BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Lung Cancer
Sponsor: M.D. Anderson Cancer Center

  
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MDACC SPONSOR VERSION #15 
 
 
 
BATTLE-2 Program: 
A Biomarker-Integrated Targeted Therapy Study in Previously 
Treated Patients with Advanced Non-Small Cell Lung Cancer  
U. T. MD Anderson Cancer Center (Lead Site) 
 
Principal Investigator:  Marcelo Vailati Negrao, M.D. 
 
Assistant Professor of Medicine 
 
Department of Thoracic/Head and Neck 
 
1515 Holcombe Boulevard, Box 432 
Houston, TX 77030 
Email: mvnegrao@mdanderson.org 
 
 
Yale Comprehensive Cancer Center (Collaborating Site) 
 
Site Principal Investigator:  Roy S. Herbst, M.D. Ph.D.  
 
Professor of Medicine 
 
Smilow Cancer Hospital at Yale – New Haven 
Yale School of Medicine 
 
333 Cedar Street, WWW221 
New Haven, CT 06520-8028 
1) Email: roy.herbst@yale.edu 
 
Support provided in part by Merck & Co., Inc., OSI Pharmaceuticals, Bayer Pharmaceuticals, AstraZeneca, and the National 
Cancer Institute(NCI). 
 

  
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        STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 1: 
Erlotinib 
 
 
 
Arm 2: 
Erlotinib + 
MK-2206 
 
 
 
Arm 3: 
AZD6244+ 
MK-2206 
 
 
 
Arm 4: 
Sorafenib 
Primary Endpoint: 8-week Disease Control  
Continue on study if stable or response.  
Consented, Registered, and Enrolled 
Biopsy performed. 
Biomarker profile obtained  
Adaptive Randomization (AR) 
Subject assigned to one of the treatment arms based on K-Ras  
EGFR Resistance Mutations are allowed on Arms 2, 3 and 4  
 
 
Biomarker analysis at end of 
Stage 1.  Identify best 
prognostic / predictive 
markers for CLIA-
certification. IRB 
resubmission of protocol.  
Stage 2          N=200 
Refined AR based on CLIA-
certified markers (n=4-6)  
Stage 1        N=200 
Initial AR based on K-ras 
mutations (CLIA-
certified); Biomarkers 
testing of candidate and 
discovery markers 
EGFR Mut + 
EML4-ALK + 
Excluded 

  
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TABLE OF CONTENTS 
SCHEMA ..............................................................................................................................2 
TABLE OF CONTENTS ....................................................................................................3 
1 
OBJECTIVES ............................................................................................................9 
 
1.1 
Primary Objectives .........................................................................................9 
 
1.2 
Secondary Objectives......................................................................................9 
1.3 
Study Design ....................................................................................................9 
2 
BACKGROUND AND RATIONALE .....................................................................10 
 
2.1 
Non-Small Cell Lung Cancer .........................................................................10 
 
2.2 
Molecularly Targeted Therapy in NSCLC ...................................................11 
 
2.3 
Biomarker Driven Targeted Therapy Clinical Trials Program  
 
 
(BATTLE-1) ....................................................................................................13 
2.4 
Rationale ..........................................................................................................14 
2.4.1 Epidermal Growth Factor (EGFR)Signaling Pathway ...................14 
2.4.2 Combination EGFR-AKT Signaling Pathway .................................15 
2.4.3 RAS Pathway Activation (MEK/PI3K/AKT) ...................................17 
3 
STUDY AGENTS ......................................................................................................17 
3.1 
ERLOTINIB BACKGROUND.....................................................................17 
3.2 
SUMMARY OF PHASE I ERLOTINIB FINDINGS .................................18 
3.3 
PHASE II TRIALS: ERLOTINIB AND ADVANCED CANCER ...........19 
3.4 
PHASE II TRIALS: ERLOTINIB AND NON-SMALL CELL LUNG  
CARCINOMA ................................................................................................19 
3.5 
MK-2206 (AKT INHIBITOR) BACKGROUND ........................................20 
3.5.1 Preclinical Summary .............................................................................20 
3.5.2 Combined Inhibition of AKT Inhibition and EGFR  
Inhibition .........................................................................................................22 
3.5.3 Clinical Summary of MK-2206 .............................................................23 
3.6 
AZD6244 .........................................................................................................37 
3.6.1 Background ............................................................................................37 
3.6.2 Preclinical Studies ..................................................................................39 
3.6.3 Clinical Studies .......................................................................................42 

  
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3.6.4 Potential Drug Interactions ...................................................................48 
4 
EXPERIMENTAL PLAN ........................................................................................48 
4.1 Overview of Study Design ..............................................................................48 
4.2 Treatment Plan................................................................................................50 
4.3 Subject Assignment in the Biomarker-Integrated Clinical Trials .............50 
4.4 Subject Eligibility ............................................................................................51 
4.4.1 Inclusion Criteria .............................................................................51 
4.4.2 Exclusion Criteria ............................................................................52 
4.4.3 Drug Specific Eligibility Criteria based on Treatment Arms ......54 
4.5 Study Withdrawal ...........................................................................................54 
 5  
ERLOTINIB ...............................................................................................................55 
 
5.1 
Investigational Product Description ..............................................................55 
 
5.2 
Drug Accountability........................................................................................55 
 
5.3 
Packaging and Storage ...................................................................................55 
 
 
5.4 
Preparation and Administration ...................................................................55 
 
5.5 
Pretreatment Medications ..............................................................................56 
 
5.6 
Warnings and Precautions .............................................................................56 
 
5.7 
Treatment Schema ..........................................................................................56 
 
5.8 
Treatment Duration ........................................................................................56 
 
5.9 
Concomitant Medications and Therapy .......................................................57 
 
5.10 Treatment of Erlotinib Toxicity and Dose Modifications ...........................58 
 
5.11 Dose Reductions ..............................................................................................60 
6 
MK-2206 (AKT INHIBITOR) .................................................................................60 
6.1 
Package and Storage .......................................................................................60 
6.2 
Drug Accountability........................................................................................61 
6.3 
Preparation and Administration ...................................................................61 
6.3.1 Pretreatment Medications ..................................................................62 
6.3.2 Warnings and Precautions .................................................................62 
6.3.3 Potential Risks of MK-2206 in combination with Erlotinib ............62 
6.4 
Treatment Schema for MK-2206 + Erlotinib ...............................................66 
6.5 
Treatment Duration ........................................................................................67 

  
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6.6 
Guidelines for Dose Delay, Modification and Discontinuation for  
MK-2206 ..........................................................................................................67 
7 
AZD6244 (MEK INHIBITOR) ................................................................................69 
 
7.1 
Investigational Product Description ..............................................................69 
 
7.2  
Mode of Action ................................................................................................69 
 
7.3 
Labeling ...........................................................................................................69 
 
7.4 
Storage .............................................................................................................69 
 
7.5  
Accountability and Mechanism of Drug Destruction ..................................70 
 
7.6 
Administration ................................................................................................70 
 
 
7.6.1   Route of Administration ......................................................................70 
 
 
7.6.2   Pretreatment Medications ...................................................................70 
 
 
7.6.3   Warnings and Precautions ..................................................................70 
 
 
7.6.4   Treatment Schema ...............................................................................74 
 
 
7.6.5   Concomitant Medications and Therapy ............................................75
 
7.6.6   Potential Risks of MK-2206 in combination with AZD6244 ......................76 
 
 
7.6.7  Drug-Drug Interactions ........................................................................77 
 
 
7.6.8  Treatment of Toxicity and Dose Modifications ..................................77 
 
 
7.6.9  Dose Modifications for AZD6244 + MK-2206 Arm ...........................79 
8 
SORAFENIB (BAY43-9006®) .................................................................................83 
 
8.1 
Investigational Product ..................................................................................83 
 
8.2 
Dosage and mode of administration ..............................................................83 
 
8.3 
Clinical Experience .........................................................................................83 
 
8.4 
Route of Excretion ..........................................................................................84 
 
8.5 
Rationale for studying Sorafenib in Patients with NSCLC ........................84 
 
8.6 
Selection of Doses in the Study ......................................................................85 
 
8.7 
Dose Delays or Dose Modifications ...............................................................86 
 
8.8 
Treatment of Toxicity and Dose Modifications ............................................86 
 
8.9 
Prior and Concomitant Therapy ...................................................................88 
9 
STUDY CONDUCT ..................................................................................................90 
 
9.1 
Subject Accrual and Subject Identification ..................................................90 
 
9.2 
Subject Enrollment .........................................................................................91 

  
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9.3 
Replacement of Subjects .................................................................................91 
 
9.4 
Screening Procedures .....................................................................................91 
 
 
9.4.1  Tumor Tissue Biopsy ............................................................................92 
 
 
9.4.2  Serologies ...............................................................................................93 
 
9.5 
Study Treatment Procedures .........................................................................93 
 
9.6 
End of Therapy Procedures ...........................................................................94 
 
9.7 
Follow-Up Procedures ....................................................................................95 
 
9.8 
Evaluation Criteria .........................................................................................95 
 
 
9.8.1  Tumor Response....................................................................................95 
 
 
9.8.2  Volumetric Tumor Analysis .................................................................95 
 
9.9 
Treatment Compliance and Drug Accountability .......................................96 
 
9.10 Study Monitoring ............................................................................................97 
10 
SAFETY DATA COLLECTION, RECORDING AND REPORTING ...............97 
 
10.1 Adverse Events ................................................................................................97 
 
10.2  Site Communication with Merck & Co, Inc. .................................................100 
 
10.3  Site Communication with OSI Pharmaceuticals. ..........................................101 
 
10.4 Site Communication with AstraZeneca ...........................................................101 
 
10.5  Site Communication with Bayer/Onyx ...........................................................101 
 
10.6  Exclusions to SAE Reporting Requirements .................................................102 
 
10.7 Adverse Event Reporting on Case Report Form .........................................102 
 
10.8 Reproductive Risks and Reporting of Pregnancy ........................................102 
11 
STATISTICAL DESIGN AND DATA ANALYSIS CONSIDERATIONS .........104 
 
11.1 Background and Design .................................................................................104 
 
11.2 Assumptions ....................................................................................................107 
 
11.3 Statistical Models ............................................................................................109
 
11.4 Adaptive Randomization Procedures ...........................................................110 
 
11.5 Variable Selection and Model Building  .......................................................111 
 
11.6 Implementation ...............................................................................................113 
 
11.6.1 Model updating and adaptive randomization ..............................................113 
 
11.6.2 Biomarker selection for Stage 2 adaptive randomization design ...............113 
 
11.7 Simulation Results ..........................................................................................115 

  
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REFERENCES .....................................................................................................................121 
 
APPENDIX I  
 
ECOG PERFORMANCE STATUS ........................................................................125 
APPENDIX II 
 
RECIST ......................................................................................................................126 
APPENDIX III 
 
PATHOLOGY TISSUE PROCESSING AND BIOMARKER ANALYSIS .......132 
APPENDIX IV 
Clinically relevant drug interaction: substrates, inducers and inhibitors of isoenzyme 
CYP3A ........................................................................................................................135 
APPENDIX V 
 
NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION ...............136 
APPENDIX VI 
 
STUDY PROCEDURES ...........................................................................................137 
APPENDIX VII 
 
LVEF ALGORITHM ................................................................................................139 
APPENDIX VIII 
MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL AND/OR 
INDUCE TORSADES DE POINTES (TDP) ..........................................................140 
APPENDIX IX 
 
VOLUMETRIC CT ..................................................................................................142 
APPENDIX X 
 
ALOGRITHM FOR DYSPNEA ..............................................................................144 
APPENDIX XI 
 
INSTRUCTIONS ON HOW TO PREPARE A SORAFENIB LIQUID  
 
SUSPENSION ............................................................................................................145 
APPENDIX XII    
 
BLOOD BASED BIOMARKERS ...........................................................................146 
 

  
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APPENDIX XIII 
BLOOD BIOMARKERS – COLLECTION, PROCESSING AND                  
STORAGE .................................................................................................................149 
 
 
 
 
 
 
 
 
 
 

  
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1 
OBJECTIVES 
1.1 
Primary Objectives 
The primary objectives of this study will be: 
 To determine the 8-week disease control rate (DCR) for the four proposed treatment 
regimens in subjects with non-small cell lung cancer (NSCLC) who have received 
prior cytotoxic chemotherapy or epidermal growth factor receptor (EGFR) tyrosine 
kinase inhibitor for metastatic disease. 
 To identify the prognostic and predictive markers for the four proposed treatment 
regimens. 
 To determine the best individualized treatment based on the biomarker profile of the 
subjects cancer. 
 
1.2 
Secondary Objectives 
The secondary objectives of this study will be: 
 
To determine the overall response rate by RECIST response criteria. 
 
To assess the overall response rate by volumetric analysis. 
 
To determine the progression-free survival. 
 
To determine the overall survival. 
 
To determine the time to disease progression.  
 
To assess the safety/toxicity of the combination. 
 
To assess biomarker modulation in the tumor tissue from the treatment. 
 
To assess biomarker modulation in the serum/blood from the treatment. 
 
1.3 
Study Design 
This is a multi-center, randomized Phase II, open-label study in subjects with previously treated 
NSCLC.  The study will consist of four arms, including two arms with combination targeted 
therapies. Subjects will be administered erlotinib (Arm 1), or erlotinib in combination with an 
AKT small molecule inhibitor (MK-2206) (Arm 2), MK-2206 in combination with a MEK 
inhibitor (AZD6244) (Arm 3) or Sorafenib (BAY 43-9006) (Arm 4).  The study is designed to 
develop individualized targeted therapy based on the identification and validation of specific 

  
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molecular pathways of NSCLC. To address these new targeted therapeutic approaches, we propose 
to implement a translational lung cancer research program entitled, “BATTLE-2: Biomarker-
integrated Approaches of Targeted Therapy of Lung Cancer Elimination-2,” and provide a strong 
rationale-based targeted treatment strategy. The study is applying similar principles as our prior 
BATTLE Program. The program required that all eligible subjects with advanced NSCLC undergo 
a core biopsy of their tumors and applied biomarkers in the selection of individualized targeted 
therapy.   
The study will proceed in two stages:  
Stage 1 - Initial Adaptive Randomization: 200 subjects will be adaptively randomized into one of 
the four treatment arms (three treatment arms for prior-erlotinib treated patients, who are excluded 
from the erlotinib-only arm) based solely on KRAS mutation status (present or absent), which is 
accepted in the field as having relevance to the sensitivity or resistance to erlotinib and other 
targeted agents. 
Stage 2 – Refined Adaptive Randomization: After enrollment of half of the total sample size, a 
refined biomarker signature (for each arm) will be generated to refine the predictive model for the 
DCR.  The second half of subjects will be adaptively randomized to the four treatment arms based 
on the refined model.  
 
 
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.1 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 subjects 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 subjects present with 
locally advanced unresectable or metastatic disease and their chance to be cured by current 
oncology practice is low.   

  
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At presentation, the median survival for patients with advanced disease defined as 
inoperable Stage III or IV non-small-cell lung cancer is 8 to 10 months, with a one-year survival 
of 35 to 45%.2  In NSCLC, as with other cancers, median survival following a second relapse is 
even shorter and decreases progressively with each subsequent treatment. In those patients who 
have a good enough performance score to be able to tolerate chemotherapy and receive docetaxel 
as a second chemotherapy, subsequent median survival is 7.5 months for docetaxel-treated patients 
and 4.6 months for patients treated with best supportive care.3  For those patients who have 
received two prior chemotherapy regimens, the subsequent median survival is likely to be even 
shorter and the ability to tolerate intensive or additional chemotherapy further compromised due 
to both cumulative therapy-related toxicities and prolonged periods of time with advanced disease. 
 
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 markers, 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.4,5  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.6-8 
After treatment with front-line NSCLC therapy, treatment in the salvage lung cancer setting 
becomes more difficult.9  The use of targeted agents either alone or in combination after failure of 
frontline chemotherapy for NSCLC is increasingly explored as a means of overcoming resistance 
to standard chemotherapy and exploiting the molecular pathways that are determining tumor 
growth and progression. The major reasons for suboptimal results are either the agent used for 
treatment does not effectively hit the target, or the agent does hit the target, but activates other 
pathways, which promotes survival and leads to further progression. Thus, it is unlikely that the 

  
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empirical use of targeted agents in the treatment of lung cancer is going to make a more significant 
impact without a greater focus on prognostic markers and scientific data.  
A well-studied pathway in NSCLC is the EGFR signaling pathway.  The relationship 
between EGFR-related biomarkers (EGFR-gene-copy number, EGFR mutation, EGFR protein 
expression, and K-ras mutation) and the response to EGFR-TKIs has been widely investigated, 
with the aim of identifying those patients most likely to respond to treatment.  Some single-arm 
studies of gefitinib-treated patients have shown that survival, progression-free survival (PFS), and 
objective response rate (ORR) were better in patients whose tumors have a high EGFR-gene-copy 
number compared with those with a low EGFR-gene-copy number.10,11  Also, randomized, 
placebo-controlled studies have suggested that high EGFR-gene-copy number might be a predictor 
of longer survival benefit for EGFR-TKIs compared with placebo.12,13 
Several studies demonstrated that the proportion of EGFR mutation-positive patients is 
higher among gefitinib responders than non-responders 10,14,15 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 
12 or no evidence that EGFR mutation predicts for a greater survival advantage over placebo.13 
The discovery that somatic mutations in the EGFR kinase domain correlate and predict 
responses to the EGFR kinase inhibitor, gefitinib or erlotinib, underscores the importance of 
tailored individualized therapy based on the tumors’ underlying molecular biological 
profiles.14,16,17 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 18 and the INTEREST study demonstrating 
similarly significant improvement in PFS and OS with gefitinib in patients with EGFR mutation 
positive tumors.19 Resistance to EGFR inhibitors has emerged through development of acquired 
resistance 20 or de novo resistance through other signaling pathways.21-23  
 
2.3 
Biomarker Driven Targeted Therapy Clinical Trials Program (BATTLE-1) 

  
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The BATTLE-1 program 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 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 marker 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.  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 lung tumor for biomarker analysis, each tumor is 
then profiled for prespecified biomarkers and marker groups.  From November 2006 to October 
2009, 341 patients have been enrolled into the program with 255 randomized24 to Erlotinib (59 
pts), Vandetanib (V) (54 pts), Erlotinib+Bexarotene (E+B) (37 pts), and Sorafenib (105 pts). 
Patient demographics were as follows: Median age 62 yrs (26-84); male 54%; ECOG PS 0-1 86%, 
PS 2 14%; Caucasian 82%, Asian 5%, other 13%; never/former/current smokers 22%/69%/9%; 
adenocarcinoma 63% squamous cell 18%, NSCLC NOS 19%; prior Erlotinib 45%, median prior 
therapies for metastatic NSCLC: 2 (range 1-9); prior brain metastases 33%. 244 pts were evaluable 
for 8 wk DC. All 11 biomarkers were assessable in 215 pts (82% of the patient population).  The 
remaining 18% of the patient samples yielded no viable tumor tissue due to necrotic tissue and 
dense fibrosis.  Biopsy sites were lung 55%, liver/adrenal 19%, other 26%. Pneumothorax 
incidence was 11.5%, and 6.5% of pts had treatment-related grade 3-4 toxicity. EGFR status 
included mutations in 15%, FISH amplification (A) in 16% and high polysomy in 28%; Other 
biomarkers were KRAS mutations in 20%; VEGF/R2 staining in 83%; RXR alpha nuclear staining 
in 79%; Cyclin D1 staining in 53%. Overall DCR at 8 weeks was 46%, median overall survival 
(OS) was 9 months, 1 year survival was 39%, and progression-free survival (PFS) was 1.9 months. 
Better DC was seen with EGFR mutations for Erlotinib (p=0.04); Cyclin D1 IHC positivity (IHC+) 

  
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(p=0.011) and EGFR FISH A (p=0.006) for E + B; VEGFR2 IHC+ for V (p=0.05); and absence 
of EGFR mutations (p=0.012) or high polysomy (p=0.048) for S. Pts with both EGFR mutations 
and FISH A had 100% DC (n=6) with E and 0% DC (n=6) with S. Pts with KRAS mutations tended 
to respond better with S (8-wk DC 61%) compared to other three regimens (8-wk DC 32%) 
(P=0.11). Pts with mutant KRAS Cys amino acid (aa) substitution had worse OS (all pts) and PFS 
(S-treated pts) compared to pts with wild type or all other KRAS amino acid substitutions (p=0.015 
and p=0.013).  
 
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-2 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. 
 
2.4 
Rationale  
2.4.1 Epidermal Growth Factor Receptor (EGFR) signaling pathway   
EGFR overexpression is associated with an overall poor prognosis in patients with cancer and 
disruptions in the signal transduction pathways may cause tumor transformation, cell proliferation, 
as well as progression of invasion and metastasis.25-28  Multiple EGFR compounds are being used 
and tested in NSCLC.29-31 
Erlotinib (Tarceva®), an EGFR tyrosine kinase inhibitor (TKI) which is currently approved 
for treatment in patients with NSCLC who have failed chemotherapy, will be one of the agents 
included in this study.31  Patients who carry a mutation of EGFR are more sensitive to these 
compounds and this correlates with a clinical response.  However, if a patient harbors a K-ras 
mutation or other possible cellular abnormalities, these EGFR targeting agents seem less 
effective.32 Correlates such as EGFR amplification, 10 mutation as well as new mutations which 
develop after treatment (i.e. resistance genes) have been described.33,34 
The discovery that somatic mutations in the EGFR kinase domain correlate and predict 
responses to the EGFR kinase inhibitor gefitinib or erlotinib underscores the importance of tailored 

  
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individualized therapy based on the tumors’ underlying molecular biological profiles. Both 
acquired and de novo resistance to erlotinib has been documented. Acquired resistance is well 
studied and emerges either through acquisition of secondary EGFR mutations such as EGFR 
T790M or activation of downstream signaling especially the PI3K/AKT pathway.  It is critical in 
this juncture to emphasize that the use of oncogene-addicted, highly drug-sensitive cell line models 
to uncover escape mechanisms has been fruitful but yet to be validated in human tumors.  
Therefore, it is of paramount importance that biopsies be obtained in refractory patients in order 
to confirm or refute these mechanisms.  The availability of drugs that therapeutically target these 
escape pathways provides a unique opportunity for validations of these targets in a biomarker- 
driven clinical trial.   
 
2.4.2 Combination EGFR-AKT signaling pathway   
The PI3K-AKT pathway is often activated downstream of most tyrosine kinases involved in 
carcinogenesis, including EGFR, Her2, IGF1R, and c-Met.35 This pathway may have a significant 
role in tumor progression.  In NSCLC, AKT activation has been reported in >30% of tumors and 
may be due to overexpression or activating mutations of receptor tyrosine kinases, PI3K and Ras, 
inactivation of tumor suppressor PTEN, and amplification or mutation of AKT itself.  As inhibitors 
of AKT target the growth signaling pathways downstream from other tyrosine kinase inhibitors 
(i.e. erlotinib, herceptin, cetuximab, IGF-R inhibitors, and c-Met inhibitors), it is presumed that 
these AKT inhibitory agents will have broader utility and may have a synergistic effect with other 
systemic targeted agents.   
AKT plays a key role in cell survival and serves as a critical escape mechanism for tumor 
cells to evade apoptosis induced by chemo-, radiation and targeted therapies. Furthermore, 
constitutive or residual AKT activation are often found in tumor cells that have developed 
resistance to conventional chemotherapy, radiation or targeted agents such as EGFR antagonists.  
Therefore, targeting AKT in combination with conventional chemotherapy or targeted agents has 
the potential to synergize the tumor cell killing effects and may also re-sensitize resistant tumor 
cells to such treatments. 
Most, if not all laboratory models of acquired resistance to EGFR tyrosine kinase inhibitors 
(TKI)  show continued activation of the PI3K pathway despite TKI treatment 36-39 and TKI 
resistance is also conferred by ectopically expressed p110 a-activating mutation of PIK3CA.36  

  
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Studies in NSCLC suggest that resistance to EGFR can be impacted by additional targeting of the 
AKT pathway.37,40-43  In the NSCLC cell lines, Janmaat et al41 suggested that resistance to gefitinib 
was due to upregulation and persistent activation of the PI3K/AKT and MAPK pathways.  Li et 
al. conducted a supportive analysis of the p-EGFR: p- AKT ratios and noted that erlotinib sensitive 
cells had a 10-fold higher ratio than that found in erlotinib resistant cells.  A higher ratio indicates 
that activation of a downstream signaling molecule primarily results from the activation of 
upstream EGFR, whereas a low ratio indicates that the downstream signaling arises from 
alternative pathways and is not EGFR dependent.  Recent data also suggests that the persistent 
activation of PI3K/AKT pathway could be secondary to MET amplification in EGFR inhibitor 
resistant cell lines via activation of erbB3-dependent activation of PI3K.37 Additional in vitro 
studies confirm that inhibiting both the EGFR and AKT pathways could lead to an improved anti-
tumor effect.44 Therefore, in EGFR resistant cell lines, targeting persistent AKT activation may be 
an important strategy to enhance therapeutic outcome.  
In NSCLC, erlotinib is an approved salvage therapy.  However, not all patients derive 
clinical benefit from this agent.  AKT inhibitors, which target the pathway downstream of the most 
common mutations, are hypothesized to have broader utility and be less subject to resistance in the 
clinic. Because of its key function in cell survival, AKT plays a pivotal role in rendering tumor 
cells insensitive or resistant to chemotherapy or targeted agents. In vitro and in vivo data have 
demonstrated that AKT inhibition is additive or synergistic to chemotherapy or targeted agents. 
AKT inhibitors therefore may augment clinical efficacy of chemotherapy, or targeted agents, as 
well as radiotherapy. As upregulation of the AKT pathway may influence sensitivity to EGFR 
TKIs, dual inhibition of both EGFR and AKT may improve clinical outcome.  
MK-2206 is a potent, orally active, allosteric inhibitor of human AKT1, AKT2, and AKT3 
with preclinical anti-tumor activity.  Preclinical studies in mice demonstrate tolerability at MK-
2206 doses that were efficacious in inhibiting tumor growth and pharmacodynamic markers, either 
as a single agent or in combination with chemotherapy or targeted agents.  The combination of 
erlotinib with MK-2206 will be evaluated in effort to determine if the combination of these 
complementary pathways leads to enhanced antitumor activity. 
 
2.4.3 RAS pathway activation (MEK/PI3K/AKT)  

  
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Lung tumors frequently overexpress RAS or harbor activated RAS with a point mutation, which 
contributes substantially to tumor cell growth, invasion and angiogenesis.45 Cell plasma receptor 
tyrosine kinases activate RAS GTPases, and GTP-bound RAS activates A-RAF, B-RAF and -146-
48 leading to the phosphorylation and activation of the MEK1 and MEK2 pathway.  ERK further 
amplifies the RAS-MEK signaling pathway by targeting transcription factors, kinases and other 
substrates. Although successful therapeutic targeting of K-ras mutations in NSCLC so far remains 
elusive, abundant knowledge of downstream signaling activation such as PI3K/AKT and 
Raf/MEK signaling may provide opportunities for rational combined targeting.  Recent literature 
suggests that preclinical combination therapy with a PI3K and a MEK inhibitor (both in Phase I 
clinical trials in humans currently) in the setting of animal K-ras induced lung tumors results in 
substantial tumor regressions.49  The synergistic effect of the inhibition of PI3K and MEK 
pathways on the reversal of RAS-induced malignant transformation has been noted many times in 
cultured cells in vitro b both pharmacological and genetic approaches.50 Others have shown similar 
synergistic effects preclinically with combinations of MEK and mTOR inhibitors hinting at the 
critical role of AKT downstream signaling for both development and maintenance of an existing 
malignant phenotype.51  Therefore although RAS has remained obdurately resistant to direct 
assault, its actions through downstream pathway activation can be tamed by using combined 
targeting of these pathways. 
 
 
3 
STUDY AGENTS 
3.1 
Erlotinib Background 
Erlotinib (Tarceva®; OSI-774), a quinazoline, is an orally active, potent, selective inhibitor of the 
EGFR (HER-1) tyrosine kinase FDA approved for chemorefractory patients with NSCLC.  An 
overview of selected non-clinical and clinical information is presented here; complete details are 
available in the OSI-774 Investigator Brochure. 
Erlotinib inhibits the human EGFR (HER-1) tyrosine kinase with an IC50 of 2 nM 
(0.786 mg/mL) in an in vitro enzyme assay and 20 nM (7.86 ng/mL) in intact tumor cells.  This 
inhibition is selective for EGFR (HER-1) tyrosine kinase, results in cell cycle arrest at G1, and is 
reversible.  Oral administration of OSI-774 in mice results in a >70% reduction in EGFR (HER-
1) autophosphorylation in human xenografts.  Marked growth inhibition of HN5 (head and neck 

  
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carcinoma) and A431 (squamous cell carcinoma) xenografts in nude mice has been demonstrated.  
Data on drug exposure and antitumor responses in these xenograft models were analyzed to 
estimate the optimal plasma concentration of OSI-774 for antitumor activity in humans.  Based on 
these models, a target plasma concentration of   500 ng/mL was selected. 
 
3.2 
Summary of Phase I Erlotinib Findings  
Phase I trials of erlotinib have explored both schedule and dose to evaluate the safety, tolerability, 
and pharmacokinetic profile of the compound.  Two Phase I trials in healthy subjects and two 
Phase I trials in subjects with advanced cancer have been completed.52 The primary toxicities 
consisted of diarrhea, rash, nausea, headache, emesis, and fatigue.  The only dose-limiting toxicity 
was diarrhea.  This event was dose related and was generally controlled with the addition of 
loperamide therapy and treatment with erlotinib doses of < 200 mg/day.  The appearance of the 
rash seen in the clinical trials of erlotinib conducted in healthy subjects and cancer subjects has 
been similar.  It was only loosely dose related and was seen commonly at doses of > 25 mg/day.  
The rash was variable in onset, duration, and severity.  The mechanistic basis of the rash remains 
uncertain; histopathologic examination of biopsies of the rash demonstrated polymorphonuclear 
leukocyte infiltration and mild epidermal hyperproliferation.  In some cases, the rash improved 
despite continued dosing, and in general, it gradually resolved without sequelae following erlotinib 
discontinuation.  The rash did not result in study discontinuation in cancer subjects in either of the 
Phase I trials.  In the phase I study, 50% of patients developed rash and 86% diarrhea at the 
recommended Phase II dose of 150 mg daily. 52 
Based on the ocular changes observed in the 12-month toxicology study in dogs, screening 
and follow-up ophthalmologic examinations were instituted in the Phase I and II trials in cancer 
subjects.  In the weekly dosing study (Study 248-005) the only reported erlotinib–related ocular 
event was an episode of mild watery eyes.  In the daily dosing study (Study 248-004), 1 subject 
experienced moderate corneal edema/keratitis attributed to wearing contact lenses, although an 
influence of erlotinib was not discounted.  The event resolved with temporary discontinuation of 
both erlotinib and contact lens use; there was no recurrence of symptoms with erlotinib rechallenge 
in the absence of continued use of contact lenses.  No increased incidence of ocular toxicity related 
to erlotinib treatment compared to placebo was noted in the randomized Phase III trial of 
carboplatin/paclitaxel +/- erlotinib (see Erlotinib Investigator’s Brochure).  

  
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3.3   
Phase II Trials:  Erlotinib and Advanced Cancer  
The 150 mg/day dose of erlotinib selected for all subsequent trials was based on pharmacokinetic 
parameters as well as the safety and tolerability profile of this dose level in Phase I trials in 
advanced, heavily pretreated cancer subjects.  Three Phase II trials of the safety, tolerability, and 
antitumor activity of erlotinib have been conducted in subjects with advanced, refractory 
malignancies, including NSCLC, squamous cell carcinoma of the head and neck, and ovarian 
carcinoma.  Subjects in each of these studies received 150 mg/day of erlotinib.  Dose reductions 
were allowed in the case of intolerance.  Diarrhea was treated with loperamide therapy and/or dose 
reduction.  Rash was treated with a variety of agents, including oral and topical antibiotics, 
corticosteroids, and other agents.  Available data from the two reported Phase II trials in NSCLC 
and head and neck cancer demonstrate objective response rate of 4%–12%.30,53 
 
3.4  
Phase II Trials:  Erlotinib and Non–Small Cell Lung Carcinoma 
Study 248-1007 enrolled 57 subjects at five centers with progressive, recurrent NSCLC previously 
treated with a platinum-based chemotherapy regimen.  Erlotinib was administered at a daily dose 
of 150 mg.  In this study, enrolled subjects had measurable tumors that expressed at least minimal 
levels of EGFR (HER-1) as detected by immunohistochemical (IHC) analysis.  All 57 subjects 
were evaluable for antitumor response.  Eight subjects (12.3%) achieved an objective response (1 
complete response, 7 partial responses; 6 were confirmed at Week 12 and beyond).  The median 
and 1 year survivals were 8.4 months and 40% respectively.30  A relationship between response 
and the degree of EGFR (HER-1) over expression has not been established.  Rash was observed 
in 75% of enrolled subjects.   
A Phase II study of single agent erlotinib in 80 subjects > 70 years of age with previously 
untreated advanced NSCLC has completed accrual within the Dana Farber Partners Cancer Care. 
Sixty-six are evaluable for response and outcome.  The results from the study thus far demonstrate 
a response rate of 12% (8/66) with an additional 48% (32/66) of subjects achieving stable disease 
at 2 months after starting treatment. All 8 of the responders have adenocarcinomas.   Three of the 
5 patients with a partial response who had tumors available for study had a mutation of EGFR.  
Two of the 14 with stable disease had a mutation of EGFR.  The median survival of the elderly 

  
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patients with NSCLC treated with single agent erlotinib was 10 months. Erlotinib is currently 
approved for treatment in patients with NSCLC who have failed chemotherapy.54   
 
3.5 
MK-2206 (AKT Inhibitor) Background 
MK-2206 is an orally active, allosteric AKT inhibitor that is under development for the treatment 
of solid tumors.  The agent is a highly specific non-ATP competitive AKT inhibitor 55 and has 
equal potency towards purified recombinant human AKT 1 (IC50 = 8 nM) and AKT 2 (IC50 = 12 
nM).  It is approximately 5-fold less potent against human AKT3 (IC50 = 65 nM) in enzyme assays.    
Preclinical studies with MK-2206 have shown an anti-cancer benefit in various cell lines 
including lung cancer and in multiple xenograft models with lung in nude mice and rats.  The 
xenograft studies have been conducted with single agent MK-2206 and the combinations of MK-
2206 with EGFR or HER2 inhibitors and various chemotherapeutic agents.   
 
