Clinical trial NCT01263782
Conditions: Lung Cancer
Keywords: Non-Small Cell Lung Cancer NSCLL Nonsquamous cell Metastatic disease Cixutumumab IMC-A12 Carboplatin Paraplatin Pemetrexed LY231514 Alimta MTA Multitargeted Antifolate NSC-698037 Bevacizumab Avastin Anti-VEGF monoclonal antibody rhuMAb-VEGF
Sponsor: M.D. Anderson Cancer Center
Start date: 2011-05-17; Completion date: 2017-08-15
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if knowing biomarker status can help researchers find better treatment combinations for patients with advanced NSCLC.

Researchers want to use biomarker status to decide what drug (bevacizumab, or cixutumumab) to give in combination with carboplatin and pemetrexed. The safety of these drug combinations will also be studied.

Detailed description:
The Study Drugs:

Carboplatin is designed to interfere with the growth of cancer cells by stopping cell division, which may cause the cells to die.

Pemetrexed is designed to block enzymes in the body that play a part in tumor growth.

Bevacizumab is designed to block the growth of blood vessels that supply nutrients necessary for tumor growth. This may prevent or slow down the growth of cancer cells.

Cixutumumab is a monoclonal antibody, which means that it attaches to specific targets on cancer cells. These targets are called IGF-1R and help the cancer cells grow and divide. Cixutumumab is designed to block these receptors on tumor cells that may cause tumors to grow.

Study Groups and Drug Administration (Combination Therapy):

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of dice) to 1 of 3 groups. You will have an equal chance of being assigned to each group. Each cycle is 21 days (+/- 5 days).

* If you are in Group 1, you will receive carboplatin and pemetrexed on Day 1 of each cycle. Carboplatin will be given by vein over 10 minutes. Pemetrexed will be given by vein over 30 minutes.
* If you are in Group 2, you will receive bevacizumab, carboplatin, and pemetrexed on Day 1 of each cycle. Bevacizumab will be given by vein over about 90 minutes for the first dose, about 60 minutes for the second dose, and about 30 minutes for all other doses. Carboplatin will be given by vein over 10 minutes. Pemetrexed will be given by vein over 30 minutes.
* If you are in Group 3, you will receive cixutumumab, carboplatin, and pemetrexed on Day 1 of each cycle. Cixutumumab is given by vein over 60 minutes. Carboplatin will be given by vein over 10 minutes. Pemetrexed will be given by vein over 30 minutes.

Study Visits During Combination Therapy:

If you are in Group 3, before you begin receiving study drugs, you will have a hearing test.

On Day 1 (+/- 5 days) of Cycles 1, 2, and 4:

* You will have a physical exam, including measurement of your weight and vital signs.
* You will be asked about any drugs you may be taking and any side effects you may be having.
* Your performance status will be recorded.
* Blood (about 3 teaspoons) will be drawn for routine tests.
* If you are in Group 2, urine will be collected for routine tests.

On Days 8 and 15 of Cycle 1:

°If you are in Group 3, blood (about 1 teaspoon) will be drawn for routine tests.

On Day 1 of Cycle 3:

* You will have a physical exam, including measurement of your weight and vital signs.
* You will be asked about any drugs you may be taking and any side effects you may be having.
* Your performance status will be recorded.
* Blood (about 3 teaspoons) will be drawn for routine tests.
* You will have a CT scan and/or MRI scan of the chest (and abdomen if the doctor thinks it is needed) to check the status of the disease.
* You will have an MRI scan of the brain.
* You will have a chest x-ray to check the status of the disease.
* If you are in Group 2, urine will be collected for routine tests.

At any time your doctor thinks it may be needed, blood (about 1 teaspoon) will be drawn to check how well your blood clots.

Maintenance Therapy:

After you have completed 4 cycles of combination therapy, you may be eligible for maintenance therapy.

If you are in Group 1,you will receive pemetrexed by vein over 10 minutes on Day 1 (± 5 days) of every 21-day cycle.

If you are in Group 2, you will receive pemetrexed by vein over 10 minutes and bevacizumab over about 30 minutes on Day 1 (± 5 days) of every 21-day cycle.

If you are in Group 3, you will receive pemetrexed by vein over about 10 minutes and cixutumumab by vein over about 60 minutes on Day 1 (± 5 days) of every 21-day cycle.

Study Visits During Maintenance Therapy:

On Day 1 of each cycle:

* You will have a physical exam, including measurement of your weight and vital signs.
* You will be asked about any drugs you may be taking and any side effects you may be having.
* Your performance status will be recorded.
* Blood (about 3 teaspoons) will be drawn for routine tests.
* You will have a CT scan and/or MRI scan of the chest (and abdomen if the doctor thinks it is needed) to check the status of the disease.
* You will have an MRI scan of the brain.
* You will have a chest x-ray to check the status of the disease.
* If you are in Group 2, urine will be collected for routine tests.

Length of Study:

You may continue taking the study drug(s) for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse or intolerable side effects occur.

Your participation on the study will be over once you have completed the end-of-dosing visit and follow-up.

End-of-Dosing Visit:

When you go off study for any reason, you will have an end-of-dosing visit. The following tests and procedures will be performed:

* Your medical history will be recorded.
* You will have a complete physical exam, including measurement of your weight and vital signs.
* You will be asked about any drugs you may be taking and any side effects you may be having.
* Your performance status will be recorded.
* Blood (about 3 teaspoons) and urine will be collected for routine tests.
* You will have a CT scan and/or MRI of the chest (and abdomen if the doctor thinks it is needed) to check the status of the disease.
* You will have an MRI scan of the brain.
* You will have a chest x-ray.
* You will have an ECG.
* If you are in Group 3, you will have a hearing test.

Follow-Up:

You will have follow-up every 4 weeks after you are no longer taking the study drugs. You will be contacted at a clinic visit or by phone. You will be called every 3 months for up to 3 years and asked about any cancer treatments you may be receiving. This phone call should take about 10 minutes.

This is an investigational study. Carboplatin and pemetrexed are FDA approved and commercially available for the treatment of certain types of NSCLC. Bevacizumab is FDA approved and commercially available for treatment of certain types of colon or rectal cancer, NSCLC, and renal cell carcinoma. Cixutumumab is not FDA approved or commercially available. At this time, cixutumumab is only being used in research.

Up to 225 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: The chemotherapy will be Carboplatin (AUC 6) and Pemetrexed (500 mg/m2) every 3 weeks for 4 cycles.

Then maintenance Pemetrexed (500 mg/m2 every 3 weeks) will be administered until disease progression or excessive toxicity.

If patients are randomized into one of the arms with a biologic therapy, patients will take the chemotherapy prescribed above, but will also receive the biologic therapy during the same time period. arm 2: Carboplatin AUC 6 by vein on day 1 of every 21 day cycle for 4 cycles. Pemetrexed 500 mg/m2 by vein on day 1 of each 21 day cycle. Bevacizumab 15 mg/kg by vein on day 1 of each 21 day cycle. arm 3: Carboplatin AUC 6 by vein on day 1 of every 21 day cycle for 4 cycles. Pemetrexed 500 mg/m2 by vein on day 1 of each 21 day cycle. arm 4: Carboplatin AUC 6 by vein on day 1 of every 21 day cycle for 4 cycles. Pemetrexed 500 mg/m2 by vein on day 1 of each 21 day cycle.

Cixutumumab 20 mg/kg by vein on day 1 of each 21 day cycle.
Interventions: intervention 1: Carboplatin intervention 2: Pemetrexed intervention 3: Bevacizumab intervention 4: Cixutumumab
Intervention descriptions: intervention 1: AUC 6 by vein on day 1 of every 21 day cycle for 4 cycles. intervention 2: 500 mg/m2 by vein on day 1 of each 21 day cycle. intervention 3: 15 mg/kg by vein on day 1 of each 21 day cycle. intervention 4: 20 mg/kg by vein on day 1 of each 21 day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
 
MDACC Protocol  2010-0097 
BATTLE-FL Protocol 
March 7, 2013 
 
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BATTLE-FL:  A Biomarker-Integrated Study in Patients with 
Advanced Non-Small Cell Lung Cancer Treated in the  
Front-Line (FL) Setting  
 
Principal Investigator:    
 
John Heymach, MD, PhD 
Co-Principal Investigator:     
William N. William, Jr., MD 
 
 
 
 
 
George Simon, MD 
 
Biostatistician:   
 
 
J. Jack Lee, PhD 
Pathology:    
 
 
Ignacio Wistuba, MD 
 
Dept. of Thoracic/Head and Neck Medical Oncology 
University of Texas  
M. D. Anderson Cancer Center 


 
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Study Schema 
 
  
 
 
 
(Arm 1) 
Carboplatin + 
Pemetrexed x 4 
cycles followed 
by maintenance 
Pemetrexed  
(Arm 2) 
Carboplatin + 
Pemetrexed + 
Bevacizumab 
followed by 
maintenance 
Pemetrexed + 
Bevacizumab 
Pemetrexed  
(Arm 3) 
Carboplatin + 
Pemetrexed + 
Cixutumumab 
followed by 
maintenance 
Pemetrexed + 
Cixutumumab 
Restaging after 2 cycles of therapy 
Optional biopsy of tumor for biomarkers after 2 cycles 
Continue on study if stable or response.  
Up to 4 cycles of Pemetrexed/Carboplatin +/- biologic, then biologic treatment with Pemetrexed  
If progression, then off-study 
The trials with their respective drugs will be compared to one another.  They will be analyzed individually based on their biomarker 
profiles and the likelihood of enhancing PFS based on the biomarkers. 
Consented, registered, and enrolled 
Biopsy performed 
Biomarker profile sent  
Biomarker results not needed prior to initiating treatment 
Treatment assignment 
Proceed with randomization 
Interim Analysis for 
Futility (at the time 
of half the expected 
failures)
Primary Endpoint is PFS; 
Sample size 225 patients. 


 
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Table of Contents 
 
 
1  OBJECTIVES ............................................................................................................................. 7 
1.1  Primary Objectives ............................................................................................................... 7 
1.2  Secondary Objectives ........................................................................................................... 7 
1.3  Study Design ........................................................................................................................ 7 
2  BACKGROUND AND RATIONALE ....................................................................................... 8 
2.1  Non-Small Cell Lung Cancer ............................................................................................... 8 
2.2  Molecularly Targeted Therapy in NCSLC ........................................................................... 9 
2.3  Biomarker Driven Targeted Therapy Clinical Trials Program (BATTLE-1) .................... 10 
2.4  RATIONALE ..................................................................................................................... 11 
3  STUDY AGENTS .................................................................................................................... 13 
3.1  Pemetrexed Background .................................................................................................... 13 
3.2  Pemetrexed in Second-Line NSCLC Therapy ................................................................... 13 
3.3  Pemetrexed in First-Line NSCLC Therapy ........................................................................ 14 
3.4  Pemetrexed with Carboplatin in First-Line NSCLC Therapy ............................................ 15 
3.5  Pemetrexed Maintenance Therapy in NSCLC ................................................................... 16 
3.6  Bevacizumab Background .................................................................................................. 17 
3.7  Bevacizumab in NSCLC .................................................................................................... 17 
3.8  Cixutumumab (IMC-A12) Background ............................................................................. 18 
3.8.1  Nonclinical Studies with Cixutumumab ...................................................................... 20 
3.8.2  Cixutumumab Preclinical Toxicology and Pharmacokinetics ..................................... 20 
3.8.3  Cixutumumab Clinical Studies .................................................................................... 24 
3.8.4  Phase I ......................................................................................................................... 24 
4  EXPERIMENTAL PLAN ........................................................................................................ 27 
4.1  Overview of Study Design ................................................................................................. 27 
4.2  Patient Assignment in the Biomarker-Integrated Clinical Trials ....................................... 28 
4.3  Patient Eligibility ................................................................................................................ 29 
4.3.1  Inclusion Criteria ......................................................................................................... 29 
4.3.2  Exclusion Criteria ........................................................................................................ 30 
4.4  Study Withdrawal ............................................................................................................... 31 


 
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4.5  Treatment Plan ................................................................................................................... 32 
5   CARBOPLATIN...................................................................................................................... 32 
6   PEMETREXED ....................................................................................................................... 32 
6.1  Investigational Product Description ................................................................................... 32 
6.2  Drug Accountability ........................................................................................................... 33 
6.3 Packaging and Storage ........................................................................................................ 33 
6.4  Preparation and Administration ......................................................................................... 33 
6.5  Pretreatment Medications ................................................................................................... 34 
6.6  Treatment Schema .............................................................................................................. 34 
6.7  Treatment Duration ............................................................................................................ 35 
6.8  Concomitant Medications and Therapy ............................................................................. 35 
6.9  Treatment of Pemetrexed Toxicity and Dose Modification: .............................................. 36 
6.10  Hematologic Toxicity ....................................................................................................... 36 
6.11  Creatinine Clearance ........................................................................................................ 36 
6.12  Non-hematologic Toxicity ............................................................................................... 37 
6.13  Dose Reductions ............................................................................................................... 37 
7   BEVACIZUMAB .................................................................................................................... 39 
7.1  Investigational Product Description ................................................................................... 39 
7.2  Product Descriptions .......................................................................................................... 39 
7.3  Pretreatment Medications and Testing ............................................................................... 39 
7.4  Warnings and Precautions .................................................................................................. 39 
7.5  Treatment of Infusion Reactions due to Bevacizumab ...................................................... 40 
7.6  Treatment Schema .............................................................................................................. 40 
7.7  Treatment Duration ............................................................................................................ 40 
7.8  Treatment of Toxicity and Dose Modification ................................................................... 43 
7.9  Other Toxicities .................................................................................................................. 45 
8   CITUXUMUMAB ................................................................................................................... 45 
8 Cixutumumab ......................................................................................................................... 45 
8.1  Investigational Product Description ................................................................................... 45 
8.2  Drug Accountability ........................................................................................................... 46 
8.3  Package and Storage ........................................................................................................... 46 


 
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8.4  Cixutumumab Dosage and Administration ........................................................................ 46 
8.4.1  Preparation for Administration .................................................................................... 46 
8.4.2  Administration ............................................................................................................. 47 
8.5  Pretreatment Medications ................................................................................................... 48 
8.6  Treatment Schema .............................................................................................................. 49 
8.7  Maintenance Period dose of Cixutumumab ....................................................................... 49 
8.8  Treatment of Toxicity and Dose Modification ................................................................... 49 
8.9  Cixutumumab Infusion Reactions ...................................................................................... 49 
8.11  Hyperglycemia ................................................................................................................. 52 
8.12  Dose Reductions ............................................................................................................... 53 
9  STUDY CONDUCT ................................................................................................................. 55 
9.1  Patient Accrual and Patient Identification .......................................................................... 55 
9.2  Patient Enrollment .............................................................................................................. 56 
9.3  Replacement of Patients ..................................................................................................... 56 
9.4  Screening Procedures ......................................................................................................... 56 
9.4.1  Tumor Tissue Biopsy .................................................................................................. 57 
9.4.2  Serologies .................................................................................................................... 58 
9.5  Study Treatment Procedures .............................................................................................. 58 
9.6  End of Therapy Procedures ................................................................................................ 59 
9.7  Follow-up Procedures ........................................................................................................ 60 
9.8  Evaluation Criteria ............................................................................................................. 60 
10  SAFETY DATA COLLECTION, RECORDING AND REPORTING ................................. 61 
10.1  Adverse events ................................................................................................................. 61 
10.2  Serious Adverse Event Reporting (SAE) ......................................................................... 62 
10.3  Reporting Procedures for Adverse Events ....................................................................... 62 
10.3.1  Reporting to FDA ...................................................................................................... 63 
10.3.2  Investigator Communication with Eli Lilly and Company ....................................... 64 
10.3.3  Investigator Communication regarding Cixutumumab Serious Adverse Events ...... 65 
10.3.4  Exclusions to SAE Reporting Requirements ............................................................. 65 
10.3.5  Reporting of Patient Death to MDACC IRB ............................................................. 66 
10.4  Adverse event reporting on Case Report Form ................................................................ 66 


 
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10.5  Reproductive Risks and Reporting of Pregnancy ............................................................ 66 
11  STATISTICAL DESIGN AND DATA ANALYSIS CONSIDERATIONS ......................... 68 
11.1  Sample Size and Design ................................................................................................... 68 
11.2  Toxicity Monitoring ......................................................................................................... 69 
11.3 Interim Futility Analysis ................................................................................................... 71 
11.4 Final Analysis .................................................................................................................... 75 
12  PUBLICATION STATEMENT ............................................................................................. 77 
REFERENCES ............................................................................................................................. 78 
Appendix A:  ECOG Performance Status ..................................................................................... 85 
Appendix B: Response Evaluation Criteria in Solid Tumors ....................................................... 86 
Appendix C:  Pathology Tissue Processing .................................................................................. 92 
Appendix D:  Clinically relevant drug interaction ........................................................................ 94 
Appendix E: New York Heart Association (NYHA) Classification ............................................ 95 
Appendix F:  Study Procedures .................................................................................................... 96 
APPENDIX G: Biomarker Analyses ............................................................................................ 98 
APPENDIX H: Blood biomarkers .............................................................................................. 100 
 
 
 
 
 


 
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1  OBJECTIVES 
1.1  Primary Objectives 
The primary objective of this study will be to: 
 Determine the progression-free survival in patients with NSCLC who are being treated 
with front-line therapy for metastatic disease 
 
1.2  Secondary Objectives 
The secondary objectives of this study will be to: 
 Determine the best individual treatment based on the biomarker profile of the patients 
cancer 
 Determine the overall response rate 
 Determine the overall survival 
 Determine the time to disease progression  
 Assess the safety/toxicity of the combinations 
 Assess biomarker modulation in the tumor tissue from the treatment 
 Assess biomarker modulation in the serum/blood from the treatment 
 
 
1.3  Study Design 
This is a single-center, Phase II open-label study in patients treated as front-line NSCLC.  The 
study will consist of three arms, including two arms with combination targeted therapies. 
Patients will be administered carboplatin + pemetrexed (Arm 1), carboplatin + pemetrexed in 
combination with VEGF monoclonal antibody (Bevacizumab) (Arm 2), or carboplatin + 
pemetrexed in combination with a IGF-1R monoclonal antibody (Cixutumumab) (Arm 3). 
The study is designed to develop individualized targeted therapy based on the 
identification and validation of specific molecular pathways of NSCLC. To address these new 
targeted therapeutic approaches, we propose to implement a translational lung cancer research 
program entitled, “BATTLE-FL: Biomarker-integrated Approaches of Targeted Therapy of Lung 
Cancer Elimination-Front-Line,” and provide a strong rationale-based targeted treatment 
strategy. The study is applying the same principles as our prior BATTLE-1 Program. The 
BATTLE-1 Program required that all eligible patients with advanced NSCLC undergo a core 


 
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biopsy of their tumors and applied biomarkers in the selection of individualized targeted 
therapy.   
 
2  BACKGROUND AND RATIONALE 
2.1  Non-Small Cell Lung Cancer 
Lung cancer is the leading cause of cancer death in the United States and worldwide.  An 
estimated 215,020 new cases of lung cancer were diagnosed in the US in the year 2008 leading 
to approximately 161,840 deaths in the United States alone (Jemal 2008). Non-small cell lung 
cancer (NSCLC) accounts for almost 80% of newly diagnosed cases.  Lung cancer deaths in the 
US surpass those resulting from breast, prostate, and colon cancers, and its incidence continues 
to rise. Only 16% of these patients in whom lung cancer develops live 5 years or more after the 
diagnosis is made.  Despite substantial effort in developing methods for early diagnosis and 
treatment of lung cancer in the last two decades, currently at the time of diagnosis, more than 
80% of patients present with locally advanced unresectable or metastatic disease and their 
chance to be cured by current oncology practice is low.   
At presentation, the median survival for patients with advanced disease defined as 
inoperable Stage 3 or 4 non-small-cell lung cancer (NSCLC) is 8 to 10 months, with a one-year 
survival of 35 to 45% (Reck 2004).  Most patients with inoperable NSCLC are candidates for 
palliative chemotherapy consisting of standard induction therapy with 4 to 6 cycles of a 
platinum-based chemotherapy doublet, per American Society of Clinical Oncology ASCO 
(Pfister 2004) and European Society for Medical Oncology guidelines (ESMO) (D’Addario 
2008).  Recent reviews and meta-analyses of randomized trials in advanced NSCLC have 
suggested that 4 cycles is the optimal duration of platinum-based first-line treatment, regardless 
of response to initial therapy; platinum-based chemotherapy beyond 4 cycles was found to 
improve progression-free survival (PFS) but not overall survival (OS), and led to increased 
toxicity (Larsen 1995; Smith 2001; Socinski 2002; Lustberg 2007; Park 2007; Socinski 2007; 
Soon 2007).  
In 2006, bevacizumab received FDA approval as an initial therapy for advanced NSCLC 
on the basis of Study ECOG 4599 (Sandler et al. 2006). Approval was based on improvement in 
OS for bevacizumab when combined with carboplatin and paclitaxel, as compared with the 
platinum doublet alone.  This triplet regimen is now recommended by the National 


 
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Comprehensive Cancer Network (NCCN 2008) for patients with advanced, nonsquamous 
NSCLC and has become one of the standards of care in that setting.  
Maintenance therapy for advanced NSCLC has also been explored in a large number of 
studies, although most were powered only for assessment of the entire regimen, and not just the 
maintenance phase of therapy (Prior et al. 1999; Socinski et al. 2002; Belani et al. 2008; Herbst 
et al. 2004; Herbst et al. 2005; Brodowicz et al. 2006; Davies et al. 2006; Sandler et al. 2006; 
Manegold et al. 2007). Despite methodological problems, studies with docetaxel (Sekine et al. 
2006; Fidias et al. 2009), paclitaxel (Belani et al. 2008), gemcitabine (Brodowicz et al. 2006), 
and bevacizumab (Sandler et al. 2006) have suggested possible benefit of single-agent treatment 
beyond the recommended 4 to 6 cycles of platinum-based chemotherapy.  
 
