Pilot Trial of Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung, Carcinoma, Small Cell Lung, Carcinoma, Thymic
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: Molecular Profiling NSCLC 
Version Date: 01/07/2020 
 
Abbreviated Title: 
Molecular Profiling NSCLC 
CC Protocol #: 
11-C-0096 V 
Version Date: 
January 7, 2020 
NCT Number: 
NCT01306045 
 
TITLE: 
Pilot Trial of Molecular Profiling and Targeted Therapy for 
Advanced Non-Small Cell Lung Cancer, Small Cell Lung 
Cancer, and Thymic Malignancies 
Coordinating Center: 
 
 
Center for Cancer Research / National Cancer Institute 
10 Center Drive 
Bethesda, MD 20892 
 
NCI Principal Investigator:  
Arun Rajan, MD  
Thoracic and GI Malignancies Branch / CCR / NCI 
9000 Rockville Pike 
Bldg 10, Rm 4-5332 
Bethesda, MD 20892 
Telephone: 240-760-6236 
Email rajana@mail.nih.gov 
 
 
 
 
 
 
 
 
 
 
 
Drug Sponsor: 
 
 
CTEP, NCI 
CTEP Protocol #: 
 
 
8639 
 
Study Drug 
AZD6244 
MK-2206 
Lapatinib 
Erlotinib 
Sunitinib 
NSC # 
748727 
749607 
727989 
718781 
736511 
IND # 
77782 
109493 
70252 
63383 
Commercial Supply 
NOTE:  Trial administratively completed with CTEP 03/22/2016; trial remains open under 
NIH Intramural IRB for molecular profiling arm only 
 
 
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PRÉCIS 
Background 
• A better understanding of the genetic make-up of the individual tumor may offer 
potentially improved therapies.  This approach may also give rapid access to response 
data in patients with sometimes rare genetic abnormalities.   
• In addition, it will allow us to test targeted therapies in a select population of patients that 
is more likely to have a favorable response based on their molecular profile and the 
specific mechanism of action of the drug being tested.   
• This approach will also speed up drug development and potentially approval, and rescue 
an otherwise ineffective drug candidate for the specific subgroup that can benefit. 
Primary Objectives 
• To determine the feasibility of the use of tumor’s molecular profiling and targeted 
therapies in the treatment of advanced stage non-small cell lung cancer (NSCLC), small 
cell lung cancer (SCLC) and thymic malignancies. 
• To estimate the response rate of molecular-profile directed treatments in NSCLC, SCLC 
and thymic malignancies patients. 
Eligibility 
• Patients with histologically confirmed advanced lung cancer or thymic malignancies for 
whom surgical resection with curative intent is not feasible. 
• Patients must either have biopsiable disease and be willing to undergo biopsy for 
molecular profiling or have paraffin embedded tissue blocks suitable for molecular 
profiling analysis. 
• Individuals are eligible for EGFR germline mutation testing if they have:  
o a personal history of invasive lung cancer or one of the pre-invasive histologies 
associated with the development of lung cancer and more than two affected family 
members with invasive lung cancer or one of the pre-invasive histologies associated 
with the development of lung cancer; OR  
o a first-degree relative with a known EGFR germline mutation (EGFR exon 20 
T790M, exon 21 V843I, exon 21 R831C and exon 20 R776G). 
Design 
• All patients will have their tumors undergo molecular profiling.  Based on these results 
and on other eligibility criteria, the patients will be offered enrollment into different 
targeted therapy arms according to the schema shown below. 
• At the NCI site only, individuals eligible for EGFR germline mutation will undergo 
testing for germline mutations affecting the EGFR gene; if a mutation is detected, their 
first-degree relatives would be invited to undergo testing for the index germline mutation 
found in the proband and appropriate follow-up on trial. 
• Effective with Amendment I, the participating site, OHSU, will discontinue new 
enrollments and data entry for existing patients on the NOS arm on this protocol in favor 
of the OHSU protocol L8639, “Personalized Cancer Medicine Registry.”  The data from 
these patients will be included with the data from 11-C-0096 (8639) NCI patients at the 
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time of publication.  Any OHSU patients who are eligible for a treatment arm will 
continue to be enrolled and followed per protocol.     
 
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Schema 
 
 
 
EGFR germline 
mutation testing in 
eligible patients† 
A 
Biopsy and 
molecular  
profiling 
EGFR  
Mutation* 
KRAS,  HRAS 
NRAS, or 
BRAF, 
 Mutation* 
PTEN 
Akt  or PI3K 
Mutation or 
PI3K Amp* 
ERBB2 
Mutation 
or  
Amp* 
KIT, 
PDGFR-A  
Mutation 
or 
Amp* 
Other* 
Erlotinib 
AZD6244 
MK2206 
Lapatinib 
Sunitinib 
NOS 
Disease 
Progression 
A 
Yes 
Yes 
Yes 
Yes 
Yes 
No 
No 
No 
No 
No 
* See Sections 3.2 and 3.3 for eligibility criteria for the treatment arms.  Patients will be 
allowed to crossover to different treatment arms as long as they meet eligibility criteria. 
† See separate eligibility criteria (Section 3.4) and schema for EGFR germline mutation 
testing. 
No = No or not available 
Amp = gene amplification by FISH 
NOS = non-otherwise specified arm 
         = optional re-biopsy for patients that responded to previous line of therapy 
A 
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Schema: EGFR Germline Mutation Testing 
 
1 Consent II: Informed consent for testing for EGFR germline mutations of proband. 
2 EGFR germline mutation panel: EGFR exon 20 T790M, exon 21 V843I, exon 21 R831C and 
exon 20 R776G. 
 