3.5.1 Preclinical Summary 
In vitro and in vivo anti-cancer efficacy of MK-2206 was demonstrated in various cancer cell lines 
including breast, lung, and ovarian cancer cell lines and in multiple xenograft models such as 
ovarian, breast, lung, and prostate in nude mouse and rat, either as a single agent or in combination 
with EGFR or HER2 inhibitors, and multiple chemotherapeutic agents.  The pre-clinical toxicity 
profile of MK-2206 has been defined in rats and dogs. In addition to safety pharmacology analyses, 
repeated-dose toxicity studies, and short-term toxicity studies, the safety of MK-2206 
administration to humans is also supported by genetic toxicology studies. Treatment-related 
changes included slight to moderate hematologic changes, slight to moderate increase in insulin, 
glucose, cholesterol, and ALT/AST. Histomorphologic changes included biliary hyperplasia, 
inflammation, and crystals in the liver; tubular degeneration, acute inflammation, and tubular 
crystals in the kidney; decreased colloid in the thyroid gland; marginal zone depletion of the 
spleen; and islet cell hyperplasia and vacuolation of the pancreas, retinal inflammation, gastric 
ulceration, lymphoid depletion of the Peyer's patches, lymph nodes, spleen, and thymus, 
inflammation of the mucosa of the large intestine, necrosis of renal pelvis epithelium with 
associated inflammation, bile duct necrosis with associated inflammation, bile ductule hyperplasia 
and periportal hepatocellular vacuolation in the liver, and erythroid depletion and myeloid 
hyperplasia of the bone marrow. In oral toxicity studies with rats, 75 mg/kg, dosed QOD was 

  
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considered the NOAEL. This dose provides an exposure margin (based on the Cmax value) of 
approximately 39-fold over the human IC70 (58 nM). In oral toxicity studies with dogs, 2.5 mg/kg 
(AUC0-48 hr = 8.5 μM•hr and Cmax = 0.37 μM) was considered the NOAEL. In an anesthetized 
dog cardiovascular study, there was no effect on cardiovascular function, including QT/QTc 
interval, after intravenous doses of 1, 2, and 7 mg/kg MK- 2206. At the highest dose in this study, 
an average exposure of 32 μM was achieved, which is approximately 550-fold above the human 
IC50 for AKT1. While there was no evidence of QT/QTc interval prolongation in the anesthetized 
dog assay, there were significant cardiovascular effects observed in conscious dogs monitored via 
radiotelemetry.  Cardiovascular changes such as decreases in heart rate, prolongation of QT and 
QTc intervals and increases in mean arterial pressure were observed at 2.5, 5 and 10 mg/kg. No 
cardiovascular effects were observed at 1 mg/kg (AUC0-24 hr = 1.6 μM•hr and Cmax = 0.092 μM) 
in dogs. This dose provides an exposure margin (based on Cmax value) of approximately 2-fold 
above the human IC70 (58 nM). An additional safety concern is for MK-2206-induced 
hyperglycemia/hyperinsulinemia which is a mechanism-based effect. In all preclinical species 
tested, MK-2206 induced dose-dependent hyperglycemia and concomitant hyperinsulinemia. In 
the dog, the most sensitive preclinical species, glucose elevation was slight (~24 to 34%) at 
exposures corresponding to an AUC0-48 hr of 19.6 μM•hr and a Cmax of 0.73 μM after 5 mg/kg QOD 
dosing for 4 weeks. The exposures correspond to exposures expected at the upper range of dosing 
in oncology patients. 
In the dose-limiting toxicity study in the rat, dose-limiting toxicity was observed at ≥ 200 
mg/kg/day. In the 10-day oral tolerability study in dogs, daily dosing with MK-2206 was poorly 
tolerated and dose limiting toxicity was achieved at ≥15 mg/kg/day. In a 4-week safety study in 
rats, MK-2206 was administered orally every other day at 75, 150, or 300 mg/kg, followed by a 2-
week recovery period. Treatment-related changes at 150 and 300 mg/kg included mortality of one 
rat with body weight loss in the 300 mg/kg group; decreases in body weight gain in the surviving 
rats, with complete recovery in female rats at 150 mg/kg and a trend towards recovery in the 
remaining rats at 150 and 300 mg/kg; slight to moderate hematologic changes with recovery; slight 
to moderate increase in glucose and ALT/AST with recovery; decreases in the size and weight of 
spleen, thymus, thyroids, and prostate and histomorphologic changes of included biliary 
hyperplasia, inflammation, and crystals in the liver; tubular degeneration, acute inflammation, and 
tubular crystals in the kidney; decreased colloid in the thyroid gland; marginal zone depletion of 

  
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the spleen; and islet cell hyperplasia and vacuolation of the pancreas. At the end of recovery period, 
there was resolution of the changes in the 150 mg/kg group and there was a trend towards recovery 
at 300 mg/kg. There were no treatment-related changes in the 75 mg/kg group at end of dosing 
phase. The NOAEL was established at 75 mg/kg (AUC0-48 hr: 24.2 μM•hr, Cmax: 2.25 μM).  In 
a 4-week safety study in dogs, MK-2206 was administered every other day at 2.5, 5, and 10 mg/kg, 
followed by a 2-week recovery period. Treatment-related changes at 10 mg/kg included severe 
body weight loss and physical signs of toxicity (decreased activity, blood-like substance in feces, 
sore gums and lateral recumbency) requiring early sacrifice of 6 dogs and cessation of dosing at 
10 mg/kg by the end of Study Week 2. 
 
3.5.2 Combined Inhibition of AKT inhibition and EGFR inhibition 
Rationale and Preclinical Studies of dual EGFR and AKT inhibition 
The PI3K/ AKT pathway is among the critical effectors of oncogenic EGFR, and persistent EGFR-
independent signaling through this pathway appears to contribute to erlotinib resistance in some 
NSCLCs.  Preclinical studies in NSCLC suggest a potential benefit to dual inhibition of both the 
EGFR and AKT pathways.37,40,42 In the NSCLC cell lines, resistance to EGFR TKIs was associated 
with upregulation and persistent activation of the PI3K/AKT and MAKK pathways.41,42  
Additional in vitro studies confirm that inhibiting both the EGFR and AKT pathways could lead 
to an improved anti-tumor effect.44 As upregulation of the AKT pathway may influence sensitivity 
to EGFR TKIs, dual inhibition of both EGFR and AKT may improve clinical outcome. 
Combinations of MK-2206 with erlotinib, an orally bioavailable EGFR inhibitor, were evaluated 
in NSCLC cell lines. The effect of each compound on cell proliferation was measured and 
compared to the potency of the combined agents by using the Chou-Talalay method. Various 
degrees of synergism (combination index (CI) <0.9) between MK-2206 and erlotinib were 
observed in eight cell lines, including A431 epidermoid cells, which overexpress EGFR. In vitro 
synergistic tumor growth inhibition by combination of these two inhibitors was supported by the 
parallel inhibition of both the AKT and Erk pathways when the two inhibitors were combined.  
The ability of MK-2206 to enhance the anti-tumor efficacy of erlotinib was evaluated in the NCI-
H292 human non-small cell lung cancer mouse xenograft model. Mice were treated with two 
regimens of MK-2206 alone (120 mg/kg PO, three times per week on Monday, Wednesday, Friday 
for 2 weeks, or 360 mg/kg PO once a week on Monday for 2 weeks), erlotinib alone (50 mg/kg 

  
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PO, once per day Monday to Friday), and the binary combination. Although erlotinib alone 
mediated significant tumor growth suppression, co-treatment with MK-2206 produced a dramatic 
enhancement including tumor regression. MK-2206 alone in the three treatments per week regimen 
was not efficacious, and the once a week regimen mediated only moderate anti-tumor efficacy. All 
treatments were well tolerated, and no animals died during the course of the treatment. Animals 
experienced weight loss (10.6% or 20.7%) during the treatment period, but they returned to their 
normal weight by Day 16. 
 
3.5.3 Clinical Summary of MK-2206 
The safety of MK-2206 administered on an every other day schedule for 28 days in humans is 
supported by preclinical studies and data obtained from a Phase I study of MK-2206 in healthy 
volunteers. In the clinic, multiple-dose MK-2206 administered every other day as monotherapy 
and as combination therapy in patients with advanced cancer has been generally well tolerated; 
however, moderate to severe skin rash has been identified as a common dose-limiting toxicity. 
Clinical pharmacokinetic data demonstrate the half-life (t½) of MK-2206 to be approximately 55-
81 hours. This information, together with safety data from clinical studies supports assessment of 
a once weekly dosing schedule. In addition, pharmacokinetic modeling and simulation analysis 
suggests potential benefit of a less frequent schedule as adverse experiences may be associated 
with accumulated exposure to MK-2206. The efficacy of once weekly dosing was assessed in 
several ovarian and lung xenograft studies which directly compared both dosing regimens. Data 
from these studies demonstrate that weekly dosing of MK-2206 as single agent results in similar 
or enhanced efficacy compared to every other day dosing. 
In healthy volunteers, pharmacokinetics of single-dose MK-2206 (0.25- to 100-mg) 
demonstrated dose proportional behavior. Median Tmax ranged from 6.0 – 8.0 hours and mean 
apparent t1/2 ranged from approximately 55 – 79 hours. Pharmacodynamic activity of MK-2206 
at single doses of 40-, 80-, and 100-mg inhibited AKT to a greater extent than placebo, single 
doses at 80- and 100-mg demonstrated statistically significant inhibition of AKT compared to 
placebo: 74.78% and 77.85%, respectively. Based on the mechanism of action of AKT inhibition 
(PI3K pathway) hyperglycemia and hyperinsulinemia are events expected to indicate 
pharmacodynamic activity. These events were not observed in healthy volunteers who received 
single-dose MK-2206/Placebo up to 100 mg. MK-2206 is being evaluated in patients with 

  
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advanced cancer. Four (4) open-label, nonrandomized dose escalation studies (Protocol 002, 003, 
010 and 015) in patients with solid tumors are ongoing to assess the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of multiple-dose MK-2206 administered as 
monotherapy and in combination with selected chemotherapies and targeted agents. Overall MK-
2206 has been generally well tolerated when administered as monotherapy once every other day 
(QOD) and once weekly (QW), as well as once every other day in combination with other anti-
cancer therapies. Grade 1 to Grade 4 skin rash, associated with pruritus and stomatitis (Grade 1 to 
Grade 3), has been reported as a common treatment-related adverse experience. Other treatment-
related adverse experiences reported with MK-2206 administration include fatigue, nausea, 
vomiting, and diarrhea. In the majority of patients, these adverse experiences are Grade 1 and 
Grade 2 and are manageable with standard medical and supportive care measures. In addition, 
transient and reversible mild to moderate hyperglycemia have been reported. 
Grade 4 hyperglycemia observed in 1 patient who received MK-2206 in combination with 
erlotinib required interruption in study therapy as well as insulin and oral antihyperglycemic 
medication for management of blood glucose. QTc prolongation and bradycardia were preclinical 
findings in an oral cardiovascular telemetry study in conscious dogs. Clinically significant 
cardiovascular effects have not been observed in oncology patients treated with MK-2206. 
Although Day 1 AUC0-48hr and Cmax values up to 90 mg in cancer patients overlapped with the 
ranges observed in HVs (Protocol 001), overall, MK-2206 exposures in patients with cancer 
trended somewhat higher on average than those observed in HVs. Tmax and apparent terminal t1/2 
values from cancer patients were generally within the ranges observed in HVs. In all cohorts 
evaluated up to 200 mg QW, first dose and last Cycle 1 dose exposures were below the dog 
NOAEL AUC0-48hr and Cmax values of 8.52 μM•hr and 365 nM, respectively. The variability in 
AUC0-48hr and Cmax following the first dose, where it could be assessed, was low to moderate 
across all dose levels, with CV% values ranging from approximately 10 – 60%. For QOD dosing, 
a PD target of ≥70% inhibition of phosphorylated AKT (pAKT) in whole blood over a period of 
12 hours has been established, corresponding to a 56.8 nM C12hr PK target. The PK target was 
achieved in the 60 mg QOD cohort; MK-2206 Ctrough was above 56.8 nM by Day 7 in most 
patients at this dose level and remained above the target after approximately 2 weeks of dosing. 
Following the last Cycle 1 dose, MK-2206 concentrations in the 200 mg QW cohort exceeded 56.8 
nM over a period of at least 2 days. 

  
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Meso-scale enzyme-linked immunosorbent assay (ELISA) was used to measure pre- and 
post-treatment pAKT in whole blood (QOD and QW) and tumor tissue (QOD). Although initial 
pAKT assay variability was high and the numbers of patients in each dose cohort are limited, it 
does appear that substantial pAKT inhibition is demonstrated in both whole blood and tumor at all 
doses levels. 
 
Protocol 002 
A Phase I Dose-Escalation Study of Oral MK-2206 in Patients with Locally Advanced or 
Metastatic Solid Tumors 
Protocol 002 is an ongoing Phase I, multi-center, open-label, non-randomized, dose escalation 
study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of MK-2206. 
The study population includes patients with locally advanced or metastatic solid tumors. Study 
medication is administered on 28-day repeating cycles. Blood samples for measurement of MK-
2206 plasma concentrations are collected during the first 28 days of treatment (Cycle 1) and during 
the 7-day off-drug period following Cycle 1. Samples were collected predose and at prespecified 
postdose time points for pharmacokinetic and pharmacodynamic assays. MK-2206 was 
administered 2 hours prior to or 2 hours following food or a meal. 
 
Preliminary PK results are available for 58 patients who received: 
• MK-2206 QOD: 30 mg (n=3), 60 mg (n=35), 75 mg (n=3), 90 mg (n=7) 
• MK-2206 QW: 90 mg (n=3), 135 mg (n=4) and 200 mg (n=3) 
For all cohorts evaluated, deviations in PK sampling (particularly collection of trough 
concentrations) resulted from patient scheduling difficulties, early discontinuations due to disease 
progression and DLT, missed doses, inadvertent overdoses, and dose reductions due to toxicity. 
Although Day 1 AUC0-48hr and Cmax values up to 90 mg in cancer patients overlapped with the 
ranges observed in HVs (Protocol 001), overall, MK-2206 exposures in patients with cancer 
trended somewhat higher on average than those observed in HVs. Median Tmax of approximately 
6 hours (median values ranged from 4 – 10 hours) was observed in both the QOD and QW dosing 
regimens, and harmonic mean apparent terminal half-life (t1/2) values ranged from approximately 
60 – 80 hours, with the exception of the 90 mg QOD cohort. At 90 mg QOD, apparent terminal 
t1/2 was estimable in 1 patient and was approximately 50 hours. Tmax and apparent terminal t1/2 

  
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values from cancer patients were generally within the ranges observed in HVs. In all cohorts 
evaluated up to 200 mg QW, first dose and last Cycle 1 dose exposures were below the dog 
NOAEL AUC0-48hr and Cmax values of 8.52 μM•hr and 365 nM, respectively. The mean first 
dose MK-2206 AUC0-48hr and Cmax were 1.77 μM•hr and 62.2 nM, respectively, for the 60 mg 
QOD dose, and 14.8 μM•hr and 466 nM for the 300 mg QW dose. The dog NOAEL exposures 
were exceeded following the first dose of 300 mg QW. The variability in AUC0-48hr and Cmax 
following the first dose, where it could be assessed, was low to moderate across all dose levels, 
with % CV values ranging from approximately 10 – 60%. There does not appear to be a substantial 
or consistent departure from dose-proportionality for either AUC0-48hr or Cmax following the 
first dose up to the 300 mg dose level, except for an apparent plateau in exposures observed at 200 
mg (n=3). Dose proportionality could not be reliably assessed beyond 135 mg (n=4) due to limited 
numbers of patients at each dose level. This study was not designed to rigorously assess dose 
proportionality, nor was a formal statistical analysis carried out; as such, this conclusion should be 
viewed with some caution. For patients who completed dosing as scheduled, steady state appeared 
to have been approached by the second week of dosing. Based on data from HVs, the expected 
AUC, Cmax, and Ctrough geometric mean accumulation ratios ranged from approximately 1.2 –
2.4 for the QOD schedule and were approximately 1.2 for the QW schedule. Where evaluable, 
geometric mean accumulation ratios ranged from approximately 2.5 – 4.3 for the QOD schedule 
and approximately 1.0 – 1.8 from the QW schedule.  
 
 
 
 
3.5.3.1 Preliminary Pharmacodynamic Summary 
Biomarkers of target engagement (i.e., inhibition of AKT phosphorylation) will be utilized in 
tumor and surrogate tissues to assess the PD activity of MK-2206 in patients with cancer. AKT 
inhibition in whole blood is the primary surrogate PD biomarker. Based on preclinical data, ≥70% 
AKT inhibition in whole blood is expected to be required for efficacy with QOD dosing. AKT 
inhibition will also be evaluated in tumor tissue to assess target engagement and to correlate with 
AKT inhibition in whole blood. For QOD dosing, a PD target of a minimum of 70% AKT 
inhibition in whole blood over a period of 12 hours has been established, corresponding to a 56.8 

  
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nM C12hr PK target (determined from PK/PD modeling of HV and oncology patient data). The 
PK target was achieved in the 60 mg QOD cohort; from an inspection of the concentration-time 
data, MK-2206 trough concentrations were above 56.8 nM by Day 7 of dosing in 20 of 33 patients 
with available PK data who had completed dosing as scheduled up to that point (mean Ctrough = 
64.7 nM). MK-2206 concentrations in most patients (23 out of 29) remained above 56.8 nM 
throughout the dosing interval after approximately 2 weeks of dosing (Day 15 predose 
concentration = 98.0 nM). Appropriate PK and PD targets for QW dosing remain to be determined. 
Following the last Cycle 1 dose, MK-2206 concentrations in the 200 mg QW cohort exceeded 56.8 
nM over a period of at least 2 days. Meso-scale enzyme-linked immunosorbent assay (ELISA) was 
used to measure pAKT in whole blood (QOD and QW) and tumor tissue (QOD) obtained at 
protocol-specified pre and post-treatment time points during Cycle 1. Some whole blood PD data, 
particularly from patients in the 90-mg cohort, were not interpretable because of variability in 
results due to pAKT instability and dosing interruption or reduction due to toxicity. Although 
initial pAKT assay variability is high and the numbers of patients in each dose cohort are limited, 
it does appear that substantial pAKT inhibition is demonstrated in both whole blood and tumor at 
all doses levels. Based on the mechanism of action of AKT inhibition (PI3K pathway) 
hyperglycemia and hyperinsulinemia are events expected to indicate PD activity. In patients with 
cancer, reversible Grade 1 to Grade 3 hyperglycemia was observed at all dose levels evaluated on 
both the QOD and QW dosing schedules. Preliminarily, these events do not appear to be dose-
dependent. 
 
 
 
Combined inhibition with MK-2206 based therapy in Humans 
Protocol 003 
Dose-Escalation Study of MK-2206 in Combination with Selected Chemotherapy or 
Targeted Agents in Patients with Solid Tumors 
Protocol 003 is an ongoing Phase I, multi-center, open-label, non-randomized, dose escalating 
study to assess the safety, tolerability, and pharmacokinetics of MK-2206 in combination with 
standard doses of selected chemotherapy and targeted agents. The study population includes 
patients with locally advanced or metastatic solid tumors. 

  
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Three (3) treatment arms are under evaluation in this study: 
• Treatment Arm 1: MK-2206 + carboplatin + paclitaxel 
• Treatment Arm 2: MK-2206 + docetaxel 
• Treatment Arm 3: MK-2206 + erlotinib 
Doses and regimens planned for evaluation include MK-2206 45- and 60-mg QOD and MK-2206 
90- to 250-mg every 3 weeks (Q3W) combined with standard doses of intravenous 
chemotherapy/oral erlotinib. Preliminary PK results for MK-2206 are available for 13 patients who 
received: 
• MK-2206 45 mg QOD + carboplatin + paclitaxel (Treatment Arm 1): n=4 
• MK-2206 45 mg QOD + docetaxel (Treatment Arm 2): n=5 
• MK-2206 45 mg QOD + erlotinib (Treatment Arm 3): n=4 
 
Preliminary pharmacokinetic data for MK-2206  
MK-2206 PK parameter values for all treatment arms were generally consistent with historical 
data from Protocol 001 and Protocol 002.  Mean Day 1 AUC0-48hr and Cmax values ranged from 
1320 – 1690 nM•hr and 42.9 – 56.9 nM, respectively, across all treatment arms.  By inspection, 
steady state was approached by Day 21 in Treatment Arm 3.  
 
Preliminary Pharmacodynamic Summary 
A PD target of a minimum of 70% AKT inhibition in whole blood over a period of 12 hours has 
been established for the QOD monotherapy schedule and corresponds to a 56.8 nM C12hr PK 
target (determined from PK/PD modeling of HV and oncology patient data). The PD target for 
AKT inhibition was determined for monotherapy and, as suggested by preclinical study results, a 
different degree of AKT inhibition may be required for combination therapy. In Treatment Arm 3, 
the mean Ctrough exceeded the monotherapy concentration target by Day 7; 2 out of 4 patients 
did not attain the PK target. Two (2) out of 3 patients in this treatment arm completed Cycle 1 
dosing and had concentrations exceeding the monotherapy target following the last dose. 
 
MK-2206 Safety and Efficacy in Humans 
Efficacy in Humans 

  
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No formal efficacy studies have been conducted with MK-2206. In patients with advanced solid 
tumors (Protocol 002), stable disease has been observed in 16 patients on study who received MK-
2206 monotherapy for ≥3 months (range, 3 – 8 months). Early indications of anti-tumor activity 
included substantial decreases in CA125 in some patients with ovarian cancer and PSA 
stabilization in some patient with prostate cancer. Minor RECIST responses, e.g., <30% decreases 
in tumor size, have also been observed in a patient with melanoma (-16%), a patient with pancreatic 
cancer (- 23%), and in a patient with neuroendocrine tumor (-20%). No partial responses, e.g., 
confirmed >30% decreases in tumor size, have been observed. 
 
Safety in Humans – Phase I Studies (Protocol 002 and Protocol 003) 
Protocol 002 
A Phase I Dose-Escalation Study of Oral MK-2206 in Patients with Locally Advanced or 
Metastatic Solid Tumors 
Protocol 002 is an ongoing Phase I, multi-center, open-label, non-randomized, dose escalating 
study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of MK-2206 in 
patients with locally advanced or metastatic solid tumors. Patients are administered oral MK-2206 
in repeating 28-day cycles. A 7-day protocol-specified off-drug period occurs following Cycle 1. 
Cohorts of 3-6 patients are enrolled sequentially on escalating doses of MK-2206. Dosing 
regimens under evaluation include: once every other day (QOD) and once weekly (QW).  
Sequential Dosing for QOD and QW regimens in protocol 002: 
QOD: 30 mg, 60 mg, 90 mg, 135 mg, 200 mg, 300 mg, 75 mg 
QW: 90 mg, 135 mg, 200 mg, 300 mg, 250 mg. 
Study medication is administered in 28-day repeating cycles. Cohorts of 3-6 patients are enrolled 
sequentially on escalating doses of MK-2206. Dose escalation will proceed until the MTD of each 
dosing regimen is determined. Patients will be monitored for the development of DLTs, and safety 
and tolerability will be assessed at the end of the first cycle of therapy for dose 
escalation/confirmation decisions. Dose-limiting toxicities in this study include adverse 
experiences such as Grade 3 neutropenia (≥7 days), Grade 3 or Grade 4 febrile neutropenia, Grade 
4 thrombocytopenia and Grade 3 to Grade 5 non-hematological adverse experience (excluding 
adverse experiences in the setting of inadequate compliance with supportive care measures). 
 

  
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Study Status of Protocol 002 
As of 13-Jan-2010 a total of 71 patients have been enrolled: 30 mg QOD (n=3), 60 mg QOD 
(n=43), 90 mg QOD (n=7), 75 mg QOD (n=3), 90 mg QW (n=3), 135 mg QW (n=4), 200 mg QW 
(n=5), and 300 mg QW (n=3). Sixty-five (65) patients have discontinued study medication: 11 
patient due to clinical adverse experiences, 53 patients due to disease progression, and 1 patient 
withdrew consent. Five (5) deaths due to disease progression have been reported in this study. 
Dose escalation on the QOD schedule proceeded up through 90 mg. Following observations of 
Grade 3/Grade 4 skin rash in 4 out of 7 patients at 90 mg, dose escalation above 90 mg QOD 
ceased. Further accrual at 60 mg QOD confirmed safety at this dose; therefore, an intermediate 
dose of 75 mg QOD was explored. Two (2) out of 3 patients experienced the DLT of Grade 3 rash 
at 75 mg QOD. No additional patients were enrolled at this dose. Following completion of accrual 
to an expanded cohort of patients at 60 mg QOD, this dose has been established as the MTD for 
this regimen. Accrual at this dose continues in specific expansion cohorts including patients with 
ovarian and prostate cancer and patients eligible for evaluation of anti-angiogenesis activity by 
dynamic contrast-enhanced magnetic resonance imaging. Dose escalation on the QW schedule 
proceeded up through 300 mg. Following observations of Grade 3 skin rash in 3 out of 3 patients 
at 300 mg, dose escalation above 300 mg QW ceased. Further accrual at 200 mg QW confirmed 
safety at this dose; therefore, an intermediate dose of 250 mg QW is currently under evaluation. 
 
Preliminary Safety Summary of Protocol 002 
As of 13-Jan-2010, preliminary adverse experience data are available for 69 patients who received 
oral MK-2206. Adverse experiences have been observed in all patients (100.0%). The National 
Cancer Institute (NCI) – Common Terminology Criteria for Adverse Events (CTCAE) version 3, 
publishing date 09-Aug-2006 was used when reporting adverse experiences. Among those enrolled 
in the dose escalation (QOD and QW regimens) and expansion cohorts, skin rash was reported as 
a DLT in 13 patients:  
• 4 patients at 90 mg QOD 
• 2 patients at 75 mg QOD 
• 3 patients at 300 mg QW 
• 4 patients at 60 mg QOD 

  
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Twenty-one (21) other patients treated at 60 mg QOD developed the adverse experience of skin 
rash during the course of the study. The severity of the skin rash in the majority of these patients 
was Grade 1/Grade 2. No skin rash was observed in patients at 30 mg QOD, 90 mg QW and 200 
mg QW at the time of data cut-off. However, a review of unaudited data since this date indicated 
that an adverse experience of Grade 3 skin rash was reported in 1 patient at 200 mg QW. One (1) 
patient who received MK-2206 135 mg QW developed Grade 1 skin rash. At higher doses of MK-
2206 evaluated (i.e., 75 mg and 90 mg QOD and 300 mg QW), onset of the rash was within 1.5-2 
weeks of study therapy initiation. Severity at onset at these higher doses was Grade 3. At all other 
dose levels evaluated, onset was generally following 3-4 weeks of treatment. On average, 
regardless of grade, the duration of the skin rash was 7 to 14 days and is characterized by maculo-
papular lesions on the trunk and limbs, and occasionally on the face. An acneiform rash was also 
observed in 1 patient. The rash is at times associated with pruritus (Grade 1 and 3) and at the higher 
doses evaluated stomatitis (Grade 2/3) and conjunctivitis (Grade 1). In the majority of cases, 
Investigators considered the skin rash related to study therapy. In cases of moderate to severe skin 
rash, patients were treated with oral and topical corticosteroids, anti-pruritic medication and anti-
histamines and antibiotics. This adverse experience resolved following interruption or 
discontinuation of study medication. Several patients reported ongoing sequelae of dry skin. Other 
DLTs observed in this study include: Grade 3 pruritus, associated with Grade 3 skin rash at 90 mg 
QOD, Grade 3 hyperglycemia at 60 mg QOD and Grade 2 diarrhea at 75 mg QOD. The adverse 
experiences of Grade 3 hyperglycemia and Grade 2 diarrhea were considered by the Investigator 
to be serious. With the exception of Grade 3 hyperglycemia, these adverse experiences resolved 
following dose interruption and study therapy was re-initiated at a reduced dose. Skin rash (i.e., 
rash, erythematous rash, rash macular, exfoliative rash, rash papular, rash pruritic) was the most 
common treatment-related adverse experience reported across all dose levels, occurring in 34 out 
of 69 patients (49.3%). Other common treatment-related adverse experiences included nausea 
(20.3%), fatigue (17.4%), pruritus (14.5%), diarrhea and decreased appetite (13.0%), vomiting and 
hyperglycemia (11.6%), and dry skin (10.1%). These adverse experiences were generally Grade 1 
and Grade 2. 
Adverse experiences indicating ocular effects of treatment with MK-2206 are of interest 
based on preclinical safety evaluations. Treatment-related eye disorders were observed in 6 

  
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patients who received MK-2206 and included: conjunctivitis, dry eyes, eye swelling, foreign body 
sensation, and decreased visual acuity. These adverse experiences were mild (Grade 1).  
Serious adverse experiences were observed in 26 out of 69 patients (37.7%). Drug related 
serious adverse experiences were observed in 8 out of 69 patients (11.6%) and included Grade 
3/Grade 4 skin rash and pruritus in 6 patient, Grade 3 hyperglycemia in 1 patient and Grade 2 
vomiting in 1 patient. Five (5) deaths were reported during the course of this study. All deaths 
were due to disease progression and were not considered by Investigators to be related to study 
medication.  Dose interruption or modification occurred in 22 patients. Four (4) patients required 
a dose reduction due to skin rash (Grade 2 to Grade 3). Grade 2 diarrhea and Grade 3 
hyperglycemia resulted in dose reduction in 2 patients. Seventeen (17) patients required an 
interruption in dosing due to treatment-related adverse experiences. The majority of these adverse 
experiences were skin rash ranging in severity from Grade 1 to Grade 3. 
Most adverse experiences responded to standard measures of supportive care and resolved 
following an interruption in therapy of approximately 1 – 2 weeks.  Pre-defined events of clinical 
interest (ECI) included ≥ Grade 3 hyperglycemia and hyperinsulinemia. Patients with a history of 
diabetes on insulin or anti-diabetic agents are not permitted to enroll in this study. Additionally, 
patients with poorly controlled hemoglobin A1c or abnormally elevated fasting blood glucose at 
screening are also ineligible. Grade 1 to Grade 3 hyperglycemia was reported as an adverse 
experience in 11 out of 69 patients (15.9%). This adverse experience was considered drug-related 
in 8 out of 69 patients (11.6%), including 2 patients with Grade 3 hyperglycemia observed 
following treatment with MK-2206 60 mg QOD and 75 mg QOD. Adverse experiences of 
hyperglycemia have not been observed in patients treated with MK-2206 QW. In the majority of 
patients no interruption or modification to study medication was required. One (1) patient initiated 
therapy on MK-2206 75 mg QOD and was dose reduced to 60 mg QOD following Grade 2 diarrhea 
during the first cycle of treatment. This patient experienced Grade 3 hyperglycemia in Cycle 4, 
and as the patient was deriving clinical benefit, a second dose reduction to 45 mg QOD was 
permitted. The patient continued at this dose for an additional 5 cycles at which time they were re-
escalated to 60 mg QOD. The patient discontinued study medication due to disease progression 
after 9 cycles of treatment. An interruption in study therapy was required in 1 patient. This patient 
entered the study with a history of steroid-induce glucose intolerance. While Day 1 predose blood 
glucose was 8.2 mmol/L (upper limit of normal = 6.0 mmol/L), hemoglobin A1c was 6.1% (upper 

  
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limit of normal = 6.5%) and c peptide was 1764 pmol/L (upper limit of normal = 1803 pmol/L). 
The patient was asymptomatic and supportive care measurements were implemented to manage 
blood glucose levels and included treatment with oral anti-hyperglycemic medication. Prior to re-
initiating therapy, the patient was discontinued from study medication due to disease progression. 
The adverse experience was continuing at the time of discontinuation. During the course of the 
study, blood glucose evaluations were carried out at protocol specified time points. Sixty-eight 
(68) patients had both baseline and at least 1 post-baseline blood glucose evaluation. Forty-nine 
(49) out of 68 patients (72.1%) were observed to have elevated blood glucose levels defined as 
hyperglycemia by NCI CTCAE v3 Metabolic/Laboratory. In addition to hyperglycemia, ≥ Grade 
3 QTc prolongation is a pre-defined ECI based on preclinical findings in the oral cardiovascular 
telemetry study in conscious dogs. Patients with baseline QTc >450 msec, congenital long QT 
syndrome, and/or current anti-arrhythmic therapy with known effects of QT prolongation were not 
eligible for enrollment. Cardiac monitoring included multiple ECG evaluations in Cycle 1 and 24-
hour Holter monitoring beginning Day 1 predose. Preliminary QTc interval data obtained by 12-
lead ECG monitoring are available for 64 out of 69 patients included in the current safety 
population. Seventeen (17) out of 64 patients (26.6%) enrolled were observed to have QTc interval 
prolongation (>450 msec): 
• 12 out of 50 patients (24.0%) who received MK-2206 QOD (30- to 90-mg) 
• 3 out of 14 patients (21.4%) who received MK-2206 QW (90- to 300-mg) 
• 2 patients enrolled on the QOD regimen entered the study with a QTc interval >450 msec  
These patients were asymptomatic and the episodes of prolongation were not considered clinically 
significant by Investigators. 
 