2.2  Molecularly Targeted Therapy in NCSLC 
Advances in molecular biology, particularly the completion of the Human Genome Project, have 
led to substantial knowledge about the molecular basis of lung cancer, which provides a unique 
opportunity to develop novel strategies to target key pathways crucial for lung cancer 
development. This has led to emerging targeted therapy to attack lung cancer. However, to 
answer the question of how to develop “smarter” clinical trials using informative molecular 
biomarkers, these biomarkers must first be identified and then targeted with specific molecular 
inhibitors. Several large, randomized trials using targeted agents either alone or combined with 
chemotherapy failed to demonstrate the contribution of the targeted agent in the treatment of 
lung cancer (Gatzemeier 2004, Herbst 2004).  Even when positive, such as the recent 
bevacizumab or cetuximab trials with chemotherapy, the magnitude of benefit has been small, 
suggesting the need for optimization of patient selection and more active agents (Pirker 2008, 
Reck 2009, Sandler 2006).  
As described above, bevacizumab, a VEGF mononclonal antibody, is currently approved 
in combination with chemotherapy for patients with nonsquamous NSCLC.  Other pathways of 
interest have completed studies or will shortly.  These include the FLEX study and BMS 099 
studies, chemotherapy with the addition of cetuximab, an EGFR monoclonal antibody, which 
demonstrated modest survival benefit in patients with NSCLC.  IGFR has also been studied and 
Figitumumab (CP-751,871), a fully human, IgG2 monoclonal antibody against the insulin-like 
growth factor type I receptor (IGF-IR), is currently in Phase III studies in combination with 


 
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chemotherapy in both squamous and nonsquamous NSCLC (Karp 2009).  However, no validated 
biomarkers have been discovered with regards to treatment of monoclonal antibodies.   
Promising biomarkers have been identified with regards to therapy with oral EGFR 
tyrosine kinase inhibitors.  Several studies, however, have demonstrated that the proportion of 
EGFR mutation-positive patients is higher among gefitinib responders than nonresponders 
(Capuzzo 2005, Lynch 2004, Paez 2004, Sequist 2007) and showed that ORR and time to 
progression were significantly improved in gefitinib-treated EGFR mutation-positive patients 
than in those with wild-type EGFR, with a nonsignificant trend for longer overall survival.  In 
placebo-controlled studies, there were either too few EGFR mutation-positive patients to 
evaluate survival (Hirsch 2006) or no evidence that EGFR mutation predicts for a greater 
survival advantage over placebo (Tsao 2005). 
The discovery that somatic mutations in the EGFR kinase domain correlate and predict 
responses to the EGFR kinase inhibitors (gefitinib or erlotinib) underscores the importance of 
tailored individualized therapy based on the tumors’ underlying molecular biological profiles 
(Lynch 2004, Ding 2008, Kobayashi 2005). Indeed, the scientific advisory committee of the 
European Medicines Agency (EMEA), has issued a positive opinion supporting approval of the 
targeted oral anti-cancer drug, gefitinib, for adults with locally advanced or metastatic NSCLC 
with activating mutations of EGFR-TK in all lines of therapy based on findings from the IPASS 
study demonstrating significantly longer progression-free survival for patients with EGFR 
mutation-positive tumors treated with gefitinib than with doublet chemotherapy (Mok 2009) and 
the INTEREST study demonstrating similarly significant improvement in PFS and OS with 
gefitinib in patients with EGFR mutation positive tumors(Kim 2008).Resistance to EGFR 
inhibitors has emerged through development of acquired resistance (Bean 2008) or de novo 
resistance through other signaling pathways. (Marks 2008, Massarelli 2007, Pratilas 2008)  
 
2.3  Biomarker Driven Targeted Therapy Clinical Trials Program (BATTLE-1) 
The BATTLE-1 program (Kim 2009) was developed to establish individualized targeted therapy 
for NSCLC patients in whom standard therapy had failed by prospectively examining patients’ 
tumor biomarker profiles, obtained from a mandated fresh core tumor biopsy and assigning them 
to corresponding targeted therapies with the expectation to yield a better clinical 
outcome.  Several unique aspects of this Department of Defense (DoD)-sponsored program 


 
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included: a) the unprecedented mandate for fresh tumor biopsies in an NCSLC clinical trial; b) 
using molecular classifications to guide selection of targeted therapies; and c) the use of a novel 
hierarchical Bayesian modeling approach to associate biomarkers with treatment outcome and, 
subsequently, apply “adaptive randomization” to guide treatment assignments towards the 
therapy arms most likely to benefit patients according their biomarker profiles and, conversely, 
away from arms that demonstrate lack of efficacy. Adaptive randomization under a Bayesian 
paradigm continues to “learn” by incorporating updated biomarker/outcome data over the course 
of the trial to guide treatment assignments (Zhou 2008).  BATTLE-1 is composed of four Phase 
II clinical trials, including therapy with erlotinib, sorafenib, vandetanib, and bexarotene + 
erlotinib.  Once patients are enrolled, consented and undergo a core biopsy of their tumor for 
biomarker analysis, each tumor is then profiled for prespecified biomarkers and biomarker 
groups.  As of September 1, 2009, 327 patients have been enrolled into the program with 
acquisition of 290 biopsies.  Biomarkers were successfully yielded in 82% of the patient 
population.  The remaining 18% of the patient samples yielded no viable tumor tissue due to 
necrotic tissue and dense fibrosis.   
Our ability to study efficacy in the Phase II setting as well as to correlate clinical data 
reliably with real-time biomarker analysis, and the knowledge gained through these programs 
regarding key regulatory mechanisms in NSCLC, has significant potential to lead to the 
identification of new therapeutic targets and strategies to be tested in future Phase III 
studies.  The BATTLE-FL program capitalizes on our increased understanding of lung cancer 
biology, our capacity for timely development and analysis of biomarkers, our experience with 
clinical trial implementation and the enrollment of large numbers of patients with advanced 
NSCLC, and the availability of several promising agents of great interest to this group.  This 
undertaking in front-line NSCLC is an area of unmet need:  to move a step towards identifying 
biomarkers in these unselected patients. 
 
2.4  RATIONALE  
Vascular Endothelial Growth Factor (VEGF) 
Angiogenesis plays a central role in non-small cell lung cancer (NSCLC) carcinogenesis, 
through one of its key mediators, the vascular endothelial growth factor (VEGF). Merrick et al. 
demonstrated that VEGF expression levels in bronchial epithelial cells of smokers progressively 


 
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increase in low to high grade dysplasia (Merrick 2005). In patients with established lung tumors, 
there is an association between high circulating levels or intratumoral overexpression of VEGF 
and poor prognosis (Yuan 2001, Shimanuki 2005, Kaya 2004, Han 2001, Fontanini 
2006).  VEGF may also facilitate pleural dissemination of lung cancers (Ishii 2004). In pre-
clinical models of NSCLC, VEGF blockade has been shown to inhibit angiogenesis (Savai 2009) 
decrease tumor growth (Takayama 2000) stimulate apoptosis of cancer cells and enhance anti-
neoplastic chemotherapy effects (Kabbinavar 2005). Taken together, these data support the 
evaluation of anti-VEGF therapies in patients with NSCLC.   
 
Insulin-like Growth Factor Receptor (IGFR) 
The type I insulin-like growth factor receptor (IGF-IR) is a member of a family of 
transmembrane tyrosine kinases that includes the insulin receptor and the orphan insulin 
receptor-related receptor (Adams 2000). The IGF-IR binds and is activated by two high affinity 
binding ligands, insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II) 
(Wang 2002).  
A variety of strategies have been developed to inhibit the IGF-IR signaling pathway in 
tumor cells.  Approaches utilizing antisense oligonucleotides, inhibitory peptide, soluble 
receptor, and dominant-negative receptor mutants that target IGF-IR have been effective at 
inhibiting the proliferation of tumor cell lines in vitro and in experimental cancer models in vivo 
(Wang 2002, Pollak 2004).  Murine antibodies directed against the human IGF-IR have also been 
shown to inhibit the proliferation of a variety of human tumor cell types in vitro and in 
vivo.  Notably, anti-IGF-IR antibodies, IGF-IR kinase inhibitors, and antisense oligonucleotides 
to the IGF-IR have been shown to inhibit the growth of prostate cancer both in vitro and in vivo 
(Blum 2003, Burfeind 1996, Pandini 2005) 
These studies have established targeting the IGF-IR as an attractive anticancer 
therapeutic strategy and validated an antibody approach as an effective mechanism to inhibit 
IGF-IR signaling.  As murine antibodies may induce specific immune or allergic reactions, 
human antibodies offer the greatest potential for success as human therapeutics since they are 
less likely to elicit an immune response and in general possess a longer half-life in vivo. 
 
 


 
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3  STUDY AGENTS 
3.1  Pemetrexed Background 
Pemetrexed, a novel, multitargeted, antifolate antineoplastic agent approved for the first-line 
treatment of malignant pleural mesothelioma and the second-line treatment of NSCLC, is the 
chemotherapy agent most recently demonstrated to have activity in the first-line (Scagliotti 2008) 
and maintenance treatment (Ciuleanu 2008) of NSCLC.  
The antitumor activity of pemetrexed likely derives from inhibition of several key folate-
requiring enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), and 
glycinamide ribonucleotide formyltransferase (GARFT) (Shih 1997). This diversity of enzyme 
targets and the potential to overcome inherent resistance suggest that pemetrexed could have a 
greater degree and broader scope of antitumor activity than other antifolate therapies, such as 
methotrexate and 5-fluorouracil.  The mechanisms of action and molecular pharmacology of 
pemetrexed are well characterized (Shih 1998). This allows for correlative research of 
biomarkers in blood samples that may be predictive for high clinical benefit from pemetrexed-
containing treatment.  
The observed side effects of pemetrexed are similar to those of other antifolate therapies. 
These side effects include myelosuppression (mainly transient neutropenia), oral mucositis, 
diarrhea, and skin rash.  Supplementation with folic acid and vitamin B12 reduces the severity 
and frequency of hematologic and non-hematologic toxicities. Pemetrexed has been investigated 
in a number of tumor types as a single agent and in combination with other cytotoxic 
agents.  More detailed information about the known benefits and risks of pemetrexed may be 
found in the investigator's brochure (Lilly 2008).  
 
3.2  Pemetrexed in Second-Line NSCLC Therapy 
Global regulatory approvals of pemetrexed for the second-line treatment of patients with NSCLC 
were granted on the basis of the pivotal, randomized, open-label, Phase III study, H3E-MC-JMEI 
(JMEI). Patients with recurrent NSCLC received pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 
on Day 1 of each 21-day cycle until disease progression.  In this study of 571 patients, 
pemetrexed resulted in clinically similar efficacy outcomes with significantly fewer side effects 
compared with docetaxel, the established standard of care (Hanna 2004). The RR was 9.1% and 
8.8% for pemetrexed and docetaxel respectively, median PFS was 2.9 months in each arm, 


 
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median OS was 8.3 and 7.9 months for pemetrexed and docetaxel respectively, and the 1-year 
survival was 29.7% in each arm. 
Subsequently, a retrospective subgroup analysis of Study JMEI revealed statistically 
significant treatment-by-histology interactions for OS (p = 0.001) and PFS (p = 0.004) (Peterson 
2007). In the nonsquamous population, improved survival was demonstrated for patients who 
received pemetrexed compared with patients who received docetaxel, consistent with the 
statistically significant treatment-by-histology interaction (adjusted hazard ratio [HR] 0.778; 
95% confidence interval [CI]:  0.607 to 0.997; p = 0.047; 9.3 months versus 8.0 
months).  Patients with predominantly squamous cell histology had shorter OS time with 
pemetrexed compared with docetaxel (adjusted HR 1.563; 95% CI:  1.079 to 2.264; p = 0.018; 
6.2 months versus 7.4 months).  No clinically relevant differences were observed for the safety 
profile of pemetrexed between the histologic subgroups. Because this was a retrospective 
analysis, the potential for different treatment results based on NSCLC histology was further 
evaluated in planned analyses for Studies H3E-MC-JMDB (JMDB) and H3E-MC-JMEN 
(JMEN). 
 
3.3  Pemetrexed in First-Line NSCLC Therapy 
Data from the multicenter, randomized, open-label, Phase III study, JMDB, formed the basis for 
global applications to regulatory authorities for the initial treatment of patients with locally 
advanced or metastatic NSCLC (first-line NSCLC).  Study JMDB, which compared pemetrexed 
500 mg/m2 plus cisplatin 75 mg/m2 on Day 1 of a 21-day cycle (PC) versus gemcitabine 1250 
mg/m2 on Day 1 and Day 8 plus cisplatin 75 mg/m2 on Day 1 of a 21-day cycle (GC), met its 
primary endpoint and demonstrated that OS with PC was non-inferior to GC, with significantly 
fewer side effects (Scagliotti 2008).  
In the intent-to-treat (ITT) population (all histologies), the 2 arms of the study were 
equivalent in terms of OS (unadjusted HR 0.93; 95% CI:  0.83 to 1.04; median 10.3 months for 
both arms), PFS (unadjusted HR 1.04; 95% CI:  0.95 to 1.15; median 4.8 and 5.1 months for the 
pemetrexed and gemcitabine arms, respectively), and RR (30.6% versus 28.2% for the 
pemetrexed versus the gemcitabine arm).  
Preplanned analyses evaluating the differences in OS with respect to baseline patient and 
disease characteristics identified a differential effect on survival according to NSCLC histologic 


 
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subgroups.  Overall survival time with PC was statistically superior to GC in patients with 
nonsquamous histology (adjusted HR 0.844; 95% CI:  0.74 to 0.96; p = 0.01 [data on file]).  For 
patients with squamous histology, OS time with PC was shorter than with GC (adjusted HR 
1.229; 95% CI:  1.00 to 1.51; p = 0.050).  
In April 2008, the European Medicines Agency issued an approval for use of pemetrexed 
with cisplatin in the initial treatment of NSCLC other than predominantly squamous histology. 
The previously approved indication for use in second-line NSCLC was amended to include 
NSCLC with other than predominantly squamous histology only. In September 2008, the FDA 
approved pemetrexed in combination with cisplatin for the initial treatment of advanced 
nonsquamous NSCLC. The previously approved indication for use in second-line NSCLC was 
amended to include nonsquamous NSCLC only.  
 
3.4  Pemetrexed with Carboplatin in First-Line NSCLC Therapy 
The combination of pemetrexed and carboplatin was first tested in Study H3E-MCJMAU, a 
Phase I mesothelioma study that tested and verified the safety of this combination.  A 32% 
response rate (RR) was noted with acceptable toxicity.  Doses for the combination of pemetrexed 
and carboplatin were established at 500 mg/m2 and area under the curve (AUC) 6, respectively 
(Hughes 2002).  
Two Phase II trials demonstrated that the regimen of pemetrexed with carboplatin is 
tolerable and that its activity in first-line treatment of advanced-stage NSCLC is comparable with 
other standard platinum doublets commonly used in clinical practice.  
In Study H3E-MC-JMEK, 83 chemotherapy-naïve patients with Stage IIIB or IV NSCLC 
were randomized to receive pemetrexed 500 mg/m2 plus either carboplatin AUC 6 (41 patients) 
or oxaliplatin 120 mg/m2 (42 patients) on Day 1 of a 21-day cycle, for up to 6 cycles of therapy 
(Scagliotti et al. 2005).  In the pemetrexed-carboplatin arm, 12 of the 38 evaluable patients 
(31.6%) had best overall responses of partial response (PR) and 17 (44.7%) had best overall 
responses of stable disease (SD). Median PFS was 4.5 months, the 1-year survival rate was 
43.9%, and median OS was 10.5 months.  Grade 3/4 neutropenia was observed in 10 (25.6%) of 
39 patients evaluable for safety. In Study H3E-US-JMEZ, 50 chemotherapy-naïve patients with 
Stage IIIB (with effusion) or IV NSCLC received pemetrexed 500 mg/m2 and carboplatin AUC 
6 on Day 1 every 3 weeks for 6 cycles (Zinner et al. 2005). Twelve patients (24%) had PRs, and 


 
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25 (50%) had SD. Median TTPD was 5.4 months, the 1-year survival rate was 56%, and median 
OS was 13.5 months.  Grade 3/4 neutropenia was observed in 13 (26%) patients.  One (2%) 
patient had Grade 3 thrombocytopenia, and 1 (2%) patient had Grade 4 anemia.  Three (6%) 
patients experienced Grade 3 non-hematologic side effects (nausea, fatigue, diarrhea, and 
vomiting).  
Based on the data from these Phase II studies, the toxicity with the pemetrexed and 
carboplatin combination appears to be less than that seen with other standard regimens.  
 
3.5  Pemetrexed Maintenance Therapy in NSCLC 
Pemetrexed was then tested in the maintenance setting in the randomized, double-blind, placebo-
controlled, Phase III study, JMEN. In this trial, patients received 4 cycles of induction therapy 
with 1 of 6 standard regimens (gemcitabine, paclitaxel, or docetaxel, with either carboplatin or 
cisplatin); regimen selection was at the discretion of the investigator.  Patients who achieved 
complete response (CR), partial response (PR), or stable disease (SD) were randomized to 
maintenance with pemetrexed plus best supportive care (BSC) or placebo plus BSC until 
progression (Ciuleanu 2008).  
Study JMEN demonstrated a significant improvement in PFS following induction 
chemotherapy for patients receiving pemetrexed maintenance therapy compared with placebo 
(unadjusted HR 0.60; 95% CI:  0.49 to 0.73; p < 0.00001; 4.04 versus 1.97 months) (data on 
file).  In patients with nonsquamous histology, median PFS for patients receiving pemetrexed 
versus placebo was 4.4 months versus 1.8 months (unadjusted HR 0.47; 95% CI:  0.37 to 0.60; p 
< 0.00001). With 55% censoring, preliminary OS following induction chemotherapy in the 
overall study population was 13.0 months with pemetrexed and 10.6 months with placebo 
(unadjusted HR 0.798; 95% CI:  0.63 to 1.01; p = 0.06). In the nonsquamous population median 
OS was 14.4 months for pemetrexed-treated patients and 9.4 months for patients on placebo 
(unadjusted HR 0.66; 95% CI:  0.49 to 0.88; p = 0.005). In the squamous group, median OS was 
9.6 and 11.9 months for pemetrexed and placebo treatment, respectively (unadjusted HR 1.28; 
95% CI:  0.85 to 1.93; p = 0.231).  
Response to maintenance therapy, analyzed according to Response Criteria in Solid 
Tumors (RECIST) version 1.0 guidelines (Therasse 2000), was significantly higher for the 
pemetrexed arm (3.4%; 95% CI: 2% to 6%) compared with the placebo arm (0.5%; 95% CI:  0% 


 
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to 3%; p = 0.042).  Results of the analysis of disease control rate (DCR; CR+PR+SD) also 
demonstrated a significant improvement for patients receiving pemetrexed (49.1%; 95% 
CI:  44% to 54%) compared with patients receiving placebo (28.9%; 95% CI:  23% to 36%; p < 
0.001).  
 
3.6  Bevacizumab Background 
Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth 
factor (VEGF).  Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors 
(Flt-1 and KDR) on the surface of endothelial cells.  The interaction of VEGF with its receptors 
leads to endothelial cell proliferation and new blood vessel formation in in vitro models of 
angiogenesis.  By blocking the endothelial interaction of VEGF and its receptors, bevacizumab 
serves as an antiangiogenic agent.  
Bevacizumab has been studied in more than 5000 patients and in multiple tumor types in 
Phase I, II, and III clinical trials.  In addition, data are available from 3863 patients enrolled in 2 
post-marketing studies in metastatic colorectal cancer (CRC). Approximately 130,000 patients 
have been exposed to bevacizumab as a marketed product or in clinical trials.  
 