 
Eligible patients for EGFR 
germline mutation testing 
History and Physical exam 
Pre-test genetic 
counseling
1Consent II
2EGFR germline mutation 
panel testing
No EGFR germline 
mutations 
Result disclosure and post-test genetic counseling 
Mangement of invasive carcinoma/pre-invasive histology 
per standard guidelines
EGFR germline mutation/s 
positive 
Result disclosure and post-test genetic counseling
Mangement of invasive carcinoma/pre-invasive histology 
per standard guidelines
All first-degree relatives invited to participate in the study 
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1 Between 55 and 74 years of age at enrollment with a history of cigarette smoking of at least 30 pack-years, and, 
if former smokers, those who quit within the previous 15 years.  
2 Age ≥ 45 years at enrollment with ≥ 20 pack-year smoking history or age within 5 years before the youngest 
family member was diagnosed with lung cancer. 
3 For lung nodules and incidental lesions detected on CT, follow up is per standard guidelines. 
Consent III: Informed consent for testing for EGFR germline mutations in first-degree relatives of individuals with 
known EGFR germline mutations.  
Abbreviation: LDCT, low-dose screening computed tomography scan. 
Follow-up of lung nodules recommended by Fleischner Society (1) and National Comprehensive Cancer 
Network(2)(2)(2).
History and Physical Exam 
Pre-test genetic counseling 
Consent III 
EGFR germline testing of index mutation found in proband 
Mutation negative 
Result disclosure and post-test 
genetic counseling  
1High risk  
Annual LDCT 
screening for at 
least 3 years and 
until age 74 
Mutation positive 
Result disclosure and post-test 
genetic counseling  
2High risk 
3Baseline CT 
followed by 
annual LDCT 
screening for at 
least 3 years and 
until age 74 
Not high risk 
≥ 20 pack-year smoking history 
< 20 pack-year smoking history 
LDCT at 1 year intervals for  
3 years starting 5 years before the 
youngest family member was 
diagnosed with lung cancer or 
age 45 (whichever one earlier) 
No baseline CT  
Baseline CT followed by LDCT 
at 1 year intervals for 3 years 
starting 5 years before the 
youngest family member was 
diagnosed with lung cancer or 
age 45 (whichever one earlier) 
Not high risk  
No further 
intervention 
First-degree relatives of patient with EGFR germline 
mutation (proband) 
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Table of Contents 
PRÉCIS ........................................................................................................................................... 2 
SCHEMA ........................................................................................................................................ 4 
TABLE OF CONTENTS ................................................................................................................ 7 
TABLE OF TABLES ................................................................................................................... 10 
1 
OBJECTIVES ....................................................................................................................... 11 
1.1 
PRIMARY PROTOCOL OBJECTIVES .................................................................................. 11 
1.2 
SECONDARY PROTOCOL OBJECTIVES ............................................................................. 11 
2 
BACKGROUND .................................................................................................................. 11 
2.1 
BACKGROUND AND RATIONALE..................................................................................... 11 
2.2 
CTEP-SUPPLIED INVESTIGATIONAL AGENT(S) .............................................................. 28 
2.3 
OTHER AGENTS .............................................................................................................. 28 
2.4 
HYPOTHESIS ................................................................................................................... 28 
3 
PATIENT SELECTION ....................................................................................................... 28 
3.1 
ELIGIBILITY CRITERIA FOR INITIAL ENROLLMENT .......................................................... 28 
3.2 
ELIGIBILITY CRITERIA FOR ENROLLMENT INTO THE TREATMENT ARMS (TREATMENT 
ARMS ARE NO LONGER RECRUITING AS OF 3/22/16) ................................................................... 29 
3.3 
SPECIFIC ELIGIBILITY CRITERIA FOR ENROLLMENT IN TREATMENT ARMS (TREATMENT 
ARMS ARE NO LONGER RECRUITING AS OF 3/22/16) ................................................................... 31 
3.4 
ELIGIBILITY CRITERIA FOR EGFR GERMLINE MUTATION TESTING (NCI SITE ONLY) ...... 34 
3.5 
INCLUSION OF WOMEN AND MINORITIES ....................................................................... 35 
4 
PATIENT REGISTRATION ................................................................................................ 36 
4.1 
REGISTRATION PROCESS ................................................................................................ 36 
4.2 
ON-STUDY RESEARCH EVALUATION ............................................................................. 37 
5 
STUDY DESIGN / TREATMENT PLAN ........................................................................... 37 
5.1 
SPECIMEN COLLECTION ................................................................................................. 38 
5.2 
MOLECULAR PROFILING ................................................................................................ 38 
5.3 
ENROLLMENT IN TREATMENT ARMS ............................................................................... 39 
5.4 
TREATMENT AFTER DISEASE PROGRESSION .................................................................... 41 
5.5 
THE NOS ARM ............................................................................................................... 41 
5.6 
EGFR GERMLINE MUTATION TESTING ........................................................................... 42 
5.7 
AGENT ADMINISTRATION .............................................................................................. 48 
5.8 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............... 50 
5.9 
PROTOCOL EVALUATION ............................................................................................... 53 
5.10 
DURATION OF THERAPY / OFF TREATMENT CRITERIA ..................................................... 53 
5.11 
DURATION OF FOLLOW UP .............................................................................................. 54 
5.12 
OFF STUDY CRITERIA .................................................................................................... 54 
5.13 
OFF-STUDY PROCEDURE ................................................................................................ 54 
6 
DOSING DELAYS/DOSE MODIFICATIONS .................................................................. 55 
6.1 
CTEP AGENTS ............................................................................................................... 55 
6.2 
OTHER AGENTS .............................................................................................................. 63 
6.3 
TREATMENT DELAYS AND MODIFICATIONS FOR ADMINISTRATIVE NEEDS ...................... 68 