Protocol 003 
Protocol 003 is an ongoing Phase I, multi-center, open-label, non-randomized, dose escalating 
study to assess the safety, tolerability, and pharmacokinetics of MK-2206 in combination with 
standard doses of selected chemotherapy and targeted agents. The patient population includes 
patients with locally advanced or metastatic solid tumors.  Three (3) treatment arms are under 
evaluation in this study: 
• Treatment Arm 1: MK-2206 + carboplatin + paclitaxel 
• Treatment Arm 2: MK-2206 + docetaxel 

  
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• Treatment Arm 3: MK-2206 + erlotinib 
Doses and regimens planned for evaluation include MK-2206 45- and 60-mg QOD and MK-2206 
90- to 250-mg of MK-2206 administered every 3 weeks (Q3W). Chemotherapy and erlotinib were 
administered per standard of care.  Study medication is administered in 21-day repeating cycles. 
Cohorts of 3-6 patients are enrolled sequentially on escalating doses of MK-2206. Dose escalation 
will proceed until the MTD of each regimen in each treatment arm is determined. Patients will be 
monitored for the development of DLTs, and safety and tolerability will be assessed at the end of 
the first cycle of combination therapy for dose escalation/confirmation decisions. Dose-limiting 
toxicities in this study include adverse experiences such as Grade 3 neutropenia (≥7 days), Grade 
3 or Grade 4 febrile neutropenia, Grade 4 thrombocytopenia and Grade 3 to Grade 5 non-
hematological adverse experience (excluding adverse experiences in the setting of inadequate 
compliance with supportive care measures). 
 
Study Status of Protocol 003 
As of 3-Feb-10, a total of 22 patients have been enrolled between each of 3 treatment arms: 
• Treatment Arm 1: 45 mg QOD (n=6) and 60 mg QOD (n=4) 
• Treatment Arm 2: 45 mg QOD (n=5) 
• Treatment Arm 3: 45 mg QOD (n=7) 
Thirteen (13) patients have discontinued study medication: 1 patient due to a clinical adverse 
experience and 12 patients due to progressive disease. Serious adverse experiences have been 
reported in 10 patients. To date, no deaths have been reported in this study.  Accrual continues on 
the QOD regimen in Treatment Arms 1 and 3. In Treatment Arm 3, erlotinib is currently 
administered at 100 mg daily (QD).  
No patients have been enrolled on the Q3W regimen. 
 
Preliminary Safety Summary of Protocol 003 
As of 3-Feb-10, preliminary adverse experience data are available for 18 out of 22 patients who 
received oral MK-2206. Adverse experiences were observed in 17 out of 18 patients (94.4%). The 
National Cancer Institute (NCI) – Common Terminology Criteria for Adverse Events (CTCAE) 
version 3, publishing date 09-Aug-2006 was used when reporting adverse experiences. The 

  
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evaluable period for DLTs occurs during the first 21 days of treatment with combination therapy 
(Cycle 1). 
Skin rash (i.e., rash, rash pruritic) was the most common treatment-related adverse 
experience observed in patient receiving MK-2206 in combination with selected chemotherapy 
and targeted agents. Grade 1 to Grade 3 skin rash has been reported in 9 out of 18 patients (50.0%) 
and was a DLT at MK-2206 45 mg QOD in 1 patient in Treatment Arm 1 (MK-2206 + carboplatin 
+ paclitaxel) and 1 patient in Treatment Arm 3 (MK-2206 + erlotinib). The rash is involved the 
face, torso, and limbs and was associated with pruritus (Grade 1/Grade 2). One (1) patient (MK-
2206 + erlotinib) was observed to have Grade 3 rash involving the torso, characteristic of treatment 
with MK-2206 and Grade 3 rash involving the face, more characteristic of treatment with erlotinib. 
This patient was dose reduced to MK 2206 30 mg QOD and the rash subsequently resolved without 
sequelae. All episodes were Grade 3 and met criteria for DLTs. In all cases, the adverse experience 
occurred within 7 to 11 days of taking study medication. Study medication was discontinued in 
these patients and the remaining patients in this cohort continued at 45 mg QOD and were 
subsequently discontinued for disease progression.  Other common treatment-related adverse 
experiences observed in this study included vomiting and alopecia (33.3%), fatigue, diarrhea, and 
nausea (27.8%), and decreased appetite and pruritus (22.2%). The majority of these adverse 
experiences are also commonly seen in patients treated with chemotherapy regimens alone. 
Additionally, 
hematologic 
adverse 
experiences 
such 
as 
anemia, 
neutropenia, 
and 
thrombocytopenia are also anticipated following treatment with chemotherapeutic agents; these 
adverse experiences occurred in <20% of patients treated and were not observed in patients treated 
with MK-2206 + erlotinib.  Other treatment-related adverse experiences determined to be DLTs 
included Grade 3 stomatitis occurring in 1 patient in Treatment Arm MK-2206 + erlotinib.  One 
(1) patient discontinued study medication due to the clinical adverse experience of Grade 2 skin 
rash. Dose interruption or modification occurred in 9 patients. Three (3) patients required a dose 
reduction due to skin rash (Grade 1 to Grade 3). MK-2206 in these patients, 1 in each treatment 
arm, was dose reduced from 45 mg QOD to 30 mg QOD. Six (6) patients in Treatment Arms 1 
and 3 required an interruption in dosing due to treatment-related adverse experiences. The majority 
of these adverse experiences were non-hematologic, ranging in severity from Grade 1 to Grade 4, 
and included hyperglycemia, nausea, vomiting, stomatitis, hyponatremia, skin rash, 
thrombocytopenia, and hypoglycemia.  Most adverse experiences resolved following an 

  
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interruption in therapy of approximately 1 week at which time patients resumed therapy at the 
same dose. Adverse experiences of Grade 4 hyperglycemia (MK-2206 + erlotinib Treatment Arm) 
required a 30-day interruption in study medication prior to re-initiation of therapy at the same dose. 
In addition to skin rash, other ECI include hyperglycemia and cardiovascular events of clinically 
significant bradycardia and QTc prolongation. Grade 3 QTc prolongation and bradycardia are pre-
defined ECI based on preclinical findings in the oral cardiovascular telemetry study in conscious 
dogs (Section 4.2.2.3). Patients with baseline QTc >450 msec, congenital long QT syndrome, 
and/or current anti-arrhythmic therapy with known effects of QT prolongation were not eligible 
for enrollment. In addition, patients with evidence of clinically significant bradycardia (<50 bpm), 
or a history of clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree AV 
block (MobitzType 2) or patients taking beta blockers, non-dihydropyridine calcium channel 
blockers, or digoxin were not eligible for enrollment.  ECG monitoring in this study included 
baseline evaluation and 1 postdose assessment. During the course of the study, no patients were 
observed to have QTc interval prolongation >450 msec or clinically significant bradycardia.  
Patients with a history of diabetes on insulin or other anti-diabetic agents are not permitted to enroll 
in this study. Additionally, patients with poorly controlled hemoglobin A1c or abnormally elevated 
fasting blood glucose at screening are also ineligible. Hyperglycemia was reported as an adverse 
experience in 6 out of 18 patients (33.3%). Episodes of hyperglycemia were asymptomatic, mild 
and transient. Modification to or discontinuation of study medication was not required. One (1) 
patient experienced Grade 4 hyperglycemia following 3 cycles of treatment with MK- 2206 45 mg 
QOD + erlotinib. Treatment of this adverse experience included blood glucose management, 
including insulin and oral anti-hyperglycemic medication. The Investigator did consider this 
adverse experience related to study medication. Study therapy was discontinued due to progressive 
disease.  During the course of the study, blood glucose evaluations were carried out at protocol 
specified time points. Sixteen (16) patients had both baseline and at least 1 post-baseline blood 
glucose evaluation. Fifteen (15) out of 16 patients (93.8%) were observed to have elevated blood 
glucose levels defined as hyperglycemia by NCI-CTCAE v3. 
As of early June, 2011 the MK-2206 (QOD and QW) and erlotinib combination Phase1b 
study has accrued a total of 25 patients.  Nine (9) patients have received treatment with MK-2206 
at 45 mg QOD and erlotinib at 100 mg QD. Dose-limiting toxicities were observed in two patients, 

  
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one Grade 3 skin rash and one Grade 3 mucositis.  Four (4) patients have been dosed at 45 mg 
QOD and erlotinib at 150 mg with one patient experiencing a DLT of Grade 3 rash.   
Weekly dosing of MK-2206 was investigated in 6 patients at 135 mg QW MK-2206 and 
100 mg erlotinib, without occurrence of DLT. Grade 2-3 skin rash was observed in one case. One 
DLT of Grade 2 skin rash was observed in 6 patients treated at 135 mg QW MK-2206 and 150 mg 
of erlotinib daily.  Weekly dosing of MK-2206 at 135 mg QW with 100 - 150 mg of erlotinib daily 
was considered safe and tolerable. 
 
3.6 
AZD6244 
3.6.1 Background 
The Ras-Raf-MAPK pathway is an important regulator of cell proliferation and transformation. 
56,57  The RAS/RAF/MEK/ERK signaling pathway plays a central role in the regulation of many 
cellular processes including proliferation, survival, differentiation, apoptosis, motility, and 
metabolism.58,59 This pathway is one of the most important and best understood MAP kinase signal 
transduction pathways, activated by a diverse group of extracellular signals including integrins, 
growth factor receptors (i.e., EGFR, platelet-derived growth factor receptor [PDGFR], and insulin-
like growth factor-1 receptor), and cytokines.60 Activated RAS triggers the phosphorylation and 
activation of RAF kinase which then phosphorylates MEK1 and MEK2 on 2 serine residues.61 
Activated MEK phosphorylates its only known substrates, ERK1 and ERK2. Phosphorylated ERK 
dimerizes and translocates to the nucleus62 where it is involved in several important cellular 
functions, including cell proliferation.  Overexpression of growth factors or growth factor 
receptors involved in the RAS/RAF/MEK/ERK pathway and activating genetic mutations of the 
signaling proteins may lead to uncontrolled proliferation and tumor formation. For example, RAS 
genes are the most frequently mutated oncogenes detected in human tumors.60  RAS proteins are 
guanine nucleotide binding proteins that activate RAF proteins when bound to GTP. Cancer-
associated mutations in RAS proteins stabilize the GTP-bound form of RAS, thereby providing a 
constitutive signal downstream in the cascade. In addition to being found in almost all pancreatic 
adenocarcinomas, RAS mutations are found in ~50% of colorectal carcinomas, 25-50% of lung 
adenocarcinomas, 63,64 as well as some breast or ovarian cancers. BRAF mutations have also been 
observed in many human cancers, particularly melanoma (30-60%), thyroid (30-50%), colorectal 
(5-20%), and ovarian (~30%) cancers.59 These mutations in BRAF usually involve gain-of-

  
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function substitutions that render the kinases constitutively active. Also, studies of primary tumor 
samples and cell lines have shown constitutive activation or overactivation of the MAP kinase 
pathways in cancers of the pancreas, colon, lung, ovary, and kidney.65 Therefore, agents targeting 
the RAS/RAF/MEK/ERK pathway may inhibit oncogenic signaling in tumor cells.  
AZD6244 (ARRY-142886) is a potent, selective, orally-available, and non-ATP 
competitive small molecule inhibitor of the mitogen-activated protein (MAP) kinase kinase, MEK-
1/2. 66 AZD6244 inhibited the activity of purified MEK enzyme with an IC50 of 10-14 nM, and 
was found to be inactive or only minimally active at 10 μM against a panel of other kinases, 
including epidermal growth factor receptor (EGFR), erbB2, p38α, ERK2, and MKK 6 kinases. 
Because ERK is the only known substrate of MEK, the inhibition of MEK will target only the 
ERK signal transduction pathway and other signal transduction pathways will not be blocked. 
AZD6244 is metabolized to biologically active N-desmethyl AZD6244 which is more potent than 
the parent compound. In vitro, in vivo and preliminary results from clinical studies suggest that 
AZD6244 exhibits a favorable pharmacologic and toxicologic profile.  
The formulation taken into the Phase I clinical study by Array Biopharma (Study # ARRY-
0401) was an extemporaneous preparation of an oral suspension of AZD6244 as the free-base in a 
mix and drink formulation, an aqueous solution of sulphobutylether β-cyclodextrin (SBE-CD, 
Captisol®), referred to as AZD6244 free-base. Subsequent formulation development resulted in a 
capsule formulation of AZD6244 as the hydrogen sulphate salt (referred to as AZD6244 Hyd-
Sulfate).   
 
3.6.2 Preclinical Studies 
Pharmacology summary 
The activity and specificity of AZD6244 against mitogen-activated protein kinase kinase (MEK) 
1 and a panel of other kinases were determined in a series of biochemical studies.67 AZD6244 
inhibited the activity of isolated MEK to phosphorylate extracellular signal-regulated kinase 
(ERK) 2 in enzyme assays, with a concentration which resulted in 50% inhibition (IC50) of 
approximately 10 to14 nM. AZD6244 is an uncompetitive inhibitor with respect to adenosine 
triphosphate (ATP). In contrast to its activity against MEK, AZD6244 was inactive, or only 
minimally active, against a panel of other kinases. Mechanistic and functional cell culture studies 

  
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were performed to determine the potency of AZD6244 with respect to inhibition of ERK 
phosphorylation and inhibition of cell viability. AZD6244 was particularly potent in inhibiting the 
cell viability of cell lines with the V600E BRAF gene mutation that led to a constitutively active 
BRAF and, consequently, an overactive MEK. AZD6244 was also a similarly potent inhibitor of 
some cell lines with activating KRAS gene mutations. In vivo pharmacology studies demonstrated 
activity of AZD6244 in tumor-bearing animals, including tumor growth inhibition and regression 
of established tumors derived from a range of tumor types including melanoma, breast, pancreatic, 
lung, colon, and hepatocellular carcinomas.67,68  In the Calu-6 lung cancer xenograft model, a 
minimal effective dose of 0.75 mg/kg twice daily (BID) was defined. Inhibition of ERK 
phosphorylation was found in tumors in which growth was inhibited by AZD6244. These data 
show that AZD6244 is pharmacologically active in several tumor types and that tumor 
phosphorylated ERK (pERK) levels are a potential biomarker for AZD6244 activity in vivo. Mode 
of action studies in vivo demonstrate that AZD6244 can both inhibit cell proliferation and promote 
apoptosis. In vivo studies in human cancer xenografts have demonstrated the potential for 
AZD6244 to be used in combination with a number of cytotoxic and targeted agents, including 
docetaxel, irinotecan, gemcitabine, Iressa (gefitinib) and AZD2171 (cediranib). N-desmethyl 
AZD6244 (a pharmacologically active metabolite) was identified to be approximately 2–5-fold 
more active than the AZD6244 parent compound. 
 
Pharmacokinetic summary 
In preclinical species, AZD6244 free-base showed good oral bioavailability at low doses, but there 
was dose-limited absorption with increasing dose, likely reflecting the low aqueous solubility of 
the free-base.  AZD6244 Hyd-Sulfate produced approximately linear increases in exposure with 
dose and allowed higher exposures to be achieved than with the free-base.  There was no/minimal 
accumulation of AZD6244 (whether dosed as free-base or Hyd-Sulfate) on multiple dosing in 
mouse, rat and monkey.  In rat and mouse AZD6244-related material was widely distributed, 
although tissue concentrations tended to be lower than blood concentrations. There was no 
evidence of binding to melanin, and penetration into the CNS was minimal.  Protein binding was 
high: 99.7% in rat, 98.9% in mouse, 98.4% in human, 97.7% in monkey, 94.6% in dog and 93.7% 
in Minipig (with similar protein binding of N-desmethyl AZD6244 and AZD6244 parent 

  
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compound for each animal species).  AZD6244 is a substrate but not an inhibitor of p-glycoprotein 
(PgP) and breast cancer resistance protein (BCRP). 
In vitro, AZD6244 underwent Phase I metabolic reactions including N-demethylation, 
oxidative defluorination, and loss of the side chain, to form amide and acid metabolites. The 
pharmacologically active N-desmethyl metabolite of AZD6244 was detected in vitro in human 
hepatocytes and in human plasma, but was not detected in rat and was detected only at trace levels 
in monkey. This metabolite was formed in mouse, and circulated at levels between approximately 
2% and 12% of AZD6244 levels, although there was evidence that levels declined on multiple 
dosing. Glucuronides of AZD6244 were detected in human hepatocyte incubations and plasma, 
indicating that direct conjugation is a significant route of elimination for AZD6244. Preliminary 
in vitro data in human hepatocytes indicate that AZD6244 was a weak inducer of cytochrome P450 
(CYP) 3A, 1A and 2C9. At AZD6244 concentrations approximately 10-fold higher than those 
achieved in the clinic, the level of induction was <40% of positive control inducers.AZD6244 was 
metabolised primarily by CYP 1A2 to produce N-desmethyl AZD6244. Using expressed CYP 
isoforms, it was evident that AZD6244 was also metabolised by CYP 2C19 and CYP 3A4. 
AZD6244 showed no inhibition of the CYP isoforms 1A2, 2C8, 2C19, 2D6, or 3A4 at 
concentrations up to 50 μM. It was a weak direct inhibitor of CYP2C9, with an IC50 of 44.7 μM. 
N-desmethyl AZD6244 showed weak inhibition of CYP1A2, with an IC50 of 18.9 μM. 
 
Toxicology summary 
AZD6244 or N-desmethyl AZD6244 showed no evidence of mutagenic or clastogenic potential in 
vitro. AZD6244 produced an increase in micronucleated immature erythrocytes (MIEs) in mouse 
micronucleus studies, predominantly via an aneugenic mode of action. Daily oral administration 
of AZD6244 free-base in SBE-CD for 1 month was well tolerated in rats, but produced soft stools, 
and gastrointestinal mucosal mineralization was observed. Tissue mineralization was not apparent 
in cynomolgus monkeys dosed for up to 1 month with AZD6244 free-base or AZD6244 Hyd-
Sulfate. However, mineralization was seen in multiple tissues, including cornea, kidney, liver, 
myocardium, skeletal muscle, glandular stomach in mice dosed with AZD6244 Hyd-Sulfate for 
up to 1 month. In mice and rats, tissue mineralization was associated with changes in plasma 
inorganic phosphate and albumin and, in mice, with changes in calcium. In addition, in mice and 
rats, tissue mineralization was observed in several animals at the end of a 1 month recovery period. 

  
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Twice-daily oral administration of AZD6244 free-base in SBE-CD for 1 month produced diarrhea, 
dehydration and electrolyte imbalance in some monkeys, and with renal changes (tubular epithelial 
swelling and mild vacuolation) secondary to persistent diarrhea and dehydration in some instances. 
Twice-daily oral dosing of AZD6244 Hyd-Sulfate in SBE-CD also produced fluid and/or red 
colored feces in monkeys, but with no notable gastrointestinal tract or renal pathology. In mice, 
BID oral dosing with AZD6244 Hyd-Sulfate at non-tolerated dose levels was associated with 
gastrointestinal tract toxicity and hematopoietic atrophy. Anemia, with an associated 
reticulocytosis, was also apparent in mice dosed with AZD6244 Hyd-Sulfate. It has been observed 
that AZD6244 absorbs in the ultraviolet (UV) range for phototoxicity and shows enhanced 
cytotoxicity in the presence of UV light in an in vitro 3T3 Neutral Red Uptake phototoxicity test. 
In rat, AZD6244-related material was widely distributed throughout tissues, including skin, eye 
and uveal tract, but did not show evidence of melanin binding.  In the mix and drink formulation, 
AZD6244 free-base has limited solubility and exhibited a less-than-proportional increase in 
exposure and decreasing bioavailability with increasing dose in rat and monkey. However, 
enhanced and dose-related increases in exposure were seen in the mouse and monkey with 
AZD6244 Hyd-Sulfate. With the exception of tissue mineralization in rats and mice, there was 
evidence of reversibility of most changes in the 1 month studies with AZD6244, whether free-base 
or Hyd-Sulfate. Preliminary reproductive toxicology data indicate that AZD6244 can have adverse 
effects on embryofetal development and survival at dose levels that do not induce maternal toxicity 
in mice. Six month oral toxicity studies with AZD6244 Hyd-Sulfate in mice and monkeys are 
currently ongoing. The dosing phase of these studies has completed and histopathological 
evaluation of tissues is currently ongoing. In the monkey study, the primary in-life observation 
appears to be an increased incidence of liquid feces, which is consistent with that seen in the 1 
month monkey study. In the mouse study, dosing of AZD6244 Hyd-Sulfate to male mice for 8–15 
weeks at the high dose level produced dilation of the corpus spongiosum, leading to urethral 
compression and backward flow blockage resulting in dilation of seminal vesicles and bladder. 
This ultimately led to deterioration in clinical condition, which required several high-dose males 
to be terminated prematurely in Week 16, but in the males examined to date does not appear to 
result in histopathological changes in either the bladder of kidney. The mechanism underlying 
these changes in the mice is unknown at this stage and further evaluation of tissues from animals 
on this study may help provide an understanding of this change. There have been no indications 

  
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of similar effects following dosing of AZD6244 Hyd-Sulfate for 6 months in cynomolgus 
monkeys. Other changes in the mouse 6 month study, including changes suggestive of 
gastrointestinal tract toxicity, tissue mineralization and hematological effects, are consistent with 
those seen previous in mice dosed for up to 1 month. 
 
3.6.3 Clinical Studies 
3.6.3.1 
Pharmacokinetic summary 
One hundred (100) mg bid was determined to be the maximum tolerated dose for the AZD6244 
free-base suspension.69  Seventy-five (75) mg bid was determined to be the MTD for the Hyd-
Sulfate capsule formulation.70  N-desmethyl and amide metabolites are both measured in human 
plasma after dosing with AZD6244.  AZD6244 pharmacokinetics (PK) was approximately dose 
proportional across the dose ranges studied for both the free-base suspension and Hyd-Sulfate 
capsule formulations.  Single dose pharmacokinetics showed AZD6244 had a median time to reach 
maximum plasma concentration (tmax) of 1.5 hours, and a terminal elimination half-life (t1/2) of 5 
to 7 hours.  Clearance (CL/F) and steady-state volume of distribution (Vss/F) remained largely 
consistent across the dose range studied.  N-desmethyl AZD6244 PK profile was largely similar 
to AZD6244, but exposures were much lower.  Concentrations of the amide were very variable. 
 
Based on the dose-normalised area under the plasma concentration-time curve from time 0 to 24 
h (AUC0–24), the estimated oral bioavailability of the Hyd-Sulfate capsule (N=26) relative to the 
free base suspension (N=28) was 263% (90% confidence intervals [CI] = 214 to 322%), indicating 
a statistically significant increase in the oral bioavailability with the Hyd-Sulfate capsule compared 
to the free-base suspension.71 The AUC0-24 and maximum plasma concentration (Cmax) geometric 
least squares mean (glsmeans) obtained at the MTD of the Hyd-Sulfate capsule (75 mg) were 
statistically significantly higher than those obtained at the MTD of the free-base suspension 
(100 mg): based on AUC0–24, the exposure of the Hyd-Sulfate capsule (N=26) relative to the free 
base suspension (N=28) was estimated to be 197% (90% CI = 161 to 242%); based on Cmax, 252% 
(90% CI = 182 to 348%, N = 27 and 28 for Hyd-Sulfate capsule and free-base suspension, 
respectively), however, there was a relatively large variation in relative bioavailability between 
patients, and for some the Cmax and/or AUC0-24 for the 75 mg capsule was lower than that for the 
100 mg suspension.  The plasma pharmacokinetic parameters for AZD6244 and AZD6244 N-

  
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desmethyl were similar after single and multiple dosing, suggesting minimal accumulation over 
time.  The amide metabolite showed increased exposure on multiple dosing, indicating some 
accumulation.  A food effect study involving administration of AZD6244 to patients with 
advanced solid malignancies under fasting conditions and with a high-fat meal indicated a 
statistically significant effect of food on the exposure of AZD6244.  Geometric least squares mean 
(Glsmean) Cmax and AUC were reduced by approximately 60% and 20%, respectively, under fed 
conditions.  Therefore, it is recommended for further clinical studies that AZD6244 should 
continue to be taken on an empty stomach (no food or drink other than water for 1 hour prior to 
dosing and 2 hours after dosing). There is no evidence of a PK interaction between AZD6244 and 
either docetaxel or dacarbazine, when given in combination.  TPA-induced ERK phosphorylation 
in peripheral blood mononuclear cells (PBMCs) was inhibited after administration of AZD6244, 
with the magnitude of inhibition being generally related to plasma concentrations of the drug. 
 
3.6.3.2 
Efficacy summary 
There were no significant differences in the primary endpoints of 4 monotherapy studies 
comparing AZD6244 free-base suspension formulation with standard chemotherapy regimes in 
melanoma, pancreatic cancer, colorectal cancer, or non-small cell lung cancer (NSCLC).72-74 
However, objective responses were seen in both the melanoma and NSCLC studies.  In the 
melanoma study 6 partial responses were noted in patients treated with AZD6244, 5 of which were 
in patients with the BRAF mutation.  In the NSCLC study, 2 patients treated with AZD6244 had a 
partial response (mutation status unknown).  One patient in Study D1532C00005 treated with 
AZD6244 capsule formulation (75 mg bid) had a complete response.  This patient had a BRAF+ 
melanoma. 
 
3.6.3.3 
Safety summary 
Safety findings of 100 mg dose of the free-base suspension formulation of AZD6244 free-base 
The most frequently reported specific adverse events with 100 mg bid AZD6244 free-base 
suspension formulation (irrespective of assessed causality) by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term are dermatitis acneiform, diarrhea, nausea, peripheral edema, 
vomiting and fatigue. A trend towards elevated liver transaminases has been observed in patients 
who received bid dosing of AZD6244.  The majority of transaminase elevations reported either 

  
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remained within normal limits or increased by no more than a single Common Terminology 
Criteria (Version 3) for Adverse Events (CTCAE) grade.  Increases in plasma phosphate and the 
corrected calcium phosphate product have been observed in patients treated with AZD6244, 
compared with comparator (with increases of varying degree seen in the vast majority of patients 
on AZD6244).  A small mean decrease in albumin has also been observed compared with 
comparator.  No other reports of changes in laboratory parameters were considered to be of clinical 
relevance.  Small mean increases in systolic and diastolic blood pressure (SBP and DBP) have 
been observed in patients on AZD6244, compared with comparator.  However, >30% of patients 
showed either no change at all or a reduction.  No clinically significant trends were observed for 
pulse rate in any study.  Review of electrocardiogram (ECG) parameters demonstrated no evidence 
of corrected QT interval (QTcF) prolongation. 
Safety findings from Phase I study (D1532C00005) with the Hyd-Sulfate capsule formulation 
The adverse event (AE) profile observed in this study was broadly consistent with that seen 
previously with AZD6244.  There was a trend for an increase in SBP and DBP, which had resolved 
by week 12 of the study, and a trend for a small increase in weight (at the 75 mg bid dose for Part 
A+B patients the mean increase at week 8 was 1.7 kg).  There was a trend for a decrease in LVEF 
(at the 75 mg bid dose for Part A+B patients the mean decrease at week 8 was -7.2%, range –25% 
to +10%).  Mean increases in ALT, AST and ALP were observed within 1 week of initiation of 
AZD6244 treatment, but did not continue to rise beyond 28 days of dosing, except in patients at 
time points immediately prior to withdrawal due to disease progression.  The majority of reported 
transaminase elevations occurring prior to disease progression either remained within normal 
limits or were a maximum increase of 1 CTCAE Grade.  Small increases in calcium phosphate 
product, alkaline phosphatase, phosphate, creatinine, and urea, were observed within normal 
limits.  Small decreases were observed in platelets, BNP, albumin, and total protein, but these 
remained within normal limits. 
 
Safety findings from Phase I study (D1532C00004) with the Hyd-Sulfate capsule formulation 
in combination with docetaxel 
Fifteen of the 19 patients in this study (78.9%) have reported at least one AE, of whom 9 patients 
(47.4%) had events that were CTCAE Grade 3 or higher.  The most frequently reported adverse 
events were diarrhoea, rash, nausea, vomiting, fatigue, mucosal inflammation, neutropenia, 

  
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constipation and peripheral oedema.  The limited safety data available to date indicates that the 
adverse event profile for the combination of AZD6244 with docetaxel is consistent with the two 
individual monotherapy profiles.  There is insufficient data available at the time of this IB on 
laboratory parameters, vital signs or ECG parameters to identify any clinically significant trends.  
The recommended Phase II dose for the combination of these agents is 75 mg bd AZD6244 Hyd-
Sulfate with 75 mg/m2 docetaxel (IV infusion over 60 minutes on day 1 of each 21 day cycle) 
 
Safety findings from Phase I study (D1532C00004) with the Hyd-Sulfate capsule formulation 
in combination with dacarbazine 
All 13 patients dosed with AZD6244 plus dacarbazine in Part A (dose escalation phase) of this 
study experienced at least one AE, of whom 8 patients (61.5%) had AEs that were CTCAE Grade 
3 or higher. The most frequently reported AEs were nausea, diarrhoea, dysgeusia, constipation, 
neutropenia, anaemia, thrombocytopenia, oedema peripheral, chills, pyrexia, rash, and 
asthenia/fatigue. The preliminary and unvalidated safety data available to date indicates that the 
adverse event profile for the combination of AZD6244 with dacarbazine is consistent with the two 
individual monotherapy profiles.  There is insufficient data available at the time on laboratory 
parameters, vital signs or ECG parameters to identify any clinically significant trends. The 
recommended Phase II dose for the combination of these agents is 75 mg BID AZD6244 Hyd-
Sulfate with 1000 mg/m2 dacarbazine (IV infusion over 60 minutes on day 1 of each 21 day cycle). 
 
Phase I Trial: Combined Inhibition of AKT (MK-2206) and MEK (AZD6244) 
Protocol 010 
A Phase I Study of Oral MK-2206 in Combination with Oral AZD6244 in Patients with Locally 
Advanced or Metastatic Solid Tumors 
Protocol 010 is a multi-center, open-label, non-randomized Phase I study to assess the safety, 
tolerability, pharmacokinetics, and pharmacodynamics of MK-2206 in combination with 
AZD6244 (MEK inhibitor). The study population includes patients with locally advanced or 
metastatic solid tumors. Cohorts of 3-6 patients will be enrolled sequentially in ascending dose 
levels of combination therapy with MK-2206 and AZD6244. Assessment for DLT will be based 
on events occurring during the first cycle of study drug administration. Dose-limiting toxicities in 
this study include adverse experiences such as Grade 3 neutropenia (≥7 days), Grade 3 or Grade 4 

  
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febrile neutropenia, Grade 4 thrombocytopenia and Grade 3 to Grade 5 non-hematological adverse 
experience (excluding adverse experiences in the setting of inadequate compliance with supportive 
care measures). Once the MTD of this combination is established a cohort expansion of patients 
with colorectal cancer, melanoma and pancreatic cancer will be treated with MK-2206 and 
AZD6244 to further evaluate safety of the combination and to explore anti-tumor activity. 
Preliminary safety, pharmacokinetic and pharmacodynamic data from this study are not available 
for reporting at this time. However, on review of unaudited data, 10 patients have received 
treatment with MK-2206 45 mg QOD in combination with AZD6244: 
• MK-2206 45 mg QOD + AZD6244 75 mg twice a day (BID), n=4 
• MK-2206 45 mg QOD + AZD6244 75 mg once daily (QD), n=6 
Two (2) out of 4 patients who received MK-2206 45 mg QOD + AZD6244 75 mg BID 
developed Grade 3 skin rash (DLT) following 3 to 4 weeks of therapy. These adverse 
experiences were considered by the Investigator as non-serious. No additional accrual will occur 
at this dose level. Six (6) patients have subsequently been enrolled at the next lower combination 
dose level, MK-2206 45 mg QOD + AZD6244  75 mg QD;, no DLTs were observed in these 
patients.  One patient experienced Grade 3 diarrhea which was not considered to be dose 
limiting.  Additional non-dose limiting events included Grade 1 diarrhea (1 patient), Grade 1 skin 
rash (2 patients), Grade 2 ALT/AST elevation (1 patient), Grade 1 fatigue (1 patient), Grade 1 
nausea (1 patient), and Grade 1 stomatitis (1 patient).  
Weekly dosing of MK-2206 is currently being explored with 33 patients enrolled to 6 different 
dose combinations to date. 
• MK-2206 90 mg QW+ AZD6244 75 mg twice a day (BID), n=9 
• MK-2206 90 mg QW+ AZD6244 75 mg once a day (QD), n=7 
• MK-2206 90 mg QW+ AZD6244 50 mg twice a day (BID), n=7 
• MK-2206 90 mg QW+ AZD6244 100 mg once a day (QD), n=3 
• MK-2206 90 mg QW+ AZD6244 150 mg once a day (QD), n=3 
• MK-2206 135 mg QW+ AZD6244 100 mg once a day (QD), n=4 
Dose limiting toxicities of Grade 3 Rash (1 patient), Grade 3 mucositis (1 patient) and Grade 2 
detached retinal pigment epithelium (1 patient) were observed at MK-2206 90 mg QW + AZD6244 
75 mg BID in 7 evaluable patients.  This dose level was considered not tolerable.  Subsequent 
dosing with MK-2206 90 mg QW + AZD6244 75 mg QD was tolerated with one DLT of Grade 3 

  
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diarrhea being reported in 6 evaluable patients. Grade 3 Rash (observed in two of 6 evaluable 
patients) was the dose limiting toxicity observed after escalation to MK-2206 90 mg QW + 
AZD6244 50 mg BID.  Treatment with MK-2206 90 mg QW + AZD6244 100 mg QD was 
tolerated with No DLT being observed in three patients treated.  Whereas dose limiting toxicity at 
MK-2206 90 mg QW + AZD6244 150 mg QD included Grade 4 lipase elevation (1 patient) and 
Grade 3 Retinal edema (1 patient) in 3 evaluable patients making this dose level not tolerable. 
Subsequent evaluation of MK-2206 135 mg QW + AZD6244 100 mg QD continues with the 
observation of one event of Grade 3 Fatigue in 3 evaluable patients to date.  
 