3.7  Bevacizumab in NSCLC 
In the Genentech-sponsored, randomized, Phase II study AVF0757g, bevacizumab was added to 
the ECOG reference regimen established in Study ECOG 1594 (Schiller 2002). This Phase II 
study identified a relationship between fatal hemoptysis and central lesions with squamous 
histology in lung cancer patients treated with bevacizumab (Johnson et al. 2004). Based on these 
safety data, the subsequent Phase III study excluded patients with predominantly squamous cell 
carcinoma, hemoptysis, or both.  
The Phase III study (ECOG 4599) randomized patients to either carboplatin-paclitaxel-
bevacizumab or carboplatin-paclitaxel (Sandler et al. 2006). Patients who received 6 cycles of 
bevacizumab plus chemotherapy without progression continued on single-agent bevacizumab 
until progression.  Median OS was 12.3 months for patients on the bevacizumab plus 
chemotherapy arm compared with 10.3 months for patients receiving carboplatin plus paclitaxel 
(HR 0.79; 95% CI:  0.67 to 0.92; p = 0.003). One-and 2-year survival rates were 51% and 23% 
for the Sandler regimen, compared with 44% and 15% for the chemotherapy-only regimen.  The 


 
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RR was 35% (133/381) for patients on bevacizumab and 15% (59/392) for patients on 
chemotherapy only (p < 0.001).  
The addition of bevacizumab resulted in modest changes to the expected toxicity profiles 
of chemotherapy alone (Genentech 2007).  A number of safety signals, similar to those found in 
other bevacizumab studies, such as epistaxis, hypertension, and proteinuria, were identified, the 
majority of which were of low grade and did not require discontinuation of bevacizumab.  Study 
ECOG 4599 suggested that the addition of a third noncytotoxic agent and/or maintenance 
therapy with an agent of low toxicity could result in improved outcomes in patients with 
advanced NSCLC.  This study demonstrated that the treatment paradigm for patients with 
nonsquamous NSCLC (bevacizumab eligible) is different than the treatment paradigm for 
patients with squamous histology NSCLC based on a difference in safety (NCCN 2008).  
In addition to ECOG 4599, the results of other trials exploring the incorporation of 
bevacizumab to first-line platinum-based doublets have been presented, including the 
randomized phase III AVAiL trial (cisplatin and gemcitabine +/- bevacizumab) (Reck 2009), as 
well as the single-arm phase II studies of bevacizumab combined with carboplatin plus docetaxel 
(William 2009), carboplatin plus pemetrexed (Patel 2009), oxaliplatin plus pemetrexed (Waples 
2008), and carboplatin plus nanoparticle albumin-bound paclitaxel. (Reynolds 2007). 
 
3.8  Cixutumumab (IMC-A12) Background 
ImClone LLC has developed a recombinant human immunoglobulin G, subclass 1 (IgG1) 
monoclonal antibody, cixutumumab (IMC-A12), which specifically targets the human IGF-IR 
(Burtrum 2003, Wu 2005) cixutumumab possesses high affinity for IGF-IR and acts as an 
antagonist of IGF-I and IGF-II ligand binding and signaling.  Cixutumumab does not bind to or 
recognize the human insulin receptor.  In addition to blockade of ligand binding, this antibody 
inhibits the IGF-IR pathway by effecting the internalization and degradation of IGF-IR, leading 
to a reduction in surface receptor density on treated cells.  As a result of the blockade of ligand 
signaling, the mitogenic and proliferative effects of IGF-I and IGF-II are significantly 
reduced.  IGF signaling is also one mechanism by which cancer cells can become resistant to 
chemotherapy.  By acting as an antagonist of IGF-IR signaling, cixutumumab can sensitize 
tumor cells to the damaging effects of chemotherapy.  In xenograft tumor models in vivo, IGF-
IR blockade by cixutumumab significantly inhibits the growth of a variety of tumor types, 


 
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(Burtrum 2003) including breast (estrogen receptor-positive and -negative), renal, colon, lung, 
prostate (androgen-dependent and independent), head and neck, and pancreatic 
tumors.  Histological analysis of tumor sections demonstrated a marked increase in apoptotic 
tumor cells in antibody-treated animals. 
Preclinical studies also demonstrated potential antitumor activity of cixutumumab when 
used in combination with conventional chemotherapy, including cisplatin, docetaxel, 5-
fluorouracil/leucovorin, and irinotecan.  Studies in models of lung cancer have also demonstrated 
increased benefit of cixutumumab in combination with radiation therapy.  In models of prostate 
cancer, cixutumumab has also been shown to provide increased benefit when used in 
combination with hormone-ablation therapy.  Furthermore, preliminary investigations with 
tamoxifen or trastuzumab resistant breast cancer cell lines demonstrated increased sensitivity to 
cixutumumab treatment. 
Importantly, cixutumumab has been shown to inhibit the growth of both androgen-
dependent and androgen-independent prostate cancer cell lines, enhance docetaxel-mediated 
growth inhibition in prostate cancer xenograft models, and delay the time to recurrence of 
androgen-independent prostate cancer when combined with hormone ablation therapy (Wu 2005, 
Wu 2006).  Using a cixutumumab-responsive androgen-independent prostate model, it was 
determined that the addition of cixutumumab to weekly doses of docetaxel could increase the 
antitumor effects of cytotoxic therapy, leading to complete tumor arrest and some cases tumor 
regression.  Notably, antitumor activity persisted after discontinuation of therapy in tumors 
treated with cixutumumab plus docetaxel; detectable levels of antibody present three weeks after 
discontinuation of therapy suggests that this continuation of antitumor activity is partially 
attributable to the persistence of cixutumumab.  Cell cycle and differential gene expression 
analysis of tumors in each group indicated that combination therapy affected a sharp increase in 
apoptotic cells and reduction in proliferating tumor cells, accompanied by marked change in the 
expression of genes controlling apoptosis and cell cycle progression.  Since androgen-
independent prostate cancer frequently progresses to the development of bone metastases, the 
effects of combined cixutumumab and docetaxel on established osteoblastic prostate cancer bone 
metastases were also studied. Although docetaxel alone and docetaxel plus cixutumumab were 
shown to be effective in controlling osseous prostate cancer xenografts, the antitumor effects of 
combined therapy persisted after cessation of drug treatment. 


 
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3.8.1  Nonclinical Studies with Cixutumumab 
The toxicity of intravenously-administered cixutumumab has been evaluated in three studies in 
cynomolgus monkeys that received one, four, or 13 weekly doses of cixutumumab; the results of 
this research are summarized in Table 1.  In addition, mice have been treated in numerous 
xenograft studies exploring the activity of cixutumumab.  Body weight and general health status 
are available from many of these mouse studies.  A tissue cross-reactivity study has been 
conducted with a full panel of monkey and human tissues to support the overall safety 
assessment.  Detailed descriptions of all studies are provided in the cixutumumab Investigator’s 
Brochure; results are also briefly summarized below. 
Cixutumumab cross-reacts with the mouse IGF-IR and binds with kinetics similar to the 
human IGF-IR.  In a variety of wild-type and immunodeficient mice treated with intraperitoneal 
cixutumumab, decreased weight gain and weight loss were occasionally seen.  The effects on 
body weight were reversible upon cessation of treatment.  A cross-reactivity study in a panel of 
human and monkey tissues indicated that cixutumumab cross-reactivity was consistent with the 
immunohistochemical distribution of IGF-IR in human tissues, as reported in the literature.  The 
same human tissue types that expressed IGF-IR were stained in the cynomolgus monkey 
tissues.  However, in some cases staining was observed in tissues of the cynomolgus monkey 
(granulosa and luteal cells, cytoplasmic staining of oocytes, thyroid C-cells, and lymphocytes in 
bronchial-associated lymphoid tissues) that were not observed in the human tissues.  No 
unanticipated cross-reactivities were observed.  The similarities in tissue profiles of 
cixutumumab cross-reactivity suggested that the cynomolgus monkey provides an appropriate 
animal model for nonclinical toxicity testing of cixutumumab. 
 
3.8.2  Cixutumumab Preclinical Toxicology and Pharmacokinetics 
A single-dose pilot pharmacokinetic (PK) study was conducted in cynomolgus 
monkeys.  Animals were administered cixutumumab at 2 or 10 mg/kg and observed for 42 
days.  No adverse effects were noted other than vomiting in one monkey after dosing that was 
attributed to the stress of procedures.  PK analysis indicated that the area under the serum 
concentration versus time curve from time zero extrapolated to infinity (AUCinf) and maximum 
serum concentration (Cmax) increased in a greater than dose-proportional manner.  In a 5-week 


 
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(four-dose) monkey toxicology study, animals were dosed on days 1, 15, 22, and 29 with 0, 6, 
22, or 80 mg/kg of cixutumumab.  The 2-week gap after the first dose allowed detailed PK 
characterization.  Data from the 5-week study indicate that the main toxicities in cynomolgus 
monkeys were mild weight loss and thymic atrophy.  The thymic atrophy was completely 
reversible at 6 mg/kg, partially reversible at 22 mg/kg, and not reversible within the 7-week 
recovery period at 80 mg/kg.  There were decreasing trends in erythrocytic parameters, but this 
effect also occurred in the control group and was likely due to the frequent blood 
sampling.  Only one of 24 evaluable monkeys exhibited an immune response to 
cixutumumab.  Pharmacokinetics were nonlinear and the lowest dose produced serum levels that 
exceeded the minimum trough level associated with activity (60-158 µg/mL) in murine 
colorectal (Colo205) and pancreatic (BxPC-3) xenograft models for 2 days. 
Final data from the 13-week monkey toxicology study indicated that weight loss and 
thymic atrophy became more pronounced and appeared at lower doses when the same doses 
were administered over a longer duration.  The decreased thymus weight was associated with 
minimal to marked atrophy, depletion of cortical thymocytes, and loss of a distinct 
corticomedullary junction.  Thymic tissue was replaced by adipose tissue and consisted of a 
loose fibroadipose capsular tissue with abundant white and brown fat that often formed variably 
thick anastomosing fibrovascular trabeculae separating less densely populated cortical 
lobules.  Despite the effects on the thymus, no effects were seen on the distribution of 
lymphocyte subsets in blood as assessed by flow cytometry.  The toxicologic consequences of 
thymic atrophy are uncertain, but this target organ toxicity does not appear to pose a significant 
concern for adult patients with advanced cancers.  In addition to the effects on the thymus, 
cixutumumab caused decreasing trends in red blood cells, hematocrit, and hemoglobin in both 
sexes (statistically significant in high-dose females) as well as decreased mean platelet volume in 
all treated female groups.  Decreased absolute and relative uterine weights associated with 
diffuse hypoplasia were noted.  Ovarian immaturity, consisting of a relative increase in the 
ovarian cortex with a less developed medulla and decreased follicles in different stages of 
development, was seen in the 22- and 80-mg/kg groups.  The ovarian immaturity and 
corresponding effects on the uterus may have been an adaptive response of the animals to 
nutritional stress and weight loss, but a direct effect of cixutumumab cannot be ruled out.  An 
increasing trend was observed in relative heart-to-body weights in all males and mid-dose 


 
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females.  This finding may be a result of the effects of cixutumumab on body weight, since the 
heart-to-brain weight ratios were not statistically significantly different from the control animals 
and there was no electrocardiographic, heart rate, blood pressure, or histopathologic 
correlates.  No serious toxicity affecting any vital organ has been observed following 
cixutumumab administration for up to 13 doses. 
 
 


 
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Table 1:  Repeated-Dose Toxicology/Pharmacokinetic Studies 
Species/  
Group Size 
Route and 
Schedule  
Doses  
(mg/kg) 
Major Findings 
Single-dose 
  
cynomolgus monkey/  
3 females 
I.V. slow bolus 
single dose 
2 or 10 
 One animal at 10 mg/kg vomited a foamy clear substance and displayed 
lethargy 23 minutes after dosing; believed to be due to stress from dose 
administration and blood sampling.  
 Cmax and AUCinf increased in a greater-than-dose-proportional manner. 
 Mean Values: Cmax = 40 and 368 μg/mL, AUCinf = 2783 and 
27572 h•μg/mL. 
Four-dose  
  
cynomolgus monkey/  
3/sex in main study 
and 3 males per 
recovery groups 
examined 7 weeks 
after last dose 
I.V. slow bolus 
once per week 
with   
2-week gap after 
the first dose 
0, 6, 22, 80 
 No treatment-related effects on survival, clinical signs, food consumption, 
clinical chemistry, hematology (other than procedure-related anemia and 
reticulocytosis), urinalysis, ophthalmology, or blood pressure. 
 Dose-dependent slight body weight losses. 
 Decreasing trends in absolute and relative thymus and spleen weights. 
 Dose-dependent thymic atrophy.  After 7-week recovery period thymic 
atrophy was reversible at low-dose, partly recovered at mid-dose, and not 
recovered at high-dose. 
 Anti-cixutumumab antibody incidence was 0 of 6, 0 of 8, 1 of 8, and 0 of 
8 evaluable for the 0-, 6-, 22-, and 80-mg/kg groups, respectively. 
 Mean Values: Cmax = 153, 528, and 2182 μg/mL; AUCinf = 14032, 60620, 
and 253726 h●μg/mL; half-life = 5.0, 7.0, and 7.7 days; clearance = 0.436, 
0.371, and 0.330 mL/h/kg. 
13-dose  
  
cynomolgus monkey/  
3/sex in main study  
4 to 6 per sex 
distributed in recovery 
groups that were 
examined 8 and 12 
weeks after last dose 
10-min I.V. 
infusion 
once per week 
0, 6, 22, 80 
 No treatment-related effects on survival, clinical signs, urinalysis, 
immunophenotyping, ophthalmology, or cardiovascular endpoints. 
 Body weight losses were 0%-14%, 4%-16%, and 4%-21% for the 6-, 22-, 
and 80-mg/kg groups, respectively.  Weight was regained in recovery. 
 Decreasing trends in RBCs, HCT, and hemoglobin in both sexes 
(statistically significant in high-dose females) on Day 86; decreased RBCs 
and HCT in high-dose females on Day 28. 
 Decreased mean platelet volume in all female groups. 
 Decreased absolute and relative thymus weights associated with minimal to 
marked atrophy, depletion of cortical thymocytes, loss of corticomedullary 
junction, and fat replacement. 
 Decreased absolute and relative uterine weights associated with diffuse 
hypoplasia. 
 Ovarian immaturity consisting of a relative increase in the ovarian cortex 
with a less developed medulla and decreased follicles in different stages of 
development. 
 Increasing trend in relative heart:body weights in males and mid-dose 
females, but not relative heart:brain weights. 
 Anti-cixutumumab antibody incidence was 1 of 12, 4 of 8, 0 of 8, and 1 of 
12 evaluable for the 0-, 6-, 22-, and 80-mg/kg groups, respectively. 
 Mean Values: Cmax = 186, 748, and 2434 μg/mL; AUCinf = 16276, 67659, 
and 267733 h•μg/mL; half-life = 3.6, 4.6, and 4.4 days; clearance = 0.413, 
0.377, and 0.332 mL/h/kg. 
AUCinf = area under the serum concentration vs. time curve from time zero extrapolated to infinity; Cmax = maximum serum concentration; 
HCT = hematocrit; I.V. = intravenous; RBCs = red blood cells. 
 
 
 


 
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3.8.3  Cixutumumab Clinical Studies 
The clinical information in this section represents data available as of the finalization of this 
protocol.  Please refer to the most recent version of the cixutumumab Investigator’s Brochure, 
including any Safety Updates (Investigator Notifications), for updated clinical information on 
safety and efficacy. 
 
3.8.4  Phase I 
Two Phase I studies, evaluating the safety and antitumor effects of cixutumumab administered 
either weekly (CP13-0501) or every other week (CP13-0502) at doses beginning at 3 mg/kg, 
have been conducted.  Clinical data from these studies available to date are described in the 
sections below. 
 
CP13-0501 
A total of 24 patients were enrolled and treated in CP13-0501 (cixutumumab administered 
weekly to patients with advanced solid tumors), including seven at the 3-mg/kg dose level, nine 
at the 6-mg/kg dose level, six at the 10-mg/kg dose level, and two at the 15-mg/kg dose 
level.  This patient population included 14 males and 10 females.  The median patient age was 
57.2 years, and patients ranged in age from 25 to 70 years. 
All patients experienced at least one adverse event (AE) regardless of relationship to 
cixutumumab; the most frequently reported adverse events overall were fatigue (41.7%), nausea 
(33.3%), and vomiting (33.3%).  Fifteen patients (62.5%) experienced at least one adverse event 
of Grade ≥ 3, including four in the 3-mg/kg cohort (57.1%), six in the 6-mg/kg cohort (66.7%), 
four in the 10 mg/kg cohort (66.7%), and one in the 15-mg/kg cohort (50%). 
A total of 17 patients (70.8%) experienced adverse events possibly, probably, or 
definitely related (related) to treatment with cixutumumab.  Hyperglycemia was the most 
common, affecting a total of four patients (16.7%) and considered a dose-limiting toxicity 
(Grade 3) in two.  Section 9.11 details proposed management for potential therapy-related 
hyperglycemia. 
The only possibly-, probably-, or definitely-related Grade ≥ 3 events reported during this 
study have been the two cases of Grade 3 hyperglycemia described above (one at the 3-mg/kg 


 
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dose level and one at the 10-mg/kg dose level), both of which resulted in treatment 
discontinuation, and one case of Grade 3 fatigue at the 6-mg/kg dose level. 
A small increase in body fat percentage was noted in five of six patients for whom DEXA 
scan results were available both pretreatment and following 6 weeks of initial cixutumumab 
therapy (median 1% absolute increase).  Mild weight loss was noted in seven of nine patients 
over this initial study period (median decrease 1 kg; 1% of body weight).  The contribution of 
cixutumumab to these modest changes in body fat/weight is not easily discernible in these 
patients with advanced cancer. 
Final efficacy data are not yet available.  To date, 11 patients have experienced a best 
overall response of stable disease (SD), including two patients at the 3-mg/kg dose, five patients 
at the 6-mg/kg dose, two patients at the 10-mg/kg dose, and two patients at the 15 mg/kg 
dose.  Among these eleven patients were four patients with SD greater than 8 months (male 
breast cancer [3 mg/kg], hepatocellular cancer [3 mg/kg], pheochromocytoma [10 mg/kg], and 
lymphangiomatosis [15 mg/kg]). 
 
CP13-0502 
A total of 16 patients were enrolled in study CP13-0502, a Phase I dose-escalation trial of 
cixutumumab administered every other week in advanced solid tumors: five patients at 6 mg/kg, 
nine patients at 10 mg/kg, and two patients at 15 mg/kg.  The median age of these patients was 
55.4 years (range: 19 - 79 years); the group includes six male patients and 10 female patients. 
This regimen has been well-tolerated at all dose levels.  The most frequently reported 
adverse events overall were fatigue (43.8%) and nausea (37.5%).  Nine patients (56.3%) 
experienced at least one adverse event of Grade ≥ 3, including three patients (18.8%) with 
dyspnea (all in the 10-mg/kg cohort).  Other reported AEs Grade ≥ 3 included fatigue, pain, 
cellulitis, dehydration, mental status changes, nausea, and vomiting. 
Cixutumumab-related adverse events affected nine patients (56.3%).  The most common 
related AEs were fatigue (three cases) and nausea (two cases).  Two patients experienced AEs of 
Grade ≥ 3 that were considered at least possibly related to cixutumumab, both in the 10-mg/kg 
cohort: one patient with fatigue and one patient with Grade 3 QTC prolongation (the latter 
resulting in study discontinuation). 


 
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PK data obtained during the course of this study suggest that cixutumumab should be 
present at sufficient concentrations to have therapeutic benefit when dosed at 10 mg/kg every 
14 days.  This dose has been established as the recommended dose for Phase II studies utilizing 
an every-other-week dosing schedule; study CP13-0502 was accordingly closed to 
enrollment.  Four patients experienced stable disease lasting at least 3.5 months, including one 
patient with stable disease > 7 months and another with stable disease > 9 months. 
 
Lymphocyte Counts 
Absolute lymphocyte counts are available from Phase I cixutumumab studies for 15 patients, 
including both pretreatment values and levels following at least one cycle (four weekly doses 
over 6 weeks) of therapy.  T-lymphocyte counts are available for seven patients, including both 
pretreatment values and levels following at least one cycle (four weekly doses over 6 weeks) of 
therapy.  Across four dose levels (3 mg/kg – 15 mg/kg per week), absolute lymphocyte counts 
increased in eight of 15 patients, remained unchanged in two of 15 patients, and decreased in five 
of 15 patients (range -39% to +49% change from pretreatment baseline; median: 2% increase 
[30/μL]).  Across three dose levels (3 mg/kg – 10 mg/kg per week), T-lymphocyte counts 
increased in four of seven and decreased in three of seven patients (range -42% to +45% change 
from pretreatment baseline; median: 10% increase [82/μL]).  Increases and decreases were noted 
in patients treated both at 3 mg/kg and 10 mg/kg.  Alterations in absolute lymphocyte count 
correlated highly with alterations in T-lymphocyte count (r = 0.99; Spearman coefficient).  There 
was also a high level of correlation between absolute lymphocyte and T-lymphocyte counts both 
prior to and following cixutumumab therapy. 
Long-term data regarding lymphocyte counts are available from two patients who 
experienced disease stabilization for at least 9 months while receiving cixutumumab therapy.  In 
these patients (a 69-year-old man with metastatic breast cancer and extensive thoracic disease 
and a 54-year-old man with hepatocellular carcinoma, hepatitis C infection, and extensive 
hepatic tumor), absolute lymphocyte and T-lymphocyte counts remained largely stable and in the 
range of pretreatment baseline during the initial 6 to 8 months of therapy.  In one patient (male 
breast cancer), reduced levels of lymphocytes and T-lymphocytes were noted only after 9 months 
of therapy, at the time of disease progression.  Lymphocytes and T-lymphocytes remained at 
pretreatment levels in the other patient (hepatocellular carcinoma) over 6 months of initial 


 
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therapy, with a modest reduction (17% - 19% below pretreatment levels) noted during the 
subsequent months prior to disease progression.  
No infectious adverse events have been noted during Phase I studies of 
cixutumumab.  Preliminary investigations of another anti-IGF-1R antibody (CP-751,871) have 
also indicated an acceptable safety profile without significant infectious complications (Lacy 
2006).  Phase II studies of cixutumumab in combination with chemotherapy are underway.  
 