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6.4 
TREATMENT DELAYS AND MODIFICATIONS FOR MEDICAL NEEDS ................................... 68 
7 
SPONSOR SAFETY REPORTING REQUIREMENTS ...... ERROR! BOOKMARK NOT 
DEFINED. 
7.1 
DEFINITIONS ............................................................ ERROR! BOOKMARK NOT DEFINED. 
7.2 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................ 68 
7.3 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) ............. 68 
7.4 
ADVERSE EVENT CHARACTERISTICS ............................................................................. 84 
7.5 
EXPEDITED ADVERSE EVENT REPORTING ...................................................................... 85 
7.6 
ROUTINE ADVERSE EVENT REPORTING ......................................................................... 88 
8 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN .. 88 
8.1 
DEFINITIONS .................................................................................................................. 88 
8.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING .............................. 88 
8.3 
NCI CLINICAL DIRECTOR REPORTING ........................................................................... 88 
8.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN ............................................... 88 
9 
PHARMACEUTICAL INFORMATION ............................................................................. 89 
9.1 
CTEP-SUPPLIED INVESTIGATIONAL AGENT(S) .............................................................. 89 
9.2 
OTHER AGENT(S) ........................................................................................................... 95 
9.3 
AGENT ORDERING ......................................................................................................... 96 
9.4 
AGENT ACCOUNTABILITY .............................................................................................. 97 
10 CORRELATIVE / SPECIAL STUDIES .............................................................................. 97 
10.1 
SAMPLE STORAGE, TRACKING AND DISPOSITION .......................................................... 97 
10.2 
LARGE SCALE DETECTION OF MUTATIONS IN CANDIDATE GENES ................................ 98 
10.3 
OTHER MOLECULAR PROFILING ANALYSES IN TUMOR SAMPLES ................................... 103 
10.4 
NON-INVASIVE BIOMARKERS STUDIES (ONLY FOR PATIENTS ENROLLED AT THE NCI 
INTRAMURAL PROGRAM) .......................................................................................................... 104 
10.5 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS .............................................................. 106 
11 DATA COLLECTION AND EVALUATION ................................................................... 107 
11.1 
DATA COLLECTION ...................................................................................................... 107 
11.2 
GENOMIC DATA SHARING PLAN .................................................................................. 107 
12 STUDY CALENDAR ........................................................................................................ 108 
13 MEASUREMENT OF EFFECT......................................................................................... 110 
13.1 
ANTITUMOR EFFECT – SOLID TUMORS ........................................................................ 110 
14 DATA REPORTING / REGULATORY REQUIREMENTS ............................................ 116 
14.1 
DATA REPORTING ........................................................................................................ 116 
14.2 
CTEP MULTICENTER GUIDELINES ............................................................................... 116 
14.3 
COLLABORATIVE AGREEMENTS LANGUAGE ................................................................ 117 
15 STATISTICAL CONSIDERATIONS................................................................................ 119 
15.1 
STUDY DESIGN/ENDPOINTS ......................................................................................... 119 
15.2 
SAMPLE SIZE/ACCRUAL RATE ..................................................................................... 120 
15.3 
STRATIFICATION FACTORS ........................................................................................... 120 
15.4 
ANALYSIS OF SECONDARY ENDPOINTS ........................................................................ 120 
15.5 
REPORTING AND EXCLUSIONS ...................................................................................... 121 
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16 HUMAN SUBJECTS PROTECTIONS ............................................................................. 121 
16.1 
RATIONALE FOR SUBJECT SELECTION .......................................................................... 121 
16.2 
JUSTIFICATION FOR EXCLUSIONS ................................................................................. 122 
16.3 
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT ........................................... 122 
16.4 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS ................................................. 122 
16.5 
RISK/BENEFIT ANALYSIS ............................................................................................. 123 
16.6 
CONSENT AND ASSENT PROCESS AND DOCUMENTATION............................................. 123 
16.7 
DATA AND SAFETY MONITORING PLAN .......................................................... 124 
17 REFERENCES ................................................................................................................... 125 
18 APPENDICES .................................................................................................................... 137 
18.1 
APPENDIX A: STUDY AGENT BACKGROUND INFORMATION ......................................... 137 
18.2 
APPENDIX B: MEDICATION DIARIES ............................................................................ 167 
18.3 
APPENDIX C: PERFORMANCE STATUS CRITERIA .......................................................... 179 
18.4 
APPENDIX D: NEW YORK HEART ASSOCIATION CLASSIFICATIONS ............................. 180 
18.5 
APPENDIX E:  MEDICATIONS THAT MAY CAUSE QTC PROLONGATION ....... 181 
18.6 
APPENDIX F:  LIST OF CYP3A4 INHIBITORS AND INDUCERS ........................... 184 
18.7 
APPENDIX G: INFORMATION ON POSSIBLE INTERACTIONS WITH OTHER 
AGENTS FOR PATIENTS AND THEIR CAREGIVERS AND NON-STUDY HEALTH 
CARE TEAM .......................................................................................................................... 186 
18.8 
APPENDIX H: HYPERTENSION MANAGEMENT TOOLS FOR PATIENTS IN SUNITINIB ........ 188 
18.9 
APPENDIX I:  CTEP MULTICENTER GUIDELINES ................................................ 191 
18.10 
APPENDIX J:  MOLECULAR PROFILING FOLLOW-UP WORKSHEET ........................... 193 
18.11 
APPENDIX K: TOBBACCO USE HISTORY QUESTIONNAIRE........................................ 194 
18.12 
APPENDIX L: ACQUISITION, STORAGE, INTERPRETATION AND REPORTING OF LOW-
DOSE CT SCANS FOR ENROLLED FIRST-DEGREE RELATIVES .................................................. 195 
 
