as outlined in Section 10. 
4.2 
Step 2: Randomization to Arm A, Arm B or Arm C 
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
 
Institution and affiliate name 
 
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 
 
Ethnicity 
 
Nine-digit ZIP code 
 
Method of payment 
4.2.4 
Stratification Factors  
4.2.4.1 
Gender 
 
Male 
 
Female 
4.2.4.2 
Stage 
 
IIIB-T4Nx (with nodule in ipsilateral lung lobe and not 
candidate for combined chemotherapy and 
radiation)/IV M1a 
 
IV M1b 
 
Recurrent 
4.2.4.3 
Best response to first-line therapy 
 
CR/PR 
 
SD 
4.2.4.4 
Smoking Status 
 
Never Smoker 
 
Ever-Smoker 
4.2.5 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 
3.2. An eligibility checklist has been appended to the protocol.  A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office – Boston. 
4.2.6 
Additional Requirements 

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4.2.6.1 
Specimens are to be submitted as outlined in Section 10. 
4.2.7 
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 E5508 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. 

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5. 
Treatment Plan 
5.1 
Administration Schedule 
All doses should be based on the patient’s actual body weight. 
After registration, all eligible patients will receive the combination regimen of 
paclitaxel, carboplatin, and bevacizumab. This will be referred to as ‘induction 
therapy (Arm I)’. After 4 cycles of induction therapy, patients who experience 
complete response, partial response or stable disease will be randomized to one 
of the 3 maintenance therapy arms (Arms A, B and C). Patients with progressive 
disease will be removed from protocol treatment and enter long-term follow-up. 
5.1.1 
Induction Therapy (Step 1, Cycles 1-4) (Arm I) 
The regimen consists of: 
(The agents will be administered in the order written) 
Paclitaxel 200 mg/m2 IV over 3 hours. For Paclitaxel pre-
medication information, see Section 5.1.1.1. 
If the study is experiencing shortage in supply with pacitaxel, 
docetaxel can be used as a substitute. The dosing guidelines 
and modifications are outlined in Appendix VIII. 
Carboplatin AUC=6 mg/ml IV over 15–30 minutes, immediately 
following paclitaxel infusion. See section 5.1.1.2 for information 
on calculation of carboplatin dose. 
Bevacizumab 15 mg/kg IV infusion over 30–90 minutes. For 
infusion information, see Section 5.1.1.3. 
All of the above three drugs will be administered on day 1 of each 21 
day cycle.  
5.1.1.1 
Pre-Medications for Paclitaxel 
Prior to receiving paclitaxel, all patients will receive the 
following pre-medications: 
Dexamethasone 20 mg p.o. 12 and 6 hours prior to 
paclitaxel infusion (Patients may be treated with 
dexamethasone 20 mg IV < 1 hour prior to infusion with 
paclitaxel if the patient did not take the oral 
dexamethasone) 
Diphenhydramine 50 mg IV (or equivalent) < 1 hour prior 
to paclitaxel infusion. 
Cimetidine 300 mg IV < 1 hour prior to paclitaxel infusion 
(alternatively ranitidine 50 mg IV or other H2-blockers may 
be used). 
Substitutions may be made to the above pre-medication 
regimen based on local institutional guidelines. 
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5.1.1.2 
Calculation of Carboplatin Dose 
Carboplatin (AUC=6) will be administered on Day 1 of 
each cycle after paclitaxel as an IV infusion over 30 
minutes. The dose will be calculated based on the patient’s 
actual body weight at each treatment visit and the AUC 
(area under curve) dosing. 
The dose of carboplatin is calculated (in mg, not mg/m2) as 
follows, using the Calvert formula based on creatinine 
clearance: 
Dose = Target AUC¹ x (Creatinine clearance² + 25) 
1 The target AUC for carboplatin treatment is AUC=6. GFR 
should not exceed 125 mL/min. 
2 The carboplatin dose will be based on estimated GFR 
(glomerular filtration rate) based on measurement of 
creatinine clearance where creatinine clearance is 
calculated using the Cockroft-Gault formula (see 
Appendix VI and below). Thus, maximum carboplatin 
dose is: 6 x (125 + 25), or 900mg. When concerned about 
safety for a specific patient, use measured GFR. 
For males: 
CrCl (mL/min) =  
(140-age) x (weight in kg) 
72 x serum creatinine in mg/dL 
For females: 
CrCl (mL/min) =  
0.85 x 
(140-age) x (weight in kg) 
72 x serum creatinine in mg/dL 
5.1.1.3 
Bevacizumab Administration 
Once every 3 weeks, 15 mg/kg of bevacizumab will be 
given by IV infusion after paclitaxel and carboplatin has 
been given. 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. 
A urine dipstick should be performed at baseline and prior 
to every course of bevacizumab. Treatment may proceed if 
dipstick result is 0-1+. If the result of urine protein dipstick 
is > 1+, hold bevacizumab until the UPC ratio is known. 
UPC ratio must be < 3.5 for patient to receive treatment 
bevacizumab. (See Section 8.3.13 for calculation details). 
Rate of Infusion: The initial bevacizumab dose should be 
delivered over 90 minutes as a continuous IV infusion after 
completion of the carboplatin infusion. If the first 
infusion is tolerated without infusion-associated adverse 
events (fever and/or chills), the second infusion may be 
delivered over 60 minutes. If the 60-minute infusion is well 
tolerated, all subsequent infusions may be delivered over 
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30 minutes. A rate-regulating device should be used for all 
bevacizumab infusions. When the bevacizumab IV bag is 
empty, 50 mL of 0.9% Sodium Chloride Injection, USP, 
should be added to the IV bag or an additional bag should 
be hung. An alternative method of flushing the infusion line 
would be to replace the empty bevacizumab infusion bag 
with a 50 mL bag of 0.9% sodium chloride injection and 
infuse a volume equal to that of the tubing to ensure 
complete delivery of the bevacizumab. The infusion should 
be continued for a volume equal to that of the tubing to 
ensure complete delivery of the bevacizumab. If a patient 
experiences bevacizumab infusion-associated adverse 
events, patient may receive premedication at the 
investigators discretion prior to the next bevacizumab 
infusion. If premedication is required, the infusion time may 
not be decreased for the subsequent infusion. However, if 
the next infusion is well tolerated with premedication, the 
subsequent infusion time may then be decreased by 30 
minutes per infusion to a minimum infusion time of 30 
minutes as long as the patient continues to receive the 
same premedication. 
If a premedicated patient experiences infusion-associated 
adverse events with the 60-minute infusion, all 
subsequent doses should be given over 90 minutes. 
Similarly, if a premedicated patient experiences infusion- 
associated adverse events with the 30-minute infusion, all 
subsequent doses should be given over 60 minutes. 
Anaphylaxis Precautions: 
 
Anaphylaxis precautions should be observed during 
bevacizumab administration. 
 
The patient’s blood pressure and heart rate should be 
monitored every 15 minutes during the first infusion. 
 
After that, the infusion can be given without requiring 
vitals every 15 minutes if the patient tolerated the 
previous infusion without anaphylaxis or allergic 
reactions. 
 
Emergency agents including oxygen, oral and 
endotracheal airways, intubation equipment, 
epinephrine, antihistamines and corticosteroids   
should be available. 
 
In the event of a suspected anaphylactic reaction 
during bevacizumab infusion, stop the bevacizumab 
infusion and apply a tourniquet proximal to the injection 
site, if possible, to slow systemic absorption of 
bevacizumab. Administer antihistamines, epinephrine, 
or other medications at the investigator’s discretion. 
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Bevacizumab Infiltration: Should infiltration of the 
bevacizumab infusion occur, the following steps are to be 
taken: 
 
Discontinue the IV. 
 
If a significant volume of the bevacizumab infusion 
remains, restart the IV and complete the infusion. 
 
Treat the infiltration according to institutional guidelines 
for infiltration of a noncaustic agent 
5.1.2 
Maintenance Therapy (Step 2, Cycles 1 and up) (Arm A, Arm B, Arm 
C) 
Patients must be registered to Step 2 within 6 weeks of the last 
day of chemotherapy administration on Step 1. If there is more 
than a 6 week delay, then the patient must go off study. Patient doses 
should be recalculated at the start of Step 2 treatment. Patients 
eligible for Step 2 will be randomized to treatment with one of the 
three following treatment arms: 
5.1.2.1 
Arm A 
Bevacizumab 15 mg/kg IV over 30-90 minutes on day 1 of 
each cycle. For infusion information, see Section 5.1.1.3. 
Each cycle consists of 21 days. 
5.1.2.2 
Arm B 
Pemetrexed 500 mg/m2 IV over 10 minutes on day 1 of 
each cycle. Each cycle consists of 21 days. For 
Pemetrexed premedication information, see Section 
5.1.2.4. 
5.1.2.3 
Arm C 
Administer Pemetrexed then bevacizumab as follows:  
Pemetrexed 500 mg/m2 IV over 10 minutes. For 
Pemetrexed premedication information, see Section 
5.1.2.4. 
Bevacizumab 15 mg/kg IV over 30-90 minutes. For 
infusion information, see Section 5.1.1.3. 
Both drugs will be given on day 1 every cycle. Each cycle 
consists of 21 days. 
NOTE: 
The dose for maintenance therapy medications 
should be calculated based on the weight 
measured on Step 2, cycle 1, day 1. This 
weight would be the new baseline reference for 
maintenance therapy. 
5.1.2.4 
Pre-medications for Administration of Pemetrexed 
NOTE: 
Patients randomized to either pemetrexed arm 
(Arm B or C) are expected to delay the initiation 
of maintenance (Step 2) therapy approximately 
1 week after Step 2 registration to 
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accommodate the administration of 
premedications. 
Folic acid should be administered by the oral route at a 
dose of at least 400 micrograms up to 1000 micrograms on 
daily basis. This should be initiated approximately 1 week 
before the first dose of pemetrexed and should be 
continued for approximately 21 days after the last dose of 
pemetrexed.  
Vitamin B12 should be given at a dose of 1000 
micrograms by the intramuscular route approximately 1 
week before the first dose of pemetrexed and should be 
repeated every 3 cycles of therapy until patient goes off 
protocol treatment (with cycles 4, 7, 10, 13, 16). 
Dexamethasone should be given at a dose of 4 milligrams 
twice daily for 3 consecutive days, starting 1 day before 
administration of pemetrexed with every cycle of 
pemetrexed. 
NOTE: 
Vitamin B12 and folic acid supplementation are 
only required for patients receiving pemetrexed 
as part of maintenance therapy (arms B and C). 
5.2 
Adverse Event Reporting Requirements 
5.2.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E5508 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting).  Additionally, certain adverse events must be reported in 
an expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting. 
5.2.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
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Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: Identify the type of event: Effective April 1, 2018, the 
descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for expedited AE reporting done via CTEP-
AERS. All appropriate treatment areas should have access to 
a copy of the CTCAE version 5.0. A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov). 
Step 2: Grade the event using the NCI CTCAE version 5.0. 
Step 3: Determine whether the adverse event is related to the 
protocol therapy (investigational or commercial). Attribution 
categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite. 
Step 4: Determine the prior experience of the adverse event. 
Expected events are those that have been previously 
identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the 
severity of the event is NOT listed in:  
 Arm I, A, B, and C – the drug package insert or protocol 
Step 5: Review Section 5.2.6 for E5508 and/or ECOG-ACRIN specific 
requirements for expedited reporting of specific adverse 
events that require special monitoring.   
NOTE: 
For general questions regarding expedited reporting 
requirements, please contact the AEMD Help Desk at 
aemd@tech-res.com or 301-897-7497. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS).  CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG 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) 
 
the FDA (800-332-1088) 
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) in the same 
timeframe.  
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CTEP Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the CTEP Technical Help Desk at 
ncictephelp@ctep.nci.nih.gov or by phone at 1-888-283-7457. 
5.2.4 
When to Report an Event in an Expedited Manner 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Section 5.2.6. 
NOTE: 
Adverse events that meet the reporting requirements in 
Section 5.2.6 and occur within 30 days of the last dose of 
protocol treatment must be reported on an expedited 
adverse event report form (using CTEP-AERS). For any 
adverse events that occur more than 30 days after the last 
dose of treatment, only those that have an attribution of 
possibly, probably, or definitely AND meet the reporting 
requirements in Section 5.2.6 must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
5.2.5 
Other Recipients of Adverse Event Reports 
Adverse events determined to be reportable 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. 
5.2.6 
Expedited Reporting for Commercial Agents 
Commercial reporting requirements are provided below. The 
commercial agents used in arms I, A, B and C of this study are 
Paclitaxel, Carboplatin, Bevacizumab, and Pemetrexed. 
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Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents 
only – Arms I, A, B, and C. 
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 A death occurring while on study or within 30 days of the last dose of treatment requires both routine and 
expedited reporting, regardless of causality.  Attribution to treatment or other cause must be provided. 
NOTE: A death due to progressive disease should be reported as a Grade 5 “Disease progression” 
under the System Organ Class (SOC) “General disorder and administration site conditions”.  
Evidence that the death was a manifestation of underlying disease (e.g. radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted. 
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. 
5.2.7 
Reporting Second Primary Cancers 
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 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).  
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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 
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5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Bevacizumab (rhuMAb VEGF, NSC 704865) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. They are 
developed and continuously monitored by the CTEP Investigational Drug Branch 
(IDB). The information listed in the CAEPR(s) below, as well as the other 
resources described in the 'Determination of reporting requirements' part of the 
Adverse Event Reporting section in this protocol, can be used to determine 
expectedness of an event when evaluating if the event is reportable via CTEP-
AERS. Frequency is provided based on 3540 patients. Below is the CAEPR for 
bevacizumab (rhuMab VEGF). 
Version 2.5, May 2, 20181 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
Febrile neutropenia 
 
 
 
Hemolytic uremic syndrome 
CARDIAC DISORDERS 
 
Cardiac disorders - Other 
(supraventricular arrhythmias)2  
 
 
 
Chest pain - cardiac3 
 
 
Heart failure 
 
 
Left ventricular systolic dysfunction 
 
 
Myocardial infarction3 
 
 
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 
 
 
Non-cardiac chest pain 
 
Rev. 12/11, 5/14, 
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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Pain 
 
HEPATOBILIARY DISORDERS 
 
 
Gallbladder perforation 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
 
 
 
Anaphylaxis 
INFECTIONS AND INFESTATIONS 
 
Infection9 
 
 
 
Infections and infestations - Other 
(necrotizing fascitis) 
 
Infections and infestations - Other (peri-
rectal abscess) 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Infusion related reaction 
 
 
 
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 
 
 
Creatinine increased 
 
Neutrophil count decreased 
 
 
 
Platelet count decreased 
 
 
Weight loss 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Dehydration 
 
 
Hyperglycemia 
 
 
Hypokalemia 
 
 
Hyponatremia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
 
Avascular necrosis11 
 
Generalized muscle weakness 
 
 
Musculoskeletal and connective tissue 
disorder - Other (bone metaphyseal 
dysplasia)12 
 
 
Myalgia 
 
 
Osteonecrosis of jaw13 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 

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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Intracranial hemorrhage 
 
 
Ischemia cerebrovascular 
 
Peripheral sensory neuropathy14 
 
 
 