 
4  EXPERIMENTAL PLAN 
4.1  Overview of Study Design 
The main objective of this phase II study is to determine the progression free survival in patients 
with advanced NSCLC. We plan to enroll 225 evaluable patients. 
This study will be an open-label randomized Phase II design. Upon enrollment, each 
patient will be assigned a study ID number. A biomarker analyses will be performed on the 
available tumor tissue. If adequate tumor tissue is not available for molecular analyses a tumor 
biopsy will be performed at MDACC. Once the patient meets eligibility criteria the patient will 
be randomized into one of three treatment arms based on their clinical eligibility.  The patient 
may be initiated on therapy while the biomarker analysis is pending. If biomarker results reveal 
an actionable molecular avberration, then the treating Physicians and/or Principal Investigator 
will discuss continued protocol participation versus off study standard of care treatment options.  
If the patient is removed from study, then the patient will be replaced to ensure that 225 eligible 
patients are enrolled on the study.  The primary endpoint will be PFS for each of the individual 
arms (analyzed separately).  Patients will be consented by the treating physician.  Patients may 
request information and decide to enroll at a later date.  Follow-up will occur through the 
research nurse.   
The chemotherapy will be carboplatin (AUC 6) and pemetrexed (500 mg/m2) every 3 
weeks for 4 cycles.  Then maintenance pemetrexed (500 mg/m2 every 3 weeks) will be 
administered until disease progression or excessive toxicity.  If patients are randomized into one 
of the arms with a biologic therapy, patients will take the chemotherapy prescribed above, but 
will also receive the biologic therapy during the same time period [bevacizumab 15 mg/kg every 
3 weeks (Arm 2) or cixutumumab (IMC-A12) 20 mg/kg every 3 weeks (Arm 3)]. 


 
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A second optional biopsy will be performed after 2 cycles while on study.  This biopsy 
will be performed only for biomarker modulation purposes and not diagnostic information. There 
are three treatment arms planned at this time with up to 75 patients to be enrolled into each 
arm.  In the BATTLE-FL Trial, patients with advanced NSCLC who are eligible to be treated 
with a front-line chemotherapy regimen will be enrolled.  Progression-free survival will be 
evaluated after every two cycles of therapy.  Responses will be confirmed 2 cycles after its initial 
assessment.  Patients without progression (either complete or partial response or stable disease) 
will continue on therapy.   
As an exploratory endpoint, we will assess the biomarkers (to be determined) to 
determine the role in relation to treatments.  The selection of these biomarkers will be based on 
the current available literature as well as our preclinical testing.  The combined information with 
these biomarker sets will allow us to hypothesize which biomarker(s) may predict best benefit in 
patients treated with chemotherapy alone or in combination with a targeted agent.  These 
biomarkers will be subject to a Bayesian variable selection algorithm (see Section 12: Statistical 
Design and Data Analysis Considerations) with a goal to identify the important prognostic or 
predictive biomarkers.    
Patients with progressive disease may be evaluated for other studies or treatments per 
their primary physician.  There are no limits to the number of cycles of therapy a patient may 
receive while on protocol.  If a patient, in the absence of progressive disease, experiences 
intolerable toxicities, the investigator may request of the Principal Investigator that the offending 
drug be discontinued or the patient be withdrawn from study.  Optional serum samples will be 
performed at baseline, cycle 1, cycle 2, every 2 cycles thereafter and at disease 
progression.  Patients will be seen and enrolled in the Thoracic/Head and Neck Medical 
Oncology clinics.  Patients may be referred from outside referring physicians. 
 
4.2  Patient Assignment in the Biomarker-Integrated Clinical Trials  
Patients enrolled in the BATTLE-FL study will then be randomized into a specific treatment 
arm.  If the patient’s eligibility does not allow participation in a specific arm, the patient's 
randomization will exclude that arm(s). 
 
 
 
 


 
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4.3  Patient Eligibility 
4.3.1  Inclusion Criteria 
The following inclusion criteria must be met for entry into the study.  Patients will also be 
clinically eligible for their specific treatment arm: 
1) The patient has a diagnosis of pathologically confirmed nonsquamous (nonpredominant 
squamous) NSCLC by tumor biopsy and/or fine-needle aspiration.  Mixed tumors will be 
categorized by the predominant cell type; if small cell elements are present, the patient is 
ineligible.  
2) The patient has a diagnosis of either stage IIIB or stage IV NSCLC or has recurrent 
NSCLC and is not a candidate for curative treatment. Patients may not have had 
chemotherapy for the advanced setting. 
3) The patient has measurable NSCLC. 
4) The patient’s ECOG performance status is ≤ 2 at study entry. 
5) The patient should have tumor available for EGFR mutations, ALK fusions and other 
molecular analyses (Appendix C). If there is no tissue then the patient should have biopsy 
accessible tumor. 
6) The patient has adequate hematologic function as defined by an absolute neutrophil count 
(ANC) >/= 1,500/mm3, platelet count >/= 100,000/mm3, WBC >/= 3,000/ mm3, and 
hemoglobin >/= 9 g/dL. 
7) The patient has adequate hepatic function as defined by a total bilirubin level </= 1.5 X 
the upper limit of normal (Serum bilirubin >/= 1.5x Upper Limit of Normal in the setting 
of known Gilbert’s disease is allowed), and alkaline phosphatase, AST and ALT </= 2.5 
X the upper limit of normal or </= 5.0 x ULN if liver metastases are present.  
8) The patient has adequate renal function as defined as CrCl of at least 45ml/min. 
9) If patient has brain metastasis, they must have been stable (treated and/or asymptomatic) 
and off steroids for at least 2 weeks.   
10) The patient is >/= 18 years of age. 
11) The patient has signed informed consent. 
12) Pregnancy Test.  Women of childbearing potential must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) for the duration 
of study participation and for six (6) months after discontinuation of the study drugs. 


 
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Childbearing potential will be defined as women who have had menses within the past 12 
months, who have not had tubal ligation, hysterectomy or bilateral 
oophorectomy.  Should a woman become pregnant or suspect that she is pregnant while 
participating in this study, she should inform her treating physician immediately.  The 
patient, if a man, agrees to use effective contraception or abstinence for the duration of 
study participation and for six (6) months after discontinuation of the study drugs.  
13) The ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day 
of, and 2 days following administration of Pemetrexed.  
  
4.3.2  Exclusion Criteria 
 
A patient meeting any of the following criteria is not eligible to participate in this study: 
1) The patient has received prior definitive therapy (chemotherapy, surgery, or radiotherapy) 
within 3 months of initiating study drug or within, 2 weeks of localized palliative 
radiotherapy. Patients treated with initial biologic therapy that progresses are eligible (no 
drug within 4 weeks). Patients must have recovered (≤ Grade 1 or baseline) from the 
acute toxic effects prior to Day 1 of Cycle 1. 
2) Patients may not have had prior chemotherapy for first line treatment for NSCLC Stage 
IIIB/IV.  Patient with activating EGFR mutations could have been treated with an EGFR 
tyrosine kinase inhibitor. Similarly patient with ALK or ROS1 fusions could have had 
treatment with crizotinib or other ALK inhibitors. Patients may not have had prior 
biologic therapy with antibodies targeting VEGF, or IGFR. 
3) The patient has undergone prior thoracic or abdominal surgery within 30 days of study 
entry, excluding prior diagnostic biopsy. 
4) The patient has a history of uncontrolled angina, arrhythmias, or congestive heart failure.  
5) The patient has inadequately controlled hypertension (defined as systolic blood pressure 
> 140 and/or diastolic > 90 mm Hg on antihypertensive medications).  
6) The patient has a history of stroke or transient ischemic attack within 6 months prior to 
Day 1 of Cycle 1. 
7) The patient is unable or unwilling to take folic acid, vitamin B12 supplementation or 
dexamethasone according to protocol. 
8) The patient has neuropathy >/= grade 2.   


 
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9) The patient has a history of gastrointestinal fistula, perforation, or abscess, inflammatory 
bowel disease, or diverticulitis. 
10) The patient is currently receiving ongoing treatment with full-dose warfarin or equivalent 
(that is, unfractionated and/or low molecular weight heparin).   
11) The patient is pregnant   
12) The patient is breastfeeding.    
13) Presence of significant third space fluid which cannot be controlled by drainage.  
14) The patient’s tumor harbors the EML4-ALK fusion gene. 
15) Drug Specific Eligibility for Treatment Arms.  Patients are excluded from the 
Bevacizumab arm if they have a history of hemoptysis (≥ ½ teaspoon of bright red blood 
per episode) within 3 months prior to randomization.  
16) Drug Specific Eligibility for Treatment Arms.  Patients are excluded from Bevacizumab 
arm if the Urine Protein Creatinine (UPC) ratio is not within the institutional normal 
limits. 
17)  Drug Specific Eligibility for Treatment Arms.  Patients are excluded from the IMC-A12 
containing arm if they have poorly controlled diabetes: HBA1C>8% or if the patient has 
abnormally elevated fasting serum glucose (defined >110% ULN). 
18) Drug Specific Eligibility for Treatment Arms.  Patients are excluded if they have known 
hypersensitivity to any of the drugs. 
. 
 
4.4  Study Withdrawal 
Patients will be removed from the study for any of the following reasons: 
1. Patient requests to withdraw 
2. Unwilling or unable to comply with study requirements 
3. Identification of recurrent or new cancer 
4. Unrelated intercurrent illness that will affect assessment of clinical status to a significant 
degree as determined by the principal investigator or the treating physician. 
 


 
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The treating physician or investigator must discontinue the patient’s study treatment if 
he/she thinks that the patient’s health or well-being is threatened by continuation on study 
treatment. 
Appropriate safety monitoring will continue until the patient is discharged from the 
study.  Patients withdrawn from the study will be followed for survival.  The reason for 
withdrawal and date of the discontinuation will be obtained.  If a patient is non-compliant or lost 
to follow-up, the research nurse or his/her designee will make three attempts to call the patient 
over the period of one month.  Attempts to contact will be documented.  If the research nurse or 
his/her designee is unable to make contact with either the patient or a family member after three 
phone calls, then a letter will be sent to the patient’s last known address. 
 
 
 
4.5  Treatment Plan 
Patients who meet the general eligibility criteria will be enrolled into the BATTLE-FL 
trial.  Patients will be equally randomized into one of the three treatment arms based on the 
individuals’ clinical eligibility.  
 
 
5   CARBOPLATIN 
Carboplatin is a standard treatment for NSCLC.   Commercially available supplies will be used 
for this study. Preparation instructions can be found in the FDA approved package insert. 
Carboplatin will be administered per institutional guidelines. Carboplatin will be provided by the 
institutional pharmacy.  Carboplatin is administered after pemetrexed by intravenous infusion 
with standard antiemetics per local practice guidelines.   
 
 
6   PEMETREXED 
6.1  Investigational Product Description 
Pemetrexed for injection will be provided by Eli Lilly and Company.  Pemetrexed is FDA 
approved in combination with cisplatin therapy for the initial treatment of patients with locally 


 
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advanced or metastatic nonsquamous non-small cell lung cancer. Pemetrexed is also approved 
for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-
small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-
line chemotherapy.  
 
6.2  Drug Accountability 
All pemetrexed required for completion of the study will be provided by Eli Lilly and Company. 
The investigator will be responsible for drug accountability. Upon completion or termination of 
the study, all clinical supplies including partial and empty containers will be destroyed per 
institutional policy.  
 
6.3 Packaging and Storage 
Pemetrexed is supplied as a sterile, lyophilized powder for intravenous infusion packaged in a 
single-use glass vial.  Each vial contains pemetrexed disodium equivalent to 500 mg of 
pemetrexed. The freeze-dried drug product is pemetrexed disodium and mannitol in a 1:1 ratio. 
Sodium hydroxide and/or hydrochloric acid solution may have been added during processing to 
adjust the pH. Each vial contains an excess of pemetrexed to facilitate the withdrawal of the label 
amount. The drug product is stable when stored at controlled room temperature and normal 
lighting conditions. For further details, see the Pemetrexed Investigator Brochure.  
 
6.4  Preparation and Administration 
Each vial must be reconstituted with sodium chloride (0.9%) solution for injection, without 
preservative, resulting in a solution containing 10 mg/mL to 50 mg/mL.  Gently swirl each vial 
until the powder is completely dissolved.  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 solution is between 6.8 and 7.8. Further dilution is required. Parenteral drug 
products should be inspected visually for particulate matter and discoloration prior to 
administration.  If particulate matter or a dark green color is observed, do not administer.  The 
appropriate volume of reconstituted pemetrexed solution should be further diluted to 75 to 125 
mL with sodium chloride (0.9%) solution for injection, without preservative. Pemetrexed 
infusion solutions prepared in this manner are compatible with polyvinyl chloride (PVC) and 


 
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polyolefin line administration sets and infusion bags. When prepared as directed, reconstituted 
and infusion solutions of pemetrexed contain no antimicrobial preservatives.  Chemical and 
physical stability of reconstituted and infusion solutions were demonstrated for up to 24 hours 
following initial reconstitution, when stored at refrigerated or room temperatures.  From a 
microbiological point of view, the product should be used immediately or within 24 hours 
following initial reconstitution. Discard any unused portion. Reconstitution and further dilution 
prior to intravenous infusion is recommended with sodium chloride (0.9%) solution for injection, 
without preservative, only.  Pemetrexed is physically incompatible with diluents containing 
calcium, including Lactated Ringer's injection and Ringer’s Injection.  Co administration of 
pemetrexed with other drugs and diluents has not been studied, and therefore, is not 
recommended.  Clinical trial materials will be labeled according to local regulatory requirements. 
 
6.5  Pretreatment Medications 
Premedications for pemetrexed include: 
 Folic acid 350-1000 micrograms po QD beginning day one of the first infusion of 
pemetrexed and continuing until the 3 weeks after discontinuation of pemetrexed.   
 Vitamin B12 1000 microgram IM Q9weeks day one of the first infusion of pemetrexed 
and continuing until 3 weeks after discontinuation of pemetrexed. 
 Dexamethasone dosing will be administered by the attending physician using the 
standard of care dosing recommendations. 
 
6.6  Treatment Schema 
Pemetrexed will be administered 500 mg/m2 IV on Day 1 (± 5 days) of a 21-day cycle per 
institutional guidelines. The pharmacy’s standard method of preparing pemetrexed for infusion 
will be used following the manufacturer’s instructions provided in the package insert.  Patients 
will receive pretreatment medications as described in Section 6.5.   
 Patients taking non-steroidal anti-inflammatory drugs (NSAIDs) must not take the 
NSAIDs 2 days before, the day of, and 2 days after receiving pemetrexed. If a patient is taking 
an NSAID with a long half-life (e.g., naproxen, piroxicam, diflunisal, or nabumetone), it should 
not be taken 5 days before, the day of, and 2 days after receiving pemetrexed. 


 
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Investigators should refer to the package insert for additional information such as safety 
issues, adverse reactions, and storage information. 
 
6.7  Treatment Duration 
Patients will take a maximum of 4 cycles of combination carboplatin and pemetrexed.  If the 
patient has stable disease after 4 cycles, the patient will take maintenance pemetrexed every 21 
days (± 5 days) until disease progression or excessive toxicity. 
Patients will continue receiving pemetrexed maintenance 500 mg/m2 IV q3weeks until 
they refuse further therapy, develop evidence of progressive disease, unacceptable toxicity, or 
any condition, which would, in the judgment of the investigator, affect assessments of clinical 
status to a significant degree or would pose undue risk to the patient through continuation. 
Should drug toxicity develop, dose delays and/or dose reductions will be carried out according to 
prespecified criteria. 
For the purposes of this study, patients will undergo repeat radiographic evaluation via 
chest x-ray and CT or MRI after cycle 2 (6 weeks of therapy) and every two cycles of therapy 
thereafter. See Appendix B for methods of response assessment and classification.  
 
6.8  Concomitant Medications and Therapy 
Information on concomitant medications will be collected on this study. Medications for 
supportive care will be allowed as needed to treat nausea, pain, fever, rash, diarrhea, 
etc.  Granulocyte growth factors (GCSF or GMCSF) will not be given routinely.  Commercial 
suppliers of growth factors will be utilized.  The use of growth factors will be according to 
ASCO guidelines. According to NCCN guidelines (Rodgers et al. 2008), erythropoiesis-
stimulating agents (ESAs) are not indicated for treatment of cancer-related anemia in patients 
with solid tumors. Erythropoietic therapy may be considered for treatment of chemotherapy-
induced anemia for a hemoglobin < 10 g/dL after the patient has been counseled about the risks 
and benefits of ESA use.  Because recommendations on the use of ESAs are rapidly evolving, 
investigators should frequently refer to the NCCN, ASCO, and/or Centers for Medicare and 
Medicaid Services web sites for the latest guidelines.  The use of bisphosphanates for the 
purposes of treating bone metastases can be administered at the discretion of the treating 
physician.  Other chemotherapeutic agents or investigational medications will not be allowed. 


 
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Other medication, which is considered necessary for the patient’s safety and well being, may be 
given at the discretion of the investigator(s). 
Leucovorin is allowed:  (1) for treatment of CTCAE Grade 4 leukopenia or Grade 4 
neutropenia lasting more than 3 days, beginning on the third day of Grade 4 myelosuppression; 
or (2) immediately, for treatment of Grade 4 thrombocytopenia, bleeding associated with Grade 
3 thrombocytopenia, or Grade 3 or 4 mucositis associated with pemetrexed. Appropriate doses of 
the oral formulation may also be used at the investigator’s discretion.  
Patients taking NSAIDs or salicylates will not take the NSAID or salicylate for 2 days 
before, the day of, and 2 days after receiving pemetrexed.  Patients taking NSAIDs or salicylates 
with a long half-life (for example, naproxen, piroxicam, diflunisal, or nabumetone) will not take 
the NSAIDs or salicylates for 5 days before, the day of, and 2 days after pemetrexed.  
 
6.9  Treatment of Pemetrexed Toxicity and Dose Modification: 
All toxicities will be graded according to the CTCAE Version 4 guidelines. Any patient who 
requires a dose reduction will continue to receive a reduced dose for the remainder of the 
study.  Any patient with 2 prior dose reductions who experiences a toxicity that would cause a 
third dose reduction must be discontinued from all study treatment.   Discontinuation of study 
drug typically requires withdrawal from the study.   
All patients will be evaluable for toxicity if they have received any study drug. Safety 
parameters will include description of toxic deaths, premature withdrawals from treatment for 
toxicity reasons, description of adverse events, serious adverse events (SAE), and evaluation of 
toxicity. 
 
6.10  Hematologic Toxicity 
At the start of each cycle, ANC must be ≥ 1.5 × 109/L and platelet count must be ≥ 100 × 109/L. 
Treatment should be delayed for up to 42 days to allow sufficient time for recovery.  Dose 
adjustments will be based on neutrophil values at the start of the subsequent cycle of therapy.   
 
6.11  Creatinine Clearance  
Creatinine clearance will be estimated using the original, weight-based Cockcroft and Gault 
formula or measured using the appropriate radiolabeled method (51-CrEDTA or Tc99m-DTPA) 


 
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to determine glomerular filtration rate (GFR). The method of CrCl assessment used at baseline 
should be used throughout the study.  Enrollment and dosing decisions based on CrCl may be 
made using locally determined clinical laboratory results (calculated using the original, weight-
based Cockcroft and Gault formula).  The serum creatinine must be assayed at the same local lab 
each time for that patient. If a local lab is being used to monitor a patient’s renal function, the 
central laboratory sample still must be drawn for safety analysis.  
At the start of each cycle, creatinine clearance should be ≥ 45 mL/min.  The cycle may be 
delayed for up to 42 days to allow the patient time to recover from the toxicity.  If a patient has 
not recovered on the CrCl and has not experienced disease progression within the 42 day 
window, the Principal Investigator and the treating physician may decide to allow the patient to 
remain on trial and continue with protocol treatment provided the patient meets the minimum 
creatinine clearance ≥ 45 mL/min. 
 
6.12  Non-hematologic Toxicity 
For Grade 3 or 4 non-hematologic toxicities, treatment should be delayed until resolution to less 
than or equal to the patient’s baseline value.  Dose reductions at the start of the subsequent cycle 
will be based on non-hematologic toxicities from the dose administered in the current cycle.  
 
6.13  Dose Reductions 
Any patient who requires a pemetrexed dose reduction will continue to receive a reduced dose 
for the remainder of the study. Any patient with two prior dose reductions who experiences a 
toxicity that would cause a third dose reduction must be discontinued from pemetrexed therapy 
and followed for survival. Patients who require a delay of more than 42 days in starting a new 
cycle of chemotherapy must be withdrawn from the study. 
Hematologic Toxicity  
Dose adjustments will be based on platelet and neutrophil nadir (lowest value) counts at the start 
of a subsequent cycle of therapy. The ANC must be ≥1.5 x 109/L and the platelet count must be 
≥100 x 109/L prior to treatment of the subsequent cycle. Treatment should be delayed to allow 
time for recovery. Upon recovery, if treatment is resumed, it must be according to the guidelines 
in Table 6.1 below.  
 


 
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Table 6.1:  Dose Adjustments for Pemetrexed Based on Nadir Blood Counts 
Platelet (x 109/L) 
Nadir 
ANC (x 109/L) Nadir
% of Previous Dose 
≥50 
≥50 
<50 
  and ≥0.5 
  and <0.5 
and any 
100% 
75% 
50% 
 
For patients who develop neutropenic fever, treatment should be delayed for up to 2 weeks until 
recovery of the ANC ≥1.5 x 109/L, resolution of fever, and treatment of documented infections 
are complete. Treatment should be resumed at 75% of the previous pemetrexed dose. 
 