 
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Table of Tables 
Table 1. Top 5 mutated genes in SCLC ........................................................................................ 12 
Table 2. EGFR drug-sensitive and resistant mutations ................................................................. 14 
Table 3. Frequency of mutated KRAS in selected tumors............................................................ 16 
Table 4. PI3K mutations in NSCLC ............................................................................................. 18 
Table 5. Previously reported germline mutations in lung cancer, clinico-pathologic features of 
the patients and their response to TKI .......................................................................................... 26 
Table 6. Erlotinib Monotherapy Dose Level Reductions ............................................................. 55 
Table 7. Dosage Modification Criteria for Erlotinib–related Toxicities....................................... 56 
Table 8:  AZD6244 Monotherapy Dose Level Reductions .......................................................... 57 
Table 9:  Dosage Modification Criteria for AZD6244–related Toxicities ................................... 57 
Table 10: MK2206 Monotherapy Dose Level Reductions ........................................................... 59 
Table 11:  Dosage Modification Criteria for MK2206–related Toxicities ................................... 59 
Table 12: Lapatinib Monotherapy Dose Level Reductions .......................................................... 61 
Table 13:  Dosage Modification Criteria for Lapatinib –related Toxicities ................................. 61 
Table 14: Sunitinib Monotherapy Dose Level Reductions ........................................................... 63 
Table 15. Management of Treatment-Emergent Hypertension .................................................... 64 
Table 16. Dosage Modification Criteria for Sunitinib –related Toxicities ................................... 66 
Table 17. Management of Other Clinically Significant Sunitinib-related AEs ............................ 67 
Table 18.  Summary of nonclinical pharmacokinetics for MK-2206 ......................................... 139 
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1 
OBJECTIVES 
1.1 
Primary Protocol Objectives 
1.1.1 To determine the feasibility of the use of tumor’s molecular profiling and targeted 
therapies in the treatment of advanced stage non-small cell lung cancer (NSCLC), small 
cell lung cancer (SCLC) and thymic malignancies. 
1.1.2 To estimate the response rate of molecular-profile directed treatments in NSCLC, SCLC 
and thymic malignancies patients. 
1.2 
Secondary Protocol Objectives 
1.2.1 To determine the progression free survival (PFS), duration of response and overall 
survival (OS) of patients with NSCLC, SCLC and thymic malignancies who undergo 
molecular profiling and receive molecular-profile directed treatments.  
1.2.2 To evaluate changes in the tumor’s molecular profile on serial biopsies when patients 
progress after an initial response to treatment.    
1.2.3 To identify molecular profiles in patients with NSCLC, SCLC and thymic malignancies 
and characterize their natural histories, clinical course and response to treatments. 
1.2.4 To determine the frequency of EGFR germline mutations in families with high 
susceptibility to lung cancer. 
2 
BACKGROUND 
2.1 
Background and Rationale 
2.1.1 Background and rationale for the use of molecular profiling and molecularly based 
treatment in NSCLC, SCLC and thymic malignancies. 
The current management of lung cancer and thymic malignancies is primarily based on the broad 
classification of tumors into categories based on histopathology and clinical stage at 
presentation.  However, the existing classifications and staging systems have remained largely 
unchanged for decades and it seems that they have reached their limit in providing critical 
information that may influence management strategy.  This is evident by the small improvement 
in overall survival of patients with this disease in the last few decades.   
The heterogeneity of lung cancer and thymic malignancies at each disease stage with respect to 
outcome and treatment response suggests that additional subclassification and substaging 
remains possible.  Molecular heterogeneity within individual lung cancer diagnostic categories is 
evident in the variable presence of specific mutations, deletions of tumor suppressor genes, and 
numerous chromosomal abnormalities found to date (3, 4).  Reports that some of these genetic 
aberrations are prognostic factors for patients provide evidence that additional information on 
risk of relapse or death from cancer may be defined at molecular levels (4). Molecular-profiling 
studies indicate that activating mutations in the epidermal growth factor receptor (EGFR) and 
KRAS genes are generally nonoverlapping and identifiable in approximately 30 to 40% of non–
small-cell lung cancers. Rarer oncogene mutations have been reported in less than 5% of lung 
cancer patients including mutations in ERBB2, ERBB4, MET, MEK, PI3K, AKT, FGFR1-4, and 
PTEN, among others (3).  In addition, a fusion gene, EML4/ALK has been reported in about 6 to 
13% of NSCLC patients (5).  These mutations, plus others that contribute to tumor progression 
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("driver" mutations), can be found in almost half of non–small-cell lung cancers.  Thus, 
correlations of molecular profiles from individual tumor samples to clinical outcome data hold 
the promise of a better classification of lung cancer, improved diagnostic and prognostic 
information and ultimately influence patient management and improve outcomes (6). 
 