Reversible posterior 
leukoencephalopathy syndrome 
 
Syncope 
 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
 
Hematuria 
 
 
 
Nephrotic syndrome 
 
Proteinuria 
 
 
 
Urinary fistula 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
Reproductive system and breast 
disorders - Other (ovarian failure)15 
 
 
 
 
Vaginal fistula 
 
Vaginal hemorrhage 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Allergic rhinitis 
 
 
 
Bronchopleural fistula 
 
 
Bronchopulmonary hemorrhage 
 
Cough 
 
 
Dyspnea 
 
 
Epistaxis 
 
 
Hoarseness 
 
 
 
Pulmonary hypertension 
 
 
Respiratory, thoracic and 
mediastinal disorders - Other (nasal-
septal perforation) 
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(tracheo-esophageal fistula) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Dry skin 
 
 
Erythroderma 
 
 
 
Palmar-plantar erythrodysesthesia 
syndrome 
 
Pruritus 
 
 
Rash maculo-papular 
 
 
Urticaria 
 
VASCULAR DISORDERS 
 
 
Arterial thromboembolism3,16 
Hypertension 
 
 
 
Thromboembolic event 
 
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 

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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 Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation, and atrial 
flutter. 
3 The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and 
in patients with a history of diabetes. 
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, and Small intestinal perforation. 
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. 
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 There have been reports of non-mandibular osteonecrosis (avascular necrosis) in patients under the 
age of 18 treated with bevacizumab. 
12 Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
13 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. 
14 Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab 
and chemotherapy compared to chemotherapy alone. 
15 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. 
16 Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart 
attack, and stroke. 
Adverse events reported on bevacizumab (rhuMAb VEGF) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that bevacizumab 
(rhuMAb VEGF) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Disseminated 
intravascular coagulation; Hemolysis; Thrombotic thrombocytopenic purpura 
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 

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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 (ischemic CRVO); Eye disorders - Other 
(macular pucker); Eye disorders - Other (transient increased IOP > or =30 mm Hg); Eye pain; 
Floaters; Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; Retinal tear; 
Retinopathy; Vitreous hemorrhage; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Cheilitis; 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 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; 
Dermatitis radiation; Fracture 
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; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone 
pain; Chest wall pain; Fibrosis deep connective tissue; Head soft tissue necrosis; Joint effusion; 
Muscle weakness lower limb; Muscle weakness upper limb; Musculoskeletal and connective 
tissue disorder - Other (polymyalgia rheumatica); Neck pain; Osteonecrosis; 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; Myasthenia gravis; 
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; Dysuria; Renal and urinary disorders - Other (ureterolithiasis); Renal hemorrhage; 
Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary 
tract pain 

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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; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (dry nares); Respiratory, thoracic and 
mediastinal disorders - Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; Pain 
of skin; 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 
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5.4 
Dose Modifications  
All toxicities should be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
The CTCAE version 4.0 is identified and located on the CTEP website at 
http://ctep.cancer.gov. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. 
All dose reductions are considered permanent. Re-escalation of the dose of 
therapy is not allowed. All toxicities should have resolved to grade 1 or less 
before initiation of a new cycle of therapy, with the exception of anemia, alopecia, 
neuropathy, proteinuria, and non-treatment related clinically insignificant 
laboratory abnormalities. Patients with thromboembolism that are on therapy with 
appropriate anti-coagulation are allowed to resume therapy if they are clinically 
stable. For proteinuria, please follow the guidelines in Section 5.4.1.2. 
If chemotherapy must be withheld 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. 
5.4.1 
Dose Modification Guidelines for the Induction Therapy Phase 
NOTE:  
If induction therapy is discontinued before Cycle 3, patient 
will be removed from protocol treatment. If induction 
therapy is discontinued after Cycle 3, patient may be 
considered for maintenance phase (Step 2) (See Section 
3.2) 
NOTE:  
Paclitaxel and carboplatin dose delays will also necessitate 
holding bevacizumab. However, bevacizumab delays will 
not result in holding chemotherapy. If bevacizumab must 
be delayed due to toxicities, chemotherapy should proceed 
as scheduled. 
NOTE: 
An overall maximum of 2 dose reductions are allowed per 
patient at each step (Step 1 and Step 2), regardless of the 
cause. 
5.4.1.1 
Paclitaxel + Carboplatin 
Hematologic Toxicity 
Red blood cells 
Dose reductions are not necessary for the management of 
anemia. Patients with clinically significant anemia should 
be treated with erythrocyte growth factor and RBC 
transfusion based on local institutional guidelines. 
Neutrophils 
Absolute Neutrophil Count (Reduce doses only for febrile 
neutropenia). ANC must be ≥ 1,500/mm³. If the counts are 
lower than the limit, then treatment should be delayed until 
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The doses of paclitaxel and carboplatin will be reduced as 
follows: 
Grade 3/4 Febrile 
neutropenia 
Paclitaxel 
Carboplatin 
1st episode 
175 mg/m2 
AUC = 5.0 
2nd episode 
150 mg/m2 
AUC = 4.0 
3rd episode 
No further induction therapy. If patient has 
CR, PR or SD, consider maintenance 
phase (see Section 3.2). 
The use of prophylactic neutrophil growth factors is not 
allowed for the first cycle of therapy. If the patient 
experiences fever with neutropenia, then neutrophil growth 
factors can be given based on standard clinical practice 
guidelines. 
Platelets 
Platelet count must be ≥ 100,000/mm³ on day 1 of each 
cycle. 
Dose reduction will only be done for grade 4 platelet 
toxicity. 
The dose of carboplatin will be reduced to AUC = 5.0 for 
the first episode and AUC = 4.0 for the second episode. If 
it recurs for the third time, then no further induction therapy 
will be administered. If a patient has CR, PR or SD, they 
may be considered for Step 2 (maintenance phase).See 
Section 3.2. 
Non-hematological toxicity 
Gastrointestinal Toxicity (Paclitaxel, Carboplatin) 
Nausea and/or vomiting should be controlled with 
adequate antiemetics. If grade 3 or 4 vomiting or grade 3 
nausea occurs despite maximal anti-emetic therapy, the 
dose of both agents should be reduced per the table 
below.  Nausea and/or vomiting should have resolved to 
grade 1 or less before initiation of a new cycle of therapy. If 
nausea and/or vomiting has not resolved to grade 1 or less 
in 3 weeks with appropriate anti-emetic therapy, then the 
patient’s induction treatment will be discontinued. 
If, on day 1 of any treatment cycle, the patient has 
stomatitis, the treatment should be withheld until the 
stomatitis has resolved to grade 1 or less. If the stomatitis 
has not resolved to grade 1 or less in 3 weeks, the 
patient’s induction treatment will be discontinued. (Refer to 
the NCI CTCAE version 4.0 for specific grading criteria). If 
acute grade 3 or 4 stomatitis occurs at any time, the dose 
should be reduced per the table below when the stomatitis 
is resolved to grade 1 or less.  

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These are permanent dose reductions. 
The doses of paclitaxel and carboplatin will be reduced as 
follows: 
Gr 3 nausea, vomiting or  
Gr 4 vomiting, or  
Gr 3 or 4 stomatitis 
Paclitaxel 
Carboplatin 
1st episode 
175 mg/m2 
AUC = 5.0 
2nd episode 
150 mg/m2 
AUC = 4.0 
3rd episode 
No further induction therapy. If patient 
has CR, PR or SD, consider 
maintenance phase (see Section 3.2). 
Hepatic Toxicity (Paclitaxel) 
The day 1 value for each cycle should be used in 
determining the dose. 
AST 
 
Total Bilirubin 
Paclitaxel Dose 
≤ 5 X ULN 
And 
Within normal 
limit 
No dose reduction 
> 5 X ULN 
And/Or 
< 1.5 X ULN 
Reduce by 25 mg/m2 
Any 
And 
> 1.5 X ULN 
Hold, then reduce by 
25 mg/m2 
A patient will be allowed a maximum of two dose 
reductions. If a third reduction is required, the patient 
should discontinue induction treatment. If paclitaxel is 
withheld due to hepatic toxicity, carboplatin should also be 
withheld, and administered when the paclitaxel is resumed. 
If paclitaxel is withheld, hepatic values must recover to  
≤ grade 1 within 3 weeks or patient’s induction treatment 
will be discontinued. No dose reductions for carboplatin will 
be made for hepatic toxicity. 
Cardiovascular Toxicity (Paclitaxel) 
Cardiac rhythm disturbances have occurred infrequently in 
patients in clinical trials; however, most patients were 
asymptomatic and cardiac monitoring is not required. 
Transient asymptomatic bradycardia has been noted in as 
many as 29% of patients. More significant AV block has 
rarely been noted. Cardiac events should be managed as 
follows: 
Asymptomatic bradycardia - no treatment required. 
Symptomatic arrhythmia during infusion - stop paclitaxel 
infusion, manage arrhythmia according to standard 
practice. Induction treatment will be discontinued. 
Chest pain and/or symptomatic hypotension < 90/60 (mm 
Hg) or requires fluid replacement – stop paclitaxel infusion. 
Perform an EKG. Give intravenous diphenhydramine and 
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considered. Also, consider epinephrine or bronchodilators 
if chest pain is not thought to be cardiac. Induction 
treatment will be discontinued. 
Neurologic Toxicity (Paclitaxel) 
Paclitaxel doses should be modified as follows for 
neuropathy-sensory. The dose of carboplatin will not be 
reduced for neurologic toxicity. 
Neurological 
toxicity grade 
Paclitaxel dose 
0/1 
No change 
2 
Hold until recovery to grade 1 or less. Then reduce 
dose by 20% to 160 mg/m2 
3 or worse 
Hold until recovery to grade 1 or less. Then reduce 
dose by 30% to 140 mg/m2 
A patient will be allowed a maximum of two dose 
reductions. If a third reduction is required, the patient 
should discontinue induction treatment. If paclitaxel is 
withheld due to neurologic toxicity, carboplatin should also 
be withheld and administered when the pacitaxel is 
resumed. Dose modifications made for neurotoxicity are 
permanent reductions. If recovery to grade 1 toxicity does 
not occur within 3 weeks, the patient’s induction treatment 
will be discontinued. 
Allergic Reaction/Hypersensitivity (Paclitaxel) 
CAUTION: 
Patients who had a mild to moderate 
hypersensitivity reaction have been 
successfully re-challenged, but careful 
attention to prophylaxis and bedside 
monitoring of vital signs is recommended.  
Mild symptoms: Complete paclitaxel infusion. Supervise at 
bedside. No intervention 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 40 ml/hour for 15 
minutes, then, if no further symptoms, at full dose rate until 
infusion is complete. If symptoms recur, paclitaxel infusion 
should be discontinued. Induction treatment will be 
discontinued.  
Severe life-threatening symptoms: Stop paclitaxel infusion. 
Give intravenous diphenhydramine and dexamethasone as 
above. Add epinephrine or bronchodilators if indicated. 
Induction treatment will be discontinued. 

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Other Toxicity 
For any grade 3 or 4 toxicity not mentioned above that is 
deemed related to therapy, the induction treatment should 
be withheld until the patient recovers completely or to 
grade 1 toxicity. The induction treatment should then be 
resumed at a reduced dose per the Other Gr 3 or 4 toxicity 
table below (permanent dose reduction).  If recovery to 
grade 1 toxicity does not occur within 3 weeks, the 
patient’s induction treatment will be discontinued. A patient 
will be allowed a maximum of two dose reductions. If a 
third reduction is required, the patient should discontinue 
induction treatment. For grade 1 and 2 toxicities, no dose 
reduction should be made. 
Other Gr 3 or 4 toxicity 
Paclitaxel 
Carboplatin 
1st episode 
175 mg/m2 
AUC = 5.0 
2nd episode 
150 mg/m2 
AUC = 4.0 
3rd episode 
No further induction therapy. If patient has 
CR, PR or SD, consider maintenance 
phase (see section 3.2). 
Multiple Toxicity 
If multiple toxicities occur and conflicting dose modification 
guidelines exist, the more stringent dose modification 
criteria should be chosen. 
5.4.1.2 
Bevacizumab Dose Modification for Induction Therapy 
(Step 1) 
Paclitaxel and carboplatin dose delays will also result in 
holding of bevacizumab therapy until chemotherapy is 
resumed. Permanent discontinuation of bevacizumab 
will lead to removal of the patient from protocol 
treatment. 
Proteinuria 
A urine dipstick should be performed at baseline then prior 
to every course of bevacizumab. Treatment may proceed if 
dipstick result is 0-1+. If the result of the urine protein 
dipstick is > 1+, hold bevacizumab until the UPC ratio is 
known. UPC ratio must be < 3.5 for patients to receive 
bevacizumab treatment.  
UPC ratio of spot urine is an estimation of the 24 urine 
protein excretion – a UPC ratio of 1 is roughly equivalent to 
a 24-hour urine protein of 1 g.  UPC ratio is calculated 
using one of the following formulas: 
[urine protein]/[urine creatinine] – if both protein and 
creatinine are reported in mg/dL 
[(urine protein) x0.088]/[urine creatinine] – if urine 
creatinine is reported in mmol/L 
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If UPC is ≥ 3.5 hold bevacizumab until UPC recovers to  
< 3.5. If bevacizumab is held for > 2 months due to 
proteinuria, discontinue all protocol therapy. If patient 
experiences grade 4 proteinuria or nephrotic syndrome 
discontinue all protocol therapy. 
Hypertension 
Hypertension should be controlled with appropriate anti-
hypertensive therapy and will not result in dose reduction 
of bevacizumab. Patients with uncontrolled hypertension 
should not have bevacizumab held and appropriate 
hypersensitive therapy should be initiated. If BP is not 
controlled in 4 weeks, protocol treatment should be 
discontinued. 
Hypertension* [Treat with anti-hypertensive medication as needed.  The goal of 
BP control should be consistent with general medical practice] 
Grade 1 
Consider increased BP monitoring 
Grade 2 asymptomatic but 
diastolic BP < 100 mmHg 
Begin anti-hypertensive therapy 
and continue bevacizumab 
-Grade 2-3 
Symptomatic OR 
-Diastolic BP > 100 mmHg  
 
Hold bevacizumab should until 
symptoms resolve AND BP < 
160/90mmHg* 
Grade 4 
Discontinue bevacizumab. 
*See CTCAE version 4.0 for current definitions of 
hypertension by grade 
Thromboembolic Event 
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 Venous Thrombosis: 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. 
Bleeding/hemorrhage (Grading of bleeding can be found 
under each organ category of the CTCAE version 4.0) 
Grade 1 Hemorrhage: Hold bevacizumab until bleeding 
resolves to grade 0). Once resolved, resume bevacizumab 
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discontinued if bleeding of grade 2 or worse occurs 
following resumption of bevacizumab. 
Hemorrhage Grade 2, 3 or 4: Discontinue all protocol 
therapy.  
NOTE: 
If bevacizumab treatment is held (for up to 3 
weeks), treatment with paclitaxel and 
carboplatin should continue as scheduled. If 
bevacizumab is held for > 3 weeks, discontinue 
protocol treatment. 
Hemoptysis: Please refer to dose modification for 
hemorrhage. 
Arterial thromboembolic events (including cerebrovasular 
ischemia, cardiac ischemia/infarction, peripheral or visceral 
arterial ischemia): 
 
Grade 3 or higher: discontinue all protocol treatment. 
 