Diarrhea, Mucositis, or Other Non-Hematologic Toxicity  
In the event of diarrhea requiring hospitalization (or of at least Grade 3), treatment will be 
delayed until diarrhea has resolved. Treatment should be resumed at 75% of the previous 
pemetrexed dose.  
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals. If diarrhea is severe (requiring intravenous rehydration) 
and associated with fever or severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must 
be prescribed. Hospitalization should be considered for patients with severe diarrhea or any 
diarrhea associated with severe nausea or vomiting for intravenous hydration and correction of 
electrolyte imbalance.  
For other nonhematologic toxicities greater than or equal to Grade 3 (with the exception 
of alopecia, Grade 3 transaminase elevations, nausea, or vomiting), treatment must be delayed 
until resolution to less than or equal to the patient’s original baseline grade before proceeding. 
Treatment should resume at 75% of the previous dose if deemed appropriate by the investigator.  
Table 6.2:  Dose Modifications for Pemetrexed for Mucositis 
CTCAE Toxicity Grade 
% of Previous Dose 
Grade 0 to 2 
Grade 3 to 4 
100% 
50% 
 


 
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For patients who develop clinically significant pleural or peritoneal effusions (on the basis of 
symptoms or clinical examination) during 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 all study medication and 
followed for survival. 
Within 2 weeks following a dose interruption or reduction, study drug–related toxicity 
must improve by at least one grade, or further dose reduction by one level will be 
required.  Dosing may be interrupted for a maximum of 2 weeks if clinically indicated and if the 
toxicity is not controlled by optimal supportive medication. No more than two dose reductions 
will be allowed.  If study drug–related toxicity has not improved within 14 days of dose 
reduction or interruption, patients will be discontinued from the study. 
 
 
7   BEVACIZUMAB 
7.1  Investigational Product Description 
Bevacizumab is FDA approved in combination with carboplatin and paclitaxel for treatment of 
locally advanced or metastatic nonsquamous non-small cell lung cancer.   
 
7.2  Product Descriptions 
Commercially available supplies will be used for this study. Preparation instructions can be found in the 
FDA approved package insert. Bevacizumab will be administered per institutional guidelines.  
 
7.3  Pretreatment Medications and Testing 
Patients must have adequately controlled hypertension at time of screening (defined as systolic 
blood pressure > 140 and/or diastolic 90 mm Hg on antihypertensive medications). 
Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) 
ratio.  For UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be < 1,000 
mg for patient enrollment onto the Bevacizumab arm.  The urine protein used to calculate the 
UPC ratio must be obtained within 4 weeks prior to randomization 
 
7.4  Warnings and Precautions 


 
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Infusion Reactions 
Monoclonal antibodies have caused infusion reactions. In some cases, these reactions are severe 
and rarely have fatal outcome. Severe reactions are characterized by the rapid onset of airway 
obstruction (bronchospasm, stridor, hoarseness), urticaria, hypotension or angioedema and may 
require immediate interruption of infusion. Hypersensitivity reactions (non-IgE mediated 
reactions) have also been observed upon treatment with monoclonal antibodies and may respond 
to adjustments in the infusion rate and medical management.  
 
7.5  Treatment of Infusion Reactions due to Bevacizumab  
Guidelines for patients who experience an infusion reaction or hypersensitivity reaction during or 
after infusion with bevacizumab are shown in the Table 7.1. A two hour observation period is 
suggested after the first dose of bevacizumab infusion. For subsequent doses, a one hour 
observation period may be sufficient if the patient does not experience severe infusion reaction. 
Patients should be carefully observed until complete resolution of all signs and symptoms.  
 
7.6  Treatment Schema 
Patients will receive combination pemetrexed/carboplatin/bevacizumab after the initial 
biomarker assessment and randomization has occurred. This protocol defines the duration of one 
cycle of treatment as 3 weeks or 21 days (± 5 days).  Starting Day 1 (± 5 days) of each 21-day 
cycle patients will be given 500 mg/m2 of pemetrexed IV, AUC 6 of carboplatin IV, and 15 
mg/kg of bevacizumab IV. After the completion of 4 cycles of combination therapy, if the 
disease has not progressed, patients will receive maintenance pemetrexed maintenance 500 
mg/m2 IV q3wks in combination with bevacizumab 15 mg/kg of bevacizumab IV q3wks until 
progression of disease.  Bevacizumab will be infused over 90 ± 15 minutes for the initial dose, 
60 ± 10 minutes for the second dose and 30 ± 10 minutes for the subsequent doses if the infusion 
rate is well tolerated.   
 
7.7  Treatment Duration 
Treatment will continue until there is objective evidence (radiological progression as per the 
RECIST criteria) of tumor progression, or until evidence of toxicities that are unacceptable and 


 
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thought to be related to study drug, which requires discontinuation of drug, withdrawal of patient 
consent or at the investigator’s discretion. 
 
 


 
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Table 7.1:  Guidance on Infusion and Hypersensitivity Reactions 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 is defined as: 
Mild reaction; infusion interruption not 
indicated; intervention not indicated. 
Increase monitoring of vital signs as medically indicated 
until the patient is deemed medically stable in the opinion 
of the investigator.  
None 
Grade 2 is defined as: 
Requires therapy or infusion interruption but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, non-steroidal 
inflammatory drugs (NSAIDS), narcotics, IV 
fluids); prophylactic medications indicated for 
≤24 hrs 
Stop Infusion 
Additional appropriate medical therapy may include but is 
not limited to: 
 
IV fluids, Antihistamines, NSAIDS, 
Acetaminophen, Narcotics 
 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g. from 100mL/hr to 50mL/hr). 
Otherwise dosing will be held until symptoms resolve 
and the patient should be premedicated for the next 
scheduled dose. 
Patient may be 
premedicated 1.5h (+/- 30 
minutes) prior to infusion 
with: 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of analgesic). 
Grade 3/4 
Grade 3 is defined as: 
Prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae (e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4 is defined as: 
Life-threatening; pressor or ventilatory support 
indicated 
Stop Infusion 
Additional appropriate medical therapy may include 
but is not limited to: 
IV fluids, Antihistamines, NSAIDS. Acetaminophen, 
Narcotics, Oxygen, Pressors, Corticosteroids, Epinephrine 
Increase monitoring of vital signs as medically indicated 
until the patient is deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Patient is permanently discontinued from further 
treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events (CTCAE). 
*Note:  NSAIDS should not be used in patients who have received pemetrexed in the previous 2 days. 
 


 
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7.8  Treatment of Toxicity and Dose Modification 
Guidelines for Dose Modification 
There are no reductions in the bevacizumab dose. If adverse events occur that require holding 
bevacizumab, the dose will remain the same once treatment resumes.  Adverse events requiring 
delays or permanent discontinuation of bevacizumab are listed in the Table 7.2.  Regardless of 
the reason for holding study drug treatment, the maximum allowable length of treatment 
interruption is 42 days. 
 
 
 
 
 


 
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Table 7.2:  Bevacizumab Dose Management Due to Adverse Events – CTCAE Version 4 
Event 
Action to be Taken 
Hypertension:   
No dose modifications for grade 1/2 events 
Grade 3 
If not controlled with medication, discontinue the patient from the study. 
Grade 4 
Discontinue the patient from the study. 
Hemorrhage  
Hemoptysis of any grade – Discontinue the patient from study.  No dose modifications for grade 1/2 
events. 
Grade 3 
Patients who are also receiving full-dose anticoagulation will be discontinued from the study.   
All other patients will have study treatment held until all of the following criteria are met: 
 
The bleeding has resolved and hemoglobin is stable. 
 
There is no bleeding diathesis that would increase the risk of therapy. 
 
There is no anatomic or pathologic condition that significantly increases the risk of 
hemorrhage recurrence. 
Patients who experience a repeat Grade 3 hemorrhagic event will be discontinued from treatment. 
Grade 4 
Discontinue the patient from the study. 
Venous Thrombosis  
Note: Patients with lung cancer placed on anticoagulant therapy for a thrombotic event should be 
discontinued from study.   No dose modifications for grade 1/2 events. 
Grade 3 or Asymptomatic Grade 4 Hold study drug treatment.  If the planned duration of full-dose anticoagulation is <2 weeks, study 
drug should be held until the full-dose anticoagulation period is over.  If the planned duration of full-
dose anticoagulation is >2 weeks, study drug may be resumed during the period of full-dose 
anticoagulation if all of the following criteria are met: 
 
The patient must have an in-range INR (usually between 2 and 3) on a stable dose of 
warfarin (or other anticoagulant) prior to restarting study drug treatment. 
 
The patient must not have had a Grade 3 or 4 hemorrhagic event while on anticoagulation. 
 
The patient must not have had evidence of tumor involving major blood vessels on any 
prior CT scan. 
Symptomatic Grade 4 
Discontinue the patient from the study. 
Arterial Thromboembolic event  
Any grade 
(Angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, and any other 
arterial thromboembolic event).  Discontinue the patient from the study. 
Proteinuria:   
No dose modifications for grade 1
Grade 2 ( 2+ proteinuria; urinary 
protein 1.0 - 3.4 g/24 hrs) 
 
Grade 3  
(urinary protein >=3.5 g/24 hrs) 
Proteinuria and/or nephrotic syndrome have been associated with use; risks may be increased in 
patients with history of hypertension. Thrombotic microangiopathy has been associated with 
bevacizumab-induced proteinuria. Withhold treatment for ≥2 g proteinuria/24 hours and resume 
when proteinuria is <2 g/24 hours;  
Grade 4 (nephrotic syndrome) 
Discontinue the patient from the study 
GI Perforation requiring medical 
or surgical therapy 
Discontinue the patient from the study. 
Wound dehiscence requiring 
medical or surgical therapy 
Discontinue the patient from the study. 


 
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7.9  Other Toxicities 
Major adverse effects of bevacizumab include hypertension, proteinuria, and spontaneous 
hemorrhage including hemoptysis, epistaxis, and venous and arterial thromboses. 
Leukoencephalopathy syndrome including reversible posterior leukoencephalopathy syndrome 
(RPLS) has also been reported. Infusion related reactions commonly manifest as fever and/or 
chills. Emergency equipment in case of anaphylactic or severe reactions should be available, 
including intubation equipment, oxygen, epinephrine, antihistamines and corticosteroids. 
 
 
8   CITUXUMUMAB 
8 Cixutumumab8.1  Investigational Product Description 
Cixutumumab (IMC-A12) will be provided to participating patients free of charge by ImClone, 
LLC. Cixutumumab (IMC-A12) is a recombinant human immunoglobulin G, subclass 1 (IgG1) 
monoclonal antibody which specifically targets the human IGF-IR.  Cixutumumab possesses 
high affinity for IGF-IR and acts as an antagonist of IGF-I and IGF-II ligand binding and 
signaling. Cixutumumab does not bind to or recognize the human insulin receptor. 
Cixutumumab drug product (DP) is a sterile, preservative-free solution for infusion of 
cixutumumab formulated in an aqueous solution at a concentration of 5 mg/mL (250 mg/50 mL) 
or 10 mg/mL (500 mg/50 mL vial) or 15 mg/mL (750 mg/50 mL). The buffer contains 10mM 
sodium citrate, 100mM sodium chloride, 100mM glycine, and 0.01% polysorbate 80. 
Cixutumumab DP is a clear or slightly opalescent and colorless or pale yellow liquid without 
visible particles. The pH is 6.5. The osmolality is 310 mmol/kg. 
All excipients used for the manufacture of cixutumumab DP are of pharmacopoeial 
grade.  No animal-derived components are used in the manufacture of cixutumumab DP 
excipients. 
 
 
 
 


 
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8.2  Drug Accountability 
Upon completion or termination of the study, all unused and/or partially used investigational 
products must be returned to ImClone Systems or a designee, if not authorized by ImClone 
Systems or a designee to be destroyed at the site. 
 
8.3  Package and Storage 
Cixutumumab DP is supplied in single-use, 50-mL nominal volume, United States Pharmacopeia 
(USP) Type I glass vials. Each vial contains 250 mg of cixutumumab at a concentration of 5 
mg/mL or 500 mg of cixutumumab at a concentration of 10 mg/mL or 750 mg of cixutumumab 
at a concentration of 15 mg/mL in a sterile, preservative-free solution. Each vial has a coated 
butyl rubber latex-free plug stopper and is sealed with an aluminum seal and a flip-off cap. 
Cixutumumab must be stored under refrigeration at 2°C to 8°C (36°F-46°F) with 
protection from direct light. DO NOT FREEZE AND/OR SHAKE CIXUTUMUMAB DP. 
Stability studies have demonstrated that the drug product can withstand transient excursions to 
room temperature without adverse effect; however, storage at this temperature is not 
recommended. 
 
8.4  Cixutumumab Dosage and Administration 
Patients will receive cixutumumab 20 mg/kg intravenously via infusion. The dose of 
cixutumumab will be dependent upon the patient’s baseline body weight in kilograms; this dose 
will be recalculated if there is a ≥ 10% change in body weight from baseline. Cixutumumab may 
be administered in an appropriate outpatient setting, but physicians should remain vigilant for 
signs and symptoms of hypersensitivity reactions. 
 
8.4.1  Preparation for Administration 
Chemical and physical in-use stability for the prepared cixutumumab dosing solution has been 
demonstrated for up to 24 hours below 25°C (77°F). However, it is recommended that the 
prepared dosing solution be used immediately in order to minimize the risk of microbial 
contamination. If not used immediately, the prepared cixutumumab dosing solution must be 
stored under refrigeration at 2°C to 8°C (36°F to 46°F) for a duration not to exceed 24 hours.  If 
the prepared solution is held at room temperature (below 25°C (77°F)) it must be used within 4 


 
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hours. DO NOT FREEZE AND/OR SHAKE PREPARED CIXUTUMUMAB DOSING 
SOLUTION FOR INFUSION. 
Different drug product lots or formulations must not be mixed in a single infusion; 
additionally, on the same day of treatment there should be no mixing of lot numbers irrespective 
of whether they are from the same formulation.    
All excipients used for the manufacture of cixutumumab drug product are of 
pharmacopeial grade.  No animal-derived components are used in the manufacture of 
cixutumumab drug product excipients.  For dose volumes < 250 mL, a sufficient quantity of 
sterile normal saline  (0.9% weight/volume) solution will be added (or removed as in the case of 
prefilled AVIVA bags) to the container to make the total volume 250 mL.  The container will be 
gently inverted to ensure adequate mixing.  In the event that the total dose volume exceeds 250 
mL, the infusion rate should not exceed 25 mg/minute.  Cixutumumab is compatible with 
commonly used infusion containers. Refer to the investigator’s brochure for detailed information 
about study drug information. 
 
8.4.2  Administration 
The dose of cixutumumab should be aseptically withdrawn from the vial and transferred to a 
sterile I.V. container composed of AVIVA, EVA, polyolefin, PVC, or an evacuated glass 
container. For dose volumes other than 250 mL, a sufficient quantity of sterile normal saline 
(0.9% weight/volume) solution should be added (or removed) to the container to make the total 
volume 250 mL. In the event that the total dose volume exceeds 250 mL, the infusion rate should 
not exceed 25 mg/minute (equal to 5 mL/minute of native solution for infusion). 
 
Safe Handling and Administration 
Cixutumumab DP is compatible with infusion containers composed of polyolefin, polyvinyl 
chloride (PVC), ethylene vinyl acetate (EVA) and evacuated glass (USP Type II or local 
equivalent). An infusion bag composed of polyolefin, polypropylene, and polyethylene prefilled 
with 0.9% Sodium Chloride Injection, such as AVIVA, may also be used. 
 
The following have been found to be compatible for cixutumumab DP infusion: 
 A polyethylene-lined PVC infusion set with a 0.22 μm downstream high-pressure, 


 
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protein-sparing in-line filter made of polyethersulfone of 10 cm2 surface area 
 A PVC infusion set with a 0.2 μm protein-sparing filter made of polyethersulfone of 4.2 
cm2 surface area 
 A polyethylene-lined PVC infusion set with a 0.2 μm protein-sparing in-line filter made 
of polyethersulfone of 10 cm2 surface area 
 A polyurethane infusion set with a 0.2 μm protein-sparing in-line filter made of 
polyethersulfone of 10 cm2 surface area 
 A polybutadiene tubing with a 0.2μm protein-sparing in-line filter made of polysulfone of 
9 cm2 surface area 
 
Administration: 
a) To administer using pre-filled IV infusion containers: 
Calculate the respective dose and remove the corresponding volume of 0.9% normal 
saline from the prefilled 250 mL container of the correct composition. Aseptically 
transfer the calculated dose of cixutumumab DP to the container to bring the final volume 
in the container back to 250 mL. Gently invert the container to mix.  
b) To administer using empty IV infusion containers: 
Aseptically transfer the calculated dose of cixutumumab DP into an empty I.V. container 
of the correct composition and add a sufficient quantity of sterile normal saline (0.9% 
weight/volume) to the container to bring the total volume to 250 mL. Gently invert the 
container to mix. 
Only 0.9% normal saline should be used for dilution and post-infusion flushing of infusion 
line.  The infusion rate must never exceed 25 mg/minute. Different lot numbers of cixutumumab 
must not be mixed in a single infusion. 
The infusion set must be flushed post-infusion with sterile normal saline equal to or 
exceeding the infusion line hold-up volume to ensure delivery of the calculated dose. 
 
8.5  Pretreatment Medications 
Patients should not be routinely premedicated prior to administration of cixutumumab, except in 
the context of an infusion reaction (See Section 9.9 for infusion reaction guidelines) 
 


 
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8.6  Treatment Schema 
Patients will receive cixutumumab/carboplatin/pemetrexed after the initial biomarker assessment 
and randomization has occurred. This protocol defines the duration of one cycle of treatment as 3 
weeks or 21 days (± 5 days).  Starting Day 1 (± 5 days) of each 21-day cycle patients will be 
given 20 mg/kg cixutumumab every 3 weeks, AUC 6 of carboplatin IV every 3 weeks, and 500 
mg/m2 of pemetrexed IV every 3 weeks. After the completion of 4 cycles of combination 
therapy, if the disease has not progressed, patients will receive maintenance pemetrexed (500 
mg/m2 of pemetrexed IV every 3 weeks) in combination with cixutumumab 20 mg/kg 
cixutumumab every 3 weeks until disease progression, intolerable toxicity, or withdrawal of 
consent. 
 
8.7  Maintenance Period dose of Cixutumumab 
The maintenance dose will be 20 mg/kg once every three weeks (± 5 days).  Cycles repeat every 
3 weeks until there is disease progression, intolerable toxicity, or withdrawal of consent. 
 
8.8  Treatment of Toxicity and Dose Modification 
Adverse events of concern, which may or may not be associated with cixutumumab therapy, 
include infusion reactions, hyperglycemia, and weight loss.  If treatment with cixutumumab is 
held due to cixutumumab-related toxicity, chemotherapy may be continued without adjustment. 
 
8.9  Cixutumumab Infusion Reactions 
Cixutumumab infusion reactions will be graded based on the NCI-CTCAE Version 4.0 definition 
of infusion-related reactions (detailed below). 
Symptoms occurring during or following infusion of investigational therapy may also be 
defined according to adverse event categories such as allergic reaction, anaphylaxis, or cytokine 
release syndrome.  In the setting of symptoms occurring during or following infusion of 
investigational therapy, investigators are encouraged to use the adverse event term “Infusion-
Related Reaction” and any additional terms (including those not listed here) that best describe 
the event.  Those described above should be graded as follows: 
 
 


 
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Table 9.1: NCI-CTCAE Version 4.0 Infusion-Related Reactions 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Infusion-related 
reaction 
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, I.V. 
fluids); prophylactic 
medications indicated for 
≤ 24 hrs 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death
Definition: A disorder characterized by an adverse reaction to the infusion of pharmacological or biological substances.
Allergic 
reaction 
Transient flushing 
or rash, drug fever 
<38 degrees C 
(<100.4 degrees F); 
intervention not 
indicated 
Intervention or infusion 
interruption indicated; 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics); 
prophylactic medications 
indicated for ≤ 24 hrs 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen. 
Anaphylaxis 
- 
- 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-
like substances from mast cells, causing a hypersensitivity immune response.  Clinically, it presents with breathing difficulty, 
dizziness, hypotension, cyanosis, and loss of consciousness and may lead to death. 
Cytokine 
release 
syndrome 
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, I.V. 
fluids); prophylactic 
medications indicated for 
≤ 24 hrs 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; 
pressor or 
ventilator support 
indicated 
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused 
by the release of cytokines from the cells. 
 


 
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In general, if a patient experiences a Grade 1 or 2 infusion reaction, the infusion rate should be 
decreased for the duration of the infusion and all subsequent infusions, as directed in the 
protocol.  In addition, patients with Grade 1 and 2 infusion reactions should be treated according 
to standard medical practices.  After a Grade 1 or 2 infusion reaction, patients should be 
premedicated with antihistamines, steroids, acetaminophen, etc, as appropriate for subsequent 
infusions. 
A Grade 3 or 4 infusion reaction will require immediate treatment, including the use of 
epinephrine, bronchodilators, and/or glucocorticoids for symptomatic bronchospasm, I.V. fluids 
and/or pressors for hypotension, and immediate and permanent discontinuation of cixutumumab 
with appropriate supportive care.  The ImClone liaison should be contacted immediately if 
questions arise concerning the grade of the reaction. 
Consistent with usual medical practice, selected parenteral medications may be utilized 
for Grade 2 infusion-related reaction as detailed below.  The ImClone liaison should be 
contacted immediately if questions arise concerning the grade of the reaction.  The following are 
general treatment guidelines for cixutumumab infusion-related reactions.   
 