Figure 1. Significantly mutated genes in lung adenocarcinomas 
 
 
 
Molecular characterization of thymic malignancies has also shown several abnormalities in 
EGFR, ERBB2, TGF and AKT among others (7-10).  These abnormalities have been shown to 
correlate with response to targeted therapies in some cases (8, 11-13). Additionally, oncogene 
mutations have also been reported in small cell lung cancer patients including mutations in TP53, 
KDR, KIT, BCL-2, SRC, VHL, PTCH1, VHL, ERBB2, ERBB3, CDKN2A, BRAC2, ERCC1, 
AKT, PIK3C3, and PTEN (Table 1. Top 5 mutated genes in SCLC 
). 
 
Table 1. Top 5 mutated genes in SCLC 
(COSMIC database: www.sanger.ac.uk/genetics/CGP/cosmic) 
Gene Name 
Sample Number 
Positive Samples 
Percent Mutated 
RB1 
121 
70 
57% 
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TP53 
78 
62 
79% 
PTEN 
246 
34 
13% 
EGFR 
298 
16 
5% 
PIK3CA 
99 
11 
11% 
 
Evidence that molecular profiling can have a significant impact on patient’s management can be 
found in a recent study of molecular profiling of tumors presented at the AACR 2009 conference 
(Von Hoff, et al. AACR 2009).  This study was conducted in patients with advanced cancers that 
were progressing despite several previous treatments and was designed to determine whether 
molecular profiling of patients’ tumors at this stage in their disease could provide any clinical 
benefit.  To be eligible, patients had to undergo or have available a tumor biopsy for molecular 
profiling.  Patients’ tissue samples were submitted for molecular profiling with oligonucleotide 
microarray gene expression assays.  The primary objective was to compare progression free 
survival (PFS) using a treatment regimen selected by molecular profiling with the PFS for the 
most recent regimen on which the patient progressed.  Of 86 patients, 66 received treatments 
based on molecular profiling and a significant number of patients had a clinical benefit with a 
longer PFS treated by molecular profiling results than the PFS they had on their prior treatment 
regimen.  This prospective study demonstrated that it is feasible to measure molecular targets in 
patients' tumors and that this approach may provide clinical benefit for some patients. 
A better understanding of the genetic make-up of the individual tumor may offer potentially 
improved therapies.  This approach may also give rapid access to response data in patients with 
sometimes rare genetic abnormalities.  In addition, it will allow us to test targeted therapies in a 
select population of patients that is more likely to have a favorable response based on their 
molecular profile and the specific mechanism of action of the drug being tested.  This approach 
will also speed up drug development and potentially approval, and rescue an otherwise 
ineffective drug candidate for the specific subgroup that can benefit. 
2.1.2 Background and rationale for the use of erlotinib in patients with EGFR TKIs sensitizing 
mutations.  
EGFR is a member of the receptor tyrosine kinases (RTKs) family, known as the ErbB or human 
epidermal receptor (HER) family of transmembrane receptors.  EGFR is activated when specific 
ligands, such as EGF, bind to its extracellular domain.  Ligand binding induces a conformational 
change that leads to dimerization of the receptor with either another EGFR molecule 
(homodimerization) or another member of the HER family (heterodimerization).  Following 
receptor dimerization, activation of the intrinsic protein tyrosine kinase and tyrosine 
autophosphorylation initiates a cascade of intracellular mitogenic signaling.  The EGFR can 
activate several different signaling pathways, including the Ras/Raf/MEK/ERK, phospholipase 
C, PI3K/Akt, STAT and Src/FAK pathways.  These pathways form a network of signals that are 
important for cell growth and proliferation [7]. 
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The development of epidermal growth factor receptor (EGFR) inhibitors has significantly 
influenced the field of targeted therapeutics.  A high sensitivity to EGFR tyrosine kinase 
inhibitors (TKIs), such as gefitinib or erlotinib, has been reported in patients with EGFR-mutated 
lung cancers (14-16). Activating mutations in the epidermal growth factor receptor (EGFR) 
(Table 2. EGFR drug-sensitive and resistant mutations 
) have been found in about 15% of NSCLC patients from North America and Europe, and up to 
40% of Asian NSCLC patients (15-17).  
 