Grade 2, if new or worsen since bevacizumab therapy, 
discontinue all protocol treatment.  
Liver Function Test Abnormalities (LFT) 
Liver Function tests (LFT) should be monitored prior to 
each bevacizumab administration. Bevacizumab should be 
withheld in the event of ≥ Gr 3 ALT or AST elevations and 
should not resume until the abnormalities have recovered 
to ≤ Gr 1. If LFT elevations recur with retreatment, all 
protocol treatment should be permanently discontinued. If 
grade 3 or 4 toxicity persists for > 3 weeks or recurs after 
resumption of therapy, the patient will discontinue protocol 
treatment. 
Bowel Perforation/Anastomotic Dehiscence 
Bowel perforation and bowel anastomotic dehiscence have 
been reported in clinical trials using bevacizumab alone or 
in combination with chemotherapy. Although these events 
were likely related to co-existing factors such as tumor 
involvement, chemotherapy, recent invasive procedures or 
bowel inflammation, contribution of bevacizumab to these 
events cannot be excluded at this time. Partial delay in 
wound healing has been demonstrated in animal models 
treated with anti-VEGF antibodies and it is possible that 
bevacizumab may delay or compromise wound healing in 
patients. If these events occur, discontinue bevacizumab. 
Leukoencephalopathy Syndrome including Reversible 
Posterior Leukoencephalopathy Syndrome (RPLS) 
Bevacizumab will be held in patients with symptoms/signs 
suggestive of RPLS, pending work-up and management, 
including control of blood pressure. 
Diagnosis of RPLS should be confirmed by MRI. All 
protocol treatment will be discontinued upon diagnosis of 
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RPLS. If a patient is benefiting from therapy AND if the 
patient's RPLS was mild and has completely resolved 
clinically and radiographically within 2-4 weeks, resumption 
of protocol treatment may be considered. In this scenario, 
the study chair must be consulted and sites should receive 
approval before resuming protocol treatment. If treatment 
delay is > 3 weeks due to toxicity, discontinue protocol 
treatment. 
Other Toxicities 
If the patient develops any other grade 3 or 4 toxicity 
(except controlled nausea/vomiting) thought related to 
bevacizumab, bevacizumab should be held until symptoms 
resolve to grade 1 or less. (Paclitaxel and carboplatin 
treatment should continue as scheduled). Bevacizumab 
treatment may be resumed at full dose when toxicity is < 
grade 1. If grade 3 or 4 toxicity persists for > 3 weeks or 
recurs after resumption of therapy, the patient will 
discontinue protocol treatment. 
5.4.1.2.1 
Treatment Modification for Bevacizumab-
Related Adverse Events 
NOTE: 
There will be no dose reduction 
for bevacizumab.  Treatment 
should be interrupted or 
discontinued for certain adverse 
events, as described below 
NOTE: 
If bevacizumab is held for ≥ 3 
weeks due to toxicity, patient 
should discontinue protocol 
treatment, unless specifically 
noted otherwise. 
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Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE Version 4.0 
Grade 
Action to be Taken 
Allergic reactions  
or  
Infusion-related reactions 
Or  
Anaphylaxis 
Grade 1-2  
 
 Infusion of bevacizumab should be interrupted for 
patients who develop dyspnea or clinically significant 
hypotension.  
 For infusion-associated symptoms not specified 
above, infusion should be slowed to 50% or less or 
interrupted. Upon complete resolution of the 
symptoms, infusion may be continued at no more 
than 50% of the rate prior to the reaction and 
increased in 50% increments every 30 minutes if well 
tolerated. Infusions may be restarted at the full rate 
during the next cycle.  
 Patients who experience bronchospasm (regardless 
of grade) should discontinue bevacizumab. 
G3-4 
Discontinue bevacizumab 
Thromboembolic Event 
(Arterial); arterial  
ischemia  
- Cardiac ischemia 
- Myocardia  infraction 
- CNS ischemia (TIA, 
CVA) 
- any peripheral or 
visceral arterial 
ischemia/thrombosis 
Grade 2 (new or worsening 
since bevacizumab 
Discontinue bevacizumab. 
Grade 3-4 
Discontinue bevacizumab 
Thromboembolic Event 
(Venous) 
Grade 3 
OR 
asymptomatic Grade 4 
 Hold bevacizumab treatment.  If the planned 
duration of full-dose anticoagulation is <2weeks, 
bevacizumab should be held until the full-dose 
anticoagulation period is over. 
 If the planned duration of full-dose anticoagulation is 
>2 weeks, bevacizumab may be resumed during full-
dose anticoagulation IF all of the criteria below are 
met: 
- The patient must not have pathological 
conditions that carry high risk of bleeding (e.g. 
tumor involving major vessels or other 
conditions) 
- The patient must not have had hemorrhagic 
events > grade 2 while on study 
- The patient must be on stable dose of heparin, 
low molecular weight heparin, or have an in-
range INR (usually 2-3) on a stable dose of 
warfarin prior to restarting bevacizumab. 
 If thromboemboli worsen/recur upon resumption of 
study therapy, discontinue bevacizumab 
Grade 4 (symptomatic) 
Discontinue 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] 
Grade 1 
(SBP 120-139 mmHg or 
DBP80-89 mm Hg) 
Consider increased BP monitoring; start anti-
hypertensive medication if appropriate 
Grade 2 asymptomatic 
(SBP 140-159 mmHg or 
DBP 90-99 mm Hg) 
Begin anti-hypertensive therapy and continue 
bevacizumab 
 
 Grade 2 symptomatic 
(SBP 140-160 mmHg or 
DBP 90-100 mm Hg) 
 Grade 3 
(≥ SBP 160 mmHg or ≥ 
DBP 100 mmHg 
 Start or adjust anti-hypertensive medication 
 Hold bevacizumab until symptoms resolve AND BP < 
160/90mmHg 
 
Grade 4  
(Hypertensive crisis or 
malignant hypertension) 
Discontinue bevacizumab 
Heart Failure or LV 
dysfunction 
Grade 3 
Discontinue bevacizumab 
Grade 4 
Discontinue bevacizumab 
Proteinuria 
 
[Proteinuria should be monitored by urine analysis for urine protein creatinine (UPC) 
ratio, or dipstick prior to every other dose of bevacizumab.  If dipstick shows 2+ 
proteinuria, 24-hour urine protein should be obtained] 
UPC ratio  
< 3.5 or 24-h urine protein 
< 3.5 gm 
Continue bevacizumab. 
UPC ratio  
≥ 3.5 or 24-h urine protein 
≥ 3.5 gm 
Hold bevacizumab until it UPC recovers to < 3.5, or 24-
h urine protein < 3.5 gm.   
Discontinue bevacizumab if urine protein does not 
recover to < 3.5 after 8 weeks or bevacizumab 
interruption 
Nephrotic syndrome 
Discontinue bevacizumab. 
Bleeding/hemorrhage 
(Grading of bleeding can 
be found under each 
organ category of the 
CTCAE version 4.0) 
Grade 1 
Hold bevacizumab until bleeding resolves to grade 0. 
Once resolved, resume bevacizumab at 15 mg/kg. 
Patient’s protocol treatment will be discontinued if 
bleeding of grade 2 or worse occurs following 
resumption of bevacizumab. 
NOTE:  If bevacizumab treatment is held (for up to 3 
weeks), treatment with paclitaxel and 
carboplatin should continue as scheduled. If 
bevacizumab is held for > 3 weeks, discontinue 
protocol treatment. 
Grade 2-4 
 Discontinue all protocol therapy 

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RPLS (Reversible Posterior Leukoencephalopathy 
syndrome or PRES (Posterior Reversible Encephalopathy 
Syndrome) 
 Discontinue bevacizumab upon diagnosis of 
RPLS.   
Wound dehiscence requiring medical or surgical 
intervention 
 Discontinue bevacizumab 
Perforation (GI, or any other organ) 
Discontinue bevacizumab 
Fistula (GI, pulmonary or any other organ) 
Discontinue bevacizumab 
Obstruction of GI tract 
G2 requiring medical 
intervention 
 Hold bevacizumab until complete resolution  
 
G3-4 
 Hold bevacizumab until complete resolution 
 If surgery is required, patient may restart 
bevacizumab after full recovery from surgery, and at 
investigator’s discretion 
Other Unspecified 
bevacizumab-related AEs 
(except controlled 
nausea/vomiting). 
Grade 3 
 Hold bevacizumab until symptoms resolve to 
 
≤ grade 1 
Grade 4 
 Discontinue bevacizumab 
 Upon consultation with the study chair, 
resumption of bevacizumab may be considered if a 
patient is benefiting from therapy, and the G4 toxicity 
is transient, has recovered to ≤ grade 1 and unlikely 
to recur with retreatment. 
5.4.2 
Dose Modification Guidelines for Maintenance Therapy Phase 
NOTE: 
For Arm C patients- Bevacizumab holds do not affect 
pemetrexed administration. Similarly, holds or dose 
reductions of pemetrexed do not affect bevacizumab 
therapy. If one drug is to be held due to toxicity, the other 
may be given as scheduled. 
5.4.2.1 
Bevacizumab  
If bevacizumab is discontinued due to toxicity in the 
Maintenance Phase, the patient can continue therapy with 
pemetrexed (if patient is on the pemetrexed + 
bevacizumab arm, Arm C). If the patient is on the 
bevacizumab only arm (Arm A), they should enter long 
term follow up (and continue to have imaging studies until 
PD) following discontinuation of bevacizumab. 
The dose modification guidelines for bevacizumab are the 
same as during the induction phase (Section 5.4.1.2) 
Refer to Section 5.4.1.2.1 for “Treatment Modification for 
Bevacizumab Related Adverse Events” table. 
5.4.2.2 
Pemetrexed 
In the event of toxicity, patient should be enquired about 
compliance with intake of folic acid. Administration of 
vitamin B12 every 3 cycles of therapy should be ensured. 
Hematological toxicity 
Before initiation of a new cycle of therapy, the following 
hematological indices must be met: 
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 
ANC ≥ 1500/mm3 
 
Platelets ≥ 100,000/mm3 
If the indices have not improved to this level, pemetrexed 
should be delayed until recovery. The complete blood 
count should be checked at least once a week when the 
pemetrexed is held. If pemetrexed is delayed for > 3 
weeks, the patient should be treated as follows: Arm B – 
Discontinue all protocol treatment; Arm C – Continue on 
bevacizumab alone. 
The dose of pemetrexed will be reduced for the following 
events: 
Grade 3/4 Febrile 
neutropenia 
 
Pemetrexed dose 
1st occurrence 
Reduce to 375 mg/m2 
2nd occurrence 
Reduce to 250 mg/m2 
3rd occurrence 
Off study 
Leucovorin can be considered for grade 4 leukopenia 
lasting > 3 days, grade 4 neutropenia lasting > 3 days, and 
immediately for grade 4 thrombocytopenia, or bleeding 
associated with grade 3 thrombocytopenia. The following 
intravenous doses and schedules of leucovorin are 
recommended if it is used: 100mg/m², intravenously once, 
followed by leucovorin, 50 mg/m², intravenously every 6 
hours for 8 days. 
Non-hematological toxicity 
For non-hematologic toxicities (considered related to 
pemetrexed) ≥ grade 3, pemetrexed should be delayed 
until resolution to less than or equal to the patient’s 
baseline value by the start of the cycle, before proceeding. 
If treatment is delayed for > 3 weeks for any pemetrexed 
related toxicity, the patient should be treated as follows: 
Arm B: Discontinue all protocol treatment; Arm C: continue 
on bevacizumab alone. 
Renal Toxicity 
Caution should be used when administering ibuprofen 
concurrently with pemetrexed to patients with mild to 
moderate renal insufficiency (CrCl from 45 to 79 mL/min). 
Patients with mild to moderate renal insufficiency should 
avoid taking NSAIDs with short elimination half-lives for a 
period of 2 days before, the day of, and 2 days following 
administration of pemetrexed. All patients taking NSAIDs 
with longer elimination half-lives should interrupt dosing for 
at least 5 days before, the day of, and 2 days following 
pemetrexed administration. If concomitant administration of 
an NSAID is necessary, patients should be monitored 
closely for renal toxicity. 
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Stomatitis 
Leucovorin may be considered for grade 3 or 4 stomatitis 
and can be given on the following schedule: 100mg/m², 
intravenously once, followed by leucovorin, 50 mg/m², 
intravenously every 6 hours for 8 days. 
Clinically Significant Effusions 
For patients who develop or have baseline clinically 
significant pleural or peritoneal effusions (on the basis of 
symptoms or clinical examination) before or during 
initiation of pemetrexed therapy, consideration should be 
given to draining the effusion prior to dosing. However, if, 
in the investigator's opinion, the effusion represents 
progression of disease, the patient should be discontinued 
from study therapy after confirmation of progression of 
disease. 
Upon resolution, pemetrexed treatment will resume as 
follows: 
In the event of grade 3 nausea or vomiting, and/or grade 4 
vomiting, pemetrexed may resume without dose reduction. 
Grade 3 nausea or vomiting and/or Grade 4 vomiting 
should be managed with appropriate changes in antiemetic 
regimen. 
In the event of grade 3 or 4 mucositis, pemetrexed should 
be resumed at 50% of the previous level. 
In the event of grade 4 transaminase elevation, grade 3 or 
4 diarrhea, or any grade diarrhea requiring hospitalization, 
a 25% dose reduction of pemetrexed is mandatory. Thus, 
pemetrexed should resume at 75% of the previous dose 
level. 
For other grade 3 or 4 non-hematologic toxicities, 
treatment should resume at 75% of the previous dose 
level, if deemed appropriate by the treating physician. 
5.5 
Supportive Care  
5.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.5.2 
The use of bisphosphonates is allowed for patients with bone 
metastasis or hypercalcemia. 
5.5.3 
The use of erythrocyte growth factor is allowed if clinically indicated 
based on the recommendations by the American Society of Clinical 
Oncology (2008). 
5.5.4 
The use of prophylactic neutrophil growth factors is not allowed for the 
first cycle of therapy. If the patient experiences fever with neutropenia, 
then neutrophil growth factors can be given based on standard clinical 
practice guidelines. 
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5.5.5 
Palliative radiation is not allowed while patient is on protocol 
treatment. 
5.6 
Duration of Therapy  
The Induction Phase of therapy will be given for a maximum of 4 cycles. In the 
Maintenance Phase, treatment will be continued until disease progression, 
unacceptable toxicity or withdrawal of patient consent. 
Other reasons for discontinuation of protocol therapy include: 
5.6.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E5508 Forms Packet. 
5.6.2 
Patient withdraws consent. 
5.6.3 
Patient becomes pregnant  
5.6.4 
Patient develops a serious illness that interferes with the ability to 
continue therapy. 
5.7 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression and for survival for 5 years 
from the date of registration (every three months if patient is < 2 years from study 
entry; every 6 months if patient is 2-5 years from study entry). All patients must 
also be followed through completion of all protocol therapy. 
 