Grade 1 
• 
Slow the infusion rate by 50% 
• 
Monitor the patient for worsening of condition 
• 
For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg I.V. 
(or equivalent); additional premedication may be administered at the investigator’s 
discretion 
 
Grade 2 
• 
Stop the infusion 
• 
Administer diphenhydramine hydrochloride 50 mg I.V. (or equivalent), acetaminophen 
650 mg orally for fever, and oxygen 
• 
Resume the infusion at 50% of the prior rate once the infusion reaction has resolved or 
decreased to Grade 1; the infusion duration should not exceed 2 hours 
• 
Monitor for worsening of condition 


 
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• 
For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg I.V. 
(or equivalent); additional premedication may be administered at the investigator’s 
discretion 
 For a second Grade 1 or 2 infusion reaction, administer dexamethasone 10 mg I.V. (or 
equivalent); then, for subsequent infusions, premedicate with diphenhydramine 
 hydrochloride 50 mg I.V. (or equivalent), acetaminophen 650 mg orally, and 
dexamethasone 
 10 mg I.V. (or equivalent). 
 
Grade 3 
• 
Stop the infusion and disconnect the infusion tubing from the patient 
• 
Administer diphenhydramine hydrochloride 50 mg I.V. (or equivalent), dexamethasone 
10 mg I.V. (or equivalent), bronchodilators for bronchospasm, and other 
medications/treatment as medically indicated 
• 
Patients who have a Grade 3 infusion reaction will not receive further cixutumumab 
treatment, but will continue to be followed on the protocol 
 
Grade 4 
• 
Stop the infusion and disconnect the infusion tubing from the patient 
• 
Administer diphenhydramine hydrochloride 50 mg I.V. (or equivalent), dexamethasone 
10 mg I.V. (or equivalent), and other medications/treatment as medically indicated 
• 
Give epinephrine or bronchodilators as indicated 
• 
Hospital admission for observation may be indicated 
• 
Patients who have a Grade 4 infusion reaction will not receive further cixutumumab 
treatment, but will continue to be followed on the protocol 
 
8.11  Hyperglycemia 
Hyperglycemia that was at least possibly related to cixutumumab therapy has been observed in 
multiple studies of cixutumumab. Guidelines presented below are intended to enable 
cixutumumab administration in the context of clinical studies while minimizing the potential to 
develop AE-related symptoms or more severe AEs. 


 
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For the assessment of hyperglycemia (diabetes), Metabolism/Nutrition Terms (Version 
4.0) should be used preferentially over Laboratory terms. If hyperglycemia/diabetes occurs 
during treatment with cixutumumab, treatment is dependent upon symptom severity. For Grade 1 
or 2, cixutumumab treatment should continue; oral agents for hyperglycemia/diabetes may be 
used as clinically indicated. 
For Grade 3 (“symptoms interfering with activities of daily living [ADL] or insulin 
indicated”), cixutumumab treatment may continue if the patient is asymptomatic and glucose < 
300 mg/dL; the investigator should consider initiating insulin therapy if the patient is not 
controlled using oral agents. Cixutumumab should be held for Grade 3 hyperglycemia if there 
are symptoms interfering with ADL or if glucose is ≥ 300 mg/dL; cixutumumab may be restarted 
when the patient is asymptomatic, glucose is consistently (in the opinion of the investigator) 
below 300 mg/dL, and the patient is on a stable insulin regimen (if necessary). 
Reintroduction of cixutumumab following stabilization of a Grade 3 hyperglycemic event 
may occur with no dose reduction if glucose is ≤ 200 mg/dL after stabilization. If glucose is 
between 200 mg/dL and 300 mg/dL, a 20% reduction to the dose of cixutumumab may be 
warranted. 
For Grade 4, cixutumumab therapy should be withheld until the patient is asymptomatic, 
glucose is consistently (in the opinion of the investigator) below 300 mg/dL, and the patient is on 
a stable insulin regimen. When treatment resumes, the cixutumumab dose should be reduced by 
20%. 
 
8.12  Dose Reductions 
Patients will undergo dose reduction, if necessary, according to the following guidelines. 
Table 9.2:  Cixutumumab Dose Reduction Guidelines 
Starting Dose 
Level -1 
Level -2 
20 mg/kg q 3 weeks 
Decrease starting dose by 
20% 
Decrease Level -1 by an 
additional 20% 
 
 


 
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Hematologic Toxicity 
For Grades 1-2 hematologic toxicity, no dose modification is required.  For Grade 3 toxicity not 
adequately controlled with appropriate supportive care (including hematopoietic growth factors, 
if indicated), withhold dose until toxicity ≤ Grade 2, or has returned to pretreatment baseline; at 
this time, dose should be reduced by 20% and treatment resumed.  In the case of Grade 4 
hematologic toxicity associated with cixutumumab, withhold dose until toxicity is ≤ Grade 2, 
then reduce dose by two levels and resume treatment. 
 
Non-Hematologic Toxicity 
PLEASE NOTE: Specific guidelines for dose reduction in patients who experience infusion 
reactions or hyperglycemia while receiving treatment with cixutumumab may be found in 
Section 8.10 and 8.11. 
General guidelines for dose modification for other non-hematologic toxicities related to 
cixutumumab are as follows: 
 For Grade 1, no dose modification is required. 
 Patients with any Grade 2 cixutumumab-related clinical adverse event may, at the 
investigator’s discretion, continue to receive cixutumumab per protocol provided that the 
event does not pose a serious health risk or is easily treated; if necessary, the patients may 
be dose reduced up to two times during the study. 
 For a Grade 3 clinical toxicity not adequately controlled with appropriate supportive care, 
withhold dose until toxicity is ≤ Grade 1 or has returned to pretreatment baseline, and 
then resume treatment with a dose reduction of one level.  If toxicity recurs after therapy 
resumes, a second dose reduction is permitted; if more than two toxicity-related 
cixutumumab dose reductions are required, treatment with this agent will be permanently 
discontinued. 
 For Grade 4 clinical toxicity, withhold dose until toxicity is ≤ Grade 1 or has returned to 
baseline, then resume treatment with dose reduced by two levels.  If toxicity recurs after 
therapy resumes, cixutumumab treatment will be discontinued. 
 If treatment with cixutumumab is withheld for more than 3 continuous weeks from the 
next scheduled dose due to a treatment-related toxicity that does not resolve, the patient 
will be withdrawn from the study, unless the Investigator feels that the patient should 


 
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remain in the study because of evidence that the patient is/may continue deriving benefit 
from continuing study therapy. 
 Patients who enter the study with symptoms or laboratory values equivalent to NCI-
CTCAE Version 4.0 Grade 1-2 adverse events should not have dose reductions related to 
the persistence or mild worsening of these symptoms or laboratory values; dose 
reductions may be warranted if worsening of symptoms or laboratory values is clinically 
significant in the opinion of the investigator. Asymptomatic Grade 3-4 laboratory 
abnormalities should not result in dose interruptions, modifications, or discontinuation of 
study therapy unless determined to be clinically significant by the investigator. 
 
 
9  STUDY CONDUCT 
9.1  Patient Accrual and Patient Identification 
Patients will be enrolled at MD Anderson Cancer Center only.  A total of 225 patients will be 
equally randomized into one of the three treatment arms.  An accrual of rate of 5 patients per 
month is expected.  The projected trial duration is 4 years with 30 months of accrual and an 
additional 18 months of follow up period.  A 3-digit accession number will be assigned to each 
patient as the master ID.  A password protected secured file will be created to store the cross 
reference list between the master ID and confidential patient information such as name, birth 
date, hospital number, and social security number (if available), etc. Master ID will be used 
throughout the trial and in database for patient identification purpose. Confidential patient 
information will be used only when it is necessary such as in patient care setting. 
 
Note:  Patients must be enrolled and have protocol assessments completed at the MD 
Anderson Cancer Center main institution.  Labs can be completed at the RCCs if 
appropriate. 
 
 
 


 
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9.2  Patient Enrollment 
Patients must be consented prior to any study-related procedures being performed.  Once patients 
are consented for the BATTLE-FL protocol and appropriate procedures are completed, they will 
be assigned into one of the treatment arms. 
 
9.3  Replacement of Patients 
Participants who withdraw from the study prior to completion of the study treatments for reasons 
other than serious adverse events, unacceptable toxicity or progressive disease will be defined as 
dropouts and will be replaced.  Replacement participants will be assigned the next sequential 
number. 
 
9.4  Screening Procedures 
All patients must undergo pre-treatment evaluations within 4 weeks (unless otherwise specified) 
prior to initiating therapy.  Pre-treatment evaluations will be used to determine the patient’s 
study eligibility.  Patients must sign an informed consent form prior to undergoing protocol-
specific evaluations and prior to receiving treatment.   
1. Signed informed consent  
2. Medical history including smoking history (duration and intensity) 
3. Full physical exam: including height, weight, and ECOG performance status 
assessment.  Vital signs including pulse, blood pressure, temperature 
4. Serum chemistry and electrolytes to include: total protein, uric acid, blood urea nitrogen 
(BUN), creatinine, LDH, AST, ALT, alkaline phosphatase, phosphorus, total bilirubin, 
sodium, potassium chloride, magnesium, calcium, albumin, glucose, CO2, and HbA1c 
done within 4 weeks prior to treatment. 
5. Hematology to include: CBC with automated differential and platelet count 
6. Brain MRI/CT 
7. Chest x-ray within 4 weeks of starting treatment 
8. CT or MRI scans of chest within 4 weeks of starting treatment. 
9. Biopsy of tumor for biomarker evaluation to include diagnostic fine needle aspiration 
(FNA) and core needle biopsies (CNB) (See Appendix C) Please Note: In some instances 
(i.e. local irradiation for the management of tumor-related symptoms, surgical procedure, 


 
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etc.), the length of time from the baseline biopsy and the initiation of study treatment may 
exceed the 28 day window stated above to allow adequate recovery of study participants 
prior to study therapy.  
10. Serum biomarker evaluation (optional)  
11. Pregnancy Test to be performed within 72 hours of dosing for women of childbearing 
potential.  Serum and/or urine may be used in the event a 2nd pregnancy test is required 
due to slightly elevated HCG levels above normal.  If a 3rd pregnancy test is required, a 
Gynecological consult will be required to satisfy inclusion criteria.   
12. Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) 
ratio.  For UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be 
< 1,000 mg for patient enrollment onto the Bevacizumab arm.  The urine protein used to 
calculate the UPC ratio must be obtained within 4 weeks prior to randomization. 
13. Electrocardiogram 
14. Diagnostic archival tumor sample (optional) 
15. Audiometry assessment (cixutumumab arm only) 
16. PT/INR within 4 weeks of starting treatment  
17. AE Assessment  
18. Concomitant Medication Assessment 
 
9.4.1  Tumor Tissue Biopsy 
Tissue biopsies (FNA and CNB) will be performed at prior to randomization and at the end of 2 
cycles of treatment (optional) while participating in the study.  In addition, archival diagnostic 
tissue samples (optional) will also be collected for biomarker analysis.  Tissue may be obtained 
via Image-guided core biopsy or other core biopsy methods to available tissue (i.e. subcutaneous 
or cutaneous or lymph node disease). 
Image-guided core biopsy:  Study patients will undergo an image-guided core biopsy 
after being NPO in regard to solid food for a minimum of six hours and NPO for oral 
medications and small amounts of liquids for two hours prior to the procedure.  The participant 
will be monitored with continuous electro-cardiographic, respiratory, and oximetric monitoring, 
with intermittent blood pressure monitoring.  At least 2 core biopsies of the tumor will be 


 
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performed (more if can be safely performed).  Specimens will be used to analyze biomarkers, 
genomic, proteomic, and other biomarker studies. 
 
9.4.1.1  Exploratory tumor biomarkers 
Pre-treatment tumor tissue will be analyzed for potential markers associated with clinical 
outcome or therapeutic response to the different treatment arms as described below. In addition, 
optional biopsies taken after two cycles of treatment will be compared to baseline tumor biopsies 
to assess biomarker modulation and its relationship to treatment response. These markers will 
include multiplex profiling of DNA mutations; DNA copy number variations; gene expression 
profiling; protein markers; and other potential molecular markers that may be relevant. These 
markers are detailed in Appendix G.   
 
9.4.2  Serologies 
Optional blood samples will be collected at baseline, end of Cycle 2 and end of study while 
participating in the study.  Blood will be collected and either immediately analyzed or stored 
frozen until ready for analysis. Cells from blood, including circulating tumor cells (CTCs) will 
be quantitated and isolated by antibody-based capture methods using tumor antigens including 
Ep-CAM. Isolated cells will be assessed for markers from relevant pathways through analysis of 
DNA (mutations, copy number variations, and single nucleotide polymorphisms (SNPs)), gene 
expression, and protein. Proteomic studies of circulating proteins including cytokines and 
angiogenic factors (CAFs) will also be conducted.  Additional details of these analyses are 
provided in Appendix G.  
 
9.5  Study Treatment Procedures 
All study evaluations and/or clinic visits may be conducted within ± 5 days of the date specified 
in the protocol.   
1.  A full physical exam including weight, ECOG performance status assessment, vital signs 
including pulse, blood pressure, and temperature will be conducted Day 1 of each cycle. 
2.  Tumor tissue biopsy after cycle 2 (optional). 
3.  Serum chemistry and electrolytes to include: total protein, uric acid, blood urea nitrogen 
(BUN), creatinine, LDH, AST, ALT, alkaline phosphatase, phosphorus, total bilirubin, 


 
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sodium, potassium chloride, magnesium, calcium, albumin, glucose, and CO2 each cycle. 
(HbA1c on Day 1 of each cycle for Cixutumumab arm only; and Cetuximab arm only 
weekly (± 1 day) labs (Days 8 and 15 of each cycle) include only magnesium). 
4.  Hematology to include: CBC with automated differential and platelet count each cycle. 
5.  Serum samples for biomarkers will be collected at end of cycle 2 (optional). 
6.  Brain MRI/CT (if clinically indicated). 
7.  Chest X-ray at the completion of cycle 2 and then every 2 cycles. 
8.  CT/MRI of the chest (and abdomen if indicated) at the completion of cycle 2 and then 
every 2 cycles. 
9. Adverse event assessment. 
10. Concomitant medication assessment. 
11. PT/INR (within 4 weeks of starting treatment and per standard of care if patient is on 
warfarin or other anticoagulant). 
12.Urinalysis and UPC ratio.  Patients on the Bevacizumab arm will undergo a urine analysis 
and a UPC ratio prior to treatment of every cycle. 
 
** Patients who have been previously randomized to the cetuximab arm will have 
magnesium levels drawn weekly (Day 8 and 15 of each cycle) prior to cetuximab infusion. 
 
 
9.6  End of Therapy Procedures 
End of therapy evaluations will be determined as:  
 Progression of disease, or symptomatic deterioration, 
 Unacceptable toxicity, 
 Treatment delay greater than 42 days, 
 The patient may withdraw from the study at any time for any reason, 
 Treating physician and/or Principal Investigator discretion. 
 
End of therapy evaluations will include a physical examination, hematology, and serum 
chemistry profiles, PT/INR (if indicated), urinalysis and UPC (if clinically indicated), imaging 


 
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studies (if indicated), audiometry assessment (cixutumumab arm only) and electrocardiogram. 
An optional serum sample will be collected at end of study visit.   
 
9.7  Follow-up Procedures 
Subjects withdrawn from the study will be followed for survival. The reason for withdrawal and 
date of the discontinuation will be obtained. If a subject is non-compliant or is lost to follow-up, 
the research nurse or his/her designee will make three attempts to call the subject over a period 
of one month. Attempts to contact will be documented. If the research nurse or his/her designee 
is unable to make contact with either the subject or a family member after three phone calls, then 
a letter will be sent to the subject’s last known address. 
Patients will have a follow-up evaluation performed 4 weeks (± 5 days) from the date of 
discontinuation to assess for resolution of any toxicities.  This evaluation may be a visit or phone 
contact by the research personnel.  Patients will be followed every three months after study 
discontinuation for up to 3 years.   
 
9.8  Evaluation Criteria 
Tumor Response 
The initial tumor response (unidimensionally measured disease) will be assessed by a Radiology 
collaborator at the completion of two cycles of therapy and will be compared to pre-treatment 
values.  Subsequent tumor response for patients receiving therapy will be assessed following the 
completion of every two cycles of therapy.  Responses will be based on a comparison to the pre-
treatment tumor evaluation.  All patients who have received treatment with at least one cycle of 
treatment will be considered evaluable for response.  Imaging and diagnostic studies of 
measurable and evaluable tumors should be repeated following every two cycles of 
therapy.  (See Appendix B)  The tumor measurements will be documented on study specific 
source documents and in the electronic database.   
 
NOTE:  The pre-treatment and all subsequent imaging and diagnostic studies should be obtained 
from the same source, for example, CT scan or MRI.  Each response parameter will be reported 
independently.  Responses are to be scored based on measurable and nonmeasurable criteria and 
overall response to therapy. 


 
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10  SAFETY DATA COLLECTION, RECORDING AND REPORTING 
Safety assessments will consist of monitoring and recording adverse events following Table 10, 
the Recommended Adverse Event Recording Guidelines for Phase II.  These safety assessments 
should be performed within ± 5 days of the scheduled day of cycle visit.  Adverse events will be 
evaluated continuously throughout the study. Safety and tolerability will be assessed according 
to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4 grading 
system.  
 
10.1  Adverse events  
Information about adverse events, whether volunteered by the patient, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected and recorded.  Documentation of the adverse events includes: grade, start/stop dates, 
attribution, action taken, no action taken, possible interruption, discontinuation (temporarily or 
permanently), concomitant medications, non-drug therapy, hospitalization/prolonged 
hospitalization), and whether it constitutes a serious adverse event (SAE).  Adverse events will 
be documented in the patient’s medical record.  Based upon best clinical judgment, the Principal 
Investigator will assign attribution of adverse events to each study agent separately.   
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered to be 
related to study drug. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after starting study drug. Abnormal laboratory values 
or test results will be documented. Based upon best clinical judgment, the investigator will 
determine if the value is clinically significant. 
Once an adverse event is detected, it should be followed until its resolution, and 
assessment should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship to the study drug, the interventions required to treat it, and 
the outcome. 
Information about common side effects already known about the investigational drug can 
be found in the Investigators’ Brochure or will be communicated between IB updates in the form 


 
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of Investigator Notifications. This information will be included in the patient informed consent 
and will be discussed with the patient during the study as needed. 
 
 
10.2  Serious Adverse Event Reporting (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes:  
 
Death 
 
Life-threatening adverse drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience 
as it occurred. It does not include an adverse experience that, had it occurred in a more 
severe form, might have caused death 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
Persistent or significant disability/incapacity – a substantial disruption of a person’s 
ability to conduct normal life functions 
 
Congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
Important medical events as defined above may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the MDACC IND Office. 
 
10.3  Reporting Procedures for Adverse Events 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “University 
of Texas M. D. Anderson Cancer Center Institutional Review Board Policy on Reporting Serious 


 
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Adverse Events”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to IND Office, regardless of attribution (within 5 working days of knowledge of 
the event).  Adverse event recording will follow Phase II recording guidelines from the IND 
Office.  
 
Table 10. Recommended Adverse Event Recording Guidelines for Phase II 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
N/A 
N/A 
Yes 
Yes 
Yes 
Unlikely 
N/A 
N/A 
Yes 
Yes 
Yes 
Possible 
Yes 
Yes 
Yes 
Yes 
Yes 
Probable 
Yes 
Yes 
Yes 
Yes 
Yes 
Definitive 
Yes 
Yes 
Yes 
Yes 
Yes 
 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of the 
event to the Safety Project Manager in IND Office.  The MDACC “Internal SAE Report Form 
for Prompt Reporting” will be used for reporting to IND Office. Serious adverse events will be 
captured from the time of the first protocol-specific intervention, until 30 days after the last dose 
of drug. Serious adverse events must be followed until clinical recovery is complete and 
laboratory test have returned to baseline, progression of the event has stabilized, or there has 
been acceptable resolution of the event.  Additionally, any serious adverse events that occur after 
the 30 day time period that are related to the study treatment must be reported to IND Office. 
This may include the development of a secondary malignancy. 
 
10.3.1  Reporting to FDA 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32.  It is the responsibility of the PI and the research team 
to ensure that serious adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the MDACC IND Office guidelines, and 
Institutional Review Board policy. 
 