Table 2. EGFR drug-sensitive and resistant mutations 
 
 
Exon 
Mutation / Deletion 
Drug sensitive 
18 
G719A/C 
 
19 
delE746-A750 
 
21 
L858R 
 
21 
L861Q 
Drug Resistant 
19 
D761Y 
 
20 
T790M 
 
20 
D770_N771insNPG 
 
The specific EGFR tyrosine kinase inhibitors erlotinib and gefitinib have been shown to have 
activity in patients with activating EGFR mutations and response and survival rates are higher 
compared with multi-agent chemotherapy in this population.  In contrast, chemotherapy is 
superior in patients with wild type EGFR genes (15, 17, 18). A recent phase III, randomized, 
controlled clinical trial in an Asian population (IPASS) has demonstrated a considerable benefit 
in progression free survival with the use of gefitinib as a first-line therapy for the treatment of 
patients with metastatic NSCLC with an EGFR TKI sensitizing mutation compared to 
chemotherapy (RR = 71.2% vs 47.3%; P<0.001; hazard ratio for progression, 0.48; 95% CI, 0.36 
to 0.64; P<0.001) (18). Additionally, a large, non-randomized clinical trial conducted in a 
primarily Caucasian population from Spain has shown outstanding results with the use of EGFR 
TKIs in patients with NSCLC with EGFR TKI sensitizing mutations.  In this trial, 217 patients 
with EGFR TKI sensitizing mutations that were either chemotherapy naïve or previously treated 
with chemotherapy received erlotinib until disease progression.  PFS and OS for these patients 
(14 months and 27 months, respectively) was significantly higher than historical controls for 
unselected populations (17).  
In SCLC, EGFR mutations are a rare event that represents 5% of the samples analyzed (Table 1. 
Top 5 mutated genes in SCLC). Interestingly, most of these mutations appear in patients with 
mixed histological features of SCLC and NSCLC or in patients who have never smoked.  
Remarkably, the EGFR mutations observed in SCLC (L858R, G719A/C and deletions in exon 
19) are similar to the active mutations in NSCLC that have been reported to be predictors of a 
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therapeutic response to EGFR-TKIs.  Furthermore, anecdotal evidence shows efficacy with the 
use of TKIs in these patients (19, 20). 
In thymic malignancies, only one phase II study has been conducted using anti-EGFR targeted 
therapies.  In this study, twenty-six (female = 15, male = 11) previously treated patients with 
metastatic thymoma (n = 19) or thymic carcinoma (n = 7), with ECOG performance status of 0 
or 1, were enrolled.  Patients received gefitinib orally at 250 mg daily.  There were 0 CRs, 1 PR 
(response duration = 5 months), and 14 SDs.  Six patients had SD for > 4 months.  Grade 3/4 
adverse events noted were: dyspnea (grade 4, n = 1; grade 3, n = 2), fatigue (grade 4, n = 1), 
anemia/thrombocytopenia (grade 4, n = 1), and myocardial infarction (n = 1).  After completing 
3 cycles, the patient with a PR developed presumed gefitinib-induced Grade 2 pneumonitis, 
which resolved following steroids and discontinuation of treatment.  Median time to progression 
(TTP) was 4 months (range, 1 - 17+).  None of the 5 pts (including 1 PR), analyzed by DNA 
sequencing, had evidence of EGFR or KRAS mutations and there was no EGFR expression 
analysis.  
In thymic malignancies EGFR mutations are a rare event that represents < 2% of the thymic 
tumors analyzed (9, 10).  Remarkably, the EGFR mutations (L858R and G863D in exon 21) 
observed in thymic tumors are similar to the active mutations in NSCLC that have been reported 
to be predictors of a therapeutic response to EGFR-TKIs.  Even though there are no prospective 
trials to demonstrate the efficacy of EGFR TKIs in patients with thymic malignancies harboring 
EGFR mutations, anecdotal reports suggest that these patients are in fact sensitive to EGFR 
TKIs(9).   
2.1.3 Background and rationale for the use of AZD6244 in patients with Ras/Raf/Mek/Erk 
pathway mutations. 
The RAS/RAF/MEK/ERK pathway regulates proliferation and survival of normal cells.  
Hyperactivation of this pathway results in deregulated cell proliferation and malignant 
transformation (21).  In human tumors, RAS/RAF/MEK/ERK pathway activation is a common 
feature which results from unregulated activation of upstream RTKs, such as EGFR, or 
mutations in pathway intermediates, such as KRAS, BRAF, NRAS or NF-1 (22).  
The Ras superfamily of GTP binding proteins consists of more than 150 proteins, and can be 
grouped into at least five families (Ras, Rho, Rab, Arf, and Ran).  The Ras subfamily itself 
includes at least 21 members (23, 24); however, there are just three closely related human Ras 
genes, KRAS, HRAS and NRAS, which constitute the founding members of the RAS super 
family.  Ras signaling requires the activation of Ras by exchange of GDP for GTP, followed by 
interaction of Ras-GTP with Ras-effector molecules, and inactivation of Ras by GTPase-
activating proteins.  This signaling pathway requires the anchorage of Ras to the inner leaflet of 
the plasma membrane through their C-terminal S-farnesylcysteine by either a stretch of lysine 
residues (KRAS 4B isoform) or S-palmitoyl moieties (NRAS, NRAS and KRAS 4A 
isoforms)(25). The farnesyltransferase (FTase) catalyses the post-translational addition of the C-
terminal cysteine residue in a process called farnesylation which is critical for the biological 
function of Ras (26).  Ras relays its signal downstream through a high affinity complex with Raf.  
Activated Raf phosphorylates and activates two MAPK kinases (MEK1 and MEK2) and 
activated MEK then phosphorylates ERK which in turn activates multiple nuclear transcription 
factors (27). 
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Mutations in the Ras/Raf/Mek/Erk pathway are some of the most frequently mutated oncogenes 
in patients with NSCLC.  KRAS mutations account for 20 to 38% of NSCLC cases and NRAS 
and BRAF for less than 3% each (3, 28-30).  KRAS mutations occur more frequently in smokers 
and adenocarcinoma histologies.  Up to 90% of the KRAS mutations are activating point  
mutations localized in codons 12 and 13, and less frequently in codons 61 and 63 (31).  
Although mutational activation of RAS in human cancer was first demonstrated in 1982, somatic 
activating mutations in BRAF were only detected in 2002.  Mutationally activated BRAF is 
detected in melanoma (70%), colorectal (15%), papillary thyroid (40%), ovarian (30%), and non-
small-cell lung cancers (NSCLCs) (3%) (32, 33).  Sequence analysis of the BRAF gene 
associated with human cancers has identified over 30 single site missense mutations, mostly 
within the kinase domain in exon 15.  Most of the mutations of BRAF are clustered to two 
regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions.  A 
Glu for Val substitution at residue 599 in the activation segment, adjacent to the conserved DFG 
motif, accounts for 90% of BRAF mutations in human cancers.  The V599E (a.k.a. V600E) 
mutant of BRAF possesses the hallmarks of a conventional oncogene.  The kinase activity of this 
mutant protein is greatly elevated, it constitutively stimulates ERK activity in vivo independent 
of RAS, and it potently transforms NIH3T3 cells.  Interestingly, the conserved regulatory 
phosphorylation sites within the activation segment of BRAF, Thr598 and Ser601, flank Val599, 
leading to the suggestion that the Glu substitution at this position functions as a phospho-
mimetic.  Analysis of three other oncogenic mutants of BRAF showed that they stimulate kinase 
activity in a manner similar to V600E (32, 34, 35).  In addition, non-V-600E mutations mostly 
localized in exon 11 have also been described in NSCLC with different frequencies but in 
general accounting for less than 3% of tumor or cell line samples (32, 33, 36, 37).  Interestingly, 
both V600E and non-V600E mutations (i.e. G469A, G466V, L597V) have been shown to be 
sensitive to MEK inhibition in preclinical models (NSCLC cell lines)(33).  
Mutations of either BRAF, NRAS or KRAS lead to constitutive activation (phosphorylation) of 
their downstream target, mitogen-activated protein kinase (MAPK), also known as extracellular 
signal-regulated protein kinase (ERK) (29, 30, 32, 34, 35).  Patients with Ras/Raf/Mek/Erk 
pathway mutated tumors are less likely to respond to EGFR TKIs and no specific targeted 
therapy has thus far demonstrated activity in this patient population (14).  
 
Table 3. Frequency of mutated KRAS in selected tumors 
(3, 38) (31). 
 