3.6.4 Potential Drug Interactions   
In vitro metabolic studies of AZD6244 using hepatocytes from humans and animals found that the 
biologically active N-desmethyl derivative was detected in mouse and human hepatocytes, was 
detected minimally in monkeys; and was not detected in rats.67 
 Cytochrome P450 (CYP) 1A2 was 
the enzyme primarily responsible for the formation of the N-desmethyl derivative; CYP2C19 and 
CYP3A4 were also minimally involved in the transformation. Neither AZD6244 nor its active 
metabolite was found to be inhibitors of CYP isoforms 1A2, 2C8, 2C19, 2D6, or 3A4. However, 
AZD6244 was found to be a weak inhibitor of CYP2C9 (IC50 = 44.7 uM) and the N-desmethyl 
derivative was a weak inhibitor of CYP1A2 (IC50 = 18.9 µM). Thus, at the systemic AZD6244 
concentrations observed following 100mg AZD6244 mix and drink formulation in man, no 
significant cytochrome P450 interactions would be expected. Since the formation of N-desmethyl 
AZD6244 from AZD6244 may occur through the CYP 1A2 pathway and smoking induces this 
pathway, the smoking status of the subjects should to be recorded in all studies (i.e., smoker or 
non-smoker) to investigate whether smoking status influences systemic drug exposures of N-
desmethyl AZD6244.  
 
4 
EXPERIMENTAL PLAN 
4.1 
Overview of Study Design 
The main objective of this Phase II study is to determine the 8-week disease control rate for the 
four proposed treatment regimens in prior treated patients who have failed at least one prior 
treatment regimen with advanced NSCLC. Sufficient subjects will be enrolled into the BATTLE-

  
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2 trial to meet the sample size goal of 400 fully evaluable patients.  Upon enrollment, each subject 
will be assigned a study ID number.  Subjects will then have a required baseline tumor tissue 
biopsy for biomarker analysis, which will determine which treatment arm they will be assigned.  
The tumor tissue will be tested for a comprehensive series of biomarkers (Pathology Core 
Appendix III).  Once the subject’s tumor tissue has been profiled, the data will be processed 
through our statistical model where the patient will then be adaptively assigned into one of four 
treatment arms based on the results of the biomarker and statistical modeling.  The goal is to assign 
the subject into the treatment arm which most favors the characteristics of the subject’s tissue 
biomarker profile with high probability. Bayesian adaptive randomization will be based on the 
updated posterior probability of disease control rate from the underlying logistic model. The model 
parameters will be continuously updated during the trial when the 8-week disease control status 
for each patient becomes available. Subjects will be consented by the treating physician and the 
research nurse.  Subjects may request information and decide to enroll at a later date.  Follow-up 
will occur through the research nurse.  Once enrolled into the BATTLE-2 trial, subjects will be 
randomized into one of the four treatment arms if they did not receive prior erlotinib treatment 
(erlotinib naïve). For subjects who received prior erlotinib (erlotinib resistant), they will be 
randomized into one of the three treatment arms (Arms 2, 3 or 4).  Subjects will receive treatment 
for 2 cycles. 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. 
Response status will be evaluated after the second cycle of therapy, with confirmation of efficacy 
2 cycles after its initial assessment.  Subjects with no progression of disease (complete response, 
partial response, or stable disease) will continue on therapy.    There are no limits to the number 
of cycles of therapy a patient may receive while on protocol.  If a subject, in the absence of 
progressive disease, experiences intolerable toxicities, the investigator may request that the patient 
be discontinued off study.  Optional blood samples for biomarkers will be collected at screening, 
end of Cycle 2, and at end of study.  Subjects will be seen and enrolled in the Thoracic/Head and 
Neck Medical Oncology clinics.  Subjects may be referred from outside referring physicians.  
Research nurses will promote awareness of the protocol and facilitate enrollment.  MDACC sees 
about 2300 new patients and consults annually in the lung cancer clinics. 

  
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4.2   
Treatment Plan 
Subjects who meet the general eligibility criteria will be enrolled into the BATTLE-2 Trial.  After 
tumor biopsy and biomarker profiling is complete, subjects will be adaptively randomized into one 
of four treatment arms based on their biomarker profiles as well as the individual clinical 
eligibility.  
 
4.3 
Subject Assignment in the Biomarker-Integrated Clinical Trials  
Subjects enrolled in the BATTLE-2 study will be adaptively randomized into a specific treatment 
arm based on the tumor biomarker profile.  Note that randomization will be performed only among 
the treatment arms for which the subject is eligible.  Subjects will go through the eligibility 
assessments in order to determine the eligible treatment, then, randomized subsequently.              
 

  
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 4.4 
Subject Eligibility 
4.4.1 Inclusion Criteria 
The following inclusion criteria must be met for entry into the study.  Criteria below in bold print 
must be met before patient is eligible for biopsy to be performed.  Subjects will also be 
clinically eligible for their specific treatment arm: 
1) The subject has a diagnosis of pathologically confirmed NSCLC by tumor biopsy 
and/or fine-needle aspiration. 
2) The subject has a diagnosis of either advanced, incurable stage IIIB or stage IV 
NSCLC, and failed at least one front-line metastatic NSCLC chemotherapy regimen, 
or EGFR TKI. (Subjects who have failed adjuvant or locally advanced therapy within 
6 months are also eligible to participate in the study). 
3) The subject has measurable NSCLC (subjects with active new disease growth in 
previously irradiated site are eligible). 
4) The subject’s ECOG performance status is ≤ 2 at study entry. 
5) The subject has biopsy accessible tumor. 
6) The subject 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 subject has adequate hepatic function as defined by a total bilirubin level  1.5 X the 
upper limit of normal (ULN) (2.5 X ULN for patients with 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) Serum creatinine clearance >50ml/min, either by Cockcroft-Gault formula or 24-hour urine 
collection analysis. 
9) If subject has brain metastasis, they must have been stable (treated and/or asymptomatic) 
and off steroids for at least 2 weeks.   
10) The subject is  18 years of age. 
11) The subject has signed informed consent. 

  
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12) The subject is eligible if disease free from a previously treated malignancy, other than a 
previous NSCLC, for greater than two years. Subjects with a history of prior basal cell 
carcinoma of the skin or pre-invasive carcinoma of the cervix are allowed. 
13) Women of childbearing potential must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) for the duration of the study and for 30 days 
after the last dose of study drug.   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 subject, if a man, agrees to use effective contraception or abstinence for 
the duration of the study and for 3 months after the last dose of study drug. 
14) Subject is able to swallow capsules and has no surgical or anatomical condition that will 
preclude the subject from swallowing and absorbing oral medications on an ongoing basis. 
 
4.4.2 Exclusion Criteria 
A subject meeting any of the following criteria is not eligible to participate in this study: 
1) The subject has received prior chemotherapy, surgery, or radiotherapy within 3 weeks of 
initiating study drug, or 4 weeks for bevacizumab or investigational drug or 72 hours for 
erlotinib or the subject has not recovered (</= Grade 1) from side effects of the prior 
therapy (localized palliative radiotherapy within 2 weeks is allowed).  
2) The subject has undergone prior thoracic or abdominal surgery within 30 days of study 
entry, excluding prior diagnostic biopsy. 
3) The subject has cardiac conditions as follows:  uncontrolled hypertension BP > 140/90 
despite optimal therapy, uncontrolled angina, ventricular arrhythmias, or congestive heart 
failure New York Heart Association Class II or above (See NYHA in Appendix V), 
baseline LVEF ≤ 50%. (See LVEF  algorithm in Appendix  VII),  prior or current 
cardiomyopathy, atrial fibrillation with heart rate >100 bpm, unstable ischaemic heart 
disease (MI within 6 months prior to starting treatment, or angina requiring use of nitrates 
more than once weekly). 
4) The subject has neuropathy  Grade 2.   

  
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5) The subject is pregnant (confirmed by serum -HCG if applicable) or is 
breastfeeding.  In the event of inconclusive pregnancy test results, the attending 
physician will have final determination of pregnancy status. 
6) Subjects will be excluded for other concurrent severe and/or uncontrolled medical 
disease which could compromise participation in the study (i.e., uncontrolled 
diabetes, severe infection requiring active treatment, severe malnutrition, chronic 
severe liver or renal disease). 
7) Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory 
bowel disease), or significant bowel resection that would preclude adequate 
absorption. 
8) Subjects with poorly controlled diabetes (HbA1c >8%) are excluded.  
9) Subjects whose tumor harbors the EML4-ALK fusion gene are excluded unless the patient 
has failed treatment with Anaplastic Lymphoma Kinase (ALK) inhibitor.  
10) Subjects are excluded if they have QTc prolongation >450 msec (Bazett’s Formula) 
for males or >470 ms for females on screening or other factors that increase the risk 
of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family 
history of long QT interval syndrome) including heart failure that meets New York 
Heart Association (NYHA) class II or above or require use of a concomitant 
medication that can prolong the QT interval. (See Appendix VIII)  
11) Subjects who have abnormal K+ or Mg++ levels will be excluded if these levels cannot 
be corrected to within normal range with adequate supportive treatment prior to study 
drug initiation.   
12) Subjects whose tumor harbors an EGFR mutation are excluded unless the subject failed 
treatment with EGFR TKIs in which case the subject can be randomized to Arms 2, 3, and 
4. 
 
 
 
4.4.3 Drug Specific Eligibility Criteria based on Treatment Arms 
1) Subjects are excluded from the erlotinib monotherapy arm if they have progressed on 
prior EGFR TKI therapy; from the AKT inhibitor arm(s) if they have received prior AKT 

  
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inhibitor therapy; from the MEK inhibitor arm if they have received prior MEK inhibitor 
therapy; and from Sorafenib arm if they have previously received the drug or have 
prior history of clinically significant hemoptysis or bleeding diathesis as per 
principal investigator judgment. 
 
4.5 
Study Withdrawal 
Subjects will be removed from the study for any of the following reasons: 
1. 
Subject 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 
5.      Subjects who are randomized to the treatment arm will be withdrawn from the study if they 
fail to recover to CTCAE Grade 1 or less from a drug-related toxicity within 4 weeks, 
unless the Investigator feels that the subject should remain in the study because of evidence 
that the subject is/may continue deriving benefit from continuing study therapy. 
 
The treating physician or investigator must discontinue study if he/she thinks that the Subject’s 
health or well-being is threatened by continuation on study.  Appropriate safety monitoring will 
continue until the subject is discharged from the study (See Section 9 for study specific 
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 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. 
 
 
5 
ERLOTINIB  
5.1 
Investigational Product Description 

  
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Erlotinib (OSI-774, TarcevaTM) is supplied by OSI Pharmaceuticals, Melville, NY. Erlotinib is 
FDA approved for treatment of locally advanced or metastatic non-small cell lung cancer after the 
failure of at least one prior chemotherapy regimen.   
 
5.2  
Drug Accountability 
All study drug required for completion of the study will be provided by OSI Pharmaceuticals, Inc. 
The recipient will acknowledge receipt of the drug by returning the INDRR-1 form indicating 
shipment content and condition to OSI Pharmaceuticals, Inc. Damaged supplies will be returned. 
The principal investigator at each participating institution will be responsible for drug 
accountability. 
 
5.3 
Packaging and Storage 
In addition to the active ingredient, erlotinib, tablets contain lactose, hydrous microcrystalline 
cellulose, sodium starch glycolate, sodium lauryl sulfate, and magnesium stearate.  Study drug for 
daily oral administration will be supplied as 25, 100, and 150 mg tablets of erlotinib, in bottles.  
Study drug is stored at room temperature. For further details, see the erlotinib Investigator 
Brochure.  
 
5.4 
Preparation and Administration 
Tablets should be taken preferably in the morning one hour prior or two hours after a meal with 
up to 200 mL of water.  Subjects who are unable to swallow tablets may dissolve the tablets in 
distilled water for administration.  If a subject forgets to take a dose, the last missed dose should 
be taken as soon as the subject remembers, as long as it is at least 12 hours before the next dose is 
due to be taken.  The daily treatment schedule will be resumed the next day with the subject taking 
their scheduled dose at their usual time. In subjects who have emesis and are unable to retain 
erlotinib for 30 minutes or longer, every attempt should be made to obtain control of nausea and 
vomiting.  The dose of erlotinib may be repeated if emesis occurs within 30 minutes of taking the 
tablet. 
 
5.5 
Pretreatment Medications 

  
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Although no pre-medication is necessary prior to taking erlotinib, pre-medication will be allowed 
if needed. 
 
5.6 
Warnings and Precautions 
Based upon clinical experience to date, the following adverse effects may be associated with 
erlotinib administration: The primary toxicities consist of diarrhea, rash, nausea, vomiting, 
headache, and fatigue.  The only dose-limiting toxicity observed to date is diarrhea.  This event is 
dose-related and is generally controlled with the addition of loperamide therapy, starting doses of 
erlotinib of < 200 mg/day, and dose reductions.  Additional rare side effects have included: 
interstitial pneumonitis, gastrointestinal irritation including gastrointestinal perforation, increased 
risk of gastrointestinal bleeding when combined with NSAIDS, stomatitis, anorexia, alopecia, 
pruritis, myalgias, bone pain, cough, dyspnea, and ocular changes.  
 
5.7 
Treatment Schema 
Subjects in treatment Arm 1 will take erlotinib (150 mg) orally once daily at approximately the 
same time each day. Tablets should be taken preferably in the morning one hour prior or two hours 
after a meal with up to 7 ounces of water. 
 
5.8 
Treatment Duration 
Subjects will be treated with erlotinib (150 mg) once daily without interruption. There is no pre-
determined number of cycles or planned dose interruptions. For the purposes of evaluation, toxicity 
and clinical efficacy, a four week (28 days) period of treatment will be considered 1 cycle of 
therapy.  
Subjects will continue receiving erlotinib 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 subject through continuation. Should drug toxicity develop, dose delays, 
dose reductions and study discontinuation will be carried out according to criteria outlined in 
Section 5.10 Table 5.1.   

  
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For the purposes of this study, subjects will undergo repeat radiographic evaluation via 
chest x-ray and CT or MRI after cycle 2 (8 weeks of therapy) and every two cycles of therapy 
thereafter. See Appendix II for methods of response assessment and classification.  
 
5.9 
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.  Although this drug 
rarely causes hematologic toxicity, these agents can be administered only in the presence of febrile 
neutropenia (defined as ANC<1000 cells/L and oral temperature >38.5C) or Grade 4 
neutropenia lasting more than 4 days.  Erythropoietin can be administered for anemia at the 
discretion of the treating physician.  Commercial suppliers of growth factors will be utilized.  The 
use of growth factors (GSCF, GMCSF and erythropoietin) will be according to ASCO guidelines.75 
The use of bisphosphonates 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. Other medication, which is considered necessary for the subject’s 
safety and well being, may be given at the discretion of the investigator(s). 
 
Data on potential interactions between erlotinib and CYP3A4 inhibitors are lacking. 
Although caution and careful monitoring are recommended when use of these compounds are 
necessary, usage does not exclude subjects from participating in this trial (see Appendix IV for a 
list of CYP3A4 inhibitors). 
 
Because of the potential for drug-drug interaction between erlotinib and warfarin, subjects 
in this study who are receiving concomitant warfarin therapy will have INR results obtained at 
screening and during treatment per standard of care.  If radiation therapy is considered necessary 
for the subject at any point during this study, then this will be considered progressive disease and 
the subject will be removed from the study. 
Antacids and other anti-ulcer medications such as proton pump inhibitors and histamine 
H2-receptor antagonists may be used if clinically indicated. To avoid significantly altering gastric 
pH, when needed, these medications should be used 4 hours after study drug administration. 
 

  
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5.10 
Treatment of Erlotinib Toxicity and Dose Modification: 
Toxicity grading is based on NCI Common Terminology Criteria for Adverse Events (v4.0) and a 
treatment algorithm for the most common toxicities of diarrhea and skin rash is outlined in Table 
5.1.   
Management of a tolerable Grade 2 or 3 rash should include continuation of erlotinib at the 
current dose and symptomatic management.  If skin rash is intolerable, dose reduction should occur 
as described in Table 5.2.  When skin toxicity improves by at least one Grade level, the dose may 
be re-escalated as tolerated.  In Phase II trials, this approach enabled dose re-escalation for the 
majority of subjects requiring dose reduction for skin toxicity.  Subjects experiencing Grade 4 skin 
toxicity should be discontinued from study treatment.     
For Grade 1 or 2 diarrhea, early intervention should include continuation of erlotinib at the 
current dose and initiation of loperamide therapy as described in Table 5.1.  Grade 2 diarrhea that 
persists over 48–72 hours, despite optimal medical management, should be managed by dose 
reduction according to Table 5.2.  Subjects experiencing Grade 3 diarrhea should interrupt erlotinib 
until resolution to Grade 1 and re-start at a reduced dose according to Table 5.2.  Subjects should 
be maintained at the reduced dose without attempt at dose re-escalation.  Subjects experiencing 
Grade 4 diarrhea should be discontinued from study treatment. 
In addition, although quite rare, interstitial lung disease (ILD) can be life threatening.  
Therefore, subjects should be monitored closely for symptoms consistent with ILD, such as new 
onset dyspnea without an obvious cause.  In the event that ILD is suspected, erlotinib treatment 
should be discontinued and the subject should receive appropriate medical management.  Although 
there is no proven therapy, systemic corticosteroids are often provided.  Erlotinib should not be 
restarted in those subjects suspected of having drug-related ILD.  See Table 5.1 for management 
guidelines, including erlotinib dose interruption.   
Subjects who are randomized to the treatment arm will be withdrawn from the study if they 
fail to recover to CTCAE Grade 1 or less from a drug-related toxicity within 4 weeks, unless the 
Investigator feels that the subject should remain in the study because of evidence that the subject 
is/may continue deriving benefit from continuing study therapy. Subjects with toxicities that are 
manageable with supportive therapy may not require dose reductions.   
 

  
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Table 5.1  
Dosage Modification Criteria and Guidelines for Management of Erlotinib-Related Toxicities 
NCI-CTCAE (v 4.0) 
Grade 
Erlotinib Dose Modification 
Guideline for Management 
Diarrhea 
Grade 1 
None 
Consider loperamide (4 mg at first onset, 
followed by 2 mg q 2–4 hours until free of 
diarrhea for 12 hours) 
Grade 2 
None 
(Dose reduction of erlotinib is 
necessary if diarrhea persists 
over 48–72 hours despite 
optimal medical management) 
Loperamide (4 mg at first onset, followed 
by 2 mg q 2–4 hours until diarrhea free for 
12 hours) 
Grade  3 
Interrupt then dose reduce 
erlotinib.  Erlotinib should not 
be re-escalated. 
Interrupt erlotinib until resolution to Grade 
1, and restart at next reduced dose 
Grade 4 
Discontinue study treatment. 
 
Pulmonary Events if possibly ILD 
All Grades 
Temporarily interrupt erlotinib 
pending the diagnostic 
evaluation.  If the pulmonary 
adverse event is assessed as 
related to erlotinib, discontinue 
the subject from study treatment. 
Unexplained dyspnea, either new or 
progressive, should be aggressively 
evaluated.   
Rash 
Tolerable rash 
(Grade 2 or 3) 
None 
Any of the following:  minocycline a, 
topical tetracycline, topical clindamycin, 
topical silver sulfadiazine, 
diphenhydramine, oral prednisone (short 
course) at discretion of investigator 
Intolerable rash 
(Grade 2 or 3) 
Consider interruption and or 
dose reduction if unresponsive 
to symptomatic management.  
Re-escalation is allowed. 
Manage as described above 
Grade 4 
Discontinue study treatment. 
Manage as described above 
a Recommended dose for minocycline :  200 mg po bid (loading dose) followed by 100 mg po bid for 7–
10 days. 
 
All subjects 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. 
 
 
 
 
5.11  Dose Reductions 
The dose of erlotinib should be reduced according to the following schema: 

  
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Table 5.2 
Erlotinib Dose Level Reductions 
Starting Dose  
First Reduction 
Second Reduction 
150 mg/day 
100 mg/day 
50 mg/day 
 
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, 
subjects will be discontinued from the study. 
 
 
6 
MK-2206 (AKT INHIBITOR) 
6.1 
Package and Storage 
Supplies will be packaged in HDPE bottles as described below: 
 
MK-2206 Product Description 
Product Name & Potency 
Dosage Form 
MK-2206 5 mg 
Tablet 
MK-2206 25 mg 
Tablet 
 
Packaging of Clinical Supplies 
Product Name & 
Potency 
Fill Count 
Dosing Instructions 
MK-2206 5 mg 
50 
Take as directed by the 
study physician. 
MK-2206  25 mg 
50 
Take as directed by the 
study physician. 
 
 
 
Container label text may include the following:  
 
 
Lot Trace ID # 
 
Fill Count & Dosage Form 
 
Dosing Instructions 
 
Storage Conditions  

  
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 
Product Name & Potency 
 
Re-evaluation date (if 
applicable) 
 
Compound ID - Protocol # 
 
Country regulatory requirements 
 
Company address (If applicable) 
 
Translation Key (If applicable) 
 
Clinical supplies should be kept in a secured location.  Do not store above 30ºC.  The clinical 
supplies storage area at the site must be monitored by the site staff for temperature consistency 
with the acceptable storage temperature range specified in this protocol or in the product label.  
Documentation of temperature monitoring should be maintained. 
 
6.2 
Drug Accountability 
Investigational clinical supplies must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the principal 
investigator at each participating institution and his/her designated assistants have access. Clinical 
supplies are to be dispensed only in accordance with the protocol. The principal investigator at 
each participating institution is responsible for keeping accurate records of the clinical supplies 
received from the supplying company, the amount dispensed to and returned by the subjects, and 
the amount remaining at the conclusion of the study. In accordance with Good Pharmacy Practices, 
gloves should always be worn by study personnel if directly handling tablets or capsules that are 
returned (i.e., when counting returns). The supplying company should be contacted with any 
questions concerning investigational products where special or protective handling is indicated. At 
the end of the study, all clinical supplies including partial and empty containers will be returned 
or destroyed per institutional policy.  
 
6.3 
Preparation and Administration 
Guidelines for MK-2206 Administration 
Subjects will be administered oral MK-2206 once weekly (for both Arm 2 and 3) as continuous 
therapy in repeating 28 day treatment cycles. The assigned study dose will be taken in tablet form 
in the morning with at least 8 ounces of water, swallowed whole, during each 28-day treatment 
cycle.  Since the effect of food on MK-2206 has not been determined, subjects must take MK-
2206 orally at least 2 hours before and at least 2 hours after any food or a meal. Missed doses will 
not be made up.   

  
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6.3.1 Pretreatment Medications 
None required 
 
6.3.2 Warnings and Precautions 
Diet 
Subjects should maintain a normal diet. Subjects are to refrain from the consumption of grapefruit, 
grapefruit juice, and grapefruit products for approximately 2 weeks prior to administration of the 
initial dose of study drug, throughout the study (including the washout intervals between treatment 
periods) until the post-study visit (bioflavanoid compounds in grapefruit juice and/or grapefruit 
are known to inhibit CYP3A4 activity).  Subjects are also to refrain from consumption of all fruit 
juices during Cycle 1.  Subjects are required to fast for 2 hours prior to administration of study 
drug and for 2 hours post treatment. 
 
6.3.3 Potential Risks of MK-2206 in combination with Erlotinib  
A brief overview of the potential risks associated with the administration of MK-2206 in 
combination with erlotinib and measures to monitor such potential risks in this trial are outlined 
below: 
 
6.3.3.1 Hyperglycemia 
MK-2206 induced dose-dependent hyperglycemia and concomitant hyperinsulinemia, a 
mechanism-based effect of PI3K/AKT inhibition. In the dog, the most sensitive preclinical species, 
glucose elevation was slight (~24 to 34%) after 5 mg/kg (human equivalent dose of ~200 mg) 
QOD dosing for 4 weeks. In healthy volunteers, single dose administration of MK-2206 up to 100 
mg in 26 subjects did not result in any elevations in blood glucose level. In cancer subjects, mild 
and transient hyperglycemia, Grade 1 or 2, has been observed in subjects receiving multiple doses 
of MK-2206 from 30 mg to 90 mg QOD. No clinical symptoms were associated with these 
hyperglycemia events and no medical intervention was required. Plans to carefully monitor blood 
glucose and insulin and to manage hyperglycemia have been developed and incorporated into the 
protocol. Subjects with poorly controlled diabetes will be excluded.  
 

  
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6.3.3.2 Skin rash 
Multiple doses of MK-2206 administered QOD induce skin rash in cancer subjects in a dose-
dependent fashion. No skin rash was seen in 3 subjects treated at 30 mg QOD. The skin rash 
observed at 60 mg QOD was of Grade 1 or 2, and that at 90 mg QOD was of grade 2 or 3. At 90 
mg QOD, skin rash is the DLT with 4 out of 7 subjects developed Grade 3 skin rash.  The skin 
rash develops 3-4 weeks or 10-14 days after treatment initiation at 60 mg QOD or 90 mg QOD 
respectively, and is characterized by maculo-papular lesions that begin on the trunk and face, and 
can be acneiform in nature.  The rash can be pruritic and gradually decreases in severity and 
disappears upon discontinuation of MK-2206 dosing. Based upon the mechanism of action of AKT 
inhibition (PI3K pathway) and the apparent dose-response of the rashes, it is likely that this is a 
mechanism-based toxicity, similar to the rash observed with other drugs that target components of 
the PI3K pathway, such as epidermal growth factor receptor (EGFR) and mammalian target-of-
rapamycin (mTOR) inhibitors. Given the known dermatological side effects associated with 
erlotinib treatment, skin rash is an anticipated toxicity in the combination of MK-2206 and 
erlotinib. Subject assigned to this treatment will be closely monitored for any symptoms of skin 
rash and dose adjustments of MK-2206 and/or erlotinib as well as appropriate supportive care 
medications will be applied to manage such toxicities.  
 
As of 13-Jan-2010, preliminary adverse experience data are available for 69 patients who received 
oral MK-2206, among those enrolled in the dose escalation (QOD and QW regimens) and 
expansion cohorts, skin rash was reported as a DLT in 13 patients:  
• 4 patients at 90 mg QOD 
• 2 patients at 75 mg QOD 
• 3 patients at 300 mg QW 
• 4 patients at 60 mg QOD 
Twenty-one (21) other patients treated at 60 mg QOD developed the adverse experience of skin 
rash during the course of the study. The severity of the skin rash in the majority of these patients 
was Grade 1/Grade 2. No skin rash was observed in patients at 30 mg QOD, 90 mg QW and 200 
mg QW at the time of data cut-off. However, a review of unaudited data since this date indicated 
that an adverse experience of Grade 3 skin rash was reported in 1 patient at 200 mg QW. One (1) 
patient who received MK-2206 135 mg QW developed Grade 1 skin rash. At higher doses of MK-

  
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2206 evaluated (i.e., 75 mg and 90 mg QOD and 300 mg QW), onset of the rash was within 1.5-2 
weeks of study therapy initiation. Severity at onset at these higher doses was Grade 3. At all other 
dose levels evaluated, onset was generally following 3-4 weeks of treatment. On average, 
regardless of grade, the duration of the skin rash was 7 to 14 days and is characterized by maculo-
papular lesions on the trunk and limbs, and occasionally on the face. An acneiform rash was also 
observed in 1 patient. The rash is at times associated with pruritus (Grade 1 and 3) and at the higher 
doses evaluated stomatitis (Grade 2/3) and conjunctivitis (Grade 1). In the majority of cases, 
Investigators considered the skin rash related to study therapy. In cases of moderate to severe skin 
rash, patients were treated with oral and topical corticosteroids, anti-pruritic medication and anti-
histamines and antibiotics. This adverse experience resolved following interruption or 
discontinuation of study medication. Several patients reported ongoing sequelae of dry skin. Other 
DLTs observed in this study include: Grade 3 pruritus, associated with Grade 3 skin rash at 90 mg 
QOD, Grade 3 hyperglycemia at 60 mg QOD and Grade 2 diarrhea at 75 mg QOD. The adverse 
experiences of Grade 3 hyperglycemia and Grade 2 diarrhea were considered by the Investigator 
to be serious. With the exception of Grade 3 hyperglycemia, these adverse experiences resolved 
following dose interruption and study therapy was re-initiated at a reduced dose. Skin rash (i.e., 
rash, erythematous rash, rash macular, exfoliative rash, rash papular, rash pruritic) was the most 
common treatment-related adverse experience reported across all dose levels, occurring in 34 out 
of 69 patients (49.3%). 
In Protocol 003, skin rash (i.e., rash, rash pruritic) was the most common treatment-related 
adverse experience observed in patient receiving MK-2206 in combination with selected 
chemotherapy and targeted agents. Grade 1 to Grade 3 skin rash has been reported in 9 out of 18 
patients (50.0%) and was a DLT at MK-2206 45 mg QOD in 1 patient in Treatment Arm 3 (MK-
2206 + erlotinib). The rash is involved the face, torso, and limbs and was associated with pruritus 
(Grade 1/Grade 2). One (1) patient Treatment Arm 3 was observed to have Grade 3 rash involving 
the torso, characteristic of treatment with MK-2206 and Grade 3 rash involving the face, more 
characteristic of treatment with erlotinib. This patient was dose reduced to MK 2206 30 mg QOD 
and the rash subsequently resolved without sequelae. All episodes were Grade 3 and met criteria 
for DLTs. In all cases, the adverse experience occurred within 7 to 11 days of taking study 
medication. Study medication was discontinued in these patients and the remaining patients in this 
cohort continued at 45 mg QOD and were subsequently discontinued for disease progression. 

  
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6.3.3.3  
QTc Prolongation 
For this study QTc prolongation is defined as: A single QTc value of ≥ 550 msec or an increase of 
≥ 100 msec from baseline;  
OR  
• Two consecutive ECGs measurements, within 48 hours of one another, in which either of the 
following criteria are met (the second being the mean of 3 consecutive ECGs):  
1. A QTc interval ≥500 msec but <550 msec or  
2. An increase of ≥60 msec, but <100 msec, from baseline QTc to a QTc value ≥480 msec.  
The baseline will be the average of the screening and Day 1 pre-dose QTc values.  
If a QTc value is ≥550 msec or there is an increase in QTc of ≥100 msec from baseline, study 
medication must be discontinued. ECGs and electrolytes should be followed 3 times a week 
following QTc prolongation initial QTc falls below 480 msec. The subject may recommence 
treatment at a reduced dose when his or her QTc has returned to <480 msec.  
1. If a QTc value is ≥500 msec (and <550 msec), or there is an increase from baseline of ≥60 
msec, but <100 msec, to a QTc value ≥480 msec, then a repeat ECG should be performed 
within 48 hours to confirm the QTc prolongation per protocol. If QTc prolongation is 
confirmed, MK-2206 should be withheld. ECGs and electrolytes should be checked 3 times 
a week until QTc falls below 480 msec or baseline, whichever is higher.  MK-2206 
treatment may be resumed at a lower dose based upon dose reduction schedule after the 
QTc recovers to <480 msec or baseline. If the subject does not meet the criteria for QTc 
prolongation at the repeat ECG, then the subject should continue treatment and resume the 
ECG schedule as outlined in the Study Plan.  
An ECG will be performed 3 times a week following QTc prolongation until the QTc interval is 
<480 msec. If study treatment must be interrupted for more than 3 weeks to allow QTc 
prolongation to resolve, the subject’s participation in the study will be discontinued. If MK-2206 
treatment is restarted after the QTc prolongation has resolved, ECGs should be performed weekly 

  
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for the first 8 weeks and then every 4 weeks thereafter. If QTc prolongation recurs, using the same 
criteria as outlined above, the subject’s participation will be discontinued. 
 