 
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10.3.2  Investigator Communication with Eli Lilly and Company 
ImClone collects product complaints on study drugs used in clinical trials in order to 
ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements. 
Complaints related to unblinded comparator drugs or concomitant drugs are reported directly 
to the manufacturers of those drugs in accordance with the package insert.  The investigator or 
his/her designee is responsible for handling the following aspects of the product complaint 
process in accordance with the instructions provided for this study: 
 Recording a complete description of the product complaint reported and any associated 
AEs using the study-specific product complaint form provided by ImClone for this 
purpose 
 E-mailing the completed product complaint form within 24 hours to ImClone or its 
designee as listed on the product complaint form 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product. 
Adverse events classified as “serious” must be recorded on the MDACC Internal Adverse 
Event Reporting Form and reported to the Sponsor (Safety Project Manager ORE&RM) and to 
Eli Lilly & Co. to comply with regulatory requirements.  These SAEs will include deaths, 
regardless of their causal relationship to investigational product.  All SAEs must be reported 
using the MDACC Internal Adverse Event Reporting Form.  To the extent possible, the 
descriptive terminology and other SAE attributes entered on the MDACC Internal Adverse Event 
Reporting Form should approximate similar information in the patient’s medical record.  Study 
site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 24 
hours of investigator awareness of the event via a Sponsor-approved method. Alerts issued via 
telephone are to be immediately followed with official notification on study-specific MDACC 
Internal Adverse Event Reporting Form. The completed MDACC Internal Adverse Event 
Reporting Form must be faxed to Lilly’s Global Product Safety Fax Number for all SAEs at 
866-644-1697 or 317-453-3402 within 24 hours of the study site personnel’s initial 


 
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notification/awareness of the event.  Duly authorized study site personnel may sign completed 
forms; however, it is recommended that the investigator sign each final SAE report. 
 
10.3.3  Investigator Communication regarding Cixutumumab Serious Adverse Events 
All serious adverse events related to Cixutumumab must be reported, by FAX to Global Product 
Safety for Eli Lilly.  This includes serious, related, labeled (expected) and serious, related, 
unlabeled (unexpected) adverse experiences. All deaths during treatment or within 30 days 
following completion of active protocol therapy must also be reported.  Serious adverse events 
occurring more than 4 weeks after study discontinuation need only be reported if a relationship 
to the ImClone study drug (or therapy) is suspected.  
This unified organization supports the entire oncology portfolio, inclusive of Lilly and 
ImClone development projects and marketed products, and allows us to implement a single 
quality system and procedures to ensure compliance in the collection, processing, analysis, and 
reporting of adverse event data, and effective characterization and communication of the safety 
profiles of our developmental and marketed compound. 
 
10.3.4  Exclusions to SAE Reporting Requirements 
The following are not considered SAEs: 
 Pre-planned or elective hospitalization including social and/or convenience situations 
(e.g., respite care). 
 SAEs that occur within the 30-day post study treatment window but related to subsequent 
therapies. 
 Patients who have completed study treatment or who terminate from study and then 
undergo subsequent alternate therapies (such as chemotherapy, RT, biotherapy, 
immunotherapy, etc) during the 30-day safety period and experience an SAE specifically 
related to the administration of the alternate therapy will not have those events reported 
as AEs. This exclusion will include “elective” hospitalizations necessary for the 
administration of such therapies, as well as any specific adverse effect known to be due to 
the alternate therapy. 
 
 


 
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10.3.5  Reporting of Patient Death to MDACC IRB 
Any unexpected, and possibly, probably, or definitely related to study intervention death that 
occurs during and within 30 days after last day of active study intervention must be reported to 
the IRB within 24 hours by telephone.  A full written report must follow as soon as possible.   
 
10.4  Adverse event reporting on Case Report Form 
All adverse events, regardless of severity or causality, will be documented in the medical record 
and entered into the electronic case report form (PDMS/CORe) Adverse event onset and 
resolution dates, severity/grade, outcome, any action taken due to an AE, and the relationship to 
the investigational study agent(s) will be documented in the medical record. Known adverse 
events relating to the underlying clinical condition will be reported in the electronic case report 
form (PDMS/CORe). 
 
10.5  Reproductive Risks and Reporting of Pregnancy 
Investigational drugs should not be used during pregnancy or lactation. Pre-menopausal women 
of childbearing potential will follow an approved, medically accepted birth control regimen (e.g., 
abstinence, birth control pills, intrauterine device, condoms, and implants) or agree to abstain 
from heterosexual intercourse while participating in the study and for six (6) months following 
the last dose of the investigational agents. Men who are not surgically sterile must agree to 
practice a medically acceptable contraceptive regimen including barrier methods from study 
treatment initiation until at least six (6) months after the last administration of the investigational 
agents. 
All women of childbearing potential MUST have a negative pregnancy test within 72 
hours prior to receiving the investigational product.  If the pregnancy test is positive, the patient 
must not receive investigational product and must not be enrolled in the study.  It is not known 
whether the investigational drugs can cause fetal harm when administered to a pregnant 
woman.  There are no adequate and well-controlled studies of these agents in pregnant women. 
Results of animal studies indicate that investigational agents may cross the placenta and is found 
in fetal plasma.  During the course of the trial, all patients of childbearing potential should be 
instructed to contact the treating physician immediately if they suspect they might have 
conceived a child.  In addition, a missed or late menstrual period should be reported to the 


 
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treating physician.  If a female patient or the treating physician suspects that the female patient 
may be pregnant prior to administration of study drugs, the study drugs must be withheld until 
the results of a pregnancy test are available. If pregnancy is confirmed the patient must not 
receive study medications and must be withdrawn from the study.  Throughout the entire 
pregnancy, additional contact should be made with the patient and in some cases with the 
healthcare provider, to identify spontaneous abortions and elective terminations, as well as any 
medical reasons for elective termination. In addition, the study investigator should include 
perinatal and neonatal outcome. Infants should be followed for a minimum of 4 weeks.  If a male 
patient is suspected of having fathered a child while on study drugs, the pregnant female partner 
must be notified and counseled regarding the risk to the fetus. In addition, the treating physician 
must follow the course of the pregnancy, including prenatal and neonatal outcome. Infants 
should be followed for a minimum of eight weeks.  Upon live-birth delivery, the minimum 
information that should be collected includes date of birth, length of pregnancy, sex of infant, 
major and minor anomalies identified at birth. Outcomes can be obtained via mailed 
questionnaires, maternal interviews, medical record abstraction, or a combination of these 
methods. All serious adverse event reports relating to the pregnancy, including spontaneous 
abortion, elective abortion and congenital anomalies, should be forwarded to the FDA & 
supporting companies.  It is not known whether the investigational agents are excreted in human 
milk.  All of these agents can have serious risks to infants including mutagencity and 
carcinogenicity, a decision should be made whether to discontinue nursing or discontinue the 
drug, taking into account the importance of the drug to the mother.   
Any pregnancy that occurs during study participation should be reported to IND Office. 
To ensure patient safety each pregnancy must also be reported to Eli Lilly Global Product Safety. 
The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of birth, and the presence or absence of any birth defects, congenital 
abnormalities or maternal and newborn complications 
 
 
 


 
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11  STATISTICAL DESIGN AND DATA ANALYSIS CONSIDERATIONS 
11.1  Sample Size and Design 
This study is a randomized phase II trial.  Randomization is used to achieve patient 
comparability across the arms.  Patients will be equally randomized into one of the three 
treatment arms with equal number of patients within each arm by using the block randomization 
with a block size of multiples of 3.  To achieve the statistical objective of this trial, our goal is to 
enroll 225 eligible and evaluable patients.  For the interim and final analysis, we will use the 
information accrued to the trial per protocol.  For patients who have actionable molecular 
aberration and are removed from the study, the data acquired prior to the removal of study will 
be used for analysis as planned.  Additional information acquired outside the trial can also be 
used to supplement the secondary analysis.   
The primary endpoint of the study is progression free survival (PFS), which is defined as 
time from randomization to disease progression or death or last follow-up whichever occurred 
first.  Disease progression and death are events.    
The projected trial duration is 5 years with 48 months of accrual (accrual rate ~5/per 
month) and an additional 12 months of follow up.  The expected censoring rate at the end of trial 
is 10%, which includes patients who are lost-to-follow-up.  An interim analysis is planned when 
half of the expected events, i.e., 101 progression deaths are observed. 
We assume that, after the initial screening procedure, there will be 10 biomarkers in the 
full model. Some of the biomarkers could be constructed by forming composite scores of several 
biomarkers.  We further assume that there are 3 important biomarkers in the true model, with 
biomarker 1 being prognostic and biomarkers 2, and 3 being predictive for experimental arms 2, 
and 3, respectively.  For each biomarker, we assume the percentage of patients with positive 
biomarker is 50%.  Based on our preliminary data, PFS is assumed to be exponentially 
distributed with a median of 4 months under the null hypothesis.  The true PFS by treatment and 
biomarker status under the null and the alternative hypotheses are shown in Table 11.1. 
 
 
 


 
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Table 11.1. Median progression free survival in month by treatment and biomarker status under the null 
and the alternative hypotheses given the assumption in the first 4 rows. 
Biomarker 
Status 
Null Hypothesis 
Alternative Hypothesis 
(M1, M2, M3)  
Trt 1 
Trt 2 
Trt 3 
 
Trt 1 
Trt 2 
Trt 3 
 
(0,0,0) 
4 
4 
4 
 
4 
4 
4 
  
(1,0,0) 
4 
4 
4 
 
6 
6 
6 
  
(0,1,0) 
4 
4 
4 
 
4 
12 
4 
  
(0,0,1) 
4 
4 
4 
 
4 
4 
12 
  
(0, 1, 1) 
4 
4 
4 
 
4 
12 
12 
  
(1,1,0) 
4 
4 
4 
 
6 
18 
6 
  
(1,0,1) 
4 
4 
4 
 
6 
6 
18 
  
(1,1,1) 
4 
4 
4 
 
6 
18 
18 
  
 
Based on the assumptions given in Table 11.1, simulated survival times were generated from an 
exponential distribution with following hazard rate for Treatment j: 
0
1
1
exp
K
K
j
j
j
k
k
jk
j
k
k
k
T
M
T M


















,              (1) 
where Tj  is the treatment indicator for Arm j, j=2, 3 (with Arm 1 as the reference/control group), 
and Mk is the marker positive indicator for Marker k, k=1, 2, K. 
 
11.2  Toxicity Monitoring  
Unacceptable toxicities are defined as grade III or higher non-hematologic toxicities, 
grade IV hematologic toxicities or treatment related death.  With respect to the stopping 
boundaries, the time period in which toxicity events will be counted is one (1) cycle of treatment.  
We will monitor toxicity for each arm separately.  Denote the probability of unacceptable 
toxicity as P_tox E for each arm.  The intolerable level of toxicities is defined as Probability 
(P_tox_E > 0.2) > 0.9, i.e., the probability of unacceptable toxicity is high as compared to 
historical data.  We will start to monitor the toxicity in each arm after a total of 10 patients (per 
arm) are treated.  With a prior of beta (200, 800) for historical toxicity rate which has a mean 
toxicity rate of 20% with very small variance, and a non-informative beta (0.5, 0.5) prior for 
P_tox_E, the stopping boundaries for toxicity on or after the 10th patients treated are to have 
toxicities greater than or equal to a/b where a is the number of unacceptable toxicities and b is 


 
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the total number of patients treated.  Using Multc_Lean version 2, the stopping conditions are as 
follows: 
 
                  
| Stop the trial if there are 
 # Patients       | this many toxicities total: 
--------------------------------|------------------------------------------------------------ 
 5              
| Never stop with this many patients 
 10              
| 4-10 
 15              
| 6-15 
 20              
| 7-20 
 25              
| 8-25 
 30              
| 9-30 
 35              
| 11-35 
 40              
| 12-40 
 45              
| 13-45 
 50              
| 14-50 
 55              
| 15-55 
 60              
| 17-60 
 65              
| 18-65 
 70              
| 19-70 
 75            
| Always stop with this many patients 
 
 
The operating characteristics are shown in the following table.  If the true toxicity rate is 
30% for a particular arm, the probability of early stop that arm is 86%, and the averaged patients 
treated is 31. 
True Prob(Toxicity) 
Probability of Early 
Stopping 
Average patients treated 
0.05 
0.001 
75 
0.10 
0.021 
74 
0.20 
0.285 
60 
0.30 
0.857 
31 
 
 
 


 
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11.3 Interim Futility Analysis  
 At interim analysis, the following reduced model 
0 exp
j
j
jT







  (2) 
will be used to make inference on the marginal treatment effects for both experimental 
treatments, j=2, 3, where λ0 is the baseline hazard rate of the control arm (note the actual value of 
λ0 is the same as the λ0 in equation (1)), and T2, and T3 are indicators for the 2 experimental 
treatments respectively.  If the standardized coefficients z of T2 or T3 (β1, or β2 divided by their 
corresponding standard deviation) is less than a cutoff value of -1.05,  we will declare the 
corresponding treatment is not promising and suspend randomizing patients into that arm.  If 
only one experimental arm is suspended, the remaining patients will be equally randomized 
between the remaining 2 arms.  If none of the experimental treatments are promising, then the 
whole trial will be stopped.  The early stopping probabilities and the mean sample sizes under 
the null and alternative hypotheses are shown in Table 11.2. 
 
 
Table 11.2. Early stopping probabilities of each experimental arm and all arms at interim analysis when 
half of the expected death events 101 are observed. 
 
z=-1.05 
Trt 2 
Trt 3 
Both 
Experimental 
Arms are 
Stopped 
Mean Sample 
Size 
Null    hypothesis 
0.834 
0.849 
0.75 
152 
Alternative 
hypothesis 
0.078 
0.079 
0.022 
223 
 
 
Naïve Frequentist power calculation for prognostic and predictive biomarkers using 
nQuery  
We assume that the trial duration is 5 years with 48 months of accrual (accrual rate ~5/per 
month) and an additional 12 months of follow up period, and 10% of dropout rate.  We further 
assume that the percentage of patients with positive biomarker is 50%.  Given the parameters in 


 
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table 11.1, we can compute the median PFS for any combination of the true markers and 
treatments under the alternative hypothesis (Table 11.3).  
 
Table 11.3. Marginal median PFS for the treatment by marker status according to table 1, assuming each 
of the 4 top cells of each column accounts for 25% of the patients under the alternative hypothesis. 
M1 
(M2,/M3) 
Median PFS for the 
experimental arms 
(arm 2 or 3) 
Median PFS for the 
control arm (arm 1) 
Note 
0 
0 
4 
4 
 
1 
0 
6 
6 
 
0 
1 
12 
4 
 
1 
1 
18 
6 
 
0/1 
0 
5 
5 
Trt * Predictive marker       (-) 
marginal 
0/1 
1 
15 
5 
Trt *Predictive marker         
(+) marginal 
0 
0/1 
8 
4 
Trt *Prognostic marker       
(-) marginal 
1 
0/1 
12 
6 
Trt * Prognostic marker       
(+) marginal 
0/1 
0/1 
10 
5 
Treat marginal 
Note:  Overall prognostic marker (-): (8+8+4)/3=6.67 months; Overall prognostic marker (+): (12+12+6)/3=10.5 
months. 
 
 
 
 Assuming that there is a prognostic marker and a predictive marker for each 
experimental arm (under the alternative hypothesis), a sample size of 75 patients (approximate 
37 predictive marker positive vs. 37 maker negative) will achieve 91% power to detect the 
improvement of median PFS from 5 months (50% prognostic positive) to 15 months in 
biomarker positive subgroups with a one-sided 5% type I error rate based on a two group test of 
equal exponential survival with accrual rate and dropout rate using nQuery 7 (Table 11.4).   
 
 


 
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Table 11.4. Power for comparing marker positive vs. marker negative within each experimental treatment 
arm. 
 
Scenario 1  
(15 vs. 5 mon)
Scenario 2  
(15 vs. 5 mon) 
Scenario 3 
 (15 vs. 5 mon) 
  Test significance level,  
0.100 
0.050 
0.050 
  1 or 2 sided test? 
1 
1 
1 
  Length of accrual period 
48.00 
48.00 
48.00 
  Maximum length of followup 
60.00 
60.00 
60.00 
  Common exponential dropout rate, d 
0.1  
0.1  
0.15 
      Group 1 exponential parameter, 1 
0.1386 
0.1386 
0.1386 
      Group 2 exponential parameter, 2 
0.0462 
0.0462 
0.0462 
  Hazard ratio, h=1/ 2 
3  
3  
3  
  Power ( % ) 
95 
91 
84 
  n per group 
37 
37 
37 
  Total number of events required, E 
30 
30 
23 
Note:  Lambda.0= ln(2)/5 = 0.1386294; Lambda.1 ln(2)/15 = 0.04620981; Lambda.1 ln(2)/10 = 0.0693; Lambda.1 
ln(2)/6.67 = 0.1039 
 
 
Similarly, with a sample size of 75 patients per arm, we will have 89% power to detect 
the improvement of median PFS from 5 months to 10 months in each of the experimental arm as 
compared to the control arm with a one-sided 5% type I error rate (11.5).   
Table 11.5. Power for comparing the experimental arms (median PFS=10 months) to the control arm 
(median PFS=5month). 
 
Scenario 1 
(10 vs. 5 mon) 
Scenario 2 
(10 vs. 5 mon) 
  Test significance level,  
0.100 
0.050 
  1 or 2 sided test? 
1 
1 
  Length of accrual period 
48.00 
48.00 
  Maximum length of followup 
60.00 
60.00 
  Common exponential dropout rate, d 
0.1 
0.1 
      Group 1 exponential parameter, 1 
0.1386 
0.1386 
      Group 2 exponential parameter, 2 
0.0693 
0.0693 
  Hazard ratio, h=1/ 2 
2 
2 
  Power ( % ) 
94 
89 
  n per group 
75 
75 
  Total number of events required, E 
71 
71 
Note:  Lambda.0= ln(2)/5 = 0.1386294; Lambda.1 ln(2)/15 = 0.04620981; Lambda.1 ln(2)/10 = 0.0693; Lambda.1 
ln(2)/6.67 = 0.1039 
 
 
With an overall sample size of 225 patients (approximate 112 prognostic marker positive 
as 112 prognostic marker negative), we will have 77% power to detect the improvement of 


 
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median PFS from 6.67 months to 10 months in the prognostic marker positive subgroup 
compared to the marker negative subgroup with a one-sided 10% type I error rate (11.6).  
 
Table 11.6. Power for comparing overall prognostic marker positive vs. negative for all patients. 
 
Scenario 1 
(10 month vs. 6.67 month)
Scenario 2 
(10 month vs. 6.67 month)
  Test significance level,  
0.100 
0.100 
  1 or 2 sided test? 
1 
1 
  Length of accrual period 
48.00 
48.00 
  Maximum length of followup 
60.00 
60.00 
  Common exponential dropout rate, d 
0.1000 
0.0500 
      Group 1 exponential parameter, 1 
0.0693 
0.0693 
      Group 2 exponential parameter, 2 
0.1039 
0.1039 
  Hazard ratio, h=1 /2 
0.667 
0.667 
  Power ( % ) 
77 
85 
  n per group 
112 
112 
  Total number of events required, E 
100 
135 
Note:  Lambda.0= ln(2)/5 = 0.1386294; Lambda.1 ln(2)/15 = 0.04620981; Lambda.1 ln(2)/10 = 0.0693; Lambda.1 
ln(2)/6.67 = 0.1039 
 
Power calculation based on simulations and using Cox proportional hazards model  
We simulated survival data based on the parameters in Table 11.1.  We conservatively estimate 
power based on 90% of the total accrual (i.e. up front exclude the 10% of lost-to-follow up 
patients assuming that they contain no information).  We would declare that an experimental arm 
is positive if the standardized coefficients of T2 or T3 of (β1, or β2 divided by their standard 
deviation is less than a cutoff value z of -1.64, the power of comparing the experimental arms to 
the control based on the reduced model (Model (2)) is shown in Table 11.7.  With the sample 
size we proposed, we will achieve 93-94% of power to declare positive of the experimental arms 
with 4-6% of type I error rate.   
 
 
 
 


 
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Table 11.7.   Power for comparing the experimental arms to the control arm at the end of the trial based 
on simulations and Cox proportional hazards model. 
 
z=-1.64 
Trt 2 
Trt 3 
Null hypothesis 
0.055  
0.045 
Alternative 
hypothesis 
0.93 
0.94 
 
 
11.4 Final Analysis  
At the end of the trial, all existing data will be subjected to a variable selection procedure to 
identify potentially important biomarkers.  We assume that, after screening, there will be pool of 
10 biomarkers, including 3 truly important biomarkers and 7 unimportant biomarkers.  Based on 
our model parameterization, the prognostic effect will be characterized by a large biomarker 
main effect (
k), and predictive effect will be characterized by a large biomarker-treatment 
interaction term (
jk

 ).  A biomarker will be deemed as being important if it has either a 
prognostic effect or a predictive effect.  To facilitate the identification of prognostic and 
predictive effects, we apply the least absolute shrinkage and selection operator (Lasso) method 
and implement the biomarker selection procedure through a Bayesian Lasso strategy.  Laplace 
prior is used in Bayesian Lasso for covariates effects.  Laplace prior can shrink covariates 
estimation towards zero, and smaller covariate effects will be penalized more.  Therefore, 
Bayesian Lasso can result with good estimation and variable selection simultaneously (Park and 
Casella 2008).  In order to obtain more consistent estimates for the model parameters, we use a 
Bayesian version of the adaptive Lasso (Zou 2006) to provide variable selection.  
Let S  be the set of biomarkers, the prior of {
:
}
k k
S


 in the adaptive Lasso of variable 
selection is 
|
|
(
| )
exp
|
|
k
k
LS
k













, where 
k
 is a generic representation of either the 
biomarker main effect or the biomarker-treatment interaction and 
LS
k

 is the least square 
estimation of the parameter without regularization.  A variable will be selected if empirical 


 
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posterior probability of the coefficient being less than 0 is greater than 0.9.  The selections of cut 
off value can be adjusted to achieve desirable type I error rate and power.  The results for 
variable selection are shown in Table 11.8. The predictive biomarker can be correctly identified 
with >95% power under the alternative hypothesis, while the selection probability of the 
unimportant biomarkers are controlled at about 7%.  The prognostic biomarker can be correctly 
identified with 72% power under the alternative hypothesis. 
 