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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 
every 2 cycles during induction therapy and every 3 cycles during maintenance 
therapy. 
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 (for Step 1 and Step 2) should be performed as closely 
as possible to the beginning of that step’s treatment and never more than 
four weeks before registration/randomization. 
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 
NOTE: 
All disease parameters apply to registration to Step 1 and 
randomization to Step 2. 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
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as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 
with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area 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 sum 
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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 to either step of the protocol. 
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 
measured/assessed on the same pulse sequence.  It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
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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. 
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 
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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. 
c. FDG-PET may be used to upgrade a response to a CR in a 
manner similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent fibrosis or scarring. However, it 
must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
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 current step’s 
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 
current step (this includes the baseline sum of that step 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). 
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Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on current step of the protocol.  
(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 registration to that step of study at a minimum interval 
of 6 weeks (42 days). 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis) 
NOTE: 
If tumor markers are initially above the upper 
normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
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 non-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. 
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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). 
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 current step’s treatment until disease 
progression/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the current step’s 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 weeks 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 a 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 
measurement recorded since the current step’s 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 current 
step’s treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded 
since the current step’s treatment started, including that 
step’s baseline measurements.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after registration/randomization to current step at a 
minimum interval of 6 weeks (42 days). 
 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy scans and x-rays used to assess all measurable or non-measurable 
sites of disease must be done within 4 weeks prior to registration. 
2. Prestudy CBC (with differential and platelet count) should be done ≤ 2 weeks 
before registration.  
3. All required prestudy chemistries, as outlined in section 3, should be done ≤ 2 
weeks before registration. 
 
 
Baseline1 
(Step 1) 
Induction 
Phase 
Baseline1 
(Step 2) 
Maintenance 
Phase 
Off study 
visits10 
 
 
 
Day 1 of  
cycles 1-4 
 
Day 1 of  
each cycle 
 
Rev. 7/12 
History and physical exam* 
X 
X 
X 
X 
X 
 
Performance status and weight 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
Blood pressure 
X 
X 
X 
X 
 
 
Electrocardiogram2 
X 
 
X 
 
 
 
Complete blood count with differential6 
X 
X 
X 
X 
 
 
Blood chemistry tests3 
X 
X 
X 
X11 
 
Rev. 1/11, 
11/13 
PT/INR and PTT8 
X 
 
X 
 
 
 
Serum pregnancy test4 
X 
 
X 
 
 
 
Toxicity Assessment 
X 
X 
X 
X 
 
Rev. 11/13 
Imaging studies for tumor assessment5,7 
X 
Every 2 cycles 
X 
Every 3 cycles 
X 
Rev. 7/12 
Urine dipstick for protein12 
X 
X  
X 
X8 
 
 
Smoking status 
X9 
 
 
 
 
 
Biological tissue collection 
See Section 7.2 of protocol 
* History and physical exam must be done within 72 hours before day 1 of each cycle. 
1. 
All baseline assessments must be done ≤ 2 weeks before registration with the exception of imaging 
studies that should be done ≤ 4 weeks before registration.  
2  
If medically indicated. 
3  
Should include measurement of ALT, AST, alkaline phosphatase, bilirubin, creatinine, blood urea 
nitrogen, magnesium, calcium, sodium, potassium, albumin, chloride, bicarbonate and LDH. 
Chemistries must be done < 72 hours prior to the treatment cycle. For cycle 1, the test results used 
for registration are acceptable and there is no need to repeat the lab work on day 1 of cycle 1 if the 
clinical condition of the patient is unchanged. 
4  
In women of the reproductive age-group. 
5  
All efforts must be made to assess tumor from the same type of scan that was performed at 
baseline. 
6. 
CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct 
required for protocol therapy must be done < 72 hours prior to the treatment cycle. For cycle 1, the 
test results used for registration are acceptable and there is no need to repeat the lab work on day 
1 of cycle 1 if the clinical condition of the patient is unchanged. 
7. 
Imaging studies to be done every 6 weeks during induction treatment (Step 1), every 3 cycles 
during maintenance therapy (Step 2), and every 3 months during long-term follow-up until PD. 
8. 
Additional testing may be required if clinically indicated. 
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9  
Smoking status is to be collected at the pre-study visit. 
10. Every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2-5 years from 
study entry. See Section 5.7. 
11. In addition to the blood chemistries specified in footnote #3, creatinine clearance should be done 
prior to each cycle for patients on Arms B and C. See Appendix VI. 
12. Urine dipstick for protein is not required for Arm B patients.  
7.2 
Biological Sample Submissions  
Samples for the scientific research studies and banking are to be submitted from 
patients who have given written consent to participate in these studies.  See 
Section 10. 
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 (STS). 
NOTE: 
As of November 3, 2014 all samples are to be submitted to the 
ECOG-ACRIN Central Biorepository and Pathology Facility (CBPF) at 
MD Anderson. As of this date, the CBPF is the designated 
biorepository for all samples, including those previously submitted, for 
this trial. 
NOTE: 
Institutions outside the United States and Canada are not required to 
participate in the fresh tissue (blood) studies because of the costs and 
problems associated with international shipping.  Submission of tissue 
blocks is not exempt. Institutions outside the United States and 
Canada who desire to participate in the fresh tissue studies are to 
contact the ECOG-ACRIN Central Biorepository and Pathology 
Facility to discuss alternative arrangements for specimen 
submissions. 
 
Pre-study 
Step 2, Cycle 2, Prior to 
treatment 
Submit from patients who answer “Yes” to “I agree my tissue will be submitted for 
research” 
Paraffin embedded tumor 1 
X 
 
Submit from patients who answer “Yes” to “I agree to participate in the laboratory 
research studies that are being done as part of this clinical trial.” 
Plasma and residual cells (RBC 
and WBC), two 10 mL K2-EDTA 
tubes 
X 
X3 
Peripheral blood, two ACD tubes 2 
X 
 
1 
Submit within 1 month of registration to Step 1 with related pathology, surgical, 
immunological reports, and a STS generated shipping manifest. 
2 
Although it is preferred that this specimen be collected prior to start of treatment, it 
may be collected at any time during the trial. EDTA may be used if ACD not 
available. 
3 
If sample is not collected at cycle 2, it may be collected prior to treatment on any 
subsequent cycle. 
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8. 
Drug Formulation and Procurement 
8.1 
Paclitaxel 
NOTE: 
Please refer to the commercial package insert for more information. 
8.1.1 
Other Names 
Taxol, NSC 673089. 
8.1.2 
Classification 
Antimicrotubule agent. 
8.1.3 
Mode of Action 
Promotes microtubule 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 
The intact vials are stored under refrigeration. 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, 5% dextrose and 
normal saline, or 5% dextrose in Ringer’s solution are stable for up to 
27 hours when stored at room temperature and normal room light. 
8.1.5 
Dose Specifics and Administration 
200 mg/m2 IV over 3 hours, Day 1 of every cycle (Step 1, Cycles 1-4, 
Arm I) 
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) infusion sets should be used.  A small 
number of fibers (within acceptable limits established by the USP) 
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 (Abbott) 0.2 micron filters showed no 
appreciable loss of potency. 
Solutions exhibiting excessive particulate formation should not be 
used. 
8.1.7 
Incompatibilities 
Avoid the use of PVC bags and infusion sets due to leaching of DEHP 
(plasticizer). Ketoconazole may inhibit paclitaxel metabolism, based 
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8.1.8 
Availability 
A concentrated solution of 6 mg/mL in polyoxyethylated castor oil 
(Cremophor EL) 50% and dehydrated alcohol 50% is commercially 
available in 5 mL vials.  
8.1.9 
Side Effects 
Hematologic:  
Myelosuppression (neutropenia, leukopenia, 
thrombocytopenia, anemia). 
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 tachycardia.  
More severe reactions include hypotension 
requiring treatment, dyspnea 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. 
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 infarction.  
Hypertension (possibly related to concomitant 
medication -- Dexamethasone) may also occur. 
Neurologic: 
Sensory (taste changes); peripheral neuropathy; 
arthralgia and myalgia (dose-related, more 
common when colony-stimulating factors are also 
administered); seizures; mood alterations; 
neuroencephalopathy; hepatic encephalopathy; 
motor neuropathy; and autonomic neuropathy 
(paralytic ileus and symptomatic hypotension). 
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. 
Gastrointestinal: Nausea, vomiting, diarrhea, stomatitis, mucositis, 
pharyngitis, typhlitis (neutropenic enterocolitis), 
ischemic colitis, and pancreatitis. 
Hepatic: 
Increased AST, ALT, bilirubin, alkaline 
phosphatase; hepatic failure, and hepatic necrosis. 

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Other: 
Fatigue, headache, light-headedness, myopathy, 
elevated serum creatinine, elevated serum 
triglycerides, and visual abnormalities (sensation of 
flashing lights, blurred vision). 
8.1.10 
Nursing/Patient Implications 
Monitor CBC and platelet count prior to drug administration. 
Symptom management of expected nausea, vomiting, and stomatitis. 
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. 
Advise patients of possible hair loss. 
Cardiac monitoring for assessment of arrhythmias in patients with 
serious conduction abnormalities. 
Monitor liver function tests. 
Advise patient of possible arthralgias and myalgias which may occur 
several days after treatment. Monitor for symptoms of peripheral 
neuropathy. 
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. 
Evaluate IV site regularly for signs of infiltration.  It is not known if 
paclitaxel is a vesicant; however, the CremophorEL vehicle for this 
drug can cause tissue damage.  
In-line filtration with a 0.22 micron filter should be used. 
8.1.11 
References 
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, Eisenhauer 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. 
8.2 
Carboplatin 
8.2.1 
Availability 
Carboplatin is commercially available 

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8.2.2 
Chemical Name 
Carboplatin (carboplatin for injection or platinum diamine [1,1-
cyclobutane-decarbozxylate (2—0,0’)-,(SP-4-2)]) is a platinum 
compound used as a chemotherapeutic agent.  It will be supplied 
commercially. 
8.2.3 
Formulation 
Carboplatin is available as a sterile lyophilized powder in single-dose 
vials containing 50 mg, 150 mg, or 450 mg of carboplatin.  Each vial 
contains equal parts by weight of carboplatin and mannitol.  
Commercial supplies of carboplatin will be used in this trial. 
8.2.4 
Preparation 
Immediately before use, the contents of a carboplatin vial must be 
reconstituted with either sterile water for injection, USP, 5% dextrose 
in water, or 0.9% sodium chloride injection, USP.  The following 
shows the proper diluent volumes to be used to obtain a carboplatin 
concentration of 10 mg/mL. Carboplatin solution can be further diluted 
to concentrations as low as 0.5 mg/mL with D5W or 0.9% normal 
saline. 
Vial size 
Diluent volume 
50 mg 
5 mL 
150 mg 
15 mL 
450 mg 
45 mL 
Carboplatin reacts with aluminum to form a precipitate and cause a 
loss of potency. Therefore, needles or intravenous sets containing 
aluminum parts that may come in contact with the drug must not be 
used for the preparation or administration of carboplatin. 
8.2.5 
Dose Specifics and Administration 
All patients on Induction Phase of protocol treatment will receive 
Carboplatin at AUC = 6 mg/ml X min IV over 15-30 minutes, 
immediately following Paclitaxel infusion every 21 days for 4 cycles 
(Step 1, Arm 1). See Section 5.1.1.2 for information on calculation of 
carboplatin dose.  
NOTE: 
When calculating dose, GFR should not exceed 125 
mL/min. Thus, maximum carboplatin dose for this protocol 
is 6 x (125+25), or 900mg. 
8.2.6 
Storage and Stability 
Intact vials of carboplatin are stable for the period indicated on the 
package when stored at room temperature (15-30C or 59-86F) and 
protected from light. 
When prepared as described above, carboplatin solutions are stable 
for 8 hours at room temperature if protected from light.  The solution 
should be discarded after 8 hours since no antibacterial preservative 
is contained in the formulation. 
Rev. 1/11 

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8.2.7 
Adverse Events Associated with Carboplatin 
Incidence rates of adverse events associated with carboplatin are 
provided in the product package insert. Some of the adverse events 
expected with Carboplatin treatment are listed below. 
Hematologic: 
Myelosuppression is the major dose-limiting 
toxicity. Thrombocytopenia, neutropenia, 
leukopenia, and anemia are common, but 
typically resolve by Day 28 when carboplatin is 
given as a single agent. 
Allergic Reactions: Hypersensitivity to carboplatin has been reported 
in 2% of patients receiving the drug. Symptoms 
include rash, urticaria, erythema, pruritus, and 
rarely bronchospasm and hypotension. The 
reactions can be successfully managed with 
standard epinephrine, corticosteroid, and 
antihistamine therapy. 
Neurologic: 
Peripheral neuropathies have been observed in 
4% of patients receiving carboplatin with mild 
paresthesia being the most common. 
Gastrointestinal: 
Nausea and vomiting are the most common GI 
events; both usually resolve within 24 hours and 
respond to antiemetics.  Other GI events include 
diarrhea, weight loss, constipation, and 
gastrointestinal pain. 
Hepatic Toxicity: 
Elevated alkaline phosphatase, total bilirubin, and 
SGOT have been observed. 
Other: 
Pain and asthenia are the most common 
miscellaneous adverse events.  Alopecia has 
been reported in 3% of the patients taking 
carboplatin. 
8.3 
Bevacizumab   
8.3.1 
Availability 
Bevacizumab is commercially available. 
8.3.2 
Other names 
NSC 704865, RhuMAb VEGF, Recombinant Humanized Monoclonal 
Anti-VEGF Antibody 
8.3.3 
Molecular Formula: 
M.W. = 149 kilodaltons 
8.3.4 
Classification/Description 
Antiangiogenesis agent; recombinant humanized monoclonal antibody 
Bevacizumab is a recombinant humanized anti-VEGF monoclonal 
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sequences.  The agent is composed of human IgG framework and 
murine antigen-binding complementarity-determining regions. 
8.3.5 
Action 
Bevacizumab binds Vascular Endothelial Growth Factor (VEGF) 
preventing the binding of VEGF to its receptors (Flt-1 and KDR), thus 
inhibiting endothelial cell proliferation and new blood vessel formation. 
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 100 mg (25 mg/mL - 4 mL fill) glass vial contains 
bevacizumab with phosphate, trehalose, polysorbate 20 and 
Sterile Water for Injection, USP. 
 