6.3.3.4 Drug-Drug Interactions and Concomitant Therapy  
MK-2206 is not an inducer or inhibitor (IC50 > 40 μM) of major human P450 enzymes (CYP3A4, 
2C9 and 2D6).  In human hepatocytes, its metabolism involves both oxidation and direct 
glucuronidation.  The oxidation is mainly catalyzed by CYP3A4. MK-2206 also is a P-gp 
substrate. Based on literature data, erlotinib is not a potent CYP3A4 inhibitor. In general, potential 
risk for substantial drug-drug interactions of MK-2206 combination with erlotinib is low.  Other 
possible toxicities of MK-2206 in combination with erlotinib may also include bone marrow 
suppression, vomiting, and diarrhea.   
Subjects should try and avoid drugs known to be moderate to strong inhibitors/inducers 
of CYP1A2 and CYP3A4. Refer to Appendix for a list of medications with potential CYP3A4 
interaction. The list is not all inclusive, and for other concomitant medications, the Investigator 
will determine if they are known to significantly influence CYP1A2 and CYP3A4. 
 Drugs known to effect QT prolongation (Appendix VIII) or cumulative high-dose 
anthracycline therapy are prohibited. 
Antacids and other anti-ulcer medications such as proton pump inhibitors and histamine 
H2-receptor antagonists may be used if clinically indicated. To avoid significantly altering gastric 
pH, when needed, these medications should be used 4 hours after study drug administration. 
 
6.4 
Treatment Schema for MK-2206 + Erlotinib  
Treatment will be administered on an outpatient basis. MK-2206 will be administered at 135 mg 
QW and erlotinib at 150 mg daily which has been deemed to be a safe and tolerable dose.  
Subjects will be given up to a 4 week supply of study drug on Day 1 of each cycle and will be 
asked to bring their study drug with them to clinic visits before each cycle.  If the subject vomits 
after the administration of study drug, it should not be re-administered.  Subjects will receive and 
complete a subject medication diary.  The diary will be reviewed at the end of Cycle 1 and then 
Day 1 of each new cycle. 
 

  
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6.5 
Treatment Duration 
In the absence of treatment delays due to adverse experiences, treatment with MK-2206 and 
erlotinib may 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 
thought to be related to study drug, which requires discontinuation of drug, intercurrent illness that 
prevents further administration of treatment, pregnancy or other serious protocol violation, subject 
is unable to adhere to study visit schedule or comply with protocol requirements, withdrawal of 
subject consent or at the investigator’s discretion. 
 
6.6 
Guidelines for Dose Delay, Modification and Discontinuation for MK-2206 
Toxicities will be graded in severity according to the guidelines outlined in the NCI-CTCAE 
version 4.0.   
Any of the following will be considered reasons for dose reduction: 
 Grade ≥ 3 signs or symptoms of glucose intolerance (including frequent urination, 
excessive thirst, extreme hunger, unusual weight loss, increased fatigue, irritability, and 
blurred vision that interferes with activities of daily living) and is accompanied by ≥ Grade 
2 hyperglycemia (glucose >160 dL or 8.9 mmol/L) 
 Fasting glucose >250 mg/dL or 13.9 mmol/L 
 Grade ≥ 3 electrolyte (Na, K, Ca, Mg, Cl, phosphate, and bicarbonate) abnormalities due 
to glucose intolerance and not attributable to another cause 
 Diagnosis of lactoacidosis or ketoacidosis, or 
 Non-fasting Grade 4 hyperglycemia (glucose > 500 mg/dL or 27.8 mmol/L) 
 Note: Fasting blood sugars and urine ketones should be checked before breakfast. 
 Persistent increases in QTc interval (>60 ms from baseline and/or >500 ms), or 
 Clinically significant bradycardia. 
 Intolerable Grade 2 or 3 rash (Grade 4 rash will require discontinuation of treatment) 
Any subject who experiences Grade 3 or 4 unmanageable toxicity will require immediate dose 
interruption. Treatment will be withheld until toxicities have resolved to Grade ≤1. After 
resolution of the toxicity, the Investigator will determine whether the individual subject's dose 
should be reduced according to Table 6.1.  If a subject experiences toxicity but is benefiting from 

  
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treatment with a response of SD, PR, or CR, the Investigator will discuss persistent and/or 
intolerable toxicities to determine if dose modification is warranted. Dose reduction to the next 
lower dose level may be permitted for subsequent treatments.  The dose de-escalation schema is 
provided in Table 6.1.  Subjects can have a maximum of 2 dose reductions per compound for 
toxicity beyond which they will be removed from the study. 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects will be withdrawn from the study if they fail to recover to CTCAE Grade 1 or less from 
a drug-related toxicity within 4 weeks, unless the Investigator feels that the subject should remain 
in the study because of evidence that the subject is/may continue deriving benefit from continuing 
study therapy. Subjects with toxicities that are manageable with supportive therapy may not 
require dose reductions.  Delays in the treatment schedule for logistical reasons should be avoided, 
if possible. The reason for a dose delay or treatment discontinuation must be recorded. 
If a subject experiences a regimen related toxicity that requires erlotinib to be held, the 
subject should discontinue taking MK-2206. Once the toxicity has resolved and the subject 
resumes treatment with erlotinib, MK-2206 can also resume.  
 
7 
AZD6244 (MEK INHIBITOR) 
7.1 
Investigational Product Description 
Table 6.1 Dose Levels for MK-2206 QW + Erlotinib 
Please Note:  Dose reductions may occur to a single compound 
(independent of the other compound) based upon the attribution 
of the toxicity.   
 
Dose Level   MK-2206 Dose Level 
Erlotinib Dose Level  
 1 
135 mg QW 
150 mg QD 
-1 
100 mg QW 
100 
-2 
75 mg QW 
50 mg QD 
QW = once weekly, QD = once daily 

  
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AZD6244 drug product is supplied as a capsule and will be provided for use in the protocol by 
AstraZeneca.   AZD6244 capsule formulation drug product (Hyd-Sulfate) is supplied as 25 mg 
capsules in high-density polyethylene (HDPE) bottles. 
 
7.2 
Mode of Action 
 The RAS/RAF/MEK/ERK pathway is an important mediator of any cellular processes including 
proliferation, survival, differentiation, apoptosis, motility, and metabolism. AZD6244 is a 
selective mitogen-activated protein kinase (MEK) inhibitor. By inhibiting MEK, AZD6244 
inhibits ERK phosphorylation.  
 
7.3 
Labeling 
Each bottle of AZD6244 Capsules will be labeled for use in this protocol by AstraZeneca.  All 
labels will comply with good manufacturing practice (GMP) regulations, and will state that the 
drug is for clinical use only and should be kept out of reach of children. Information regarding the 
subject, for example enrollment number (E code), contents of the bottle, expiry date, dosing 
instructions as well as a space for the date of dispensing will be included on the labels. 
 
7.4 
Storage 
All investigational products must be kept in a secure place under appropriate storage conditions.  
A description of the appropriate storage and shipment conditions is specified on the investigational 
product label and investigator brochure.  The stored study drug supplies must be accessible to 
authorized staff only.  The storage area must also have adequate control of temperature in order to 
maintain stability and potency of study drug supplies. The tablets should be stored in the original 
pack until use.  For further information, investigators should refer to the investigational product 
label. 
7.5 
Accountability and Mechanism of Drug Destruction 
The principal investigator at each site and/or the designated study personnel is responsible for 
maintaining accurate dispensing records of the study drug.  All study drug must be accounted for, 
including study drug accidentally or deliberately destroyed.  All discrepancies between amounts 
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the site principal investigator allow the investigational drug to be used other than as directed by 
the protocol without prior AstraZeneca approval.  If appropriate, drug storage, drug dispensing, 
and drug accountability may be delegated to the pharmacy section of the investigative site.   
Documentation indicating study drug was destroyed will be sent to AstraZeneca. 
 
7.6       Administration  
7.6.1 Route of Administration:  Oral.  
For BID dosing: 
• The morning dose should be taken in the fasted state. Breakfast can be taken from 1 hour 
following dosing. 
• Evening doses should not be taken in the 1 hour preceding a meal or in the 2 hours after having 
finished a meal. 
The doses should be taken approximately 12 hours apart for example 08:00h and 20:00h or 09:00h 
and 21:00h.  
 
7.6.2 Pretreatment Medications 
None required 
 
7.6.3 Warnings and Precautions  
Potential Drug Interactions: AZD6244 is metabolized by CYP1A2 to N-desmethyl AZD6244 
which is 3-5 fold more pharmacologically active than AZD6244. In vitro, AZD6244 is metabolized 
to a lesser extent by CYP2C19 and CYP3A4.  In vitro, AZD6244 is a weak inhibitor of CYP2C9 
and CYP1A2.  
Patient Care Implications: Subjects should not consume grapefruit or its juice during AZD6244 
treatment. Subjects should be advised to take AZD6244 on an empty stomach either 1 hour before 
or 2 hours after eating with a glass of water.  
 AZD6244 should not be administered to pregnant or breast-feeding women and conception 
while on treatment must be avoided.  Women of child-bearing potential with cancer may 
enter clinical studies, provided that they have negative pregnancy tests, and they use 
adequate contraception.  

  
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 AZD6244 capsules contain D-α- Tocopheryl polyethylene glycol 1000 succinate (TPGS, 
a water-soluble form of vitamin E) as an excipient.  Therefore: 
o Patients should not take vitamin E supplements or multivitamin supplements 
which provide a total daily dose in excess of 100% of the recommended daily 
allowance for vitamin E.   
o High doses of vitamin E have been reported to potentiate the anticoagulant 
activity of coumadins such as warfarin. Patients who are taking coumadin 
anticoagulants should increase the frequency of assessment of anticoagulation, 
such as INR measurements, upon initiation of dosing with AZD6244.  
 Dermatologic toxicity (see below under Potential Risks of MK-2206 in combination with 
AZD6244 Section 7.6.6.2). 
 Gastrointestinal: Adverse events of diarrhea, nausea and vomiting have been reported 
frequently throughout the AZD6244 clinical program.  Most cases of diarrhea start within 
the first 2 weeks of treatment, whereas the time of onset of adverse events of nausea and 
vomiting has been more variable.  However, the majority of episodes have been self-
limiting or easily managed with anti-emetic and anti-diarrheal medication such as 
prochlorperazine, 5-HT3 receptor antagonists and loperamide.  The co-administration of 
AZD6244 with other anti-cancer agents, some of which are associated with gastrointestinal 
adverse events, may result in a higher frequency or intensity of these events.  Investigators 
are advised to monitor for signs of such gastrointestinal side effects in subjects receiving 
AZD6244. 
 Hypertension: Increases in systolic and diastolic blood pressure have been observed in 
clinical studies with AZD6244.  In some subjects these increases result in measurements 
exceeding hypertension guideline thresholds for therapeutic intervention, or exacerbation 
of pre-existing hypertension.  Vital sign measurements should be performed at regular 
intervals in all subjects receiving AZD6244.  Investigators should monitor for any increase 
in blood pressure that might require initiation or augmentation of anti-hypertension 
medication. 

  
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 Edema: Subjects receiving AZD6244 frequently report the development or worsening of 
edema, particularly at peripheral sites or the face.  The underlying etiology of the edema 
and fluid accumulation adverse events is unclear at present.  There is currently no evidence 
to suggest that the edema is due to congestive cardiac failure.  Investigators are advised to 
monitor for signs of such edema effects in subjects receiving AZD6244 that might require 
therapeutic intervention. 
 Left ventricular ejection fraction (LVEF): Some subjects receiving AZD6244 have been 
observed to develop asymptomatic decreases in LVEF in the absence of obvious 
confounding comorbidities.  The co-administration of AZD6244 with other anti-cancer 
agents, some of which are known to be associated with cardiotoxicity, may be associated 
with an increased risk of impairment of cardiac function.  Specific exclusion criteria 
relating to pre-existing cardiac conditions, such as uncontrolled hypertension and history 
of cardiomyopathy, will be incorporated into all studies.  Baseline and sequential 
echocardiogram/multiple gated acquisition (ECHO/MUGA) scans, with additional scans 
at the occurrence of signs suggesting cardiac dysfunction, will be performed, to assist the 
evaluation of potential underlying mechanisms for these symptoms.  Serial serum BNP and 
troponin I measurements may also provide additional information on the etiology of these 
events.  An algorithm for the management and investigation of asymptomatic decreases of 
LVEF has been produced, including the referral of any subject who experiences a clinically 
significant drop in LVEF in the absence of confounding co-morbidity for cardiology 
consultation.  Subjects who have a drop in LVEF >10% from baseline at time of 
discontinuation of AZD6244 should have a follow up echocardiogram performed 30 days 
after permanent discontinuation of AZD6244 in order to document reversibility. (See 
Appendix VII) 
 Respiratory events, dyspnea and exertional dyspnea have been reported in subjects 
receiving AZD6244.  The majority of these events have occurred in subjects with 
lung/pleural disease due to their underlying malignancy.  Any new dyspnea event or 
worsening of pre-existing dyspnea > 1 CTC Grade should be investigated according to the 
specific dyspnea algorithm provided, with the initial screen of chest X-ray, echocardiogram 
BNP and troponin I.  The co-administration of AZD6244 with other anti-cancer agents, 

  
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some of which have dyspnea or interstitial lung disease as listed adverse events, makes it 
essential to fully evaluate each dyspnea adverse event in subjects receiving AZD6244.   
 Visual function: Adverse events relating to visual function have been reported at a low 
frequency in all studies.  There were no specific treatment emergent structural findings 
reported from those subjects that underwent an ophthalmological evaluation after reporting 
a visual disturbance adverse event.  There were anecdotal reports of asymptomatic raised 
intra-ocular pressure at the protocol mandated Week 4 eye test in one study.  Full 
ophthalmological examinations, including slit lamp examination, should be performed on 
the occurrence of any visual disturbance adverse event in order to document any effects 
that may be linked to the administration of AZD6244.  These assessments will be 
supplemented by planned ophthalmological investigations at baseline and at Week 4 of 
continuous dosing in all future studies with the capsule formulation of AZD6244 Hyd-
Sulfate.  This will allow identification of any non-symptomatic ophthalmological changes.  
Finally, all visual adverse events should be followed to evaluate the potential for resolution. 
 Ophthalmologic exam (including slit-lamp) – to be performed in subjects experiencing 
visual disturbances whilst in the trial. 
 Hematological: A slight decrease in platelet count was seen in study one study with 
AZD6244, however this was not considered clinically significant.  No other clinically 
significant changes in hematological parameters were identified across the clinical study 
program; however hematological parameters need to be monitored. Regular measurements 
of AST, ALT and other liver function parameters will continue to be monitored and the 
health care professionals involved in clinical studies should look for signs of liver toxicity 
in subjects receiving AZD6244. Regular monitoring of serum  calcium and phosphorus 
levels and the calcium/phosphate product is advised in clinical studies with AZD6244. 
 Patients should avoid excessive sun exposure and use adequate sunscreen protection (SPF 
80 or higher is recommended for all patients.  Protective clothing (e.g. hat and sunglasses) 
is recommended. 
 Reproductive toxicology data indicate that AZD6244 has adverse effects on embryofoetal 
development and survival at dose levels that do not induce maternal toxicity in mice. 
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and conception while on treatment must be avoided.  Female patients of child-bearing 
potential will be required to use reliable methods of contraception for the duration of the 
study and until 4 weeks after the last dose of AZD6244.  Male patients with sexual partners 
who are pregnant or who could become pregnant (ie, women of child-bearing potential) 
should use acceptable methods of contraception for 16 weeks after completing the study to 
avoid pregnancy and/or potential adverse effects 
 All new dyspnea AEs or worsening of pre-existing dyspnea AEs should be followed 
according to the dyspnea algorithm in Appendix X.    
 
7.6.4 Treatment Schema 
AZD6244 + MK-2206 Administration  
Treatment will be administered on an outpatient basis. MK-2206 will be administered at 100 mg 
QW and AZD6244 at 100 mg QD which has been deemed to be a safe and tolerable dose.  Subjects 
will be given up to a 4 week supply of study drug on Day 1 of each cycle and will be asked to 
bring their study drug with them to clinic visits before each cycle.  If the subject vomits after the 
administration of study drug, it should not be re-administered.  Subjects will receive and complete 
a subject medication diary.  The diary will be reviewed at the end of Cycle 1 and then Day 1 of 
each new cycle. 
 
Table 7.1 Dose Reductions for MK-2206 + AZD6244 
 
 
7.6.4.1 Treatment Duration  
Subjects will be treated with AZD6244 and MK-2206 without interruption. There is no pre-
determined number of cycles or planned dose interruptions. For the purposes of evaluation, toxicity 
and clinical efficacy, a four week (28 days) period of treatment will be considered 1 cycle of 

  
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therapy. Subjects will continue receiving the combination therapy 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 subject through continuation. Should drug toxicity develop, dose 
delays, dose reductions and study discontinuation will be carried out according to criteria outlined 
in Section 7.6. 
 
7.6.5 Concomitant Medications and Therapy 
 
Because there is a potential for interaction of AZD6244 with drugs metabolized through the 
cytochrome P450 system, subjects should not receive any other drugs known to affect or with the 
potential to affect selected CYP450 isoenzymes. Since the formation of N-desmethyl AZD6244 
from AZD6244 may occur through the CYP 1A2 pathway and smoking induces this pathway, the 
smoking status of the subjects should to be recorded in all studies (i.e., smoker or non-smoker) to 
investigate whether smoking status influences systemic drug exposures of N-desmethyl AZD6244. 
The subject’s current smoking status will be collected. 
Subjects should try and avoid drugs known to be moderate to strong inhibitors/inducers 
of CYP1A2 and CYP3A4. Refer to Appendix IV for a list of medications with potential 
CYP3A4 interaction. The list is not all inclusive, and for other concomitant medications, the 
Investigator will determine if they are known to significantly influence CYP1A2 and CYP3A4. 
 Drugs known to effect QT prolongation (Appendix VIII) or cumulative high-dose 
anthracycline therapy are prohibited. 
Antacids and other anti-ulcer medications such as proton pump inhibitors and histamine 
H2-receptor antagonists may be used if clinically indicated. To avoid significantly altering gastric 
pH, when needed, these medications should be used 4 hours after study drug administration. 
 
7.6.6 Potential Risks of MK-2206 in combination with AZD6244 
A brief overview of the potential risks associated with the administration of MK-2206 in 
combination with AZD6244 and measures to monitor such potential risks in this trial are outlined 
below. 
 

  
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7.6.6.1  
Hyperglycemia as described for MK-2206 (Section 7.6) 
 
7.6.6.2  
Skin rash 
Dermatological adverse events are frequently reported in association with administration of 
AZD6244, with dermatitis acneiform being the most commonly reported event starting within the 
first month of treatment.  Other types of dermatological events occur only after a more prolonged 
period of administration with AZD6244, including skin fissures and palmar-plantar 
eythrodysaethesia (hand-foot syndrome).  Where the dermatological AE is CTCAE Grade 3 or 
above, or is intolerable CTCAE Grade 2, a dose holiday (either with or without dose reduction) 
may be required to bring the CTCAE intensity to within tolerable limits, although this may not 
result in total resolution of the symptoms whilst the subject is continuing to receive AZD6244.  
Additional interventions for the management of dermatological adverse events will be guided by 
the  clinical experience of management of similar dermatological effects of the EGFR tyrosine 
kinase inhibitor agents.76,77 The co-administration of AZD6244 with other anti-cancer agents, 
some of which are associated with dermatological adverse events, may result in a higher frequency 
or intensity of these adverse events. 
AZD6244 absorbs light in the UV range for phototoxicity and shows enhanced cytotoxicity 
in the presence of UV light in an in vitro 3T3 Neutral Red Uptake phototoxicity test.  In rat, 
AZD6244-related material was widely distributed throughout tissues, including skin, eye and uveal 
tract, but did not show evidence of melanin binding.  Despite the high incidence of dermatological 
adverse (e.g., acneiform rash) reported in subjects who have received AZD6244, only one case of 
skin photosensitivity has been reported in a subject taking AZD6244.  However, based on the 
potential for toxicity, investigators are requested to be vigilant for adverse events that may have 
been caused or exacerbated by exposure to sunlight during clinical trials with AZD6244.  Subjects 
should be advised to avoid situations of excessive sun exposure and to take adequate skin 
protection precautions where sun exposure may be anticipated. 
  
Given the known dermatological side effects associated with MK-2206 treatment, skin rash 
is an anticipated toxicity in the combination of MK-2206 and AZD6244. Subjects assigned to this 
treatment will be closely monitored for any symptoms of skin rash and dose adjustments of MK-
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manage such toxicities.  Additional information on MK-2206 and treatment emergent skin rash 
can be found in Section 6.3.3.2. 
 
7.6.7 Drug-Drug Interactions 
MK-2206 is not an inducer or inhibitor (IC50 > 40 μM) of major human P450 enzymes (CYP3A4, 
2C9 and 2D6).  In human hepatocytes, its metabolism involves both oxidation and direct 
glucuronidation.  The oxidation is mainly catalyzed by CYP3A4. MK-2206 also is a P-gp 
substrate. AZD6244 is primarily metabolized by CYP1A2 to N-desmethyl AZD6244 which is 3-
5 fold more pharmacologically active than AZD6244. In vitro, AZD6244 is metabolized to a lesser 
extent by CYP2C19 and CYP3A4.  In vitro, AZD6244 is a weak inhibitor of CYP2C9 and 
CYP1A2. Other possible toxicities of AZD6244 in combination with MK-2206 may also include 
vomiting, and diarrhea.  
 
7.6.8 Treatment of Toxicity and Dose Modification 
For all adverse events reported in the study that are considered at least partly due to 
administration of AZD6244, the following dose modification guidance should be applied.  
Treatment with AZD6244 should be withheld if one of the following toxicities considered 
related are observed, despite optimal supportive care: 
 Any intolerable adverse event regardless of grade 
 Any adverse events CTCAE grade ≥3  
AZD6244 treatment may not be restarted until the toxicity improves to CTCAE grade 1 or 
baseline, except for rash where patients with CTCAE grade 2 rash may restart treatment.  
Treatment may be resumed at the original dose or at a permanently reduced dose (75 mg QD) at 
the discretion of the investigator.  If a subject experiences occurrence of a new toxicity requiring 
treatment interruption after having restarted on treatment, study medication should again be 
withheld until the toxicity improves to CTCAE grade 1 or baseline, except for rash where 
CTCAE grade 2 rash is acceptable.  Upon recovery, treatment may resume at the previous dose 
level or the dose can be reduced either to 50 mg QD (if no reduction has yet occurred).  
However, if a patient experiences recurrence of the same toxicity as that causing a previous dose 
interruption and/or dose reduction, study medication should be withheld until the toxicity 

  
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improves to CTCAE grade 1 or baseline, except for rash where CTCAE grade 2 rash is 
acceptable.  Upon recovery, treatment should resume at a permanently reduced dose: 
►75 mg once daily if no dose reduction has yet occurred  
►50 mg once daily Therefore, the dose modification algorithm allows for 2 dose reductions of 
AZD 6244: 100 mg once daily (initial dose) → 75 mg daily (the dose adjustment) → 50 mg once 
daily (the final dose reduction).   
If a patient experiences recurrence of any toxicity requiring dose interruption whilst receiving  
the lowest dosing schedule for this study (50 mg once daily), the patient must discontinue 
AZD6244 treatment. 
If a patient receiving the lowest dosing schedule (50 mg once daily) experiences a novel toxicity 
that cannot be adequately managed by dose interruption and medical interventions then the 
patient must discontinue AZD6244 treatment, as no further dose reductions/adjustments are 
permitted.  
In the event of a dose delay/reduction, subjects should continue all other assessments as 
scheduled.  Subjects who are randomized to the treatment arm will be withdrawn from the study 
if they fail to recover to CTCAE Grade 1 or less from a drug-related toxicity within 4 weeks, 
unless the Investigator feels that the subject should remain in the study because of evidence that 
the subject is/may continue deriving benefit from continuing study therapy. Subjects with 
toxicities that are manageable with supportive therapy may not require dose reductions.   
 
7.6.9  Dose Modifications for AZD6244 + MK-2206 Arm 
Dose Modifications for MK-2206 
Any subject who experiences a Grade 3 or 4 unmanageable toxicity will require immediate dose 
interruption and notification to the appropriate channels. Treatment will be withheld until toxicities 
have resolved to Grade ≤1. After resolution of the toxicity, the Investigator will determine whether 
the individual subject's dose should be reduced according to Table 7.1.  For Grade 1 or 2 diarrhea, 
early intervention should include continuation of treatment at the current dose and initiation of 
loperamide therapy.  Grade 2 diarrhea that persists over 48–72 hours, despite optimal medical 

  
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management, should be managed by dose reduction according to Table 7.1.  Subjects experiencing 
Grade 3 diarrhea should interrupt treatment until resolution to Grade <1 and re-start at a reduced 
dose.  Subjects should be maintained at the reduced dose without attempt at dose re-escalation.  
Subjects experiencing Grade 4 diarrhea should be discontinued from study drug. Management of 
a tolerable Grade 2 or 3 rash should include continuation of treatment at the current dose and 
symptomatic management.  If skin rash is intolerable, dose reduction according to Section 7.6 
should be considered.  When skin toxicity improves by at least one grade level, the dose may be 
re-escalated as tolerated.  Subjects experiencing Grade 4 skin toxicity should be discontinued from 
study drug.  If a subject experiences toxicity but is benefiting from treatment with a response of 
SD, PR, or CR, the Investigator will discuss persistent and/or intolerable toxicities to determine if 
dose modification is warranted. Dose reduction to the next lower dose level may be permitted for 
subsequent treatments.  The dose de-escalation schema is provided in Table 7.1.  Subjects can have 
a maximum of 2 dose reductions for drug-related toxicity beyond which they will be removed from 
the study.  
Subjects will be withdrawn from the study if they fail to recover to CTCAE Grade 1 or less 
from a drug-related toxicity within 4 weeks, unless the Investigator feels that the subject should 
remain in the study because of evidence that the subject is/may continue deriving benefit from 
continuing study therapy. Subjects with toxicities that are manageable with supportive therapy 
may not require dose reductions.  No more than 2 study drug-related dose delays will be allowed 
for any given subject for toxicity related to study agent. Delays in the treatment schedule for 
logistical reasons should be avoided, if possible. 
Study agent may be permanently discontinued if a subject has not recovered within 4 weeks 
from the toxicity that caused the delay or if more than 2 study drug-related dose delays occur. The 
reason for a dose delay or treatment discontinuation must be recorded. Treatment for each new 
cycle will be delayed until drug-related toxicities have resolved to Grade 0, Grade 1, or the 
subject’s baseline. 
If a subject experiences a regimen related toxicity that requires AZD6244 to be held, the 
subject should discontinue taking MK-2206, at the discretion of the Investigator. Once the toxicity 
has resolved and the subject will resume treatment with both AZD6244 and MK-2206. 
  
 
Dose Modification for AZD6244  

  
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Additional cycles of therapy may be administered provided that the subject meets the following 
criteria on Day 1 of each cycle:  ANC > 1,000/mcL, Platelets > 100,000/mcL, non-hematologic 
toxicity recovered to < Grade 1 (or baseline), no evidence of progressive disease. 
• In the event of an adverse event at least possibly related to the agent, the doses of AZD6244 
should be adjusted according to the guidelines shown in the Dose Delays/Dose Modifications 
tables that follow. If an adverse event is not covered in the table, doses may be reduced or held at 
the discretion of the investigator for the subject’s safety.  
• Subjects with adverse events that are manageable with supportive therapy may not require dose 
reductions (e.g., nausea/vomiting may be treated with antiemetics, diarrhea may be treated with 
loperamide, and electrolyte abnormalities may be corrected with supplements rather than by dose 
reduction).    
The de-escalation plan for MK-2206 and AZD6244 is provided in Tables 7.1 and 7.2. 
Dose reduction to the next lower dose may be permitted and will occur as indicated in the below 
table.  A maximum of 3 dose reductions will be allowed.  De-escalation may occur to a single 
compound (independent of the other compound). 
 
 
 
 
Management of AZD6244-Related Skin Toxicity 
The etiology of skin toxicities associated with the use of AZD6244 is uncertain and there are no 
established algorithms for rash management.  An algorithm based on dermatology best practices 
for other contemporary targeted agents that cause skin toxicity is offered as guidance to managing 
skin toxicities seen in patients being treated on this protocol.78  
 
The algorithm suggests a step-wise approach to rash management.  If the rash is CTCAE grade 1, 
consider starting with topical steroids (e.g., hydrocortisone), topical antibiotics such as 
clindamycin gel, or no treatment if the patient is asymptomatic.  Use of topical steroid cream with 
higher potency may be considered early in patients with moderate rash on the face. 
 

  
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If the rash is CTCAE grade 2, continue topical steroid or pimecrolimus cream and consider adding 
an oral tetracycline or a similar agent. 
 
If the rash reaches CTCAE grade 3 or above, dose interruption and/or dose reduction, coupled with 
the addition of topical steroids is recommended. 
 
Pruritus of any grade may be treated with an antihistamine, such as diphenhydramine or 
hydroxyzine hydrochloride. 
 
Xerosis can be treated with classical emollients.  
 
Secondary infection may complicate or worsen skin toxicity.  To reduce the likelihood of nasal 
infection, intranasal mupirocin may be considered.  Infected rash may be treated with a short 
course of an oral tetracycline, such as doxycycline.  Sun exposure should be avoided in patients 
receiving doxycycline or other tetracycline antibiotics. 
 
 
 
 
 
 
 
 
Table 7.2 Selected Hematologic and Non-Hematologic Adverse Events and Guidelines for Dose Modifications 
for AZD6244 
Event  
AE Grade or Observation  
Dose Modification  
Dermatology/Skin  
Grade 1 or 2  
Maintain dose  
Grade 3 or 4 or intolerable grade 2  
Hold AZD6244 until < tolerable grade 2, then reduce 1 dose 
level and resume treatment. May resume original dose at the 
investigator’s discretion. 
Recurrent Grade 3  
Hold AZD6244 until < tolerable grade 2, then reduce 1 
additional dose level and resume treatment   
Diarrhea  
(if anti-diarrheal treatment 
is ineffective)  
Grade 1 or 2  
Maintain dose; continue anti-diarrheal treatment. Loperamide 
(4 mg at first onset, followed by 2 mg every 2–4 hrs until 
diarrhea free for 12 hrs)  

  
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Grade 3 or 4  
Hold AZD6244 until < tolerable grade 1 or baseline, 
loperamide; reduce 1 dose level and resume treatment.  May 
resume original dose at the investigator’s discretion. 
Recurrent Grade 3 or 4  
Hold AZD6244 until < tolerable grade 1 or baseline, 
loperamide; reduce 1 additional dose level and resume 
treatment  
Hematologic  
(neutrophils, platelets, 
hemoglobin)  
Grade 1 or 2  
Maintain dose  
Grade 3 or 4  
Hold AZD6244 until < grade 1 or baseline, then reduce 1 dose 
level and resume treatment. May resume original dose at the 
investigator’s discretion. 
Recurrent Grade 3 or 4  
Hold AZD6244 until < grade 1 or baseline, then reduce 1 
additional dose level and resume treatment.  
Liver Function  
(serum bilirubin,  
AST, or ALT)  
Grade 1 or 2  
Maintain dose  
Grade 3 or 4  
Hold AZD6244 until < grade 1 or baseline, then reduce 1 dose 
level and resume treatment  
Recurrent Grade 3 or 4  
Hold AZD6244 until < grade 1 or baseline, then reduce 1 
additional dose level and resume treatment  
 
 
 
 
 
 
 
8 
SORAFENIB (BAY 43-9006®) 
8.1 
Investigational product 
Sorafenib is a potent inhibitor of Raf kinase (c-Raf IC 50 = 2 nM, B-raf wild type IC50 = 25nM, B-raf 
mutant = 38nM) in vitro, in cells, and (in vivo), with significant dose-dependent anti-tumor activity in four 
different human tumor xenografts including lung, colon, pancreatic, and ovarian carcinomas.  Additionally, 
sorafenib is also a potent inhibitor of VEGF-R-2, in vitro, (with an IC50 of 90 nM).  Anti-cancer activity 
was observed in cancers that have Ras mutations, as well as in cancers without Ras mutations.  This suggests 
a potential use of this compound in a large spectrum of cancer types, including tumors with a variety of 
molecular etiologies, all of which have not yet been defined.  Observed anticancer activity was cytostatic 
in nature and was maintained upon continuation of dosing.  Sorafenib demonstrated significant anti-tumor 
activity also against large (400mg–1g) colon and ovarian tumors, producing some tumor regressions during 
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8.2 
Dosage and mode of administration 
Study Drug Administration 
Sorafenib will be administered at 400 mg BID.  Sorafenib must be taken on an empty stomach.  
For example, sorafenib should be taken 1 hour prior to ingesting food or 2 hours after ingesting 
food.  Sorafenib should be taken approximately 12 hours apart.  Sorafenib is provided in tablet 
form.  Tablets may either be swallowed whole or prepared by the subject according to the liquid 
preparation method detailed in Appendix XI in the event that the subject begins to have difficulty 
swallowing tablets while enrolled in the study.   
 