KRAS 
Incidence 
Lung Cancer (subtypes) 
16–38% 
Adenocarcinoma 
22% 
Broncho-alveolar 
Carcinoma (BAC) 
31% 
Large Cell 
22% 
Squamous Cell 
1-5% 
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MEK or MAPK/ERK kinase is an attractive therapeutic target because its only known substrate 
is ERK1/2 (39).  MEK inhibitors have shown good preclinical activity in different malignancies 
and activating mutations in the RAS (K-and N-) and BRAF genes have been reported to identify 
tumors that may be sensitive to MEK inhibition (32, 34, 35, 40, 41). Additionally, preclinical 
models have shown that synergistic cytotoxicity is achieved when combining MEK with EGFR 
inhibitors(42). However, CI-1040 which was the first MEK inhibitor ever tested in humans, 
showed poor results in clinical trials due to low systemic exposure and rapid metabolism (39).  
Furthermore, a second-generation more potent oral MEK inhibitor, PD0325901, was prematurely 
discontinued due to unexpected toxicities (Clinicaltrials.gov identifier: NCT00174369). 
AZD6244 is a potent, selective, and noncompetitive ATP inhibitor of MEK1/2 that has 
preclinical activity against many different tumors in both cell lines and xenograft models (40).  A 
recent phase I trial has shown promising results in patients harboring mutations in the Ras or Raf 
genes(43).  Of the 26 patients with samples assessable for mutational status, 10 had a single 
mutation in KRAS (n=5), NRAS (n=4), or BRAF (n=1).  The average length of time on study for 
patients carrying mutations (median, 3.5 months; range, 1 to 6 months) was greater than for those 
without a mutation (median, 2 months; range, 1 to 4 months).  Several phase II clinical trials are 
currently underway with an emphasis on determining the efficacy of AZD6244 in tumors 
harboring mutations in the Ras/Raf/Mek/Erk pathway (44).   
2.1.4 Background and rationale for the use of MK2206 in patients with PI3K/Akt/mTOR 
pathway mutations / alterations.  
The PI3K/Akt/mTOR pathway is a critical regulator of cellular growth and proliferation and is 
essential for oncogenic transformation.  It is activated through a number of tyrosine kinase 
growth factor receptors such as EGFR, insulin-like growth factor-1 receptor (IGF-1R), G-protein 
coupled receptors, and through oncogenes such as Ras (45).   PI3K stimulation and mammalian 
target of rapamycin (mTOR) activation as well as PTEN inhibition have been demonstrated to be 
intimately connected to Akt activation leading to tumor mediated angiogenesis, proliferation, and 
cell survival.  Specifically mTOR is an intracellular serine/threonine kinase that resembles that of 
the PI3 kinase enzymes.  Once activated, mTOR can form complexes with Raptor (mTORC1) or 
Rictor (mTORC2) (46).  The mTORC2 complex phosphorylates and activates Akt/PKB.  
Concurrently, the mTORC1 complex phosphorylates and activates two key regulators of 
translation: S6K1 (p70S6 kinase) and 4E-BP1, which both activate ribosomal formation and 
translation.  
In a recent study, NSCLC patient samples were evaluated by FISH for PI3K amplification with > 
7 copies/cell.  This study revealed PI3K amplification in 42% of lung squamous cell carcinomas 
(47).  Addtionally, P-Akt expression and loss of PTEN expression via IHC were shown to occur 
in NSCLC samples (48).  Specifically, P-Akt expression was noted in 49% of squamous cell 
carcinomas and 33% of adenocarcinomas.  Similarly, loss of PTEN expression was seen in 53% 
of SCC and 61% of adenocarcinomas.  Furthermore, these findings were associated with poorer 
prognosis including poor differentiation, lymph node involvement, distant metastasis, late stages, 
and lower cumulative survival rates (48).  
Mutational analyses of the PI3K/Akt/mTOR pathway in lung cancer have revealed the presence 
of several mutations in this pathway.  Eighty-six NSCLC cell lines and 691 NSCLC patient 
tumor samples were evaluated for PIK3CA mutational analysis in exon 9 and 20 and gene copy 
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number via PCR and real-time quantitative PCR respectively.  This study reported PIK3CA 
mutations in 4.7% NSCLC cell lines and 1.6% of the NSCLC patient samples.  PIK3CA copy 
number gain were revealed in 9.3% of the NSCLC cell lines and 17.1% of the NSCLC patient 
samples, where 33.1% were SCC and 6.2% were lung adenocarcinomas.  Furthermore, cell lines 
expressing these mutations and copy number gains correlated to increased PI3K expression and 
activity (49).  
 
 
Table 4. PI3K mutations in NSCLC 
(49) 
 