Each 400 mg (25 mg/mL - 16 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 
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 
Opened vials must be used within 8 hours. Vials contain no 
preservative and are intended for single use only. The calculated dose 
should be placed in a sterile, empty IV bag. Bevacizumab will be 
diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. Once the 
bevacizumab has been added to the bag with 0.9% Sodium Chloride 
Injection, the solution must be administered within 8 hours. When the 
bevacizumab IV bag is empty, an additional 50 mL 0.9% Sodium 
Chloride for Injection should be added to the IV bag and the infusion 
continued for a volume equal to that of the tubing to insure complete 
delivery of the bevacizumab. An alternative method of flushing the 
infusion line would be to replace the empty bevacizumab infusion bag 
with a 50 mL 0.9% Sodium Chloride and infuse a volume equal to that 

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of the tubing to insure complete delivery of the bevacizumab. Note 
that this flush is not included in the infusion times below. 
Bevacizumab should NOT be administered or mixed with dextrose 
solutions. 
8.3.9 
Dose Specifics and Administration 
All patients receiving bevacizumab will receive the drug at 15 mg/kg 
every 21 days, given immediately after completion of chemotherapy, 
starting with Cycle 1 (Cycles 1-4, Step 1, Arm I). After induction 
chemotherapy is completed (4 cycles), if randomized to Arm A or Arm 
C, bevacizumab will continue at 15 mg/kg every 21 days until PD 
(provided neither PD nor toxicity requiring discontinuation has 
occurred) measured from date of first dose of bevacizumab.  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 insure 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 infusion 
times. 
8.3.10 
Kinetics 
Estimated half-life of bevacizumab is approximately 20 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 

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increase the incidence of irinotecan-induced side effects such as 
diarrhea and leucopenia. 
8.3.12 
Side Effects 
See Section 1.1. 
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 the baseline then prior to 
every course of bevacizumab. Treatment may proceed if dipstick 
result is 0-1+. If the result of the urine protein dipstick is > 1+, Hold 
bevacizumab until the UPC ratio is known. UPC ratio must be < 
3.5 for patients to receive bevacizumab treatment. 
UPC ratio of spot urine is an estimation of the 24-hour urine 
protein excretion – a UPC ratio of 1 is roughly equivalent to a 24-
hour urine protein of 1 g.  UPC ratio is calculated using one of the 
following formulas: 
[urine protein]/[urine creatinine] – if both protein and creatinine are 
reported in mg/dL 
[(urine protein) x0.088]/[urine creatinine] – if urine creatinine is 
reported in mmol/L 
Should infiltration of the bevacizumab infusion occur, the following 
steps are to be taken: 
Discontinue the IV 
If a significant volume of the bevacizumab infusion remains, 
restart the IV and complete the infusion. 
Treat the infiltration according to institutional guidelines for 
infiltration of a noncaustic agent. 
 
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 5.4.2). 

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8.3.14 
References 
Bevacizumab (AvastinTM) Full Prescribing Information.  Genentech, 
Inc. December 2004. 
Bevacizumab Investigators Brochure, Genentech, December 2003. 
8.3.15 
Date/Reviewer: 
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 
Pemetrexed Disodium Heptahydrate (Alimta) 
8.4.1 
Availability 
Pemetrexed is commercially available and is approved for this 
indication. 
8.4.2 
Chemical Name 
Pemetrexed disodium heptahydrate has the chemical name L-
Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-
d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. 
8.4.3 
Classification 
An antifolate antineoplastic agent 
8.4.4 
Molecular Formula 
C20H19N5Na2O6•7H2O Molecular Weight: 597.49 
8.4.5 
Mode of Action   
Pemetrexed is an antifolate antineoplastic agent that exerts its action 
by disrupting folate-dependent metabolic processes essential for cell 
replication. 
8.4.6 
How Supplied   
Pemetrexed is supplied as a sterile lyophilized powder for intravenous 
infusion available in single-dose vials. The product is a white to either 
light yellow or green-yellow lyophilized solid. Pemetrexed is supplied 
in 100mg and 500 mg vials. Each 500-mg vial of pemetrexed contains 
pemetrexed disodium equivalent to 500 mg pemetrexed and 500 mg 
of mannitol. Each 100-mg vial of pemetrexed disodium contains 
equivalent to 100mg pemetrexed and 106mg of mannitol. 
Hydrochloric acid and/or sodium hydroxide may have been added to 
adjust pH. 
NDC 0002-7623-01 (VL7623): single-use vial with flip-off cap 
individually packaged in a carton (500 mg vial). 
NDC 0002-7640-01 (vl7640); single use vial with flip-off cap 
individuality packaged in a carton (100 mg vial). 
 

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8.4.7 
Storage and Stability  
Pemetrexed for injection, should be stored at 25°C (77°F); excursions 
permitted to 15-30°C (59-86°F) [see USP Controlled Room 
Temperature]. Chemical and physical stability of reconstituted and 
infusion solutions of pemetrexed were demonstrated for up to 24 
hours following initial reconstitution, when stored refrigerated, 2-8°C 
(36-46°F), or at 25°C (77°F), excursions permitted to 15-30°C (59-
86°F) [see USP Controlled Room Temperature]. When prepared as 
directed, reconstituted and infusion solutions of Pemetrexed contain 
no antimicrobial preservatives. Discard unused portion.  Pemetrexed 
is not light sensitive. 
8.4.8 
Dose Specifics and Administration  
All patients on Arm B or Arm C of Maintenance Phase of protocol 
treatment will receive pemetrexed at 500 mg/m2 IV over 10 minutes 
every 21-day cycle. 
8.4.9 
Preparation 
1. Use aseptic technique during the reconstitution and further dilution 
of pemetrexed for intravenous infusion administration. 
2.  Calculate the dose and the number of pemetrexed vials needed. 
Each vial contains 500 mg or 100mg of Pemetrexed. The vial 
contains an excess of Pemetrexed to facilitate delivery of label 
amount. 
3. Reconstitute 500-mg vials with 20 mL of 0.9% Sodium Chloride 
Injection (preservative free) to give a solution containing 25 
mg/mL Pemetrexed. Gently swirl each vial until the powder is 
completely dissolved, Reconstitute 100mg vials with 4.2 ml of 
0.9% Sodium Chloride injection (preservative free) to give a 
Solution containing 4.3 mg/ml pemetrexed.The resulting solution 
is clear and ranges in color from colorless to yellow or green-
yellow without adversely affecting product quality. The pH of the 
reconstituted pemetrexed solution is between 6.6 and 7.8. 
FURTHER DILUTION IS REQUIRED. 
4. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration. If 
particulate matter is observed, do not administer.  
5. The appropriate volume of reconstituted Pemetrexed solution 
should be further diluted to 100 mL with 0.9% Sodium Chloride 
Injection (preservative free) and administered as an intravenous 
infusion over 10 minutes. 
6. Chemical and physical stability of reconstituted and infusion 
solutions of pemetrexed were demonstrated for up to 24 hours 
following initial reconstitution, when stored at refrigerated or 
ambient room temperature [see USP Controlled Room 
Temperature] and lighting. When prepared as directed, 
reconstitution and infusion solutions of pemetrexed contain no 
antimicrobial preservatives. Discard any unused portion. 
Reconstitution and further dilution prior to intravenous infusion is 
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(preservative free).  Pemetrexed is physically incompatible with 
diluents containing calcium, including Lactated Ringer’s Injection, 
USP and Ringer’s Injection, USP and therefore these should not 
be used. Coadministration of pemetrexed with other drugs and 
diluents has not been studied, and therefore is not recommended. 
8.4.10 
Route of Administration  
Intravenous Infusion. 
8.4.11 
Incompatibilities and Potential Drug Interactions 
Chemotherapeutic Agents — Cisplatin does not affect the 
pharmacokinetics of pemetrexed and the pharmacokinetics of total 
platinum is unaltered by pemetrexed. 
Vitamins — Coadministration of oral folic acid or intramuscular vitamin 
B12 does not affect the pharmacokinetics of pemetrexed. 
Drugs Metabolized by Cytochrome P450 Enzymes — Results from in 
vitro studies with human liver microsomes predict that pemetrexed 
would not cause clinically significant inhibition of metabolic clearance 
of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2. 
No studies were conducted to determine the cytochrome P450 
isozyme induction potential of pemetrexed, because Pemetrexed 
used as recommended (once every 21 days) would not be expected 
to cause any significant enzyme induction. 
Aspirin — Aspirin, administered in low to moderate doses (325 mg 
every 6 hours), does not affect the pharmacokinetics of pemetrexed. 
The effect of greater doses of aspirin on pemetrexed 
pharmacokinetics is unknown. 
 
Ibuprofen — Daily ibuprofen doses of 400 mg QID reduce 
pemetrexed’s clearance by about 20% (and increase AUC by 20%) in 
patients with normal renal function. The effect of greater doses of 
ibuprofen on pemetrexed pharmacokinetics is unknown.  Pemetrexed 
is primarily eliminated unchanged renally as a result of glomerular 
filtration and tubular secretion. Concomitant administration of 
nephrotoxic drugs could result in delayed clearance of pemetrexed. 
Concomitant administration of substances that are also tubularly 
secreted (e.g., probenecid) could potentially result in delayed 
clearance of pemetrexed. Although ibuprofen (400 mg QID) can be 
administered with pemetrexed in patients with normal renal function 
(creatinine clearance (80 mL/min), caution should be used when 
administering ibuprofen concurrently with pemetrexed to patients with 
mild to moderate renal insufficiency (creatinine clearance from 45 to 
79 mL/min). Patients with mild to moderate renal insufficiency should 
avoid taking NSAIDs with short elimination half-lives for a period of 2 
days before, the day of, and 2 days following administration of 
pemetrexed. In the absence of data regarding potential interaction 
between pemetrexed and NSAIDs with longer half-lives, all patients 
taking these NSAIDs should interrupt dosing for at least 5 days 
before, the day of, and 2 days following pemetrexed administration. If 
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be monitored closely for toxicity, especially myelosuppression, renal, 
and gastrointestinal toxicity. 
8.4.12 
Side Effects   
Renal: 
creatinine elevation (10%) 
Neurologic: 
neuropathy-sensory (9%), taste disturbance (8%) 
Hematologic: 
anemia (33%), neutropenia (29%), leucopenia 
(18%), thrombocytopenia (10%) 
Gastrointestinal: 
nausea (56%), vomiting (40%), anorexia (27%), 
constipation (21%), stomatitis/pharyngitis (14%), 
diarrhea (12%), dyspepsia/heartburn (5%) 
Dermatology/skin: alopecia (12%), rash/desquamation (7%) 
Other: 
fatigue, febrile neutropenia, infection, pyrexia, 
dehydration, increased AST, increased ALT, 
creatinine clearance decrease, renal failure, 
conjunctivitis, arrhythmia, chest pain, increased 
GGT, motor neuropathy  
8.4.13 
Pregnancy 
Category D 
8.4.14 
Nursing/Patient Implications 
1. Monitor CBC’s and chemistries. 
2. Administer Adequate Antiemetics. 
3. Monitor renal toxicity:  Calculate Creatinine Clearance prior to 
administering pemetrexed. (Reference Appendix VI) 
a. Patient use of Ibuprofen: Refer to precautionary guidelines in 
Section 5.4.2.2. 
4. Administer 1000 micrograms Vitamin B12 intramuscularly within 1 
week of first dose of pemetrexed and repeat every 3 cycles until 
the end of treatment. 
5. 400-1000 micrograms of folate (folic acid) beginning at least 5-7 
days prior to initial dose of pemetrexed and continuing for at least 
3 weeks after last dose. 
6. Monitor for adequate hydration. 
7. Patients may receive dexamethasone 4mg orally twice daily (or 
equivalent corticosteroid) on the day before, day of, and day after 
each dose of pemetrexed to prevent the occurrence of rash. 
8.4.15 
References 
www.ALIMTA.com; Pemetrexed (Alimta) Clinical Investigator’s 
Brochure, version October, 2008. 
 