8.3 
Clinical Experience 
Sorafenib has been evaluated as a single agent at a dose of 400 mg orally twice daily in multiple 
tumor types and has been approved in renal cell cancer, and more recently hepatocellular 
carcinoma, 79,80  based on the results of randomized placebo-controlled phase III trials. Sorafenib 
has also has also been evaluated in unselected advanced patients with NSCLC both as a single 
agent and in conjuncture with platinum doublet chemotherapy as first-line treatment. Although the 
single-agent study in patients with refractory or recurrent NSCLC (one to two prior therapies) 
showed some activity (disease control in 30 of 48 patients and TTP of 103 days)81 of sorafenib in 
all lines of treatment, the ESCAPE phase III trial failed to improve survival when sorafenib was 
added to the commonly used paclitaxel-carboplatin doublet. A trial evaluating sorafenib in a 
randomized discontinuation phase II design, randomizing patients with stable disease after 2 
months on drug to sorafenib or placebo with cross-over allowed, in third line and beyond, revealed 
that out of 97 patients randomized revealed, SD in 47% in S arm and 19% of P, a median PFS 
favoring sorafenib (3.6 months) versus placebo (2.0 months) (p=0.009).  These data suggest that 
enriching the trial population for patients with slower growing disease, leads to clinical benefit and 
prolonged PFS  in this heavily pre-treated population.82 
Evidence from BATTLE-1 trial  (overall 8-week DCR 58% and up to 79% 8 week DCR 
within KRAS/bRAF biomarker group)  and some preliminary evidence from a small trial83 in 10 
patients selected for the presence of  K-Ras mutation in their tumor (4 G12V, 4 G12C, 1 G12A, 
and 1 G13S), in which three partial remissions (PRs) and three minimal responses (MRs) 5 of 

  
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which were associated with tumor cavitation were observed with a median PFS of 3 months (95% 
CI: 2.2–3.8 months) warrant further study of the agent in biomarker selected populations.  
 
8.4 
Route of excretion 
Data from the clinical mass-balance study have shown that, on average, less than 20% of the 
administered dose is excreted in the urine.  This is in contrast to pre- clinical data showing that the 
kidneys excrete less than 10% of BAY 43-9006.  Thus, even in the presence of complete shutdown 
of renal clearance of the drug, it is expected that a small increase in exposure may be observed; 
one, which is within the realm of the sizeable inter-patient variability that has been, observed in 
Phase I trials. 
 
8.5 
Rationale for studying Sorafenib in patients with NSCLC 
Unresectable and/or metastatic NSCLC is a cancer with few successful therapeutic options.  As 
responses were seen in multiple tumor types when sorafenib was administered to patients, 
including those with NSCLC, an expanded evaluation of the anti-cancer activity of sorafenib (a 
Raf kinase inhibitor) in patients with NSCLC is sought.  Ras functions downstream of several 
receptor tyrosine kinases (RTK) and its activation are an important mechanism by which cancer 
develops. Ras activation can be induced by mutation, or by overexpression of several different 
RTKs (epidermal growth factor, vascular endothelial growth factor, or platelet-derived growth 
factor).  Thus the Ras pathway is a central mediator of cellular proliferation and survival in human 
tumors.  Raf/Ras signaling is a principle downstream pathway in NSCLC.  Mutations in the 
Raf/Ras pathway occur in approximately 15%-30% of NSCLC, which makes the Ras/Raf pathway 
a potential target for new therapeutic agents in lung cancer. The current study is designed to further 
explore the anti-cancer activity, efficacy, safety, and tolerability of sorafenib in selected patients 
with NSCLC who express mutated Ras or Raf.  
 
8.6 
Selection of Doses in the Study 
The most frequent treatment-emergent adverse event observed at the highest doses tested was skin 
toxicity.  When all available data from the various Phase I studies/schedules were combined, the 
incidence of > grade 3 treatment emergent skin toxicity (e.g., Hand-Foot Syndrome and 
“dermatology/skin reaction”) for an initial dose of 400 mg twice daily and 600 mg twice daily, 

  
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was 3.2% and 31.6%, respectively.  Grade 3 Hand-Foot Syndrome is defined as “skin changes 
with pain, interfering with function”, according to the NCI-CTC, Version 3.0, which was used to 
grade toxicity in all 5 Phase I studies.  As sorafenib may be administered chronically, the rate of 
grade 3 Hand-Foot Syndrome at the 600 mg twice-daily dose level was considered high for a 
chronically administered oral agent.  
The continuous dosing schedule was selected over various intermittent schedules primarily 
because it offers continuous exposure without documented increased toxicity.  The pre-clinical 
experiments consistently support the importance of continuous dosing.   
In summary, 400-mg twice daily administered orally in a continuous, uninterrupted 
schedule was chosen as the dose for further exploration in Phase II and III because the available 
Phase I data suggest that this dose represents the highest, most dose-intense dose and schedule that 
can be delivered with an acceptable safety profile.  In Phase II and III studies, additional data 
regarding the safety and anti-cancer activity of this dosing schedule will be gathered.  So far over 
450 patients have been treated in 3 ongoing Phase II trials at the 400 mg bid dose.  Consistence 
with this, less than 7% of patients have experienced Grade 3 Hand-Foot Syndrome in Phase II 
trials (preliminary data).  Based on the Phase I experience, the recommended Phase II dose and 
schedule is 400 mg (2x200 mg tablets) twice daily administered orally in a continuous, 
uninterrupted fashion. 
 
8.7 
Dose Delays or Dose Modifications 
Doses will be delayed or reduced in case of toxicities, which are possibly, probably or definitely 
related to protocol therapy.  Toxicities will be graded using the NCI Common Terminology 
Criteria Version 4.0.  In all cases, patients who are prematurely withdrawn from the study due to 
toxicity event(s) must be followed until resolution of the event(s), and then every 3 months for up 
to 3 years for survival.  The toxicity should be recorded in the CRF as an adverse event. 
Doses will be delayed or reduced for clinically significant hematologic and other toxicities that are 
related to protocol therapy.  If a patient experiences several toxicities and there are conflicting 
recommendations, the recommended dose adjustment that reduces the dose to the lowest level will 
be used.  All dose modifications will follow predefined dose levels: 
Dose level 1: 400 mg (2x200 mg) po q 12 hr 
Dose level 2:  400 mg (2x200 mg) po q daily 

  
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If further dose reduction is required, the patient should be discontinued from the study. Also, at 
the discretion of the investigator, the dose may be re-escalated to 400-mg po q 12 hr after the 
resolution of the adverse event. 
 
8.8 
Treatment of Toxicity and Dose Modification 
Grading for the Hand-Foot Syndrome 
Patients experiencing Hand-Foot syndrome should have their signs and symptoms graded 
according to the following system: 
 
Sorafenib:  Skin toxicity grading 
Grade 1 
 
Numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema 
of the hands and/or feet and/or discomfort, which does not disrupt normal 
activities. 
 
Grade 2 
Painful erythema and swelling of the hands and/or feet and/or discomfort 
affecting the patient’s activities.  
 
Grade 3  
Moist desquamation, ulceration, blistering or severe pain of the hands and/or 
feet and/or severe discomfort that causes the patient to be unable to work or 
perform activities of daily living. 
 
 
Subjects who are randomized to the treatment arm will be withdrawn from the study if they fail 
to recover to CTCAE Grade 1 or less from a drug-related toxicity within 4 weeks, unless the 
Investigator feels that the subject should remain in the study because of evidence that the subject 
is/may continue deriving benefit from continuing study therapy. Subjects with toxicities that are 
manageable with supportive therapy may not require dose reductions.   
 
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Toxicity Grade 
Dose Delay/Modification6 
Grade 1 
Maintain dose level 
Grade 2 any toxicity, 
excluding alopecia, 1,3 
judged by the investigator 
to be predominantly related 
to study drug 
1st appearance 
For skin toxicity, continue treatment at investigator 
discretion and apply symptomatic treatment as appropriate. 
No change for other toxicities.  
 
2nd & 3rd appearance or 
no improvement ≥ 7 
days  
For skin toxicity interrupt until resolved to grade 0-1.  
For other toxicities interrupt2, 4 at investigator discretion. 
Decrease one dose level when resuming treatment. 
 
4th appearance 
Discontinue treatment permanently5 
Grade 3 any toxicity1, 3 & 
Grade 4 hematologic 
toxicities1 judged by the 
investigator to be 
predominantly related to 
study drug. 
1st & 2nd appearance 
Interrupt2, 4 until resolved to grade 0-1 for skin toxicity or 
grade 2 for other toxicities. Decrease one dose level when 
resuming treatment. 
 
3rd appearance 
Discontinue treatment permanently5, 7 
 
Grade 4 non-hematologic 
toxicities3 judged by the 
investigator to be 
predominantly related to 
study drug.  
1st appearance 
Interrupt2, 4 until resolved and then decrease 1 dose level.  
 
 
2nd appearance 
Discontinue treatment permanently7 

  
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For patients with Grade 2 or greater toxicities present at baseline and eligible to participate as per inclusion criteria, the CTC 
4.0 criteria will not apply to that toxicity for that particular patient.  Instead, a 1.5-2 x laboratory baseline value will be 
regarded as a grade 2 event and a >2 x laboratory baseline value will be regarded as a grade 3 event. Grade 4 events will 
be attributed according to CTC 4.0 criteria.  Anemia will be regarded as a dose-limiting event only if the drop is judged 
by the investigator to be predominantly due to drug effect in which case the CTC 3.0 criteria will apply.  
2 For patients with Grade 2 or greater toxicities present at baseline and eligible to participate as per inclusion criteria, 
resolution to at least baseline levels will apply instead.  
3 Excludes nausea/vomiting that has not been premedicated.  
4 If no recovery after 4-week delay, despite institution of all clinically appropriate symptomatic treatments, administration of 
study drug will be discontinued.  
5 For toxicities other than skin toxicity, treatment may continue if in the investigator’s judgement the toxicity is clinically 
manageable and does not jeopardize the safety of the patient and/or its compliance in the study. Protocol chairman must 
be contacted for permission in this case. 
6 At the discretion of the investigator, the dose may be re-escalated to 400 mg bid if no toxicities occur after cycle 1 
7 Subjects who are randomized to the treatment arm will be withdrawn from the study if they fail to recover to CTCAE Grade 
1 or less from a drug-related toxicity within 4 weeks, unless the Investigator feels that the subject should remain in the 
study because of evidence that the subject is/may continue deriving benefit from continuing study therapy. Subjects with 
toxicities that are manageable with supportive therapy may not require dose reductions.   
 
8.9 
Prior and Concomitant Therapy 
All concomitant medications (including start/stop dates and indication) must be recorded in the 
patient’s source documentation, as well as in the appropriate pages of the protocol specific 
electronic CRF. 
 
Permitted  
All medication which is considered necessary for the patient’s welfare, and which is not expected 
to interfere with the evaluation of the study drug, may be given at the discretion of the Investigator.  
All concomitant medications (including start/stop dates, dose frequency, route of administration 
and indication) must be recorded in the patient’s source documentation and appropriate section of 
the CRF. 
        Patients may receive palliative and supportive care for any underlying illness. Patients 
receiving bisphosphonates prophylactically for bone metastases may continue while on treatment.  
Also, megestrol acetate will be allowed for appetite stimulation. 

  
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 
Erythropoietin therapy may be used in the management of acute toxicity, such as febrile 
neutropenia, when clinically indicated or at the discretion of the investigator; however, they may 
not be substituted for a required dose reduction. Patients taking chronic erythropoietin are 
permitted provided no dose adjustment is undertaken within 2 months prior to the study or during 
the study. 
 
Antacids and other anti-ulcer medications such as proton pump inhibitors and histamine 
H2-receptor antagonists may be used if clinically indicated. To avoid significantly altering gastric 
pH, when needed, these medications should be used4 hours after study drug administration. 
 
Not Permitted  
 Radiotherapy during study or within 3 weeks (2 weeks for localized palliative therapy) of study 
entry. Patient must have recovered from radiation-induced toxicity.  
 Patients may not receive other investigational therapy. 
 Use of ritonavir  
 Use of Rifampicin 
 St. John’s Wort 
 Use of biologic response modifiers, such as G-CSF or GM-CSF, during or within 3 weeks of 
study entry. G-CSF and other hematopoietic growth factors may only be used in the 
management of acute toxicity, such as febrile neutropenia, when medically indicated, or at 
the discretion of the investigator; however, they may not be substituted for a required dose 
reduction.  Patients taking chronic erythropoietin are permitted provided no dose 
adjustment is undertaken within 2 months prior to the study or during the study. 
 Patients taking narrow therapeutic index medications should be monitored proactively.  
These include warfarin, phenytoin, quinidine, carbamazepine, phenobarbital, 
cyclosporine and digoxin. 
 
 
 
 
9 
STUDY CONDUCT 

  
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9.1  
Subject Accrual and Subject Identification 
Subjects will be enrolled at MD Anderson Cancer Center and Yale Comprehensive Cancer Center.  
Accrual of rate of 8 subjects per month is expected.  Closure to accrual is expected approximately 
4 years after activation. A 3-digit accession number will be assigned to each subject as the master 
ID. A password protected secured file will be created to store the cross reference list between the 
master ID and confidential subject 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 subject identification purpose. Confidential subject information will be used only 
when it is necessary such as in patient care setting. 
 
9.1.1  Investigational Centers 
The centers involved include the following: M. D. Anderson Cancer Center and Yale 
Comprehensive Cancer Center. Other centers may be added at a later date.  
 
Investigator Contact Information  
 
Principal Investigator (MDACC):  
Marcelo Vailati Negrao, MD  
University of Texas M.D. Anderson Cancer Center  
1515 Holcombe Blvd., Unit 432  
Houston, TX 77030  
Phone: 713-792-6363  
Fax: 713-792-1220  
e-mail: mvnegrao@mdanderson.org 
 
Collaborating Site Principal Investigator (YCCC):  
Roy S. Herbst, MD PhD 
Yale Comprehensive Cancer Center 
Smilow Cancer Hospital at Yale-New Haven 
Yale School of Medicine 
333 Cedar Street, WWW221 
New Haven, CT  06520-8028 
Phone: 203-785-6879 
Fax: 203-785-4116 
e-mail: roy.herbst@yale.edu 
 
 
9.2 
Subject Enrollment 

  
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Subjects must be consented prior to any study-related procedures being performed.  Once subjects 
are consented for the BATTLE-2 protocol and appropriate procedures are completed, they will be 
adaptively randomized into one of the treatment arms. 
 
9.3 
Replacement of Subjects 
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 subjects must undergo pre-treatment evaluations within 4 weeks (unless otherwise specified) 
prior to initiating therapy.  The ECOG performance status assessment must be performed in a 
physical exam within 28 days of the protocol biopsy.  Pre-treatment evaluations will be used to 
determine the subject’s study eligibility.  Subjects 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. 
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, magnesium, chloride, 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 
 
7. 
Chest x-ray within 4 weeks of starting treatment 
8.  
CT or MRI scans of chest (and abdomen if indicated) 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 III) 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.   
Ophthalmologic Exam (if randomized to Arm 2 or 3 with AZD6244 and/or MK-2206) 
11. 
Serum biomarker evaluation (optional)  
12. 
MUGA/Echocardiogram  
13. 
Serum Pregnancy Test (women of childbearing potential) 
14. 
Urinalysis 
15. 
Electrocardiogram (triplicate) 
16.   
Diagnostic archival tumor sample (optional) 
17. 
EML4-ALK fusion gene detection and EGFR mutation detection 
18.   
Coagulation Profile (PT/INR) will be performed prior to biopsy  
 
9.4.1  
Tumor tissue biopsy 
Tissue biopsies (FNA and CNB) will be performed at baseline and at the end of Cycle 2 (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.. 
 
Image-guided core biopsy:  Study subjects will undergo 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.  Approximately 4-5 core biopsies of the tumor will be performed.  
Specimens will be used to analyze biomarkers, genomic, proteomic, and other biomarker studies. 
 
 
 
9.4.1.1 Personalizing NSCLC Therapy Next-Generation Sequencing Sub Study – MDACC 
Participants Only (Optional) 
Study subjects will be asked to allow their tissue samples to be utilized in an optional sub study.  
The objectives of this sub study are to obtain and integrate, using novel bioinformatics analyses, 

  
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Whole Transcriptional genome and RNA sequencing (WT-seq) data specimens with available 
gene expression (Affymetrix®), mutation (Sequenom®; panel of 10 genes), and corresponding 
clinical data from patients accrued in the initial stage of the BATTLE-2 trial.   If subject consent 
and/or waiver of consent have been obtained, one fresh BATTLE-2 tissue biopsy core collected as 
indicated in section 9.4.1 will be selected for DNA and RNA extraction.  This project will be 
performed under MDACC Protocol PA11-1139 entitled: BATTLE-2 Companion Lab Protocol: 
Personalizing NSCLC Therapy: Applying Next-Generation Sequencing in the BATTLE-2 Trial. 
 
9.4.2 Serologies 
Optional blood samples will be collected at baseline, end of Cycle 2 and at 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 XII.  
 
9.5 
Study Treatment Procedures 
All study evaluations and/or clinic visits may be conducted within ± 7 days of the date specified 
in the protocol unless otherwise specified.   
1. 
Physical exam including weight, ECOG performance status assessment, vital signs 
including pulse, blood pressure, and temperature will be conducted Day 1 of each cycle.  
Cycle 1 Day 1 physical exam can be completed within 3 days of drug start. 
2. 
Updated historical information including current medications, smoking history (duration 
and intensity) and medical conditions each visit 
3. 
Tumor tissue biopsy after cycle 2 (optional) 
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, magnesium, chloride, calcium, albumin, glucose, CO2 and HbA1c 

  
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(Arms 2 and 3) each cycle.  Potassium and magnesium must be corrected to the normal 
range prior to administration of drug for subjects in Arms 2 and 3. 
5. 
Hematology to include: CBC with automated differential and platelet count each cycle 
6. 
Serum samples for biomarkers will be collected at the end of Cycle 2 (optional) 
7. 
Brain MRI (if clinically indicated) 
8. 
Chest X-ray at cycle 2 and then every 2 cycles 
9. 
CT or MRI scans of chest (and abdomen if indicated) at cycle 2 and then every 2 cycles 
10. 
Ophthalmologic exam will be performed 4 weeks after dosing of AZD6244 and/or MK-
2206  
11. 
MUGA/Echocardiogram will be performed 6 weeks (Cycle 2 Day 15 +/- 7 days) after 
dosing of AZD6244 3 months+/- 7days , every 3 months +/- 7days while on drug, and 30 
days post-treatment +/- 7days (additionally as clinically indicated) (Arm 3 only), 
12. 
Coagulation Profile (PT/INR) will be performed per standard of care if the subject is on 
warfarin or other anticoagulant.   
13. 
Electrocardiogram (triplicate) – Cycle 1, Day 1 Pre and Post-dose (4 hour +/- 15 min) for 
subjects on Arms 2 and 3 
 
9.6 
End of Therapy Procedures 
End of therapy evaluations will be assessed for subjects who are no longer receiving therapy on 
protocol.  These evaluations will occur within 7 days of treatment discontinuation and will include 
a physical examination, hematology, coagulation (if subject is on warfarin or other anticoagulant), 
and serum chemistry profiles, urinalysis, imaging (if indicated), diagnostic studies (if indicated), 
electrocardiogram (Arm 3 only), ophthalmologic exam (Arms 2 and 3 only) and tumor response 
assessments.  An optional serum sample will be collected at disease progression, if applicable.   
 
 
9.7  
Follow-up Procedures 
Subjects will have a follow-up evaluation performed 4 weeks ± 7 days after therapy is 
discontinued.  This evaluation may be a visit or contact by the research personnel.  Subjects on 
AZD6244 (Arm 3) +/- 7days will have repeat MUGA/Echocardiogram.  Subjects will be contacted 

  
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every 3 months to collect subsequent anticancer therapy and survival information (for up to 3 
years). 
 
9.8 
Evaluation criteria 
9.8.1 Tumor Response 
The initial tumor response (unidimensionally measured disease) will be assessed at the completion 
of two cycles of therapy, and will be compared to pre-treatment values.  Subsequent tumor 
response for subjects 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 subjects 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 II) 
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. 
 
9.8.2 Volumetric Tumor Analysis 
As a secondary objective, this study will assess the overall response rate by volumetric analysis 
and evaluate the utility of tumor volumes measured using volumetric image analysis tools.  This 
secondary volumetric measurement data will be correlated with RECIST measurements.  
Responses will be based on a comparison to the pre-treatment tumor volumetric analysis.  All 
subjects who have received at least one cycle of treatment will be considered evaluable for 
response assessment.  Imaging and diagnostic studies of measurable and evaluable tumors should 
be repeated following every two cycles of therapy.   This data set will not only help inform the 
design of future clinical trials for drug development, it will also make a significant contribution to 
the development of volumetric imaging tools for day to day management of lung cancer patients 
receiving standard of care treatments.   
The CT scan images obtained in the Screening, Study Treatment, and End of Study 
Treatment Procedures will be de-identified by Diagnostic Radiology and sent to Merck & Co., Inc.  
Merck & Co., Inc. will perform volumetric analysis in accordance with the Quantitative Imaging 

  
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Biomarker Alliance (QIBA) of the Radiological Society of North America standards for clinical 
trial science.  This image acquisition and processing protocol is being adopted as a global standard 
that sites will need to implement in order to participate in a wide range of industry and NIH 
sponsored 
trials.  
For 
additional 
information 
please 
refer 
to 
http://qibawiki.rsna.org/index.php?title=Main_Page.   Additional information regarding rationale 
for use of volumetric CT is contained in Appendix IX.   
 
9.9 
Treatment Compliance and Drug Accountability 
Records of study drug used, dosages administered, and intervals between visits will be recorded 
during the study. Subjects will be provided with a Subject Medication Diary.  Subjects will be 
asked to complete and return diary at each clinic visit.  Drug accountability will be noted and 
subjects will be asked to return all unused study drug at each clinic visit.  Study drug allocated by 
Merck & Co., Inc. for the study described herein, upon completion of the study or upon notice of 
the drug’s expiration, should be disposed of at the participating site, pursuant to the GCP 
Guidelines and MDACC’s Institutional policies.  Study drug allocated by OSI Pharmaceuticals for 
the study described herein, upon completion of the study or upon notice of the drug’s expiration, 
should be disposed of at the participating site, pursuant to the GCP Guidelines and MDACC’s 
Institutional policies.  Study drug allocated by AstraZeneca for the study described herein, upon 
completion of the study or upon notice of the drug’s expiration, should be disposed of at the 
participating site, pursuant to the GCP Guidelines and MDACC’s Institutional policies.  Study 
drug allocated by Bayer Pharmaceuticals for the study described herein, upon completion of the 
study or upon notice of the drug’s expiration, should be disposed of at the participating site, 
pursuant to the GCP Guidelines and MDACC’s Institutional policies. 
 
 
 
9.10 
Study Monitoring 
The University of Texas MD Anderson Cancer Center IND Office will monitor the study 
investigators to assure satisfactory enrollment rate, data recording, and protocol adherence. The 
site principal investigator and staff are expected to cooperate and provide all relevant study 
documentation in detail at each site visit on request for review. MD Anderson Cancer Center will 

  
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monitor and/or audit the other participating sites to assure satisfactory protocol adherence and 
enrollment.  
The site will be visited on a regular basis by the Clinical Study Monitor, who will check 
completed source documentation, discuss the progress of the study and monitor drug according to 
good clinical practice (GCP). The monitoring will also include source data verification (SDV). 
 
 
10 
SAFETY DATA COLLECTION, RECORDING AND REPORTING 
Safety assessments will consist of monitoring and recording all adverse events and serious adverse 
events, the regular monitoring of hematology, blood chemistry and urine values, regular 
measurement of vital signs and the performance of physical examinations.  These assessments 
should be performed within ± 7 days of the scheduled day of assessment except for adverse events 
which will be evaluated continuously through the study. Safety and tolerability will be assessed 
according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. 
 
10.1  Adverse Events and Adverse Event Reporting 
Information about all adverse events (CTC Grades 1-5 and all attributions), whether volunteered 
by the subject, discovered by investigator questioning, or detected through physical examination, 
laboratory test or other means, will be collected and recorded and followed as appropriate.  
Adverse events along with grade, start/stop dates, and attribution to each drug will be documented 
in the medical record.  Based upon best clinical judgment, the treating investigator will assign 
attribution of adverse events to each study agent separately.   
 
 
 
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 
 A 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 

  
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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 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A 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 subject 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 Site Principal Investigator or the IND Sponsor, IND Office. 
 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 Adverse Events”.  Unless stated otherwise in the 
protocol, all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 The MDACC “Internal SAE Report Form for Prompt Reporting” will be used for 
reporting to the IND Office.  
 
 
 
 
 
 
Reporting for all sites: 
 
 A written report should be submitted to the Institutional Review Board (IRB) according to 
the requirements of the assigned IRB for patients enrolled at each site.  
 SAEs will be reported to the sponsor on a template form that will be provided to each 
site.  If needed, a copy of all relevant examinations that have been carried out and the 

  
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dates on which these examinations were performed should be attached. For laboratory 
results, normal ranges should be included. Patient name should be marked out and initials 
and study number included on all attachments. 
 In case of a serious adverse event, the following actions must be undertaken by the 
investigator:  (Please note that these are in addition to reporting that is required by the 
local IRB and supporting company.) Complete the SAE form immediately and then fax 
and overnight mail the signed and dated SAE form to the sponsor representative within 
two working days to the following address: 
 
The University of Texas M.D. Anderson Cancer Center 
IND Office 
Gloria Morris, Sr. Proj. Mgr., IND Office 
1400 Pressler, FCT8.6081 
Houston, Texas  77030 
Tel no.: 713-563-0379  
Fax no.: 713-792-8987      
e-mail:  glmorris@mdanderson.org 
 
 A copy of the tracking receipt should be kept and filed in the study regulatory binder at the site. 
The research team may email or call the sponsor to confirm receipt of the SAE fax or mailed 
form. 
 
 Death or life-threatening events that are possibly, probably or definitely related to drug must be 
reported within 24 hours.  The sponsor IND safety coordinator must be notified by phone 
immediately, in addition to fax or overnight mail as listed above. 
 
 All life-threatening or fatal events, expected or unexpected, and regardless of attribution 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 the IND Office.   
 
 Serious adverse events will be captured from the time the patient signs consent until 30 
days after the last dose of drug. Serious adverse events must be followed until clinical 
recovery is complete and laboratory tests 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 the IND Office. This may include the 
development of a secondary malignancy. 
 
 All events reported the supporting company must also be report to the IND Office. 
 
 
Reporting to FDA: 
 

  
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 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 serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
10.2 
Site Communication with Merck & Co., Inc. 
When the principal investigator has determined that a Serious Adverse Event has occurred 
regardless of causality, the site principal investigator and/or designated research staff is responsible 
for providing all Serious Adverse Events to the Merck & Co., Inc., within two (2) working days.  
This applies to initial and follow-up information. Information can be faxed to Merck & Co., Inc. 
(Merck & Co., Inc. Attn: Worldwide Product Safety, Fax:  215-993-1220). 
Any SAE that occurs from the time the study Informed Consent is obtained until the first 
day of treatment needs to be reported, only if the event was related to a study procedure. Any SAE 
that occurs from the first day of study treatment through 30 days after the last study treatment must 
be reported to Merck. From 31 days after the last study treatment, subjects will continue to be 
assessed for SAEs that are related to investigational drugs. 
The Investigator should take all appropriate measures to ensure the safety of the subjects, 
notably he/she should follow up the outcome of any Serious Adverse Event and complete follow-
up forms as necessary.  The subject must be followed up until recovery, stabilization or return to 
baseline. This may mean that follow-up will continue after the subject has completed the trial and 
that additional investigations may be necessary.  
Any reportable Serious Adverse Events brought to the attention of the Investigator at any 
time after cessation of the trial and considered by him/her to be reasonably associated with 
medication administered during the period should also be submitted to Merck & Co., Inc. (Attn: 
Worldwide Product Safety, Merck & Co., Inc. FAX 215-993-1220).  Additionally, any pregnancy 
occurring in association with use of an investigational agent must be reported to Merck & Co., Inc. 
 
10.3 
Site Communication with OSI Pharmaceuticals 
All serious adverse events related to erlotinib must be reported by FAX (303-546-7706) to OSI 
Pharmaceuticals Drug Safety Department. This includes serious, related, labeled (expected) and 

  
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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 OSI study drug (or therapy) is suspected.  
 
10.4 
Site Communication with AstraZeneca 
All serious adverse events related to AZD6244, regardless of causality, must be reported by FAX 
(800-972-4533) to AstraZeneca’s ISS Safety Representative. This includes serious, related, 
unrelated, labeled (expected) and serious, and 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 AstraZeneca study drug (or therapy) is suspected.  
 
10.5 
Site Communication with Bayer/Onyx 
All serious adverse events related to sorafenib must be reported by FAX (973) 709-2185 to Bayer 
Global Pharmacovigilance - USA. 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 Bayer study drug (or therapy) is suspected.  
 
 
 
 
10.6 
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. 

  
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 Subjects 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. 
 
10.7 
Adverse event reporting on Case Report Form 
All adverse events, regardless of severity or causality, will be recorded in a timely manner in an 
electronic database.  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. 
Known adverse events relating to the underlying clinical condition will be reported in an electronic 
database. 
 
10.8 
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 30 days 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 90 days 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 subject must 
not receive investigational product and must not continue 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 subjects of childbearing potential should be instructed to contact 
the treating physician immediately if they suspect they might have conceived a child.  In addition, 

  
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a missed or late menstrual period should be reported to the treating physician.  If a female subject 
or the treating physician suspects that the female subject 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 subject must not receive study medications and must be withdrawn 
from the study.  Throughout the entire pregnancy, additional contact should be made with the 
subject 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 subject 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 the IND Office. 
To ensure subject safety each pregnancy must also be reported to Merck & Co., Inc., OSI 
Pharmaceuticals, AstraZeneca and Bayer when applicable. 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. 
 
 
11 
STATISTICAL DESIGN AND DATA ANALYSIS CONSIDERATIONS 
11.1 Background and Design 

  
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The target population for the BATTLE-2 trial is patients with advanced stage, treatment-refractory, 
non-small cell lung cancer (NSCLC).  The following four treatments will be studied: the EGFR 
inhibitor erlotinib (Arm 1, serving as a control group), erlotinib + an AKT-inhibitor (MK-2206) 
(Arm 2), a MEK-inhibitor (AZD6244) + MK-2206 (Arm 3), and sorafenib (Arm 4).  The main 
statistical goals for the BATTLE-2 trial includes: (1) to test treatment efficacy for the proposed 
agents, (2) to identify prognostic and predictive markers for novel combination therapies, and (3) 
to select treatments based on marker status of patients such that better treatments are provide 
individually for patients enrolled in the trial.  The primary endpoint for the study is the 8-week 
disease control rate (DCR).  
Based on the SWOG experience84 and a previous trial in this population, BATTLE-1, 8-
week DCR is a good surrogate of overall survival.  Patients with EGFR mutation or EML4-ALK 
mutation will be excluded as there are known effective treatments.  Patients with insufficient 
material to determine mutational status will be allowed randomization if the patient is otherwise 
eligible for the study.  Patients with prior erlotinib treatment will not be randomized into the 
erlotinib only arm.  
A total of 400 evaluable subjects with advanced stage NSCLC will be enrolled over a 4-
year period. The trial will be biopsy-based and biomarker-driven.  All subjects will be consented 
for a mandated biopsy before being randomized to the study’s treatment arms.  Biomarkers in 
subjects’ samples will be analyzed to guide the treatment choice.  With a conservative estimate 
that 10% of the subjects may have incomplete marker profiles due to limited numbers of tumor 
cells in biopsy samples, a total of 450 subjects will be enrolled. 
 
 
 
 
 
 
 
 
Figure 11.1: Study Timeline for BATTLE-2 Trial 

  
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As shown in the study timeline in Figure 11.1, the study will be conducted in three defined steps:  
 Stage 1 – Initial adaptive randomization (AR) of about 200 patients based on the KRAS 
(codons 12, 13 and 61 taken together) mutation.   
 Biomarker analysis at end of Stage 1 - Data from our previous BATTLE-1 trial and from 
the literature will be used to form a list of candidate markers.  The prognostic and predictive 
effects for the candidate markers will be validated using the BATTLE-2, Stage 1 data. All 
biomarkers will subject to a marker selection procedure. This biomarker analysis will select 
the best prognostic and/or predictive markers (either individual and/or composite markers) 
to form a refined predictive model to be applied in Stage 2 AR.  
 Stage 2 – Refined AR of the remaining 200 patients based on the model with all the markers 
selected from the previously mentioned analysis.   
 
An early futility stopping rule is implemented after 70 patients are randomized. If all the three 
experimental treatments (Arms 2, 3, 4) are not promising in all patients and all sub-populations 
determined by selected markers and prior erlotinib treatment status, the trial will be stop early. 
Starting from the 71th patient, the early stopping rules will be continuously evaluated until the end 
of the trial.  
 
In Stage 1, 200 subjects will be adaptively randomized into one of the four treatment arms (three 
treatment arms for prior erlotinib treated patients) based solely on KRAS mutation status, which is 
Year 0           
1 
2 
4 
3 
5 
Enroll 200 pts, Refined AR 
 
 
Enroll 200 pts, Initial AR 
Final Analysis (2 mon 
after last pt rand.)  
Time Line 
Start model building @ ~120 pts 
Finalize model after approval 
from the Internal and External 
Advisory Boards. Submit protocol 
amendment 
IRB Approval 

  
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generally accepted in the field as having relevance to the sensitivity or resistance to erlotinib and 
other targeted agents. Patients with insufficient material to determine KRAS mutational status will 
be allowed randomization if the patient is otherwise eligible for the study. They will be considered 
as wild type patients for the randomization purpose. Concurrently throughout Stage 1, up to 30 
putative candidate biomarkers will also be analyzed in subjects’ tissue and blood samples.   
 