Table 11.8. Variable selection probabilities of under different scenarios. The mean selection probability 
of null case is controlled at 7%. Nonzero parameters are highlighted.  A variable is selected if Prob (beta 
<0|data) >0.9. 
  
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
Null 
Hypothesis 
Biomarker 
Main Effect 
0.06
9 
0.07 
0.07
9 
0.07
1 
0.06 
0.06
8 
0.08
4 
0.07
5 
0.07
5 
0.05
1 
Biomarker:Trt2 
0.06
5 
0.07
1 
0.06
7 
0.08
3 
0.08
4 
0.07
2 
0.06
9 
0.07
9 
0.07
5 
0.06
3 
Biomarker:Trt3 
0.08
1 
0.07 
0.07
9 
0.08
3 
0.06
3 
0.07
5 
0.09
3 
0.07
5 
0.07
1 
0.06
8 
Alternative 
Hypothesis 
Biomarker 
Main Effect 
0.72 
0.11
4 
0.10
1 
0.08
2 
0.06
8 
0.07
6 
0.08
5 
0.07
5 
0.08
8 
0.06
5 
Biomarker:Trt2 
0.11
6 
0.96
6 
0.07
2 
0.08
3 
0.09
3 
0.08
1 
0.08
6 
0.09
4 
0.08
1 
0.07 
Biomarker:Trt3 
0.13 
0.07
2 
0.97
5 
0.09
1 
0.07
2 
0.07
2 
0.08
5 
0.07 
0.08
4 
0.07
4 
 
 
 


 
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12  PUBLICATION STATEMENT 
Data will be reviewed by the collaborating biostatistician prior to publication.  Participating 
sponsors will have 30 days to review all definitive publications, such as manuscripts and book 
chapters, and a minimum of 10-15 days to review all abstracts. 
  
 


 
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Bevacizumab With Maintenance Pemetrexed and Bevacizumab As First-Line Therapy for 
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Peterson P, Park K, Fossella F, Gatzemeier U, John W, Scagliotti G. 2007. Is pemetrexed more 
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Appendix A:  ECOG Performance Status* 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.:  
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
  
 
 


 
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Appendix B: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
 
Response and progression will be evaluated in this study using the new 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 the RECIST criteria.  
We will also report response as a continuous variable, as % change in tumor size from baseline. 
Definitions  
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first treatment.  
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 disease.  The response assessment 
is based on the presence, absence, or unequivocal progression of the lesions.  
Disease Parameters  
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or 
>10 mm with calipers by clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters).  
Note:  Tumor lesions that are situated in a previously irradiated area will be considered measurable if they 
have increased in size since completion of radiation.   
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. 
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 


 
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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 
diameters will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.  
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and above 
the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
Methods for Evaluation of Measurable 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 the beginning of the treatment.  
The same method of assessment and the same technique should 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 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 should 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 
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, 


 
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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.  
Tumor biomarkers  Tumor biomarkers will not be used to assess response.  
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 
(particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
a. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD will 
be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD.  
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.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported by 
disease-specific medical literature for the indication.  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.  
 
 
 


 
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Response Criteria  
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters  
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note:  the appearance of one or more new lesions is 
also considered progressions).  
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 study 
Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor biomarker 
level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis) 
Note:  If tumor biomarkers 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 biomarker 
level above the normal limits 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase.     
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).  
 
 
 
 
 
 


 
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Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend on the achievement of both measurement and 
confirmation criteria.  
        
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated
No 
SD 
documented at least once >4 
wks. from baseline** 
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. 
**    Only for non-randomized trials with response as primary endpoint.  
***  In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression.  
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. 
For Patients with 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 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  


 
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The duration of overall CR is measured from the time measurement criteria are first met for CR until the 
first date that progressive disease is objectively documented.  
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
Progression-Free Survival 
Progression-free survival will be defined as the duration of time from initiation of study drug until death, 
progression of tumor by RECIST 1.1 criteria, or for worsening of tumor that did not meet RECIST 1.1 
criteria but that did require discontinuation of therapy, whichever occurs first.  
  
 


 
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Appendix C:  Pathology Tissue Processing 
Tissue Collection and Processing 
 
For patient with existing tumor tissue, the sample will be deemed adequate if the sample is a 
Core Needle Biopsy (CNB) or a surgical specimen (Fresh or FFPE). For patients without 
adequate tissue may undergo a biopsy as part of the study. The types of tumor tissue that will be 
collected from the patients are:  
1) fresh tumor CNB samples; or  
2) resection from the original biopsy site or surgical resection will be obtained as part of the 
standard of care diagnostic workup; or 
3) archival diagnostic biopsy samples for patients with  tumor diagnostic workout that may 
have taken place before initiation of any systemic treatment will be obtained.   
In addition to the fresh CNB, FNA samples may be obtained for assessing the quality of the CNB 
specimens. Archival tissue will be used to test for biomarker evaluations for EGFR Mutation and 
ALK fusions. Additional available tissue may be used for testing for other molecular aberrations, 
IHC analyses,  expression profiling, FISH analyses for DNA copy number information and 
whole exome or whole genome deep sequencing.    
Tumor core biopsies before (baseline) and after (optional, two months) targeted therapy 
will be obtained by Interventional Radiologists. The fresh CNB samples will be collected by 
interventional radiologists, who will take 4 or 5 cores that should specimens 1 mm in diameter 
and 1.2–1.8 cm long (1.5 cm on average). The fresh CNB tissue will be collected from the IR 
suite or operating room. The specimens will be divided in the collection site in 2 types: 1) 
molecular diagnostic, at least one tissue core; and, 2) research the remaining tissue cores. The 
molecular diagnostic tissue sample will be kept always in the “chain of custody” of the MDACC 
Pathology Department and the MMDL, while the research specimen will be handled by Dr. 
Wistuba’s lab research personnel. The FNA obtained at the time of the CNB collection, and the 
archival diagnostic biopsies will be collected from the file of the MDACC Pathology Department 
or outside institutions by Dr. Wistuba’s lab personnel. 
 


 
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Appendix D:  Clinically relevant drug interaction: substrates, inducers and inhibitors of 
isoenzyme CYP3A 
Substrates (competitive inhibition) 
Antibiotics:  
clarithromycin*  
erythromycin  
telithromycin* 
Anti-arrhythmics:  
quinidine  
Benzodiazepines:  
alprazolam  
diazepam  
midazolam  
triazolam  
Immune Modulators:  
cyclosporine  
tacrolimus (FK506)  
HIV Protease Inhibitors:  
indinavir*  
ritonavir*  
saquinavir*  
Prokinetic:  
cisapride  
Antihistamines:  
astemizole  
chlorpheniramine  
Calcium Channel Blockers:  
amlodipine  
diltiazem  
felodipine  
nifedipine  
nisoldipine  
nitrendipine  
verapamil  
HMG CoA Reductase Inhibitors:  
cerivastatin  
lovastatin  
simvastatin 
 
Miscellaneous:  
aprepitant  
aripiprazole  
buspirone 
gleevac*  
haloperidol  
methadone  
pimozide  
quinine  
sildenafil  
tamoxifen  
trazodone  
vincristine 
Inducers 
Carbamazepine  
Phenobarbital  
Phenytoin*  
Rifabutin* 
Rifampin*  
St John’s wort  
Troglitazone 
Inhibitors 
Amiodarone  
Cimetidine  
Clarithromycin  
Delaviridine  
Diltiazem  
Erythromycin  
Fluvoxamine*  
Grapefruit juice  
Sevilla Orange 
Indinavir  
Itraconazole*  
Ketoconazole*  
Voriconazole  
Posaconazole  
Mibefradil  
Nefazodone*  
Nelfinavir*  
Troleandomycin  
Verapamil 
*asterisk denotes strong inhibition/induction 
Strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80% decrease in clearance of sensitive CYP substrates 
Moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 50-80% decrease in clearance of sensitive CYP 
substrates. 
Macrolide antibiotics: Azithromycin is not a CYP3A substrate. It may therefore be employed where antibiotherapy with a macrolide 
is desirable   in a patient being treated with RAD001 
Statins: Atorvastatin and pravastatin may be administered concomitantly with RAD001, since a PK interaction study has shown that 
there is no relevant PK interaction. 
Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms, Naunyn Schmiedebergs 
Arch Pharmacol. 2004 Jan;369(1):89-104 and[http://www.medicine.iupui.edu/flockhart/clinlist.htm as of February 15, 2007] 
 


 
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Appendix E: New York Heart Association (NYHA) Classification 
 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV 
(Severe) 
Unable to carry out any physical activity without discomfort. Symptoms 
of cardiac insufficiency at rest. If any physical activity is undertaken, 
discomfort is increased. 
 


 
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Appendix F:  Study Procedures 
Study Procedures 
Screening L 
- 28 to 0 
Cycle a 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
 Day 15 
Cycle 2 
Day 1 
Cycle 3 
Day 1  
Cycle 4
Day 1 
Maintenance
Cycles 
End of 
Therapy 
 
Follow-Up 
30 day  
(+/- 5 days)
Long Term 
Follow-Up 
Every 3 months 
(up to 3 years) 
Informed Consent 
X 
  
  
  
  
  
  
  
 
 
 
Eligibility Criteria 
X 
  
  
  
  
  
  
  
 
 
 
Physical Examination b  
X 
X 
  
  
X 
X 
X 
X 
X 
 
 
Tumor Biopsy 
X 
  
  
  
  
X OP   
  
 
 
 
Diagnostic Archival Tumor Sample 
(Optional) 
X 
 
 
 
 
 
 
 
 
 
 
Disease Assessment c  
(CT or MRI and Chest X-ray) 
X 
  
  
  
  
X 
  
X 
X 
 
 
Hematology (CBC with Diff, Platelets) d 
X 
X i 
 
 
X 
X 
X 
X 
X 
 
 
Chemistry d, e, k 
X 
X i 
Xk 
Xk 
X 
X 
X 
X 
X 
 
 
Urinalysis and UPC f 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
Brain MRI/CT 
X 
  
  
  
  
X m   
X m 
X m 
 
 
Electrocardiogram 
X 
  
  
  
  
  
  
  
X
 
 
Pregnancy Test g 
X 
  
  
  
  
  
  
  
 
 
 
Serum for Biomarker  
Analysis and Storage (Optional) h 
X 
 
 
 
 
X 
 
 
X
 
 
AE/Toxicity Assessment 
X 
X 
 
 
X 
X 
X
X 
X 
X 
 
Concomitant Medication(s) 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
Study Drug Administration 
  
X 
Xk  
Xk 
X 
X 
X 
X 
 
 
 
Drug Accountability 
  
  
 
 
X 
X 
X 
X 
X
 
 
Subsequent Anticancer Therapy 
  
  
  
  
  
  
  
  
 
X 
X
Survival Status 
  
  
  
  
  
  
  
  
 
X 
X 
Audiometry Assessment j 
X 
 
 
 
 
 
  
 
X
 
 
 
 
 


 
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a 
Cycle = 21 days ± 5 days 
b 
Full physical exam includes height (screening only), weight, blood pressure, pulse, temperature, smoking history (screening only) and ECOG Performance 
Status.   
c 
After every 2 cycles ± 5 days 
d 
Prior to infusion each cycle  
e 
Including total protein, uric acid, BUN, creatinine, PT/INR (screening: PT/INR within 4 weeks of starting treatment , and if clinically indicated thereafter for 
preceding cycles),  LDH, AST, ALT, alkaline phosphatase, phosphorus, total bilirubin, sodium, potassium, magnesium, chloride, calcium, albumin, CO2, 
glucose and HbA1c (HbA1c on Day 1 of each cycle for Cixutumumab arm only) 
f 
Including routine dipstick measurements, microscopic analysis, and urine protein.  Urine protein must be screened by urine analysis for Urine Protein  
                Creatinine (UPC) ratio.  For UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be < 1,000 mg for patient enrollment onto the  
                Bevacizumab arm.  The urine protein used to calculate the UPC ratio must be obtained within 4 weeks prior to randomization.  Patients on the Bevacizumab  
               arm will undergo a urine analysis and a UPC ratio prior to treatment of every cycle. 
g 
b-HCG Test and/or urine test to be performed within 72 hours of dosing for women of childbearing potential 
h 
Optional serum samples will be collected at screening, end of Cycle 2 and end of therapy. 
i 
Only performed if previous pre-treatment evaluations are not conducted within 28 days prior to initiating study therapy 
j 
Cixutumumab arm only  
k 
Patients who have been previously randomized to treatment arm Arm 3 carboplatin + pemetrexed in combination with an EGFR monoclonal antibody 
(Cetuximab) will continue with their assigned treatment arm. Cetuximab only is given on a weekly (± 1 day) basis– Weekly labs (Days 8 and 15 of each cycle) 
include magnesium only.l 
Please Note: In some instances (i.e. local irradiation for the management of tumor-related symptoms, surgical procedure, etc.), the 
length of time from the baseline biopsy and the initiation of study treatment may exceed the 28 day window stated above to allow adequate recovery of study 
participants prior to study therapy. 
m 
After 2 cycles ± 5 days of treatment and every 2 cycles ± 5 days thereafter, if  clinically indicated. 
 
 
 
 


 
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APPENDIX G: Biomarker Analyses  
 
Circulating Tumor Cells (CTCs) 
Isolation of CTCs and molecular analysis of these CTCs including mutational profiling. 
We will be isolating CTCs using methods such as the CTC microfluidic chip previously described (N 
Engl J Med 2008; 359:366-377).  Other methodologies that are not dependent on antibody are also being 
tested and will be used if their utility and technical performance has been established.  The captured cells 
of interest can be subsequently interrogated through immunohistochemistry (e.g. fluorescent in situ 
hybridization or FISH) somatic mutation profiling (e.g. Sequenome profiling), SNP profiling, and gene 
expression analysis with a focus on pathways relevant to NSCLC and drugs under investigation (e.g. 
EGFR, MEK, PI3K pathways). 
 
Previously we have established that rare circulating cells can be quantitated using frozen peripheral blood 
mononuclear cells (PBMCs) (Clin Canc Res 2007; 13(9): 2643-50). This permits batched analysis of 
stored samples. Therefore, we will isolate and freeze PBMCs using methods we have previously 
described.  From each sample, blood will be subjected to gradient separation of mononuclear cells, placed 
in DMSO-containing freeze media, cooled using a controlled freeze protocol, and stored at -80C until 
analysis as described above. 
 
Cytokines and Angiogenic Factors (CAFs) 
CAF profiling using serum or plasma to detect biomarkers and signatures of response 
The availability of multiplexing technologies permits the simultaneous assessment of large numbers of 
biologically relevant proteins, such as cytokines, angiogenic factors, and receptors, and soluble markers of 
hypoxia and endothelial damage, using small amounts (i.e., less than one milliliter) of plasma. We refer to 
the broad assessment of these multiple markers as the CAF (cytokine and angiogenic factor) profile.  We 
and other investigators have studied a number of these circulating biomarkers in peripheral blood and 
observed that baseline levels , or changes in these factors, may be markers of drug response or the 
emergence of therapeutic resistance 1-5.   
 
Circulating CAFs will be assessed using established methods as we have previously described 1-5.  A CAF 
profile (typically 60-70 analytes) of plasma biomarkers will be assessed using a combination of multiplex 
technology (e.g. Luminex and Searchlight platforms) and enzyme-linked immunosorbent assays (ELISA). 
Multiplex magnetic bead-based technology enables the simultaneous quantitation of up to 100 analytes. 
These Luminex based assays contain dyed beads conjugated with monoclonal antibodies specific for a 
target protein. The antibody-conjugated beads are allowed to react with sample and a secondary, or 
detection, antibody in a microplate well to form a capture sandwich immunoassay. Multiplex assays can be 
created by mixing bead sets with different conjugated antibodies to simultaneously test for many analytes 
in a single sample. The use of this technique has been well documented in the literature and results are 
comparable to that of ELISA (8-10).  Currently up to 50 human cytokines can be analyzed from 3 separate 
kits using a total volume of less than 1 milliliter.  The remainder of analytes will be determined using by 
validated, enzyme-linked immunosorbent assays (ELISA) assays such as Human Osteopontin (OPN), CA-


 
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9, Collagen IV, sVEGFR2, NGAL; and using the Searchlite multiplex platform.  Other analytical 
platforms will be considered if they are established to have advantages (e.g. lower volume requirements or 
greater sensitivity). For each plate, the standard curves will be assessed to ensure that the expected assay 
range was achieved. For each individual sample, the mean concentration is calculated for duplicate 
samples, and the coefficient of variance % (CV%) is calculated for each of the analytes. If the median 
CV% is greater than 25%, analysis of the sample was repeated. In our experience, less than 10% of 
samples require repeat analysis.  
 
Single Nucleotide Polymorphism Analysis.  Prior studies have established that germline SNPs in cancer 
related pathways (e.g. VEGF, VEGFR2) may be markers for therapeutic response 6.  To identify new 
markers for the treatments in this study we will investigate germline SNPs relevant to the treatment 
regimens in this study. SNPs will be selected based on several criteria including: previous report of an 
association with an inflammatory disorder, angiogenesis, lung cancer, or another cancer; minor allele 
frequency (prioritizing those with frequency of at least 5%); location in the promoter, untranslated region 
(UTR), or coding region of the gene.  The SNPs will be genotyped using standard methods such as 
SNPlex, a technology developed by Applied Biosystems that enables simultaneous genotyping of up to 48 
SNPs in a single tube using an oligonucleotide ligation assay. The assay principle and procedures are 
detailed in the manufacturer’s user guide (PN4360858). As methods for assessing SNPs are rapidly 
improving we will evaluate and potentially incorporate other available methods for SNP assessment at the 
time of analysis.  
1. 
Byers LA, Holsinger FC, Kies MS, et al: Serum signature of hypoxia-regulated factors is associated with 
progression after induction therapy in head and neck squamous cell cancer. Mol Cancer Ther 9:1755-63, 
2010 
2. 
Kopetz S, Hoff PM, Morris JS, et al: Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab 
for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic 
resistance. J Clin Oncol 28:453-9, 2010 
3. 
Hanrahan EO, Lin HY, Kim ES, et al: Distinct patterns of cytokine and angiogenic factor modulation and 
markers of benefit for vandetanib and/or chemotherapy in patients with non-small-cell lung cancer. J Clin 
Oncol 28:193-201, 2010 
4. 
Hanrahan EO, Ryan AJ, Mann H, et al: Baseline vascular endothelial growth factor concentration as a 
potential predictive marker of benefit from vandetanib in non-small cell lung cancer. Clin Cancer Res 
15:3600-9, 2009 
5. 
Nikolinakos PG, Altorki N, Yankelevitz D, et al: Plasma cytokine and angiogenic factor profiling identifies 
markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with 
pazopanib. Cancer Res 70:2171-9, 2010 
6. 
Schneider BP, Wang M, Radovich M, et al: Association of vascular endothelial growth factor and vascular 
endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared 
with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26:4672-8, 2008 


 
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APPENDIX H: Blood biomarkers -Collection, processing, and storage of plasma, serum, 
and peripheral blood mononuclear cells (PMBCs).  
 
Blood sample collection and processing 
 
Collect a total of 56 mL of blood:  
 
Whole Blood --- 2 x 10 mL tubes 
1) Collect blood for Circulating Tumor Cells using established laboratory procedures. 
 
Plasma Processing --- 2 x 10 mL "EDTA Vacutainer"  
1) Place blood into "EDTA Vacutainer"  
2) Mix gently  
3) Centrifuge tubes at 1500 RPM x 20 minutes  
4) Into each cryovial, place 500 microliters of plasma aliquot and screw cap the vial  
5) Appropriately label each vial  
6) Place labeled-vials into freezer and note exact location in THNMORDB  
7) All samples information will be logged into Tissue Station.  
 
Peripheral Blood Monomuclear Cells (PBMC) Collection and Processing  
1) Using two (2) BD Vacutainer sodium citrate "CPT" blood collection tube,  
a) The Vacutainer™ CPT™ Tube with Sodium Citrate should be at room temperature  
(18-25° C) and properly labeled for patient identification.  
2) Collect blood into the Tube using the standard technique for Vacutainer™ Brand  
Blood Collection Tubes  
3) After collection, store Tube upright at room temperature until centrifugation. Blood samples 
should be centrifuged within two hours of blood collection for best results.  
4) Centrifuge Tube/blood sample at room temperature (18-25° C) in a horizontal rotor  
(swing-out head) for a minimum of 20 minutes at 1500 to 1800 RCF (Relative Centrifugal Force).  
5) From upper layer, place 500 microliters of plasma aliquots and screw-cap the vial  
6) PBMC band, collect cells into cryovial and screw cap the vial (approximately 500 uL)  
7) Add equal volume (approximately 500 uL) of freezing media (RPMI-1640+20% DMSO) to 
sample vial  
8) Appropriately label each vial (no patient identifier no specific information will be used)  
9) Place labeled-vials into freezer (-80*C) (into specific protocol sample BOX) and note exact 
location of sample in THNMORDB  
10) All sample information will be logged into Tissue Station.