Rev. 1/11 
Rev. 1/11 
Rev. 7/12 
Rev. 7/12 

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9. 
Statistical Considerations 
The primary goal of this trial is to determine if either pemetrexed maintenance or 
bevacizumab plus pemetrexed maintenance therapy improves overall survival (OS) 
compared to bevacizumab maintenance alone in patients with bevacizumab-eligible 
advanced stage non-small cell lung cancer. All patients will receive induction therapy of 
carboplatin/paclitaxel with bevacizumab, and those patients with stable disease (SD), 
partial response (PR) or complete response (CR) after four cycles will be randomized 
equally to one of three maintenance therapy arms: bevacizumab, pemetrexed, or 
bevacizumab plus pemetrexed. Based on data from patients with CR/PR/SD at three 
months in E4599, it is expected that the median overall survival in the control arm will be 
12 months, measured from the date of randomization. 
9.1 
The details of the design are given below.  
A total of 1495 patients will be accrued, and it is estimated that 60% of these 
patients (897 patients) will have achieved CR/PR/SD at the end of 4 cycles of 
induction therapy. These 897 patients will be randomized equally to each of the 
three arms (299 patients per arm). The primary comparison will be an intent-to-
treat analysis including all randomized patients. As reflected by the accrual of 
ECOG trial E4599, it is estimated that patient accrual will be 33 patients per 
month (23 patients per month to the randomization). It is estimated that the 
accrual goal will be reached in approximately 39 months, with a follow-up period 
of 18 months, making the total study duration approximately 57 months, 
excluding the three months of induction therapy.  
This trial is designed to detect a 25% reduction in the hazard rate for death with 
81% power, while maintaining a Bonferroni-adjusted one-sided overall 
significance level of 0.0125 for the bevacizumab versus bevacizumab plus 
pemetrexed comparison and a Bonferroni-adjusted two-sided overall significance 
level of 0.025 for the bevacizumab versus pemetrexed comparison; there is no 
planned statistical comparison of the two experimental arms. The 25% reduction 
in the hazard rate corresponds to a 33.3% improvement in post-induction median 
overall survival, from 12 months to 16 months, assuming exponential survival. 
Full information will be reached at 490 events per comparison. The 
randomization and the primary test will be stratified by gender, stage (IIIB-T4Nx 
(with nodule in ipsilateral lung lobe and not candidates for combined 
chemotherapy and radiation)/IV M1a vs. IV M1b vs. recurrent), smoking history 
(never vs. ever smokers) and response at randomization (CR/PR vs. SD). 
Treatment assignments will be made using permuted blocks within strata with 
dynamic balancing on main institutions plus affiliates. 
Overall survival (OS) is defined as the time from randomization to death from any 
cause.   Patients that are alive at the time of analysis will be censored at the date 
at which they were last known to be alive. Secondary endpoints include 
progression-free survival, best overall response per RECIST, and toxicity. 
9.2 
Interim and Final Analyses 
The study design incorporates a group sequential testing plan using a truncated 
O'Brien-Fleming boundary function at an overall one-sided significance level of 
0.0125 for the bevacizumab versus bevacizumab plus pemetrexed comparison, 
and at an overall two-sided significance level of 0.025 for the bevacizumab 
versus pemetrexed comparison to assess the stratified logrank test at each 
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interim analysis. The bevacizumab versus pemetrexed comparison is two-sided 
because it is of interest to terminate the pemetrexed arm in the event that 
pemetrexed is much worse than bevacizumab. The O'Brien-Fleming group 
sequential boundary adjusts for the sequential testing and the use function 
methodology of Lan and DeMets will be employed to adjust the boundaries if the 
actual interim analyses do not correspond with the projected information times 
provided. 
Power calculations assume a one-sided 0.0125 level log-rank tests and a 
truncated O’Brien Fleming group sequential design (truncated at nominal 
significance level 0.0005) with 6 interim analyses of OS starting at roughly 25% 
information (130 events under the alternative hypothesis, per comparison) and 
one final analysis.  Interim analyses will continue every six months corresponding 
to scheduled ECOG-ACRIN Data Monitoring Committee meetings (at 
approximately 7-16% increments in information).  The final interim analysis will 
occur at approximately 57 months after activation (490 events per comparison).  
If the increment in information is less than 5%, an interim analysis will not be 
conducted.   
If accrual proceeds according to expectation, three interim analyses will be 
performed before accrual is completed.  Full information for the primary endpoint 
of overall survival will occur at 490 events (under the alternative hypothesis, per 
comparison).  More details of the planned interim analyses can be found in Table 
1. 
Table 1: Interim and final Analyses Characteristics for OS, per comparison 
Interim and 
final 
Analysis 
% 
Information 
Estimated 
Upper 
Boundary* 
Approximate 
Time (months) 
Estimated Number of 
Events 
1 
26% 
3.4808 
21 
130 
2 
40% 
3.4808 
27 
195 
3 
54% 
3.3751 
33 
267 
4 
70% 
2.8073 
39 
344 
5 
84% 
2.5542 
45 
410 
6 
93% 
2.4303 
51 
457 
Final 
100% 
2.3615 
57 
490 
* Since the bevacizumab versus pemetrexed comparison is two-sided, the boundary for 
stopping for efficacy is +/- the Estimated Upper Boundary value at each interim analysis. 
The comparison of bevacizumab to the combination of bevacizumab plus 
pemetrexed will also be monitored for futility using repeated confidence interval 
methodology similar to that described by Jennison and Turnbull.  At each interim 
analysis the nominal (1- 2 × alpha) confidence interval on the overall survival 
hazard ratio for this comparison will be computed, where alpha is the nominal 
one-sided significance level of the use function boundary at the information 
fraction for the particular analysis time.  If the confidence interval does not 
contain the target alternative of 0.75, then the data monitoring committee may 
consider terminating the combination arm early for overall lack of treatment 
differences. If the bevacizumab versus bevacizumab plus pemetrexed 
comparison reaches criteria for demonstrating futility, the combination arm will be 
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dropped and the bevacizumab arm and the pemetrexed only arm will continue as 
planned. 
The comparison of bevacizmub to pemetrexed will be monitored for futility using 
repeated confidence interval methodology (as above), and the futility monitoring 
for this comparison will begin after accrual to randomization/Step 2 has been 
completed.  At each interim analysis the nominal (1-alpha) confidence interval on 
the overall survival hazard ratio for this comparison will be computed, where 
alpha is 2 x nominal one-sided significance level of the use function boundary at 
the information fraction for the particular analysis time. If this interval excludes +/- 
log(0.75) at any interim analysis, we may conclude futility. Neither arm will be 
terminated since it would be of great interest to continue follow-up on these arms 
for the complete study duration to provide as much precision as possible for the 
estimated treatment difference, even though this comparison is not powered to 
determine equivalence. The futility analysis for this comparison will be conducted 
despite plans not to terminate an arm so that these results may be released early 
if ECOG-ACRIN Data Monitoring Committee decides that this release would not 
jeopardize further comparison between the two arms. 
If the bevacizumab arm is shown to be inferior to the pemetrexed only arm, the 
entire study will terminate. If the bevacizumab arm is shown to be inferior to the 
bevacizumab plus pemetrexed arm then the bevacizumab arm will be dropped, 
and a chained Bonferroni procedure will be used to shift the primary comparison 
of the study to be of overall survival between pemetrexed and bevacizumab plus 
pemetrexed. This comparison would have adequate power to detect an OS 
hazard ratio of 0.75 while preserving the overall one-sided type I error rate of 
0.0125. If bevacizumab is shown to be inferior in both comparisons, a chained 
Bonferroni procedure will be used to move the type I error for those comparisons 
to one of overall survival between pemetrexed and bevacizumab plus 
pemetrexed.  
If either of the arms, pemetrexed or bevacizumab plus pemetrexed, is suspended 
or closed (whether due to lack of efficacy, toxicity or other considerations), then 
the trial may continue accrual and randomization to the other arms during the 
time that an amendment is being prepared and processed to modify the protocol. 
Continuing accrual until the amendment is prepared is appropriate because the 
clinical questions being tested through this design are individually important, and 
because the study design remains valid if one of the arms containing pemetrexed 
is stopped. 
9.3 
Secondary endpoints 
Progression-Free Survival 
Comparison of progression-free survival (PFS) is a secondary objective, which 
will also be assessed using the stratified log-rank test.  Progression-free survival 
(PFS) is defined to be the time from randomization to progression of disease or 
death from any cause.  Patients that have not had an event reported at analysis 
will be censored at their date last documented to be free of progression.  
Assuming a control median PFS of 6 months and a one-sided 0.0125 level 
logrank test, this study will have 87% power to detect a 33% improvement in the 
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Best Overall Objective Response 
It is also of interest to compare the best overall objective response rates (per 
RECIST). 
Correlative Studies 
Please see respective laboratory research studies (Section 10). 
9.4 
Gender and Ethnicity  
Based on previous data from E4599 the anticipated accrual in subgroups defined 
by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
10 
31 
41 
Not Hispanic or Latino 
645 
809 
1454 
Ethnic Category: Total of all subjects 
655 
840 
1495 
Racial Category 
American Indian or Alaskan Native 
6 
2 
8 
Asian 
10 
6 
16 
Black or African American 
32 
43 
75 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
606 
788 
1394 
Racial Category: Total of all subjects 
655 
840 
1495 
The accrual targets in individual cells are not large enough for definitive 
treatment comparisons to be made within these subgroups. Therefore, overall 
accrual to the study will not be extended to meet individual subgroup accrual 
targets. 
9.5 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Monitoring Committee 
(DMC). The DMC meets twice each year. For each meeting, all monitored 
studies are reviewed for safety and progress toward completion. When 
appropriate, the DMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DMC. Any DMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DMC Policy can be 
obtained from the ECOG-ACRIN Operations Office – Boston. 
 
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10. 
Correlative Studies 
NOTE: 
As of November 3, 2014 all samples are to be submitted to the ECOG-ACRIN 
Central Biorepository and Pathology Facility (CBPF) at MD Anderson.  As of 
this date, the CBPF is the designated biorepository for all samples, including 
those previously submitted, for this trial. 
Research studies will be done to determine possible markers associated with prognosis 
and response to treatment. Specimen submissions are defined in Section 10.1. 
10.1 
Samples Submissions 
Specimens will be submitted from patients who answer “Yes” to “I agree to 
participate in the laboratory research studies that are being done as part of this 
clinical trial”. 
NOTE: 
Institutions outside of the United States and Canada are excluded 
from submitting blood samples because of the costs and problems 
associated with international shipping.  Submission of tissue blocks is 
not exempt. Institutions outside the United States and Canada who 
desire to allow patients to participate in the submission of blood for 
research studies are to contact the ECOG-ACRIN CBPF to discuss 
alternative arrangements for specimen submissions. 
10.1.1 
Sample Schedule 
NOTE: 
Blood samples are to be drawn in the following order: 
ACD, EDTA. 
 
Pre-study 
Step 2, Cycle 2,  
Prior to treatment 
Submit from patients who answer “Yes” to “I agree my tissue will be 
submitted for research” 
Paraffin embedded tumor 1 
X 
 
Submit from patients who answer “Yes” to “I agree to participate in the 
laboratory research studies that are being done as part of this clinical trial.” 
Plasma and residual cells (RBC and 
WBC), two 10 mL K2-EDTA tubes 
X 
X3 
Peripheral blood, two ACD tubes 2 
X 
 
1 
Submit within 1 month of registration to Step 1 with related pathology, 
surgical, immunological reports, and an STS-generated shipping 
manifest. 
2 
Although it is preferred that this specimen be collected prior to start of 
treatment, it may be collected at any time during the trial. EDTA may be 
used if ACD not available. 
3 
If sample is not collected at cycle 2, it may be collected prior to treatment 
on any subsequent cycle. 
It is preferred that the blood specimens be stored at -70°C and 
shipped quarterly on dry ice.  Peripheral blood may be shipped at 
ambient (or cool pack) the day of collection. Tissue blocks are 
submitted at ambient within one month of randomization.   
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NOTE: 
If -70oC or dry ice are not available, specimens must be 
shipped between the day of collection to 4 days after 
collection (if weekend or holiday) utilizing a frozen brick. 
See shipping guidelines. 
Questions about sample collection or submission are to be directed to 
the ECOG-ACRIN -CBPF, 844-744-2420 or by email at 
eacbpf@mdanderson.org. 
10.1.2 
Sample Preparation Guidelines 
Samples must be labeled with the protocol number, ECOG-ACRIN 
patient sequence number, date AND time of collection and sample 
type (serum, plasma, etc.). 
Tissue Samples 
Submit from patients who answer “Yes” to “I agree my tissue will be 
submitted for research.” 
When a patient is randomized to receive protocol therapy, the 
submitting pathologist and clinical research associate should refer to 
Appendix II (Pathology Submission Guidelines).  Materials to be 
submitted are: 
1. Forms: 
 
STS generated shipping manifest 
 
Copy of the surgical pathology report. 
 
Reports of immunologic studies, if performed   
2. Biological Material Submission:  
 
Diagnostic tumor tissue block  
NOTE: 
If a block is unavailable for submission, contact the 
ECOG-ACRIN CBPF (844-744-2420) to obtain 
description of alternative submission requirements. 
Blood Samples 
Submit from patients who answer “Yes” to “I agree to participate in the 
laboratory research studies that are being done as part of this clinical 
trial.” 
Peripheral blood samples are to be drawn in the following order: ACD, 
EDTA. Ideally, blood for the plasma specimens should be processed 
within 2 hours from the time the blood is drawn and must be frozen 
within 4 hours of the blood draw.  The faster the blood can be 
processed from the time of the blood draw to freezing, the better. 
A. Plasma  
1. Draw a minimum of 15-20 mL blood into two 10mL EDTA 
tubes. Mix the blood with the additive by gently inverting the 
tube 5-10 times. To avoid hemolysis, do not mix vigorously.   
2. Centrifuge the blood to separate the plasma from the blood 
cells. Ideally the blood will be centrifuged within 30 minutes of 
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protect it from light by wrapping the tube in foil and storing 
upright in a refrigerator or a bucket of ice.  
Centrifuge the blood at ~3,500 rpm at 4oC for 10 min. If the 
ideal equipment is not available, the minimum requirements 
are 3,000 rpm (~1000 x g) at room temperature for 15 min.  
The longer centrifugation time will help compensate for the 
slower speed. Avoid centrifugations without refrigeration 
longer than 15 min. as excess heat may build up in the unit 
and damage the plasma.   
3. Withdraw the plasma from the vacutainers and place into two 
sterile cryotubes.  Centrifuge the plasma at 1200-1500 rpms 
for 10 minutes. 
4. Carefully draw the plasma into a sterile syringe (or a transfer 
pipette) and then dispense (aliquot) into the labeled cryotubes 
as follows: 
 
Four (4) 1 mL aliquots 
 
Remainder into one (1) 10 mL cryovial 
Securely cap the cryogenic vials. 
5. If the vacutainer is plastic, recap the vacutainers containing 
the residual red and white blood cells. 
6. Freeze the plasma and the residual cells, in an upright position 
if possible, at -70°C or colder, and ship on a quarterly basis. If 
a -70°C freezer is unavailable, alternative shipping guidelines 
are provided below. 
B. Peripheral Blood 
1. Draw blood into two ACD tubes. Invert gently eight to ten times 
to thoroughly mix the blood and anti-coagulant. 
NOTE: 
Specimen may be shipped at ambient temperature 
the day of collection or frozen and shipped with the 
plasma. If frozen, specimens collected in glass 
vacutainers must be transferred to sterile cryovials 
prior to freezing. Plastic vacutainers may be frozen 
directly. 
NOTE: 
If an ACD tube is not available, 10 mL EDTA tubes 
may be substituted. 
10.1.3 
Shipping Guidelines 
To obtain the overnight courier account number, contact ECOG-
ACRIN CBPF, 844-744-2420. 
Specimens from multiple protocols and/or patients may be batch-
shipped together.  
1. Tissue blocks must be submitted at ambient temperature within 1 
month of patient randomization.  
2. Peripheral blood, plasma and residual cells must be shipped via 
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batched at -70°C or colder and shipped on dry ice on a quarterly 
basis.   
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 
10.1.4 
Central Laboratory: Sample Processing and Routing 
The ECOG-ACRIN CBPF will process samples and distribute the 
appropriate materials to investigators for the correlative studies as 
defined below. 
If specimen resources are limited, the priority of research studies will 
be: 
The specimens requested should be adequate to perform all of the 
proposed studies outlined below. DNA PAXgene tube provides 
several micrograms of DNA, with only 10mg needed per SNP assay. 
Tissue specimens will be processed to maximize their utility for 
current and future research, including but not limited to extraction of 
DNA and RNA and construction of tissue microassays (TMAs). 
Blood studies: 
1. SNPs 
2. Plasma for ICAM, VEGF, FGF 
Tissue Studies: 
1. Mutations 
2. Gene expression 
10.1.5 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) 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: Additionally, please note that the STS software creates 
pop-up windows, so you will need to enable pop-ups 
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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. 
10.1.5.1 
Study Specific Notes 
Generic Specimen Submission Form (#2981) (completed 
and faxed to the receiving laboratory) will be required only 
if STS is unavailable at time of sample submission. 
Indicate the appropriate Lab on the submission form: 
 
ECOG-ACRIN CBPF 
To obtain the overnight courier number, contact the CBPF 
(844-744-2420). Retroactively enter all specimen collection 
and shipping information when STS is available. 
10.2 
Genotyping Studies 
The goal of this project is to identify germline polymorphisms associated with 
response, progression-free survival, overall survival, and toxicity in patients with 
NSCLC cancer treated with carbotaxol/taxol +/- Avastin. Establishing 
associations between molecular markers and drug resistance, treatment 
response, and clinical toxicity may ultimately result in more successful and less 
toxic chemotherapeutic regimens for cancer patients. To identify relevant 
markers, we propose to focus on several key pathways, including the DNA repair 
capacity and angiogenesis. These studies will be conducted by Heinz–Joseph 
Lenz, M.D. 
Methods  
Taqman assays.  
The polymorphisms in ERCC-1, XRCC-1, XRCC-3, VEGF, ICAM, FGF  single 
nucleotide polymorphisms and will be assessed using Taqman assays.For the 
Taqman assay, the genomic DNA fragment of interest is PCR amplified. Included 
in the reaction are two hybridization probes complementary to either the wildtype 
or the variant allele. The two probes are labeled with different reporter dyes and 
a quencher dye. Hybridization conditions are chosen such that the probes do not 
anneal when there is a mismatch; e.g., the wildtype primer does not anneal to the 
variant PCR fragment and vice versa. During PCR amplification, the 5' 
exonuclease activity of Taq polymerase cleaves the 5' reporter dye from a probe 
that annealed to the template. The instrument measures the fluorescence 
generated by the reporter dye released from the wildtype and variant probes. In 
samples that are homozygous either for wildtype or for the variant, signal from 
only one probe is detected. For heterozygous samples, signal from both probes 
is detected. The advantages of using an ABI PRISM 7900 for genotyping are a 
decreased sensitivity to PCR artifacts (non-specific amplification), reduction of 
the number of procedures required and the potential error associated with them, 