Table 11.1 Molecular markers to be analyzed in Stage 1 of the BATTLE-2 clinical trial. 
Markers  
2) Biomarker 
Adaptive  
Randomization 
(AR) [n=1] 
 KRAS (codons 12, 13 and 61) mutation (for AR Stage 1) 
3) Candidate 
[n=19] 
 Protein expression (IHC): FOXO3A, nuclear EGFR, phospho-AKT 
(Ser473), PTEN, HIF-1a, and LKB1 
 Mutation analysis (Sequenom®): PI3KCA, BRAF, AKT1, HRAS, NRAS, 
MAP2K1 (MEK1), MET, CTNNB1, STK11 (LKB1) and type of KRAS 
mutation (Cys/Val vs. all others) 
 Gene expression drug response signatures (Affymetrix) 
- 
Epithelial-mesenchymal transition (EMT)  
- 
WT-EGFR-Erlotinib  
- 
Sorafenib 
4) Discovery markers will also be examined.  
 
Those data will be analyzed by the biostatistical and bioinformatics team to propose a refined 
predictive model.  We will identify the “best-performing” markers from Stage 1 to form the 
predictive model for the AR of the second stage. The approach will involve a variable selection 
and model building step. The final model for the Stage 2 AR will be reviewed and approved by 
the Internal and External Advisory Boards.  Upon approval, the 200 subjects in Stage 2 will be 
adaptively randomized based on the refined model, which could include more than one treatment-
specific markers, and the marker used in stage 1 could be dropped in stage 2. At the end of the 

  
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trial, information from all subjects enrolled in Stages 1 and 2 will be combined to test the 
prognostic effect and predictive effect of putative markers selected in the final model.  In addition, 
because the previous trial (BATTLE-1) also contained an erlotinib-only arm, predictive marker 
findings from BATTLE-1 for erlotinib will be validated in BATTLE-2 subjects.  Other findings 
from BATTLE-2 will also need to be validated in future trials.  The statistical objective is to have 
at least 80% power with a 10% type I error for testing the efficacy of each combination treatment 
as well as identifying important prognostic and predictive markers.  
 
To facilitate the trial conduct, a BATTLE-2 Web-based database application for 
registration, biomarker analysis, randomization, and follow up will be built.  In addition to 
registering into the institutional database CORe, all subjects' information will be entered into the 
BATTLE-2 database.  The biopsy and biomarker analysis results will be entered into the database.  
The adaptive randomization module is integrated to the database application through web-services.  
Subjects will be adaptively randomized to one of the four treatment arms according to their 
biomarker profiles. Follow-up information including the 8-week disease control status will be 
monitored and entered timely to facilitate the AR. 
 
11.2 Assumptions 
We assume that the true model contains 5 important markers (K=5). All markers are binary with 
20% marker positive for M1 (KRAS mutation), and 50% marker positive for M2 M3, M4 and M5. 
Based on our BATTLE-1 experience, we assume that 40% of the patients had prior erlotinib 
treatment. The true 8-week DCRs under the null and the alternative hypotheses assumed in the 
simulation studies are listed in Table 11.2. For patients with prior erlotinib treatment, they will not 
be treated on erlotinib-only arm (control arm). Under the null hypothesis, the 8-week DCRs for 
erlotinib-naïve patients are assumed to be 30% or 10% depending on the KRAS mutation status.  
For erlotinib-resistant patients, the corresponding 8-week DCRs are 20% or 1%. Under the 
alternative hypothesis, when predictive markers are identified for each of the combination 
treatments, the 8-week DCR is assumed to be 80% in erlotinib-naïve patients and 70% in erlotinib-
resistant patients. Both the null and alternative scenarios listed in Table 11.2 are evaluated via 
simulation studies.   
 
 

  
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Table 11.2: True disease control rate (DCR) by simple marker profiles 
(a) Null case 
 
Marker 
Profile 
Markers 
Erlotinib Naive Z = 0 
Resistant Z = 1 
M1  
M2 
M3 
M4 
M5 
Arm 1 
Arm 2 
Arm 3 
Arm 4 
Arm 2 
Arm 3 
Arm 4 
0 
0 
0 
0 
0 
0 
0.3 
0.3 
0.3 
0.3 
0.2 
0.2 
0.2 
1 
1 
0 
0 
0 
0 
0.1 
0.1 
0.1 
0.1 
0.01 
0.01 
0.01 
2 
0 
1 
0 
0 
0 
0.3 
0.3 
0.3 
0.3 
0.2 
0.2 
0.2 
3 
0 
0 
1 
0 
0 
0.3 
0.3 
0.3 
0.3 
0.2 
0.2 
0.2 
4 
0 
0 
0 
1 
0 
0.3 
0.3 
0.3 
0.3 
0.2 
0.2 
0.2 
5 
0 
0 
0 
0 
1 
0.3 
0.3 
0.3 
0.3 
0.2 
0.2 
0.2 
 
 
(a) Alternative case 
Marker 
Profile 
Markers 
Erlotinib Naive Z = 0 
Resistant Z = 1 
M1  
M2 
M3 
M4 
M5 
Arm 1 
Arm 2 
Arm 3 
Arm 4 
Arm 2 
Arm 3 
Arm 4 
0 
0 
0 
0 
0 
0 
0.3 
0.3 
0.3 
0.3 
0.2 
0.2 
0.2 
1 
1 
0 
0 
0 
0 
0.1 
0.5 
0.8 
0.6 
0.4 
0.7 
0.5 
2 
0 
1 
0 
0 
0 
0.6 
0.6 
0.6 
0.6 
0.5 
0.5 
0.5 
3 
0 
0 
1 
0 
0 
0.3 
0.8 
0.3 
0.3 
0.7 
0.2 
0.2 
4 
0 
0 
0 
1 
0 
0.3 
0.3 
0.8 
0.3 
0.2 
0.7 
0.2 
5 
0 
0 
0 
0 
1 
0.3 
0.3 
0.3 
0.8 
0.2 
0.2 
0.7 
 
 
 
11.3. Statistical Models 
A Bayesian logistic regression model is applied as the backbone of the statistical framework to 
model the probability of the 8-week DCR given treatments and markers.  Without loss of 
generality, we assume M1 is the pre-specified marker (KRAS mutation) and M2 to MK are the 
selected treatment-specific markers in the refined model. If we suppress the index of patients, the 
8-week DCR, pj, for patients on Arm j can be written as follows, 

  
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108 
 
0
1
1
1
logit(
)
(
)
K
K
K
j
j
j
k
k
jk
j
k
j
j
jk
j
k
k
k
k
p
T
M
T M
T Z
T M Z




















, 
            (1) 
where Tj  is the treatment indicator for Arm j, j=2, 3, 4 (with Arm 1 as the reference group), Mk is 
the marker indicator for Marker k, k=1, …, K, and Z is the indicator for prior erlotinib treatment 
(i.e., erlotinib resistance). In addition to the full model in Equation (1), a reduced model is also 
used to make inference on the overall treatment effect: 
0
1
logit(
)
K
j
j
j
k
k
j
j
k
p
T
M
T Z











.         
 
 
 
 
(2) 
The efficacy of the new treatments (Arm 2, Arm 3, Arm 4) will be compared with the erlotinib 
only arm (Arm 1).   
 
The treatment effects will be tested in two steps: First, we will test for the marginal treatment 
effect using the reduced model shown in Equation (2).  By comparing with the control arm, 
experimental treatment j (j =2, 3, 4) will be claimed as having a significant marginal treatment 
effect if Pr(
0)
j




 in erlotinib-naïve patients or if Pr(
'
0)
j
j






 in erlotinib-resistant 
patients, where  is the threshold value for posterior inference. Next, we will test the treatment 
effect under the full model in Equation (1) incorporating the treatment by marker interaction.  A 
success will be claimed for treatment j (j =2, 3, 4) in marker k positive patients, if 
Pr(
0)
j
jk






 for erlotinib-naïve patients and if 
'
'
Pr(
0)
j
j
jk
jk










 for erlotinib-
resistant patients. We choose  to control the type I error rate. As shown in Table 11.2 the true 
DCRs of erlotinib-resistant patients are expected to be lower than those in the erlotinib-naïve 
patients. A common control (erlotinib only treatment in erlotinib-naïve patients) is used for testing 
treatment efficacy in both naïve and resistant patients. It is a more conservative approach because 
the DCRs in erlotinib-resistant patients are compared to a higher bar.  
 
11.4. Adaptive Randomization Procedures 
We apply the response AR throughout the trial to treat patients more effectively in the trial.  Due 
to the delay in observing the outcome, AR will start to kick in after the first 14 patients are enrolled.  

  
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In Stage 1, the initial AR is based on the logistic model with treatment, Kras mutation, and 
erlotinib resistance. In particular, for a given patient on Arm j, we have 
0
1
1
1
1
logit(
)
j
j
j
j
j
j
j
p
T
M
T M
T Z










 
              
(3) 
The probability of a patient being assigned to the jth arm is proportional to the square root of 
'
Pr(
, '
{1,2,3,4 |
'
})
j
j
p
p
j
j
j



, which corresponds to the posterior probability of the jth arm 
having the largest DCR among all treatments. A normal prior with mean zero is used for each of 
the parameters in Equation (1), and a large variance of 10 is used to form non-informative priors 
for the parameters in the model. To ensure that the initial AR allows patients to be assigned in all 
treatment arms with reasonable probabilities, bounds of allocation probabilities between 0.2 and 
0.8 are used to guard against the extreme allocation rates. If the allocation probability to certain 
arm is less than 0.2 or greater than 0.8, the original value of allocation probability will be replaced 
by 0.2 or 0.8, and the real allocation rate will be determined by the normalized allocation 
probability by the sum of allocation probabilities to all 4 arms. Similarly, AR in Stage 2 is 
performed based on comparing the DCRs among treatments. At the time of a new patient being 
randomized, DCRs are computed from Equation (1) after incorporating all treatment, marker, and 
outcome information from all available data at the time. The randomization probability is similar 
to the one shown in Stage 1 but we do not take the square root transformation to allow more 
patients to be randomized into better arms.  Note that in both Stage 1 and Stage 2, erlotinib-naïve 
patients can be randomized to one of the four treatments while erlotinib-resistant patients will only 
be randomized to one of the three treatments (Arms 2, 3, or 4) by design.  
During AR, we also allow trial to be stopped early for the futility if all three experimental 
arms fail in all patients and in all marker groups after at least 70 patients have been treated in the 
trial.  In particular, the trial will be stopped if  
      Pr(
0)
j
jk
s








      when Z=0 
 
 
(4),    and 
                                  
s
j
jk
j











)
0
(
Pr
    when Z=1                          (5) 
for all combinations of j (j =2, 3, 4) and for all marker index k. However, the trial will not be 
stopped as long as one of the experimental arms is promising in a sub-population defined by any 
one of the markers included in the AR model. In our simulation, δ is set at -0.442 corresponding 

  
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to a 0.1 increment of DCR from 0.3.  
s is set at 0.4 to yield reasonable early stopping probabilities 
under various scenarios.  
 
11.5 Variable Selection and Model Building 
Based on our model parameterization, the prognostic effect will be characterized by a large marker 
main effect (
k
), and predictive effect will be characterized by a large marker-treatment 
interaction term (
jk

 or 
'
jk

). A marker 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 marker selection procedure through a Bayesian two-step 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 in good estimation and variable selection simultaneously85 Specifically, the first 
step of variable selection is a group selection aimed at the identification of markers with either 
prognostic effects or predictive effects. Markers without any effects will be screened out by this 
step. The second step is a step-down test to further examine each individual marker and its 
interactions with the treatments. In order to obtain more consistent estimates for the model 
parameters, we use a Bayesian version of the adaptive Lasso86 to provide finer variable selection 
and estimation in the second step. The final refined model will be used in adaptively randomizing 
patients in the second stage of the trial.    
In the first step of variable selection, we group marker main effect and marker-treatment 
interactions into a vector and apply Bayesian group Lasso method to select important markers.87,88 
In particular, let 
2
3
4
2
3
4
(
,
,
,
, ' , ' , ' )
k
k
k
k
k
k
k
k








 be the row vector of covariates 
corresponding to marker main effect, marker-treatment interaction in erlotinib-naïve and resistant 
patients respectively for marker k, then the Laplace prior for 
k
 is 


(
| )
exp
||
||
k
k







, 
where 
2
2
2
2
2
2
2 1/2
2
3
4
2
3
4
||
|| (
'
'
'
)
k
k
k
k
k
k
k
k















.  The prior for group variable 
k
 can 
be implemented through
k
2
m
~ N
( ,
)
0
I
k
k
k


, 
2
1
~ gamma(
,
)
2
2
k
k
k
m



, 
2 ~ gamma( , )
a b

, where 
mk is the dimension of 
k
, and hyperparameters a and b are 1 and 10 respectively in our simulation.  

  
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111 
 
Let 
k 
be 
a 
posterior 
sample 
of 
random 
vector
k
, 
and 
2
3
4
2
3
4
(
,
,
,
,
' ,
' ,
' )
k
k
k
k
k
k
k
k









 be the posterior mean of 
k
, we can compute the distance 
between the posterior sample and the zero vector: 
1
(
)
(
)
0
0
T
k
k
k
k









W
, where 
1
k

W
 is the 
sample variance-covariance matrix. Let 
q
 be the qth empirical quantile of 
k
, then for a given q 
we select the kth marker if 
1
T
k
k
k
q





W
. In other words, the kth marker will be selected if the 
distance between 
k
 and 0  is large enough. In our simulation, a 30% quantile of 
k
 was used for 
group selection step of variable selection. All empirical distance measures are normalized by mk 
when different marker groups have different dimensions. 
Let S be the set of markers selected in the first step, the prior distribution for {
:
}
k k
S


 
in the adaptive Lasso of the second step of variable selection is 
|
|
(
| )
exp
|
|
k
k
LS
k













, where 
k is a generic representation of either marker main effect or marker-treatment interaction and 
LS
k

 
is the least square estimation of the parameter without regularization. A variable will be selected 
if the 80% empirical posterior credible interval does not cover zero. The selections of credible 
interval in this second step and the 
q
 in the first step can be adjusted to achieve desirable false 
selection rate.  If a marker treatment interaction term is selected, the marker main effect will 
automatically be included in the AR model even though the main effect may not be significant in 
the final analysis.  
 
 
11.6 
Implementation 
11.6.1  Model updating and adaptive randomization 
In both Stage 1 and Stage 2, the corresponding model parameters will be continuously 
updated during the trial when the 8-week disease control status for each patient becomes available.  
Non-informative normal prior distributions are used to allow observed data to have major influence 
on the model.  Given the observed data, the posterior distributions of the parameters are calculated 
using the Markov Chain Monte Carlo (MCMC) method. To ensure the timely collection of the 8-
week disease control status, we have developed an e-mail notification system to alert research 

  
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nurses to schedule patient visit when a patient is 6 weeks after randomization.  The system also 
tracks the time of the 8-week endpoint being recorded. E-mail alerts will be sent out starting from 
the time when an endpoint evaluation is two weeks overdue.  Bayesian AR will be performed 
based on the updated posterior probability of DCR from the underlying logistic model at the time 
of randomizing each new patient.  A web-based application will be built to host the trial database.  
All data from the key functions including patient registration, biomarker assessment, adaptive 
randomization, and clinical follow-up including the endpoint evaluation will be entered into the 
database. 
 
11.6.2  Biomarker selection for Stage 2 adaptive randomization design 
A training-testing-validation strategy will be applied for selecting markers for Stage 2 of adaptive 
randomization in BATTLE-2. In the first stage of the trial, only one marker, KRAS mutation, is 
used to guide the initial AR. In the second stage, approximately four to six of the most robust 
prognostic and/or predictive markers will be identified for the refined AR model. We are most 
directly interested in predictive markers, but their effects will be evaluated in the light of prognostic 
markers (if any exist) for two reasons: (a) There could be interactions between the two types of 
markers. (b) Identification of the context formed by prognostic markers would increase the 
efficiency with which we can estimate the effect of a predictive marker (similar to a stratified 
analysis). Marker selection will be conducted in three steps: training, testing, and validation as 
described below.  
 
(1) Training: Gleaning from a wealth of information from the BATTLE-1 trial data, in-vitro, in-
vivo data, and the literature, we will select approximately 30 candidate markers which are likely 
to predict the treatment outcome of the four targeted treatments in the BATTLE-2 trial. These 
include the prespecified 20 markers listed in Table 11.1 as well as other promising discovery 
markers. These markers must be identified externally to the BATTLE-2 trial. 
 
(2) Testing: The candidate markers identified in the training step will be tested in Stage 1 of the 
BATTLE-2 trial in the following sequences. (a) Assessment of predictive strength: each marker 
will be evaluated for their predictive strength for each treatment.  A marker passes this screen if it 

  
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has a posterior probability of at least 0.925 that the difference in disease control rate between the 
marker positive and negative groups exceeds 20%. Specifically, each of the pre-selected markers 
or signatures will be viewed as a dichotomous variable.  In each arm of the trial, we let P be the 
DCR in the marker-positive group and let N be the DCR in the marker-negative group. We model 
the disease control R of a patient in marker group X as a binomial random variable, R ~ 
Binomial(X). We assume that both DCR parameters arise from a common beta distribution, 
Beta(a, b) and use a noninformative Jeffrey’s prior. We compute the posterior probability,  = 
Pr(|P - N|> 0.20), i.e., the difference in DCR is at least 20%. A marker passes the screening phase 
if  > 0.925 (chosen to control a 5% family-wise type I error rate in 30 markers via simulations). 
For example, if 50 patients are assigned to a treatment in Stage 1 with 5/25 (20%) DCR in the 
marker-negative group and 17/25 (68%) DCR in the marker-positive group, then  = 0.95. 
However, if there are only 10/25 (40%) DCR in the marker-positive group, then  = 0.31. The 
marker passes the screening in the former case but fails in the later case. (b) Variable selection: 
All markers that pass the assessment phase will be subject to a variable selection process applying 
a Bayesian two-step least absolute shrinkage and selection operator (Lasso) method. The Laplace 
prior is used for covariates effects to shrink covariates estimation towards zero and smaller 
covariate effects will be penalized more. Therefore, the Bayesian Lasso can result in good 
estimation and accurate variable selection simultaneously. Specifically, the first step of variable 
selection is a group selection aimed at the identification of markers with either prognostic effects 
or predictive effects. We group marker main effect and marker-treatment interactions into a vector 
and apply the Bayesian group Lasso method to select important markers. Markers without any 
effects will be dropped by this step. The second step is a step-down test to further examine each 
individual marker and its interactions with the treatments. In order to obtain more consistent 
estimates for the model parameters, we use a Bayesian adaptive Lasso to provide finer variable 
selection and estimation in the second step. A marker will be selected if the coefficient of an 80% 
highest probability interval excludes zero. The calculation incorporates uncertainty in variable 
selection and automatically prevents over-fitting of data. If more than two markers are identified 
for a given treatment, a composite marker will be formed by principal component analysis to 
choose the first few principal components that explain at least 80% of the variability. Typically, 
one or two principal components as linear combinations of predictive markers will be identified 

  
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per treatment. (c) Verification: Biomarker data from the rigorous statistical assessment and 
selection procedures will be reviewed by the internal/external advisors to ensure the validity of the 
process and efficient transition of selected markers to a CLIA-certified environment.  Upon 
verification, the refined model will be constructed to adaptively randomize patients in the second 
stage of the trial. 
 
(3) Validation: The prognostic/predictive markers identified in the testing step will be used to 
refine the predictive model, perform the AR, and validated in Stage 2 of the BATTLE-2 trial. It is 
estimated that approximately 30 candidate markers will be selected in the training step. Among 
them, 15 will pass the assessment of the markers’ predictive strength and 4 to 6 will remain after 
variable selection and verification in the testing step. These markers will be used for Stage 2 AR 
and validated accordingly.   
 
 
11.7 Simulation Results 
We assume that the true model is given in equation (1) with the parameters estimated from the 
DCRs listed in Table 11.2. Two thousand simulation runs were carried out to study the operating 
characteristics of the design.  The statistical power for testing the efficacy of the experimental 
treatments (Arms 2, 3 and 4) versus the standard treatment (Arm 1) at the end of Stage 1 is given 
in Table 11.3.  The power for the treatment main effect in naïve patients and resistant patients is 
shown in columns 2 and 3, respectively. The power for treatment effect in marker M1 subgroups 
is shown in columns 4-5 for naïve patients and in columns 6-7 for resistant patients, respectively.  
The overall treatment effect is shown in column 8 and overall trial effect (either Arm 2 or Arm 3 
or Arm 4 is effective) is shown in column 9.  Early stopping probabilities and mean sample sizes 
at the end of the first stage are shown in column 10 and 11 respectively. We choose the posterior 
probability cutoff value of 0.912 for declaring a positive treatment effect. Using this cutoff, the 
type I error rate in the null case is controlled at 10% for each treatment.  In the alternative case, 
with 200 maximum patients treated at the end of Stage 1, we have 82%, 95% and 84% power for 
testing the treatment effect for Arms 2, 3 and 4, respectively.  The overall power for the trial is 
98% in alternative case, and the overall type I error is 20% in null case. While the null case was 
stopped early 58% of the time with an average sample size of 140, the alternative case was barely 
stopped early in the 2000 simulation runs. Testing for treatment effect at the end of Stage 1 is 

  
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important for deciding whether the combinations are warranted for further development or not.  
We will also use the same posterior probability cutoff value of 0.912 at the end of stage 2 to test 
the treatment effect. The statistical power for testing the treatment effect at the end of Stage 2 will 
be sufficiently high with more patients enrolled, hence, not given. 
The marker selection probabilities for all simulation cases are shown in Table 11.4. A 
total of 15 markers were generated. Markers are selected by using credible intervals of posterior 
distribution of model parameters. A 30% quantile value of posterior distribution is used in the 
group selection. An 80% credible interval is used for the final marker selection as described in 
Section 11.4. Markers with either significant main effect (associated with Arm 1) or significant 
interactions (associated with Arm 2, 3, or 4) are defined as significant for the marginal marker 
effect.  Under the null hypothesis, the probability of selection is less than 4% in Stage 1 and less 
than 3% in Stage 2 for all markers except Marker 1(selection probabilities are 28% in both stage 
1 and stage 2). Marker 1 corresponds to Kras mutation. In both null and alternative cases, Kras positive patients 
will have a reduced response rate as compared with Kras wild type, which translate into a small negative marker 
main effect (prognostic marker) in both scenarios. Therefore, the higher selection probability of Marker 1 is 
reasonable. Under the alternative hypothesis, the probabilities of selection for M1, M2, M3, M4, 
and M5 are about 76%, 92%, 90%, 87%, and 89% at the end of Stage 2, respectively.  The 
probability of selecting unimportant marker is under 15% at the end of Stage 1 and 8% at the end 
of Stage 2. As shown in Table 11.4, M3, M4 and M5 have higher selection probabilities for 
Arms 2, 3 and 4 respectively, consistent with our model assumptions. 
The corresponding subject allocations are summarized in Table 11.5 by treatment and 
marker status. Under the null hypothesis, there is not much difference in the first and second 
stage of the proportion of treatment assignment.  Erlotinib-naïve patients are assigned slightly 
lower proportion in treatment 1, but evenly to treatment 2, 3, and 4. Erlotinib-resistant patients 
are assigned evenly to the three experimental treatments (2, 3, and 4).  Patients are also allocated 
lower proportion in treatment 1, but no differences in the treatment 2, 3, and 4 in each of the 
marker groups. Under the alternative hypothesis, erlotinib-naïve patients are assigned with 
higher proportion to Arms 2, 3 and 4 because they are more effectively than Arm 1.  For the 
erlotinib-resistant patients, although patients are still assigned about 1:1:1 to Arm 2, 3 and 4, the 
assignment rates are different in different marker groups.  In Stage 1, only M1 was used in AR, 
thus, patient allocation ratios among other markers are similar. In the second stage, M2, M3, M4, 

  
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and M5 have higher probabilities of being included in AR model. Therefore, the allocation of 
patient subgroups defined by M2, M3, M4, and M5 will be different in the second stage. For 
example, in stage2, M3+ patients are assigned more frequently to Arm 2, M4+ are assigned more 
frequently to Arm 3, and M5+ are assigned more frequently to Arm 4.  
These results indicate that the AR in both Stage 1 and Stage 2 has achieved its goal of 
treating more subjects with more effective treatments given the patients’ marker profiles. With 
model refinement in Stage 2, type I error rate is further reduced and patients are treated even 
more effectively 2 than Stage 1. As shown in the operating characteristics via simulations, the 
proposed design with a total of 400 patients in two stages can provide at least 80% statistical 
power in testing both the treatment effect and marker effect while control type I error to 10% for 
testing treatment effect and marker effect. The implement of early stopping rule was effective in 
stopping the trial early when none of the treatments works. 
 
 
 

  
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Table 11.3: Power for testing of treatment effect at the end of Stage 1, early stopping probability during Stage 1, and the mean 
sample sizes. For each treatment, the treatment effect was first tested in erlotinib naïve and resistant patients; and then 
treatment effects were tested by Marker 1 status (KRAS mutation). Therefore, 6 hypothesis tests were conducted for each 
treatment. Columns 2-7 in the table give the probabilities of rejecting the null hypothesis. The 8th column gives the 
probabilities of rejecting at least one of the six hypotheses for each experimental treatment. The value of θ used in hypothesis 
testing is 0.912, which means that the null hypothesis will be rejected if the 91.2% quantile of posterior distribution of 
treatment effect does not include zero. The column “Overall Treatment” gives the probabilities of at least one null hypothesis 
will be rejected for at least one treatment. 
 
 
Null (θ=0.912) 
Naïve 
Resistant 
Overall 
Treatment
Overall 
Trial 
Early 
Stopping 
Probability
Mean 
Sample 
Size 
Treatment
Naïve 
(Main) 
Resist 
(Main) 
M1(-) 
M1(+) 
M1(-) 
M1(+) 
Arm 2 
0.067 
0.010 
0.065 
0.023 
0.010 
0.004 
0.092 
0.199 
0.581 
140 
Arm 3 
0.075 
0.008 
0.079 
0.023 
0.008 
0.003 
0.100 
Arm 4 
0.063 
0.011 
0.062 
0.023 
0.012 
0.001 
0.088 
Alternative (θ=0.912) 
  
  
Arm 2 
0.651 
0.443 
0.529 
0.559 
0.330 
0.460 
0.823 
0.978 
0.003 
200 
Arm 3 
0.762 
0.528 
0.551 
0.857 
0.322 
0.792 
0.945 
Arm 4 
0.668 
0.456 
0.527 
0.662 
0.315 
0.567 
0.842 
 

  
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Table 11.4: Marker selection and final significance probabilities. Thirty percent and 80% posterior credible intervals were 
separately used in the group selection step and the individual step of variable selection at the end of stage 1. Therefore, in group 
selection step, a marker will be selected if the central 30% credible interval doesn’t cover zero; and in the individual selection step, 
if the central 80% credible interval doesn’t cover zero, the corresponding parameters will be selected. Similarly, an 80% posterior 
credible interval was used at the end of stage 2 to test the significance of model parameters. Markers with either significant main 
effect (in Arm 1) or significant interactions (in Arms 2, 3, or 4) are defined as significant for the marginal marker effect. 
 
 
 Null 
MK1 
MK2 
MK3 
MK4 
MK5 
MK6 
MK7 
MK8 
MK9 
MK10 MK11 MK12 MK13 MK14 MK15 
Stage 1 
Arm 1 
0.275 
0.015 
0.020 
0.010 
0.015 
0.014 
0.012 
0.011 
0.011 0.013 0.016 0.015 0.012 0.014 0.016 
 
Arm 2 
0.005 
0.010 
0.012 
0.010 
0.009 
0.008 
0.006 
0.011 
0.005 0.010 0.007 0.012 0.010 0.008 0.007 
  
Arm 3 
0.004 
0.012 
0.007 
0.010 
0.008 
0.005 
0.006 
0.009 
0.008 0.006 0.008 0.005 0.010 0.012 0.008 
  
Arm 4 
0.004 
0.009 
0.008 
0.009 
0.013 
0.005 
0.010 
0.010 
0.007 0.006 0.010 0.007 0.008 0.008 0.006 
  
Marginal Sig 
0.280 
0.038 
0.038 
0.032 
0.038 
0.029 
0.027 
0.034 
0.026 0.030 0.033 0.036 0.033 0.035 0.031 
Stage 2 
Arm 1 
0.279 
0.013 
0.015 
0.009 
0.013 
0.009 
0.010 
0.009 
0.009 0.011 0.009 0.012 0.008 0.013 0.013 
  
Arm 2 
0.002 
0.004 
0.005 
0.005 
0.004 
0.004 
0.003 
0.004 
0.002 0.002 0.004 0.002 0.003 0.005 0.002 
  
Arm 3 
0.002 
0.007 
0.003 
0.003 
0.003 
0.002 
0.003 
0.003 
0.002 0.002 0.002 0.002 0.003 0.005 0.003 
  
Arm 4 
0.001 
0.004 
0.003 
0.004 
0.005 
0.003 
0.005 
0.005 
0.003 0.002 0.005 0.001 0.005 0.003 0.004 
  
Marginal Sig 
0.280 
0.024 
0.022 
0.018 
0.022 
0.017 
0.017 
0.018 
0.014 0.017 0.018 0.016 0.018 0.022 0.020 
Alternative 
MK1 
MK2 
MK3 
MK4 
MK5 
MK6 
MK7 
MK8 
MK9 
MK10 MK11 MK12 MK13 MK14 MK15 
Stage 1 
Arm 1 
0.266 
0.789 
0.094 
0.096 
0.091 
0.065 
0.059 
0.060 
0.057 0.051 0.059 0.067 0.052 0.058 0.063 
  
Arm 2 
0.082 
0.132 
0.873 
0.066 
0.076 
0.038 
0.031 
0.031 
0.040 0.032 0.037 0.033 0.032 0.028 0.038 
  
Arm 3 
0.501 
0.129 
0.070 
0.849 
0.069 
0.033 
0.033 
0.037 
0.029 0.032 0.039 0.035 0.029 0.035 0.035 
  
Arm 4 
0.168 
0.122 
0.077 
0.073 
0.871 
0.036 
0.033 
0.031 
0.038 0.038 0.042 0.033 0.034 0.030 0.023 
  
Marginal Sig 
0.790 
0.915 
0.899 
0.875 
0.891 
0.145 
0.133 
0.134 
0.133 0.131 0.150 0.146 0.121 0.131 0.134 
Stage 2 
Arm 1 
0.419 
0.900 
0.135 
0.129 
0.132 
0.045 
0.035 
0.045 
0.039 0.031 0.046 0.042 0.040 0.039 0.045 
  
Arm 2 
0.034 
0.057 
0.863 
0.035 
0.038 
0.015 
0.016 
0.013 
0.014 0.012 0.015 0.012 0.015 0.010 0.016 
  
Arm 3 
0.401 
0.047 
0.033 
0.836 
0.035 
0.011 
0.016 
0.016 
0.008 0.014 0.016 0.012 0.013 0.015 0.014 
  
Arm 4 
0.096 
0.048 
0.031 
0.035 
0.860 
0.016 
0.012 
0.013 
0.015 0.016 0.017 0.019 0.015 0.012 0.010 
  
Marginal Sig 
0.763 
0.915 
0.895 
0.866 
0.888 
0.076 
0.072 
0.078 
0.068 0.065 0.080 0.076 0.071 0.072 0.077 

  
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Table 11.5: Patient allocation rate by treatment, erlotinib resistant of naïve status, and marker expression (positive or negative) for Stage 1 
and Stage 2 under the null and alternative hypothesis. The allocation rates to Arms 1-4 add up to 1 under each condition.  The results for 
other markers are similar to Markers 6 to 10, hence, omitted. 
 