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and the fact that lower amounts of genomic DNA template can be used. Our 
Taqman assays are validated by genotyping 100-200 individuals using both the 
Taqman assay and an alternate assay, usually RFLP or sequencing. A Taqman 
assay is considered validated if there are no discrepancies between the two 
assays.  
Tandem repeat analysis. 
The polymorphisms in the EGF-R and TS are tandem repeats or deletion and 
can be assessed based on the different length of PCR fragment amplified. One 
of the PCR primers is tagged with a fluorescent dye, thus labeling the PCR 
fragment during amplification. The fragments are separated on an ABI3100 
genetic analyzer and the allele length determined using previously sequenced 
alleles as a standard. 
Quality control.  
We use several approaches to minimize contamination and monitor quality 
control in the conduct of the genotyping assays: 1) all reagents are prepared with 
dedicated or disposable vessels, solutions, and pipettes and 2) positive 
displacement pipettes or air-displacement pipettes with aerosol-resistant tips are 
used for reaction assembly and sample analysis. To detect contamination, each 
batch of samples includes one blank, containing all reagents, but no DNA. 
Taqman assays also include control DNAs with known genotypes. The accuracy 
of the genotyping assays will be tested by repeating the assay for 15% of 
randomly chosen samples. For Taqman assays, an additional 10% of samples 
will be genotyped using either an RFLP method or sequencing. If discrepancies 
are found, the assay results will be carefully investigated and potential reasons 
for discrepancies will be explored. Assays will be repeated a third time. If no clear 
result can be obtained, the sample will be sequenced and all assays will be 
repeated if necessary. 
10.2.1 
Germline Polymorphisms associated with Response, Progression 
Free Survival and Overall Survival 
Angiogenesis 
Schneider and colleagues (25) recently reported their SNP analysis 
from E2100, demonstrating that the VEGF-2578 AA genotype was 
associated with a superior median overall survival (OS) in the 
combination arm when compared with the alternate genotypes 
combined (hazardratio = 0.58; 95% CI, 0.36 to 0.93; P = .023).The 
VEGF-1154 A allele also demonstrated a superior median OS with an 
additive effect of each active allele in the combination arm but not the 
control arm (hazard ratio = 0.62; 95%CI, 0.46 to 0.83; P = .001).  
Drug Transporter  
Pgp is a drug efflux pump that transports natural products, including 
taxanes and other chemotherapeutic agents, from cells. Several 
frequent polymorphisms in ABCB1 may influence Pgp levels and drug 
efflux. Johnatty and colleagues recently evaluated the correlation 
between ABCB1 2677G>T/A, 3435C>T, and 1236C>T 
polymorphisms and progression-free and overall survival in 309 
patients from the Australian Ovarian Cancer Study who were treated 
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at 2677, women with the minor T/A alleles were significantly less likely 
to relapse after treatment (P=0.01).  
DNA repair  
DNA repair capacity plays a critical role in the development of drug 
resistance in tumors, inionizing radiation, drugs targeting folate 
metabolism, as well as other drugs commonly used in colorectal 
cancer treatment. A better knowledge of the role of DNA repair 
capacity and genotype in tumor response, survival and toxicity may 
prove a useful tool in determining the best treatment strategies. ERCC 
is a promising predictive marker for cisplatin sensitivity in patients with 
NSCLC. A number of studies have demonstrated by 
immunohistochemistry (IHC) as well as RT-PCR that high baseline 
levels of ERCC predict poor response to cisplatin based 
chemotherapy. The strongest evidence is reported by Cobo and 
colleagues, who initially randomized patients to receive genotype 
guided therapy or usual therapy (19). Patients who were not 
genotyped received docetaxel/cisplatin while patients on the 
genotyping arm had ERCC1 status evaluated by RT-PCR and were 
assigned treatment based on gene expression; low expressers 
received docetaxel/cisplatin while high expressers received 
docetaxel/gemcitabine. Of the 346 patients assessable for response, 
objective response was attained by 53 patients (39.3%) in the control 
arm and 107 patients (50.7%) in the genotypic arm (P = .02), 
suggesting that selection of therapy by ERCC gene expression may 
be clinically beneficial (19).Since gene expression analysis is difficult 
in multi-center clinical trials, a number of investigators have evaluated 
SNPs in ERCC1 as surrogates for gene expression. This is based on 
in vitro models where the ERCC1-118 T allele variant was associated 
with higher ERCC1 mRNA levels than those observed in the presence 
of the ERCC1-118 C allele. Ryu evaluated ERCC1 polymorphisms in 
NSCLC patients receiving chemotherapy with cisplatin combinations, 
demonstrating, median survival time in patients showing C/C 
genotype was 486 days (95% CI, 333-not reached), which was 
significantly different from the 281 days (95% CI, 214-376) of patients 
with the variant genotype (T/T or C/T) (P = 0.0058). Whether this 
relationship translates to carboplatin will be evaluated in this proposal 
(23). In the second stage of the trial, subjects will be randomized to 
pemetrexed, bevacizumab or a combination of pemetrexed and 
bevacizumab.  
Our group, as well as others, has shown that these genetic variants 
can affect treatment outcomes of patients treated with antifolate 
therapies or 5-FU/platinum combination regimens.(46, 49, 45) The 
most common DNA alterations induced by anticancer agents are: 
base damages, single and double strand breaks, bulky adduct, 
mispaired bases, and alkylated bases. We propose to study common 
polymorphisms that may affect the function of genes that play key 
roles in these pathways, such as:  X-ray cross complementing type 1 
gene (XRCC1), involved in base excision repair; X-ray cross 
complementing type 3 gene (XRCC3), involved in homologous 
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and Excision repair cross-complementing type 1 gene (ERCC1) 
involved in nucleotide excision repair. Our own data support that gene 
expression levels of ERCC-1 and germline polymorphisms of XRCC-
1, ERCC-1 and XPD are associated with response and overall 
survival in patients with colon cancer treated with 5-FU/oxaliplatin 
chemotherapy. This indicates that DNA repair enzymes may play a 
significant role in efficacy of chemotherapy (49, 48, 46). Our 
hypothesis is that high levels of gene expressions levels of DNA 
repair enzymes will predict for tumor response and survival in patients 
with metastatic colorectal cancer treated with chemotherapy and that 
germline polymorphisms of DNA repair enzymes associated with high 
enzyme activity may be associated with decreased toxicity, improved 
response and survival to chemotherapy therapy.   
5-FU metabolism  
Pemetrexed has three intracellular targets, DHFR, TS and GARFT, all 
with polymorphic variability although little appears to be known about 
pemetrexed pharmacogenomics. Bepler and colleagues conducted a 
trial of neoadjuvant gemcitabine and pemetrexed (17). Like ERCC1, 
evaluation of mRNA in fresh tumor specimens in multi-institutional 
trials is impractical and polymorphisms in TSER have been evaluated 
as surrogate markers of TS expression. Polymorphic tandem repeats 
located in the TS enhancer region (TSER) influence TS expression. 
Three copies (TSER*3) of the tandem repeat give a 2.6-fold greater in 
vitro TS expression than 2 copies (TSER*2) and approximately 30% 
of Caucasians are TSER*3/TSER*3. Alleles containing 4 (TSER*4), 5 
(TSER*5), and 9 (TSER*9) copies of the tandem repeat have also 
been identified, although the phenotypic effect of these alleles is 
uncertain (22). The TSER*3/TSER*3 genotype has been associated 
with poorer survival after adjuvant 5FU based chemotherapy in stage 
III colon cancer as well as a poor response to neoadjuvant 5-FU for 
rectal or metastatic colorectal disease. An exploratory analysis to 
evaluate the relationship between TSER polymorphisms and benefit 
from pemetrexed will be conducted. 
10.2.2 
Impact of Polymorphisms in CYP2C8 (rs1058932) and TUBB 
(rs3132584) on Toxicity Related to Paclitaxel 
Rogatko and colleagues at Emory University evaluated a panel of 
candidate SNPs for several of the CYP450s and tubulins in 30 
patients with advanced malignancies that received treatment with 
paclitaxel at standard doses (56). Paclitaxel is primarily metabolized 
by CYP2C8 and CYP3A4 enzymes. The Toxicity Index (TI) was used 
as a measure of overall severity of adverse events during the first 
cycle. Polymorphisms in CYP2C8 (rs1058932) and TUBB 
(rs3132584) were found to be independent predictors of TI (p-value = 
0.008), whereas paclitaxel dose was not. These two markers and 
potentially other variations at these genetic loci may enable novel 
medical response testing for adverse events and safety prior to drug 
administration. Based on these preliminary data, we hypothesize that 
evaluation of patient samples for these polymorphisms will help in 
predicting toxicity related to paclitaxel such as grade 3/4 neutropenia 
and neuropathy. We also intend to study the correlation between such 

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polymorphism and response to therapy in patients with advanced 
NSCLC. Prior to treatment with paclitaxel, peripheral blood from 
participating patients will be collected for DNA isolation from 
peripheral blood mononuclear cells.  
To demonstrate a difference of 20% in the proportion of patients 
experiencing a particular toxicity or response in the two polymorphism 
groups (assuming rates of 20% and 40% in the groups), 216 patient 
samples will give 90% power at a 1-sided type I error rate of .025. 
This calculation assumes that these samples are equally distributed in 
the two polymorphism groups and that the statistical test does not 
implement a continuity correction. To detect a difference of 15% (35% 
vs. 50%) 452 samples would be required to maintain the same 
significance level and power.  
10.3 
Population Pharmacokinetics of Bevacizumab and Pemetrexed to Predict 
Toxicity and Response 
10.3.1 
Bevacizumab Pharmacokinetics 
A population pharmacokinetic analysis of 491 patients estimated the 
half-life of bevacizumab at 20 days, showing the accumulation ratio 
following a dose of 10 mg/kg of bevacizumab every 2 weeks was 2.8. 
and that the clearance of bevacizumab varied by body weight,  
gender, and tumor burden (Lu, 2008). Given the long half-life of 
bevacizumab and significant accumulation with repeat dosing, Dr. 
Kolesar’s laboratory will perform a population pk analysis to evaluate 
the association between bevacizumab pharmacokinetics and toxicity.  
10.3.2 
Pemetrexed Pharmacokinetics 
Latz et al., have evaluated the population pharmacokinetics to 
determine the influence of co-variates on pemetrexed induced 
neutropenia, showing that ethnicity, dug exposure and vitamin 
supplementation were the dominant predictors of neutropenia (59).  In 
an earlier study, Latz and colleagues used pooled data from phase II 
populations, reporting that the terminal elimination half-life of 
pemetrexed was approximately 3.5 hours and that renal function was 
a predictor of clearance (60) 
To date, no population model has considered the influence of 
pharmacogenetics on pemetrexed response and toxicity.  In a recently 
reported phase II trial, Adjei and colleagues demonstrated that a 
polymorphism in the folate transporter gene, SLC19A1 correlated with 
3-month progression-free status  and with PFS , and that a number of 
polymorphisms were associated with toxicity (58).  
Dr. Kolesar’s laboratory will perform a population pk analysis to 
evaluate the association between pemetrexed pharmacokinetics and 
toxicity in patients treated with pemetrexed with or without 
bevacizumab, with polymorphisms in folate transport and metabolism 
modeled as covariates.   

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10.4 
Banking 
Residual material from the samples submitted and analyzed by the designated 
laboratories will be forwarded to and retained at the ECOG-ACRIN Central 
Repository for possible use in future ECOG-ACRIN approved studies. Any 
residual blocks will be available for purposes of individual patient management 
on specific written request. If future use is denied or withdrawn by the patient, the 
samples will be removed from consideration for use in any future study. 
10.5 
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. 
10.6 
Lab Data Transfer Guidelines 
The data collected on the above mentioned correlative study(ies) will be 
submitted electronically 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 E5508 Forms Packet for the forms submission schedule and copies 
of all forms. The E5508 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 will be used in support of a US marketing application (New Drug 
Application), 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. 
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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17. Bepler G, Sommers KE, Cantor A, Li X, Sharma A, Williams C, Chiappori A, Haura 
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19. Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M, Viñolas N, Paz-
Ares L, Lopez-Vivanco G, Muñoz MA, Felip E, Alberola V, Camps C, Domine M, 
Sanchez JJ, Sanchez-Ronco M, Danenberg K, Taron M, Gandara D, Rosell R. 
Customizing cisplatin based on quantitative excision repair cross-complementing 1 
mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol. 
2007 Jul 1;25(19):2747-54. 
20. Johnatty SE, Beesley J, Paul J, Fereday S, Spurdle AB, Webb PM, Byth K, Marsh 
S, McLeod H; AOCS Study Group, Harnett PR, Brown R, DeFazio A, Chenevix-
Trench G. ABCB1 (MDR 1) polymorphisms and progression-free survival among 
women with ovarian cancer following paclitaxel/carboplatin chemotherapy. Clin 
Cancer Res. 2008 Sep 1;14(17):5594-601. 
21. Krohne TU, Eter N, Holz FG, Meyer CH. Intraocular pharmacokinetics of 
bevacizumab after a single intravitreal injection in humans. Am J Ophthalmol. 2008 
Oct;146(4):508-12. 
22. Marsh S, McLeod HL. Pharmacogenetics and oncology treatment for breast 
cancer. Expert Opin Pharmacother. 2007 Feb;8(2):119-27. 
23.  Ryu JS, Hong YC, Han HS, Lee JE, Kim S, Park YM, Kim YC, Hwang TS. 
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24. Schmid M, Malicki D, Nobori T, Rosenbach MD, Campbell K, Carson DA, Carrera 
CJ. Homozygous deletions of methylthioadenosine phosphorylase (MTAP) are 
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25. Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, Flockhart DA, 
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factor and vascular endothelial growth factor receptor-2 genetic polymorphisms 
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26. Greer EL, and Brunet A. FOXO transcription factors at the interface between 
longevity and tumor suppression. Oncogene. 2005; 24:7410-7425. 
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arrest downstream of PTEN. Mol. Cell Biol. 2000; 20:8969-8982. 
28. Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N. FOXO forkhead 
transcription factors induce G(2)-M checkpoint in response to oxidative stress. J. 
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29. Fernández de Mattos S, Villalonga P, Clardy J, Lam EW. FOXO3a mediates the 
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30. Guicherit OM, Rudolph FB, Kellems RE, Cooper BF. Molecular cloning and 
expression of a mouse muscle cDNA encoding adenylosuccinate synthetase. J 
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31. Taguchi F, Solomon B, Gregorc V, Roder H, Gray R, Kasahara K, Nishio M, 
Brahmer J, Spreafico A, Ludovini V, Massion PP, Dziadziuszko R, Schiller J, 
Grigorieva J, Tsypin M, Hunsucker SW, Caprioli R, Duncan MW, Hirsch FR, Bunn 
PA, Jr., Carbone DP. Mass spectrometry to classify non-small-cell lung cancer 
patients for clinical outcome after treatment with epidermal growth factor receptor 
tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst. 
2007;99:838-846. 
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cyclo-oxygenase-2 by activation of tyrosine kinase in bovine endothelial cells 
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Semin Oncol 29(6 Suppl 17): 21-5. 
39. Dedhar, S. and R. Saulnier (1990). Alterations in integrin receptor expression on 
chemically transformed human cells: specific enhancement of laminin and collagen 
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40. Ferrara, N. (1999). Role of vascular endothelial growth factor in the regulation of 
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41. Ferrara, N. and T. Davis-Smyth (1997). The biology of vascular endothelial growth 
factor. Endocr Rev 18(1): 4-25. 
42. Furukawa, T., A. Yoshimura, et al. (1992). Angiogenic factor. Nature 356(6371): 
668. 
43. Hurwitz, H., L. Fehrenbacher, et al. (2004). Bevacizumab plus irinotecan, 
fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23): 
2335-42. 
44. Johnson, D. H., L. Fehrenbacher, et al. (2004). Randomized phase II trial 
comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and 
paclitaxel alone in previously untreated locally advanced or metastatic non-small-
cell lung cancer." J Clin Oncol 22(11): 2184-91. 
45. Krajinovic, M., D. Labuda, et al. (2002). Polymorphisms in genes encoding drugs 
and xenobiotic metabolizing enzymes, DNA repair enzymes, and response to 
treatment of childhood acute lymphoblastic leukemia. Clin Cancer Res 8(3): 802-
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47. Marsh S, McLeod HL. Pharmacogenetics and oncology treatment for breast 
cancer. Expert Opin Pharmacother. 2007 Feb;8(2):119-27. 

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47. Park, D. J., J. Stoehlmacher, et al. (2001). A Xeroderma pigmentosum group D 
gene polymorphism predicts clinical outcome to platinum-based chemotherapy in 
patients with advanced colorectal cancer.Cancer Res 61(24): 8654-8. 
48. Sandler, A., R. Gray, et al. (2005). Randomized phase I/II trial of paclitaxel plus 
carboplatin with or without bevacizumab in patients with advanced non-squamous 
non-small cell lung cancer: An Eastern Cooperative Oncology Group Trial-E4599. J 
Clin Oncol 23(Abstract # LBA4,2). 
49. Shirota, Y., J. Stoehlmacher, et al. (2001). ERCC1 and thymidylate synthase 
mRNA levels predict survival for colorectal cancer patients receiving combination 
oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 19(23): 4298-304. 
50. Stoehlmacher, J., V. Ghaderi, et al. (2001). A polymorphism of the XRCC1 gene 
predicts for response to platinum based treatment in advanced colorectal cancer. 
Anticancer Res 21(4B): 3075-9. 
51. Streit, M., R. Schmidt, et al. (1996). Adhesion receptors in malignant 
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52. Takahashi, Y., C. D. Bucana, et al. (1996). Platelet-derived endothelial cell growth 
factor in human colon cancer angiogenesis: role of infiltrating cells. J Natl Cancer 
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53. Takahashi, Y., S. L. Tucker, et al. (1997). Vessel counts and expression of 
vascular endothelial growth factor as prognostic factors in node-negative colon 
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54. Toi, M., K. Inada, et al. (1995). Tumor angiogenesis in breast cancer: its 
importance as a prognostic indicator and the association with vascular endothelial 
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55. Yoshiji, H., D. E. Gomez, et al. (1996). Expression of vascular endothelial growth 
factor, its receptor, and other angiogenic factors in human breast cancer. Cancer 
Res 56(9): 2013-6. 
56. Zhang, W., J. Stoehlmacher, et al. (2005). Gene polymorphisms of epidermal 
growth factor receptor and its downstream effector, interleukin-8, predict oxaliplatin 
efficacy in patients with advanced colorectal cancer. Clin Colorectal Cancer 5(2): 
124-31. 
57. Rogato A, Babb JA, Wang H, Slifker MJ, Hudes GR. Patient characteristics 
complete with dose as predictors of acute treatment toxicity in early phase clinical 
trials. Clinical cancer Res 2004; 10: 4654-51. 
58. Adjei AA, Mandrekar SJ, Dy GK, Molina JR, Adjei AA, Gandara DR, Allen Ziegler 
KL, Stella PJ, Rowland KM Jr, Schild SE, Zinner RG. Phase II Trial of Pemetrexed 
Plus Bevacizumab for Second-Line Therapy of Patients With Advanced Non-Small-
Cell Lung Cancer: NCCTG and SWOG Study N0426. J Clin Oncol. 2009 Oct 19. 
[Epub ahead of print] 
59. Latz JE, Schneck KL, Nakagawa K, Miller MA, Takimoto CH. Population 
pharmacokinetic/pharmacodynamic analyses of pemetrexed and neutropenia: 
effect of vitamin supplementation and differences between Japanese and Western 
patients. Clin Cancer Res. 2009 Jan 1;15(1):346-54  
60. Latz JE, Chaudhary A, Ghosh A, Johnson RD. Population pharmacokinetic 
analysis of ten phase II clinical trials of pemetrexed in cancer patients. Cancer 
Chemother Pharmacol. 2006 Apr;57(4):401-11. Epub 2005 Dec 2. 

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Randomized Phase III Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or 
a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and 
Bevacizumab for Advanced Non-Squamous NSCLC  
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Addendum 8] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Addendum 8 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines. 

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Randomized Phase III Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or 
a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and 
Bevacizumab for Advanced Non-Squamous NSCLC  
Appendix II 
 
ECOG Performance Status 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden. Completely disabled.  
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 

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a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and 
Bevacizumab for Advanced Non-Squamous NSCLC 
Appendix III 
 
Pathology Submission Guidelines 
The following items are included in Appendix III: 
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 E5508 
4. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
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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) 
Institutions specimen-specific accession 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 Generic Specimen Submission 
Form, to the appropriate pathologist. 
3. 
The pathologist should return the required pathology samples and surgical 
pathology reports, along with the completed ECOG-ACRIN Generic Specimen 
Submission Form (#2981). If any other reports are required, they should be 
obtained from the appropriate department at this time. 
4. 
Use the  ECOG-ACRIN Generic Specimen Submission Form (#2981) as a 
reference for data entry into STS and keep for your records. 
5. 
Double-check that ALL required forms, reports, STS-generated shipping 
manifest, 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 
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 844-744-2420 or by email at eacbpf@mdanderson.org. 
Rev. 12/14 
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List of Required Material 
E5508:  Randomized Phase III Study of Maintenance Therapy with Bevacizumab 
Pemetrexed or a Combination of Bevacizumab and Pemetrexed Following 
Carboplatin Paclitaxel and Bevacizumab for Advanced Non-Squamous NSCLC 
Pre-Treatment 
1. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
2. Institutional pathology report (must be included with EVERY pathology 
submission). 
3. Reports of immunological or cytological studies 
4. Biological materials 
 
Diagnostic or surgical tumor tissue block.  
If blocks are not available, contact the CBPF to discuss alternative specimen 
submission requirements. 
NOTE:  
Blocks will be returned upon written request for purposes of patient 
management.  Be aware, 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. 12/14 

 
99 
MEMORANDUM 
TO:  
_____________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________ 
SUBJECT: 
Submission of Pathology Materials for E5508: Randomized Phase III 
Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or a 
Combination of Bevacizumab and Pemetrexed Following Carboplatin, 
Paclitaxel and Bevacizumab for Advanced Non-Squamous NSCLC 
 
The patient named on the attached ECOG-ACRIN Generic Specimen Submission Form 
(#2981) has been entered onto an ECOG-ACRIN protocol by 
______________________________ (ECOG-ACRIN Investigator). This protocol 
requires the submission of pathology materials for laboratory research studies and 
banking. 
Please complete 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. 
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 844-744-2420 or by email at 
eacbpf@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 
 
Rev.12/14, 7/15 

ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3 
Page 1 of 1 
100 
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 
E5508 
Cancer Research Group 
Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
101 
Randomized Phase III Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or 
a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and 
Bevacizumab for Advanced Non-Squamous NSCLC 
Appendix IV 
 
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. I and my research staff will 
maintain very close contact with you. This will allow me 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 
E5508 
Cancer Research Group 
Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
102 
Randomized Phase III Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or 
a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and 
Bevacizumab for Advanced Non-Squamous NSCLC 
Appendix V 
 
E5508 Shipment Notification Form 
 
NOTE: 
If the Sample Tracking System (STS) is unavailable at time of sample 
submission, complete a Generic Specimen Submission Form (#2981) and 
faxed to the receiving laboratory at 713-563-6506.  Indicate the appropriate 
Lab on the submission form: 
 
ECOG-ACRIN CBPF 
To obtain the overnight courier number, contact the CBPF (844-744-2420). Retroactively 
enter all specimen collection and shipping information when STS is available 
 
Rev. 12/14 
Rev.7/15 

ECOG-ACRIN 
E5508 
Cancer Research Group 
Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
103 
Randomized Phase III Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or 
a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and 
Bevacizumab for Advanced Non-Squamous NSCLC 
Appendix VI 
 
Cockcroft and Gault Formula 
 
Creatinine Clearance 
The standard Cockcroft and Gault formula or the measured glomerular filtration rate 
(GFR), using the appropriate radiolabeled method (51-CrEDTA or Tc99m-DTPA), must 
be used to calculate CrCl for registration or dosing. The same method used at baseline 
should be used throughout the study. No dose adjustment is needed in patients with 
creatinine clearance > 45 mL/min. Insufficient numbers of patients have been studied 
with creatinine clearance < 45 mL/min to give a dose recommendation; therefore, 
pemetrexed should not be administered to patients whose creatinine clearance is <45 
mL/min. 
 
Female Ccr = 
(140 - age in years) x (weight in kgs) x 0.85 
72 x serum creatinine in mg/dl 
 
Male  Ccr = 
(140 - age in years) x (weight in kgs) 
72 x serum creatinine in mg/dl 
 

ECOG-ACRIN 
E5508 
Cancer Research Group 
Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
104 
Randomized Phase III Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or 
a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and 
Bevacizumab for Advanced Non-Squamous NSCLC 
Appendix VII 
 
Medication Diary for Folic Acid 
Please complete this diary on a daily basis. Write in the amount of the dose of folic acid that you 
took in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your 
daily dose, please write in “0”, but remember to take your prescribed dose at the next regularly 
scheduled time. 
If you experience any health/medical complaints or take any medication other than those in this 
study, please record this information. 
Other study drugs will be administered by a healthcare professional. As a result, patients do not 
have to record these treatments in this diary. 
You should begin taking folic acid once a day starting one week before your first treatment and 
continue to take it daily until 21 days after your last dose of pemetrexed. 
Cycle # (Month): 
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Folic Acid 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Folic Acid 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Folic Acid 
 
 
 
 
 
 
 
 

ECOG-ACRIN 
E5508 
Cancer Research Group 
Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
105 
HEALTH/MEDICAL COMPLAINTS 
Please record all health/medical complaints you may have experienced below. 
Please describe what you experienced 
Date started 
Date stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OTHER MEDICATION 
Record only medication (prescription and/or over-the-counter, including herbal medications and 
vitamins) taken other than carboplatin, paclitaxel, bevacizumab, or pemetrexed. 
Name of Medication 
Why did you take the 
medication? 
Date medication 
started? 
Date medication 
stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_________________________________________________________ 
Patient Signature 
___________________________ 

ECOG-ACRIN 
E5508 
Cancer Research Group 
Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
106 
Randomized Phase III Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or 
a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and 
Bevacizumab for Advanced Non-Squamous NSCLC 
 
Version Date: September 19, 2011 
Appendix VIII 
 
Docetaxel Treatment Plan 
If a site is experiencing shortage of paclitaxel drug supply, the patient can be treated with 
docetaxel instead of paclitaxel. The dose of docetaxel and dose modification guidelines is 
described below. Carboplatin and bevacizumab should be administered as described in the 
protocol. For any questions related to this issue, please contact the study chair. 
Docetaxel 
Dosage 
 
Docetaxel will be administered 75 mg/m2 IV over 60 minutes on Day 1 of every 21-day 
cycle.  
 
Dose increases of docetaxel are not permitted in subsequent cycles, other than dose 
increases that result from recalculation based on the patient’s current weight. 
Premedication 
 
Premedication with dexamethasone decreases incidence and severity and delays the onset 
of late-occurring fluid retention and also may decrease the incidence and severity of acute 
hypersensitivity reactions. Dexamethasone 4-8 mg po bid x 3 days, starting 12-24 hours 
before the planned docetaxel infusion has been an effective schedule.  
 
Docetaxel is to be obtained by the investigator from commercial sources. The 
manufacturer’s recommendations or institutional protocol regarding preparation, 
administration, storage, stability, and precautions for handling should be followed 
Toxicity Management and Dose Modification 
 
Hold treatment on Day 1 of a new cycle if ANC ≤ 1.5 x 109/L and platelets ≤ 100 x 109/L.  
 
Treatment may be delayed up to 14 days to allow sufficient time for recovery from 
hematologic or non-hematologic toxicities for the docetaxel, carboplatin, bevacizumab 
regimen  
 
Treatment should be discontinued if any hematologic or non-hematologic Grade 3 or 4 
toxicities occur after a maximum of 2 dose reductions of docetaxel and carboplatin. 
 
All patients will receive standard supportive care, including blood and platelet transfusions, 
antibiotics, and antiemetics, as appropriate. Granulocyte colony-stimulating factor may be 
administered as needed after completion of Cycle 1 if there is persistent neutropenia despite 
dose reductions during the previous cycle or as secondary prophylaxis.  
 
Dose modifications of docetaxel to 75% of the previous dose at the start of a subsequent 
cycle should be based on nadir hematologic counts or maximum non-hematologic toxicity 
from the preceding cycle of therapy. Upon recovery, patients should be retreated using the 
following guidelines: 
 
Neutropenia 
 
Grade 1 or 2 do not require dose modifications 

ECOG-ACRIN 
E5508 
Cancer Research Group 
Version Date: October 12, 2018 
 
NCI Update Date: December 8, 2014 
107 
 
Grade 3 and 4 with recovery prior to next planned dose do not require dose 
modifications with the following exceptions: 
 
Grade 4 afebrile neutropenia ≥ 7 days 
 
Grade 4 neutropenia associated with fever (one reading of oral 
temperature > 38.5o C, or three readings of oral temperature > 38.0o C in 
a 24-hour period 
 
Thrombocytopenia 
 
Grade 4 thrombocytopenia requires a dose reduction 
 
Anemia 
 
There are no specific recommendations for the management of anemia 
 
Hepatic Dysfunction 
 
Both AST and ALT should be drawn and the more normal of the two values (AST 
or ALT) should be used in determining the dose: 
 
 
 
 
 
 
 
*Hold until recovered, maximum 14 days, then re-treat at a reduced dose. “Recoverved” 
is defined as meeting the study baseline eligibility criteria. 
 
Bilirubin 
 
Docetaxel should not be administered to patients with serum bilirubin > ULN. If 
serum total bilirubin is > ULN on treatment day, hold docetaxel until serum total 
bilirubin is ≤ ULN (maximum 14 days), then re-treat at reduced dose 
 
Stomatitis 
 
If stomatitis is present on day 1 of any cycle, treatment should be withheld until 
stomatitis has resolved 
 
If Grade 3 or 4 stomatitis occurs at any time the dose of docetaxel should be 
reduced for subsequent cycles 
 
Peripheral Neuropathy 
 
The docetaxel dose should be reduced for Grade 2 neuropathies without 
treatment delay 
 
Treatment should be discontinued for Grade 3 or 4 neuropathies 
 
Hypersensitivity Reactions 
 
There are no dose reductions for hypersensitivity reactions 
 
For any additional issues, the study chair should be contacted. 
 
 
AST or ALT: 
ALK PHOS: 
≤ ULN 
> 1x but ≤ 1.5x 
> 1.5x but ≤ 5x 
> 5x ULN 
≤ ULN 
Full Dose 
Full Dose 
Full Dose 
Hold* 
> 1x but ≤ 2.5x 
Full Dose 
Full Dose 
Reduce Dose 
Hold* 
> 2.5x but ≤ 5x 
Full Dose 
Reduce Dose 
Hold* 
Hold* 
> 5x ULN 
Hold* 
Hold* 
Hold* 
Hold*