 
Null 
Resist Naïve 
MK1- 
MK1+ 
MK2- 
MK2+ 
MK3- 
MK3+ 
MK4- 
MK4+ 
MK5- 
MK5+ 
MK6- 
MK6+ 
MK7- 
MK7+ 
MK8- 
MK8+ 
MK9- 
MK9+ MK10- MK10+ 
Stage 1 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Arm 1 
0.000 0.188 0.092 0.193 0.112 0.113 0.113 0.112 0.113 0.112 0.114 0.111 0.113 0.113 0.113 0.113 0.113 0.112 0.114 0.112 0.112 0.113 
Arm 2 
0.337 0.271 0.304 0.272 0.297 0.298 0.297 0.297 0.297 0.297 0.297 0.298 0.296 0.299 0.298 0.297 0.295 0.299 0.298 0.296 0.299 0.295 
Arm 3 
0.332 0.270 0.303 0.261 0.296 0.294 0.292 0.298 0.297 0.293 0.295 0.295 0.296 0.294 0.295 0.295 0.296 0.294 0.294 0.296 0.294 0.296 
Arm 4 
0.331 0.271 0.301 0.274 0.295 0.295 0.298 0.293 0.293 0.298 0.294 0.296 0.296 0.294 0.295 0.296 0.296 0.295 0.295 0.297 0.294 0.296 
Stage 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Arm 1 
0.000 0.210 0.126 0.128 0.128 0.126 0.128 0.126 0.126 0.128 0.128 0.126 0.128 0.126 0.127 0.127 0.125 0.128 0.126 0.128 0.127 0.128 
Arm 2 
0.346 0.263 0.295 0.300 0.292 0.299 0.294 0.297 0.295 0.296 0.296 0.295 0.296 0.296 0.296 0.296 0.296 0.296 0.296 0.296 0.298 0.293 
Arm 3 
0.331 0.263 0.291 0.284 0.290 0.290 0.290 0.290 0.291 0.288 0.290 0.290 0.289 0.291 0.292 0.288 0.291 0.289 0.289 0.291 0.288 0.291 
Arm 4 
0.323 0.265 0.288 0.287 0.291 0.285 0.288 0.287 0.288 0.288 0.286 0.290 0.288 0.287 0.286 0.289 0.288 0.288 0.289 0.286 0.287 0.288 
Alternative Resist Naïve 
MK1- 
MK1+ 
MK2- 
MK2+ 
MK3- 
MK3+ 
MK4- 
MK4+ 
MK5- 
MK5+ 
MK6- 
MK6+ 
MK7- 
MK7+ 
MK8- 
MK8+ 
MK9- 
MK9+ MK10- MK10+ 
Stage 1 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Arm 1 
0.000 0.143 0.088 0.077 0.087 0.086 0.086 0.086 0.085 0.087 0.085 0.087 0.086 0.086 0.086 0.086 0.086 0.087 0.086 0.086 0.087 0.085 
Arm 2 
0.317 0.275 0.300 0.258 0.291 0.293 0.292 0.291 0.291 0.292 0.294 0.289 0.292 0.291 0.291 0.292 0.292 0.291 0.292 0.291 0.290 0.293 
Arm 3 
0.349 0.301 0.306 0.373 0.320 0.320 0.320 0.320 0.319 0.321 0.319 0.321 0.319 0.321 0.320 0.319 0.320 0.319 0.320 0.320 0.321 0.319 
Arm 4 
0.334 0.281 0.305 0.291 0.303 0.301 0.302 0.303 0.304 0.300 0.302 0.303 0.304 0.301 0.302 0.302 0.302 0.303 0.301 0.303 0.302 0.303 
Stage 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Arm 1 
0.000 0.202 0.121 0.119 0.120 0.121 0.122 0.119 0.121 0.120 0.120 0.121 0.121 0.121 0.119 0.122 0.121 0.120 0.119 0.122 0.120 0.121 
Arm 2 
0.319 0.259 0.289 0.261 0.281 0.286 0.224 0.343 0.314 0.252 0.314 0.253 0.286 0.281 0.284 0.283 0.284 0.283 0.285 0.282 0.285 0.282 
Arm 3 
0.350 0.274 0.294 0.347 0.306 0.303 0.335 0.274 0.245 0.365 0.340 0.269 0.305 0.304 0.305 0.304 0.304 0.305 0.305 0.304 0.303 0.306 
Arm 4 
0.330 0.265 0.296 0.273 0.293 0.290 0.319 0.263 0.320 0.262 0.226 0.356 0.289 0.294 0.292 0.291 0.291 0.292 0.291 0.291 0.292 0.291 
 
Resist/Naïve: Resistance or Naïve to erlotinib treatment. MK-/MK+: Marker negative or positive group. 

  
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Appendix I 
 
 
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 II 
 
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 

  
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should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated measurements.  It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the 
next largest lesion which can be measured reproducibly should be selected.  A sum of the diameters (longest for 
non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is added into the sum.  The 
baseline sum 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, however, that the PET portion of the CT 

  
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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 markers  Tumor markers 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. 
 
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. 
 
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 

  
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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). 
 
 
 
 
 
 
 
 
 
 
 
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 marker level.  All 
lymph nodes must be non-pathological in size (<10 mm short axis) 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. 
 
 
Non-CR/Non-PD: 
 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits 
 
Progressive Disease (PD):  
Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions.  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). 
 
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. 
 
    
 
 
 
  
 
 

  
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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. 
 
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). 
 
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. 
 

  
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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 III 
 
Pathology Tissue Processing and Biomarker Analysis 
PI: Ignacio I. Wistuba, M.D. 
Co-Investigators: Heidi Erickson, Ph.D., and Raja Luthra, Ph.D. 
Collaborators: Neda Kalhor, M.D., Cesar Moran, M.D. 
 
1. Tissue Collection and Processing 
During the duration of the BATTLE-2 clinical trial, core needle biopsy (CNB) tissue and fine 
needle aspiration (FNA) specimens will be collected from each patient enrolled. Approximately 
four to five tissue cores approximately 1.5 cm long will be obtained and processed as follows: 
1.1. Tissue Specimens. Two types of tumor tissue samples will be collected from the patients: 1) 
fresh tumor CNB samples; and, 2) archival diagnostic biopsy samples obtained during tumor 
diagnostic workout that may have taken place before initiation of any systemic treatment. In 
addition to the fresh CNB, we will obtain FNA samples which will be used for assessing in the 
Interventional Radiology (IR) suite the quality of the CNB specimens.  
1.2. Tissue Collection. 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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1.3. Tissue Processing and Handling. The molecular diagnostic CNB tissues will be fixed 
immediately in the IR suite using buffered formalin and transported to MDACC Pathology 
Department for histology processing. Within 72 hours of collection, FFPE H&E-stained 
histological sections will be reviewed by our experienced lung pathologists (Drs. C. Moran or N. 
Kalhor, collaborators) to assess the presence, quantity, quality, and histological types of tumor 
tissues. The pathologist will mark in the H&E-stained slide the area of tissue containing malignant 
cells and send the molecular analysis request to the MMDL. If possible, the research CNB tissues 
will be divided in two samples: 1) two tissue cores fixed in the IR suite using buffered formalin 
and then embedded separately in paraffin for histology sectioning and exploratory molecular 
analysis; and. 2) one or two tissue cores snap-frozen in the IR suite for research molecular analysis. 
In addition to the fresh CNB tissues, the archival diagnostic biopsy specimens will be requested 
from the MDACC Pathology or outside institution files for histopathologic examination and 
banking. These specimens may vary (CNB, FNA, cell block, bronchoscopy biopsy, surgical 
resection, etc.), and depending on their characteristics could be assigned in the future for additional 
biomarker analysis. They will be examined for the same histopathological features as the fresh 
CNB specimens and filed in Dr. Wistuba’s lab files. 
 
2. Biomarker Analysis 
2.1. Diagnostic Markers.  
Three markers will be examined using the molecular diagnostic CNB specimens: EGFR (exons 
18-21) and KRAS (codons 12, 13 and 61) mutations and EML4-ALK fusion gene. These 3 tests 
will be performed by CLIA-certified laboratories.  EGFR (exons 18-21) mutation and KRAS 
(codons 12, 13 and 61) mutation tests will be performed by the CLIA-certified laboratory at 
MDACC. ALK FISH evaluation to detect the EML4-ALK fusion gene translocation will be 
performed by the CLIA certified Colorado University Molecular Correlates Laboratory. 
 
Marileila Varella Garcia, PhD 
Professor 
Colorado Molecular Correlates Laboratory 
SOM/Department of Pathology 

  
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Anschutz Medical Campus 
12801 East 17th  Ave, L18-8118 
Aurora, CO, 80045 
Phone 303-724-3147 
Fax 303-724-3889 
E-mail marileila.garcia@ucdenver.edu 
Only MDACC participants will have their specimen sent to Colorado University Molecular 
Correlates laboratory for the ALK FISH evaluation.  Yale participants will have specimen analyzed 
onsite for ALK FISH evaluation. 
 
2.2. Exploratory Markers.  A series of exploratory molecular markers will be examined in Dr. 
Wistuba’s lab. The results of these markers will not be used to assign treatment to patients. These 
markers will include, among others, protein expression by immunohistochemistry and reverse 
phase protein analysis, gene expression, copy number and mutation markers by various 
methodologies. The analysis of the exploratory markers will be performed and reported in batches 
by Dr. Wistuba’s lab to the clinical trial investigators. 
 
 

  
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Appendix IV:  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             quinine 
aripiprazole         sildenafil 
buspirone             tamoxifen 
gleevac*              trazodone 
haloperidol           vincristine 
methadone 
pimozide                             
                              
                              
 
 
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 

  
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Appendix V 
 
 
                          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 VI:  Study Procedures 
Study Procedures 
2009-0360 
 
Screening 
- 28 to 0 
 
Cycle a    
1 
Day 1 
Cycle 2 
Day 1 
± 7 
Cycle 3 
Day 1 
± 7 
Cycle 4 
Day 1 
± 7 
 
Cycle 5 
Day 1 
± 7 
Cycle 6 
Day 1 
± 7 
Subsequent 
Cycles 
End of 
Study 
 
30 Day Post 
Treatment 
Follow Up 
Long Term 
Follow-Up 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination b  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Tumor Biopsy c 
X 
 
 
X c 
 
 
 
 
 
 
 
Disease Assessment d 
(CT or MRI and Chest X-ray) 
X 
 
 
X 
 
X 
 
X d 
X 
 
 
Hematology (CBC with Diff, 
Platelets) e 
X 
X l 
X 
X 
X 
X 
X 
X 
X 
 
 
Chemistry f, g 
X 
X l 
X 
X 
X 
X 
X 
X 
X 
 
 
Coagulation Profile 
(PT/INR) g 
X 
 
 
X 
 
 
 
 
X 
 
 
Urinalysis h 
X 
 
 
 
 
 
 
 
X 
 
 
Brain MRI  
X 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
(triplicate) 
X 
X m 
 
 
 
 
 
 
X m 
 
 
MUGA/Echocardiogram 
(AZD6244 arm) i 
X i 
 
X i 
 
X i 
 
 
X i 
 
X i 
 
Serum Pregnancy Test j 
X 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic Exam k 
X 
 
X 
 
 
 
 
 
X 
 
 
Diagnostic Archival Tissue 
(Optional) 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Biomarker  
Analysis and Storage 
(Optional) n 
X 
 
 
X 
 
 
 
 
X 
 
 
AE/Toxicity Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medication(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense Study Drug 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Drug Accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subsequent Anticancer 
Therapy 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
X 

  
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a 
Cycle = 28 days 
b 
Physical exam includes height (screening only), weight, blood pressure, pulse, temperature, and ECOG Performance Status.  Full medical and smoking history will be obtained at screening 
only.  Cycle 1 Day 1 physical exam can be completed within 3 days of drug start.  If the screening exam falls outside of the 28 day window prior to drug start, both Screening exam and 
Cycle 1 Day 1 maybe the same provided criteria for both visits have been met. 
c 
The pre-biopsy ECOG performance status must be performed during a physical exam within 28 days of the protocol biopsy.  Tumor biopsy after Cycle 2 is optional 
d 
After every 2 cycles ±  7 days 
e 
Prior to each cycle  
f 
Including total protein, uric acid, BUN, creatinine, LDH, AST, ALT, alkaline phosphatase, phosphorus, total bilirubin, sodium, potassium, chloride, magnesium, calcium, albumin, CO2,  
glucose, and HBA1C.  HBA1C is performed in all subjects during screening and Arms 2 and 3 only for additional cycles and end of study.  
g 
Prior to tumor tissue biopsy. As per standard of care if patient is on warfarin or other anticoagulant 
h 
Including routine dipstick measurements, microscopic analysis, and urine protein. 
i   
At screening MUGA/echocardiogram to be performed at screening (within 4 weeks before planned first dose) for all subjects.   
For subjects on Arm 3 only - MUGA/Echo cardiogram at Week 6 +/- 7 days, 3 months +/- 7 days, and every 3 months +/- 7days while on study (and as clinically warranted) and 30 days 
+/- 7 days after study drug discontinuation  
j 
To be performed at screening.  A serum or urine pregnancy test will be repeated within 72 hours prior to dosing for women of childbearing potential and as needed 
k 
Ophthalmologic Exam at screening for subjects in Arms 2 and 3.  Subjects on Arms 2 & 3 will have eye exam after 4 weeks and at end of study.  
l 
Only performed if previous pre-treatment evaluations are not conducted within 28 days prior to initiating study therapy 
m 
Arms 2 and 3 only. C1D1 – Pre-dose and 4 hour (+/- 15 min) Post-dose. End of study ECG for Arm 3 only.  
n 
Optional blood samples for biomarkers will be collected at screening, end of Cycle 2, and at end of study. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Appendix VII:  LVEF Algorithm 
 
 

  
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Appendix VIII 
 
MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL 
AND/OR INDUCE TORSADES DE POINTES (TDP) 
It has been recognized for a number of years that certain prescription medications can prolong the QT/QTc interval 
and cause a form of acquired Long QT syndrome, known as drug induced LQTS. The drugs that prolong the QT 
interval and/or have a risk of inducing Torsade de Pointes (TdP) are listed below. We have divided these into two 
groups based on their known or perceived risk of causing TdP: 
Group 1 - Drugs that are generally accepted by authorities to have a risk of causing Torsades de Pointes 
Concomitant use of these drugs is not allowed during the study or within 2 weeks of study start (at least four weeks 
for levomethadyl). These drugs should also be avoided for up to 4 weeks following discontinuation of study 
treatment: 
Group 1 Drugs 
Drug (Generic Names) 
 
 Drug Class  
 
 
 
(Clinical Usage)  
Albuterol (inhaled acceptable)  
Bronchodilator 
 
 
  
(asthma)  
Amiodarone   
 
 
Anti-arrhythmic   
 
 
(heart rhythm)  
Arsenic trioxide  
 
 
Anti-cancer  
 
 
 
(leukaemia)  
Bepridil  
 
 
 
Anti-anginal  
 
 
 
(heart pain)  
Chlorpromazine  
 
 
Anti-psychotic/antiemetic  
 
(schizophrenia/nausea) 
Chloroquine   
 
 
Anti-malaria  
 
 
 
(malaria infection) 
Cisapride  
 
 
 
GI stimulant  
 
 
 
(stimulates GI motility) 
Disopyramide  
 
 
Anti-arrhythmic   
 
 
(heart rhythm)  
Dofetilide  
 
 
 
Anti-arrhythmic   
 
 
(heart rhythm) 
Domperidone  
 
 
Anti-nausea  
 
 
 
(nausea) 
Droperidol   
 
 
Sedative/hypnotic  
 
 
(anaesthesia adjunct) 
Erythromycin  
 
 
Antibiotic/GI stimulant 
 
 
(infection/GI) 
Halofantrine  
 
 
Anti-malarial  
 
 
 
(malaria infection)  
Haloperidol   
 
 
Anti-psychotic   
 
 
(schizophrenia, agitation) 
Ibutilide  
 
 
 
Anti-arrhythmic   
 
 
(heart rhythm)   
Levomethadyl  
 
 
Opiate agonist  
 
 
 
(narcotic dependence) 
Mesoridazine  
 
 
Anti-psychotic   
 
 
(schizophrenia) 
Methadone  
 
 
Opiate agonist  
 
 
 
(pain control/narcotic dependence) 
Pentamidine   
 
  
Anti-infective  
 
 
 
(pneumocystis pneumonia) 
Pimozide  
 
 
 
Anti-psychotic   
 
 
(Tourette's tics)  
Procainamide  
 
 
Anti-arrhythmic   
 
 
(heart rhythm) 
Quinidine  
 
 
 
Anti-arrhythmic   
 
 
(abnormal heart rhythm) 
Salbutamol   
 
 
Bronchodilator   
 
 
(asthma)  
Sotalol  
 
 
 
Anti-arrhythmic   
 
 
(heart rhythm)  
Sparfloxacin  
 
 
Antibiotic  
 
 
 
(bacterial infection) 
Thioridazine  
 
 
Anti-psychotic     
 
 
(schizophrenia) 
 
 
 
Group 2. - Drugs that in some reports may be associated with Torsades de Pointes but at this time lack 
substantial evidence of causing Torsades de Pointes. 
Group 2 Drugs 
Drug (Brand Names)   
 
Drug Class  
 
 
 
   (Clinical Usage)  
Alfuzocin  
 
 
 
Alpha 1-blocker   
 
 
 (Benign prostatic hyperplasia) 
Amantadine   
 
 
Dopaminergic/Anti-viral/Antiinfective 
 (Parkinson’s disease) 
Amitriptyline  
 
 
anti-depressant 
 
 
 
(depression) 
Amoxapine  
 
 
anti-depressant 
 
 
 
(depression) 
Azithromycin  
 
 
Antibiotic  
 
 
 
(bacterial infection) 
Citalopram   
 
 
Anti-depressant   
 
 
(depression) 
Clarithromycin  
 
 
Antibiotic  
 
 
 
(bacterial infection)  
Clomipramine  
 
 
antidepressant 
 
 
 
(depression) 
Chloral hydrate 
 
 
Sedative  
 
 
 
(sedation/insomnia) 

  
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Clozapine  
 
 
 
Anti-psychotic 
 
 
 
(schizophrenia) 
Desipramine  
 
 
anti-depressant 
 
 
 
(depression) 
Dolastron  
 
 
 
Anti-nausea  
 
 
 
(nausea and vomiting) 
Doxepin  
 
 
 
Anti-depressant   
 
 
(depression)  
Felbamate   
 
 
Anti-convulsant   
 
 
(seizures) 
Flecainide   
 
 
Anti-arrhythmic   
 
 
(heart rhythm)  
 
Fluconazole  
 
 
Anti-fungal  
 
 
 
(fungal infection) 
Fluoxetine   
 
 
Anti-depressant   
 
 
(depression) 
 
Foscarnet  
 
 
 
Antiviral  
 
 
 
(HIV infection) 
Fosphenytoin  
 
 
Anticonvulsant   
 
 
(seizures) 
Gatifloxacin   
 
 
Antibiotic  
 
 
 
(bacterial infection) 
Gemifloxacin  
 
 
Antibiotic  
 
 
 
(bacterial infection) 
Granisetron   
 
 
Anti-nausea  
 
 
 
(nausea and vomiting) 
Imipramine   
 
 
Anti-depressant   
 
 
(depression, pain, other) 
Indapamide   
 
 
Diuretic  
 
 
 
(stimulates urine & salt loss) 
Isradipine  
 
 
 
Anti-hypertensive  
 
 
(high blood pressure) 
Levofloxacin  
 
 
Antibiotic  
 
 
 
(bacterial infection)  
Lithium  
 
 
 
Anti-mania  
 
 
 
(bipolar disorder) 
Mexilitine   
 
 
Anti-arrhythmic   
 
 
(abnormal heart rhythm) 
Moexipril/HCTZ   
 
 
Anti-hypertensive  
 
 
(high blood pressure) 
Moxifloxacin  
 
 
Antibiotic  
 
 
 
(bacterial infection) 
Nicardipine   
 
 
Anti-hypertensive  
 
 
(high blood pressure) 
Nortriptyline  
 
 
Antidepressant 
 
 
 
(depression) 
Octreotide 
 
 
 
Endocrine 
 
      
 
(acromegaly/carcinoid diarrhea) 
Ofloxacin 
Ondansetron  
 
 
Anti-emetic  
 
 
 
(nausea and vomiting) 
Paroxetine   
 
 
Anti-depressant   
 
 
(depression) 
Protriptyline  
 
 
Antidepressant 
 
 
 
(depression) 
Quetiapine   
 
 
Anti-psychotic   
 
 
(schizophrenia) 
Risperidone   
 
 
Anti-psychotic   
 
 
(schizophrenia) 
Roxithromycin  
 
 
Antibiotic  
 
 
 
(bacterial infection) 
Salmeterol   
 
 
Sympathomimetic 
 
 
(asthma, COPD) 
Sertraline  
 
 
 
Antidepressant   
 
 
(depression)  
Solifenacin   
 
 
Muscarinic receptor antagonist 
 
(treatment of overactive bladder) 
Tacrolimus   
 
 
Immune suppressant  
Tamoxifen   
 
 
Anti-cancer  
 
 
 
(breast cancer) 
Telithromycin  
 
 
Antibiotic 
 
  
 
(bacterial infection) 
Tizanidine   
 
 
Muscle relaxant 
Trimipramine  
 
 
Tricyclic antidepressant   
 
(depression) 
Vardenafil   
 
 
Phosphodiesterase inhibitor 
 
(vasodilator) 
Venlafaxine   
 
 
Antidepressant   
 
 
(depression)  
Voriconazole  
 
 
Anti-fungal  
 
 
 
(fungal infection) 
Ziprasidone   
 
 
Anti-psychotic   
 
 
(schizophrenia) 
 
 

  
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Appendix IX:   
Volumetric CT 
Individual patients would benefit from the development of more sensitive technologies for 
diagnosing progressive disease.  Earlier diagnoses of progressive disease will spare patients from 
the toxicities associated with futile treatments and access alternative therapies sooner.  Oncology 
drug development trials rely primarily on the post-treatment assessment of tumor size changes 
using uni-dimensional line-lengths measured by electronic calipers in addition to OS or PFS.  
RECIST has inherent limitations, which arise in large part from the heterogeneous shapes that 
tumors assume within disease microenvironments.  While RECIST might be an effective criteria 
in the setting of perfectly spherical tumors that change size in a uniform fashion upon following 
treatment with cytoxic or targeted therapies, tumor morphologies that do not manifest this 
idealized shape can be challenging to evaluate for changes in size using uni-dimensional line 
lengths.  In a review, Shankar and colleagues noted that simple anatomical outcome measures can 
(1) underestimate the benefits of targeted therapies that prolong survival despite no visual 
evidence of tumor shrinkage, (2) signal misleading indications of disease progression when 
tumors swell due to bleeding, edema, etc., and (3) fail to reflect the appearance of new neoplastic 
tissues within complex masses [1].   
In order to more sensitively and specifically detect early responses to drug therapies, software 
algorithms that detect lesions in CT scans and render volumetric and density measurements are 
now under development and clinical testing.  For example, a recent study from Memorial Sloan-
Kettering Cancer Center (MSKCC) demonstrated that a semi-automated algorithm was able to 
accurately segment 14 out of 15 patient tumors imaged in thin section CT scans [2].  In this 
response-to-therapy study, patients were treated with gefitinib following a baseline CT scan.  A 
follow up CT scan at 3 weeks, when analyzed using a semi-automated volumetric image analysis 
algorithm, showed that 73% of patients had an absolute change in tumor volume of at least 20%.  
In contrast, only 7% and 27% of patients showed similar changes in their tumor sizes following 
gefitinib therapy using either uni-dimensional measurements or bi-dimensional measurements, 
respectively.  As a next step, the investigators assessed whether a 30% change in tumor size could 
be detected in a subset of patients at 3 weeks following gefitinib treatment.  In this case, a change 
in tumor size of at least 30% was observed in 47% of patients following 3 weeks of therapy.  On 
the other hand, no patient tumors met this threshold using uni-dimensional measures and 13% of 
patient tumors met this threshold using bi-dimensional measures.  This promising study indicates 
that CT scans, when analyzed for volumetric changes, can be used to detect treatment responses 
to targeted therapies in weeks, more akin to functional imaging than to standard uni-dimensional 
measures of disease change.  However, a weakness of this data set is that the degree to which 
these volumetric changes in tumor size at 3 weeks following commencement of therapy predicts 
long term response to therapy was not assessed. 
The reproducibility of the volumetric CT in a variety of disease settings must be determined if 
volumetric image analysis is to be routinely utilized for patient care and for therapy response 
monitoring in drug development trials.  One recent study evaluated the reproducibility of a 
commercially available (Siemens) semi-automated image analysis software program in the setting 
of isolated tumor nodules in lung cancer patients (218 nodules in all) [3].  Patients received two 

  
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low dose chest CT scans for the volumetric image analysis study.  These serial scans were 
interrupted by the patients getting off the table and returning to the table for the subsequent scan 
(so-called "coffee break" experiment).  The 95% confidence interval for differences in measured 
volumes was -21.2%, 23.8% (with a mean difference of 1.3%).  Based on this data, an increase of 
a nodule volume above 23.8% or a decrease in nodule volume of more than 21.2% could be 
attributed to real changes in disease (with 95% confidence).  In addition, if a patient's nodule could 
be completely segmented by the software tool, then the interscan variability was -11.9% to 12.4%.  
On the other hand, if incompletely segmented nodules were evaluated, the variability was more 
than twice as large (-26.8% to 30.0%).  Clearly, the ability of a volumetric image analysis 
algorithm to segment a tumor within an image plays an important role in reproducibility of that 
tool in clinical settings. 
This study will evaluate the utility of tumor volumes measured using volumetric image analysis 
tools and will correlate with RECIST.  This data set will not only help inform the design of future 
clinical trials for drug development, it will also make a significant contribution to the development 
of volumetric imaging tools for day to day management of lung cancer patients receiving standard 
of care treatments.   
1. Shankar L.K., Van den Abbeele A, Yap J, Benjamin R, Scheutze S, Fitzgerald T.J.  
Considerations for the use of imaging tools for Phase II treatment trials in oncology.  Clin 
Cancer Res 2009; 15 (6):  1891-1897.   
 
2. Zhao B, Schwartz L.H., Moskowitz C.S., Ginsberg M.S., Rizvi N.A., Kris M.G.  Lung cancer: 
computerized quantification of tumor response--initial results. Radiology 2006 Dec; 241(3):  
892-898.  
 
3. Gietema H.A., Schaefer-Prokop C.M., Mali W.P., Groenewegen G, Prokop M.  Pulmonary 
nodules: Interscan variability of semiautomated volume measurements with multisection CT-- 
influence of inspiration level, nodule size, and segmentation performance. Radiology 2007 Dec; 
245(3):888-894.  Epub 2007 Oct 8. 
 
4. van der Veldt A A.M., Meijerink M.R., van den Eertwegh A J.M., Bex A, de Gast G, Haanen J 
B.A.G., Boven E.   Sunitinib for Treatment of Advanced Renal Cell Cancer: Primary Tumor 
Response. Clin Cancer Res 2008 April 15; 14: 2431. 

  
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Appendix X:  Algorithm for Dyspnoea
 
 
Perform Chest X-ray, PA and lateral 
views, echocardiogram, BNP, 
Troponin I and ECGs to establish 
possible cause of dyspnoea 
New AE of dyspnoea or 
worsening of pre-
existing dyspnoea >1 
CTC grade 
No obvious underlying cause of 
dyspnoea found on preliminary 
investigations listed above 
If test results indicate clinical diagnosis 
e.g. pleural effusion, heart failure or 
pneumonia, underlying condition 
should be managed according to local 
protocols.  
Perform High Resolution CT scan.  
Consider respiratory consultation 
Stop study treatment and 
institute appropriate 
management as per local 
practice 
Continue to dose 
study treatment 
HRCT does demonstrate 
interstitial lung disease 
HRCT does not 
show interstitial 
lung disease 
Further evaluation 
required: Seek cardiology 
and/or respiratory consult 
if not already performed. 
 
Consider dose interruption 
Dyspnoea AE 
not resolved 
Dyspnoea AE 
resolved 
If AE considered at least 
potentially related to study 
drug, also consider dose 
interruption and/or dose 
reduction  
If AE considered not 
related to study drug, 
continue at previous 
dose  

  
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Appendix XI:   
Instructions on How to Prepare a Sorafenib Liquid Suspension 
Introduction 
Rapidly disintegrating 200 mg Sorafenib tosylate (Nexavar®) tablets are available for treatment of cancer. 
 
Some patients are unable to swallow Sorafenib tosylate Tablets due to their disease and the tablet size. In these 
cases a Sorafenib tosylate suspension can be prepared and applied by dissolving  two 200 mg tablets in drinking 
water and either swallowing directly by mouth or ingesting via gastrostomy tube.  
 
This instruction describes the making of a liquid suspension for oral application from two 200 mg Sorafenib 
tosylate tablets and drinking water.  
 
It is important to prepare your medication by following these directions exactly as written.  Please ask your study 
doctor or nurse if you have any questions about how to prepare your medication in this manner.  Remember to 
write down any deviations from this procedure and report to your study doctor or nurse. 
 
Materials 
 Two tablets:  
 
 
200 mg Sorafenib (BAY 43-9006 TABL 0.2G TOS 207 COAT)  
Dose: 
 
 
 
Two 200 mg Sorafenib tosylate tablet = 400 mg 
 Water or mineral water (without gas): Approximately 100 ml or 3.5 oz 
A drinking glass and a spoon 
A watch 
A measuring cup 


Preparation of the drinking suspension 

Fill the drinking glass with 40 ml (1.5 oz) of drinking water 

Place two 200 mg Sorafenib tablets into the drinking water. Record the time.  

Begin stirring after approximately 5 minutes. The disintegrating tablets will form a fine particular suspension. 
Continue stirring until the tablets are completely disintegrated. The tablet coating may initially form a thin film. 
However, this has no impact on dosing accuracy. Typically the suspension is ready for application after 10 minutes.  
 
Application of the suspension  

Administration of the suspension must be done within one hour after preparation. 

The suspension may be applied directly by mouth if you are able to swallow. In this case stir the  suspension 
thoroughly prior to application and rinse the drinking glass at least two times with a minimum of 10 ml (1/3 oz) 
drinking water to apply all active ingredients.  

If you are unable to swallow, you may receive the medication through a gastrostomy tube. In these cases stir 
the suspension thoroughly and withdraw the suspension subsequently from the glass with the 10 ml syringe that is 
part of the gastrostomy tube set. The suspension is then transferred into the gastrostomy tube via the adapter piece. 
Rinse the drinking glass at least twice with 10 ml water and apply the suspension with the remaining active 
ingredient. Finally rinse the gastrostomy tube with a minimum of 10 ml (1/3 oz) drinking water.  
 
This procedure will result in application of a 400 mg dose.

  
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Appendix XII:    Blood-based Biomarkers 
 
 
Isolation of circulating tumor cells (CTC) and molecular analysis of these CTCs including 
mutational profiling. 
 
We will be isolating CTCs by antibody-based method such as the current platform developed by 
Haber et al in the work with our Stand-Up 2 Cancer grant (SU2C). This method utilizes a CTC-
chip with antibody capturing technique (EpCam) and microfluidics as 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 

  
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comparable to that of ELISA (8-10).  Currently up to 50 human cytokines can be analyzed from 
3 separate kits (27-, 21 & 2-plex).  Typical sample volume required for each sample well ranges 
from 2 to 100 L. In addition, a 12-plex multiplex panel will be used to evaluate for EGFR 
related proteins such as amphiregulin, epiregulin, soluble EGFR, EGF, HB-EGF, Betacellulin 
(EMD-Millipore).   Human CVD Biomarker Panel 1 (3-plex includes MMP-9 and sE-Selectin) 
from Millipore.  The remainder of analytes will be determined using by validated, enzyme-linked 
immunosorbent assays (ELISA) assays such as Human Osteopontin (OPN), CA-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 
the rare case that the repeat CV% is greater than 25%, one of the two analyses will be selected 
based on lower CV% and consistency with prior values. 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 of response we will investigate germline SNPs that met at least two of 
three criteria: (a) minor allele frequency of at least 5%; (b) location in the promoter, untranslated 
region (UTR), or coding region of the gene; and (c) previous report of an association with an 
inflammatory disorder, angiogenesis, lung cancer, or another cancer.  Coding SNPs are described 
according to the amino acid change, whereas other SNPs are described according to the 
nucleotide change or location in the UTR. The method below has been applied successfully; 
other multiplexed technologies are also being tested and could but substituted if performance is 
superior. The SNPs will be genotyped using 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). Briefly, a list of candidate SNPs are submitted to 
Applied Biosystems, which evaluated the SNPs for suitability for the assay and designed a pool 
of SNP specific ligation probes.  Genomic DNA is then fragmented at 99C for 10 min, and 37 ng 
of fragmented DNA was dried down on each well of a 384-well plate. The SNP-specific ligation 
probes and a universal linker are phosphorylated and ligated together, and the mixture was then 
treated with exonuclease. Following purification, the probe mixture is added to the genomic 
DNA, and amplified by PCR in the presence of biotinylated universal primers. The biotinylated 
amplicons are denatured and captured on streptavidin-coated plates. To decode the genotype 
information, single-stranded PCR products were hybridized with a universal set of fluorescent 
dye-labeled, mobility-modified fragments (Zipchutes, Applied Biosystems), which were then 
eluted and separated with the Applied Biosystems 3730 Capillary DNA Analyzer.  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. Genotypes are called by Applied 
Biosystems GeneMapper software, using an analysis template file provided with each custom 
SNPlex assay.  
 
 

  
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1. 
Byers, L.A., Holsinger, F.C., Kies, M.S., William, W.N., El-Naggar, A.K., Lee, J.J., Hu, 
J., Lopez, A., Tran, H.T., Yan, S., et al. 2010. Serum signature of hypoxia-regulated 
factors is associated with progression after induction therapy in head and neck squamous 
cell cancer. Mol Cancer Ther 9:1755-1763. 
2. 
Kopetz, S., Hoff, P.M., Morris, J.S., Wolff, R.A., Eng, C., Glover, K.Y., Adinin, R., 
Overman, M.J., Valero, V., Wen, S., et al. 2010. 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 28:453-459. 
3. 
Hanrahan, E.O., Lin, H.Y., Kim, E.S., Yan, S., Du, D.Z., McKee, K.S., Tran, H.T., Lee, 
J.J., Ryan, A.J., Langmuir, P., et al. 2010. 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. 
4. 
Hanrahan, E.O., Ryan, A.J., Mann, H., Kennedy, S.J., Langmuir, P., Natale, R.B., Herbst, 
R.S., Johnson, B.E., and Heymach, J.V. 2009. Baseline vascular endothelial growth 
factor concentration as a potential predictive marker of benefit from vandetanib in non-
small cell lung cancer. Clin Cancer Res 15:3600-3609. 
5. 
Nikolinakos, P.G., Altorki, N., Yankelevitz, D., Tran, H.T., Yan, S., Rajagopalan, D., 
Bordogna, W., Ottesen, L.H., and Heymach, J.V. 2010. 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 70:2171-2179. 
6. 
Schneider, B.P., Wang, M., Radovich, M., Sledge, G.W., Badve, S., Thor, A., Flockhart, 
D.A., Hancock, B., Davidson, N., Gralow, J., et al. 2008. 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 26:4672-4678. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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APPENDIX XIII: 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.