An activating E17K mutation in exon 4 of the AKT1 gene has been demonstrated in a small 
percentage of patients (<2%) with NSCLC squamous cell subtype.  The activity of the 
endogenous kinase carrying the E17K mutation immunoprecipitated by tumour tissue was 
significantly higher compared with the wildtype kinase immunoprecipitated by the adjacent 
normal tissue.  Immunostaining or immunoblot analysis on membrane-enriched extracts 
indicated that the enhanced membrane localization exhibited by the endogenous E17K-AKT1 
may account for the observed increased activity of mutant E17K kinase in comparison with the 
wild-type AKT1 from adjacent normal tissue.  These mutations appear to be limited to patients 
with SCC subtype (50-52).  Mutations in the AKT2 gene have also been described.  One was a 
missense mutation in exon 11 [1130C-A (A377V)] in a 65 year old female with lung 
adenocarcinoma with an EGFR L858R mutation.  The other one was a deletion in intron 10 
(IVS10 + 7delG) in a 66 year old male with NSCLC squamous subtype(53).  Deletions and 
mutations have also been found on PTEN in patients with NSCLC with a frequency of 
approximately 9%(54, 55).  Mutations present in any of the crucial domains of this gene result in 
reduced phosphatase activity which affects its growth suppression functions (54). 
Preclinical studies have demonstrated encouraging results with inhibition of mTOR in NSCLC  
(56).  Furthermore, in NSCLC cell lines, everolimus, an oral mTOR inhibitor, plus gefitinib have 
induced a significant decrease in the activation of MAPK and mTOR signaling pathways and 
resulted in a growth-inhibitory effect (57).  In clinical trials RAD001 monotherapy was evaluated 
in an unselected population of 85 advanced NSCLC patients previously treated with 
chemotherapy alone (stratum 1) or with chemotherapy and EGFR inhibitors (stratum 2) (58).  
Both patient strata had to have failed two or fewer chemotherapeutic regimens including a 
previous platinum agent.  The ORR was 7.3% in stratum 1 and 2.3% in stratum 2, where in total 
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there were 4 patients achieving a PR.  No CRs were recorded.  Additionally, the PFS was 79 
days (95% CI 57-87 days) in stratum 1 and 81 days (95% CI 51-113 days) in stratum 2.   
A recent study evaluating the AKT/mTOR pathway demonstrated that 50% (15 out of 30) SCLC 
patient tumor samples expressed mTOR via IHC analysis.  Furthermore, mTOR inhibition via 
RAD001 was observed to inhibit SCLC tumor growth in an in vivo xenograft model utilizing H-
69 SCLC cells.  An additional study investigated the presence of PTEN mutations in SCLC in 34 
SCLC cell lines and 10 SCLC tumors.  This study revealed that 18% of cell lines and 10% of 
tumor samples had mutations in the PTEN gene including point mutations, small fragment 
deletions, and homozygous deletions (59). Overall, PTEN mutations have been identified in 13% 
of samples according to the COSMIC database (Table 1. Top 5 mutated genes in SCLC 
). 
In addition, a target-specific mutational search revealed mutation of the PIK3CA gene in three of 
13 SCLC cell lines and two of 15 primary SCLCs.  In this study, these mutant PIK3CA cDNAs 
were introduced into cell lines establishing artificial “PIK3CA-addicted” cells and found that 
Triciribine, a small-molecule inhibitor of AKT signaling that is located downstream from 
PIK3CA, significantly inhibited the growth and colony formation activity of these cells.  Using 
cancer cell lines, it was further shown that PIK3CA-mutated SCLC cells are more sensitive to 
Triciribine than PIK3CA wild-type cells.  Additionally, it was found that a cisplatin-resistant 
subclone of PIK3CA-mutant SCLC cells was equally sensitive to Triciribine.  This study for the 
first time uncovered PIK3CA alterations in SCLC, and suggested that anti-AKT molecular 
therapy could be effective for a subgroup of SCLC, which shows activation of specific genes, 
such as PIK3CA mutation, and that genetic stratification of SCLC according to the activation 
status of individual therapeutic target pathways could be clinically beneficial, especially for 
chemotherapy-resistant/relapsing tumors(60). 
Temsirolimus is an inhibitor of mTORC1 which binds to an intracellular protein, FKBP12, and 
the protein-drug complex inhibits the activity of mTOR that controls cell division.  The 
inhibition of mTOR prevents the transcription of mRNAs and translation of proteins required for 
cell cycle progression from G1 to S phase by mediating the activation of p70S6K and 4E-BP12. 
Inhibition of mTOR activity results in a G1 growth arrest in treated tumor cells.  A randomized 
phase II study (E1500) utilizing temsirolimus in patients with extensive stage SCLC following 
induction chemotherapy has been conducted to study the progression-free survival (PFS) and 
toxicity with 25- or 250-mg doses of temsirolimus (CCI-779).  Patients with either stable or 
responding disease to four to six cycles of cisplatin or carboplatin plus etoposide or irinotecan 
were randomized between 4 and 8 weeks after completion of induction therapy to receive either 
25 or 250 mg of temsirolimus intravenously every week until disease progression.  Eighty-seven 
patients entered between January 2002 and December 2003, of whom 85 were eligible: 44 
received 25 mg (arm A), and 41 received 250 mg (arm 13).  The overall median follow-up time 
for all eligible patients was 34.6 months.  Median age was 59 years (range, 39-80); 42 (49.4%) 
were male and 43 (50.6%) female; 12.9% had brain metastases.  The overall median and 1-year 
PFS were 2.2 months (95% confidence interval [CI]: 1.8, 2.9) and 4.7% (95% Cl: 0.2%, 9.2%), 
respectively.  The median PFS (95% CI) for arm A was 1.9 months (1.6, 2.3); for arm B, it was 
2.5 months (1.9, 3.4; p = 0.24).  The median overall survival from randomization was 8 months 
(95% Cl: 6.5, 9.5).  Among the 86 patients with reported toxicities, 36 (42%) had grade 3 
toxicities, the most common of which were thrombocytopenia, hypophosphatemia, and fatigue, 
and an additional 12 (14%) had grade 4 toxicities, the most common of which was neutropenia.  
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No patients experienced lethal toxicities.  In conclusion, temsirolimus given to responding or 
stable patients with extensive-stage SCLC after induction chemotherapy did not seem to result in 
any prolongation in PFS compared with what has been reported in the literature.  However, it is 
important to note is that this study was conducted in a molecularly unselected population and 
that correlative analysis to determine alterations in the  PI3K / mTOR pathway were not 
conducted(61).         
MK-2206 is the first allosteric AKT inhibitor to enter clinical development.  As an AKT 
inhibitor, it is equally potent towards purified recombinant human AKT1 and AKT2 isoenzymes, 
and 5-fold less potent against AKT3 (Investigator's Brochure, 2008).  It has an advantage of 
having a higher intrinsic selectivity for AKT compared to the active-site AKT-specific inhibitors, 
i.e., ATP-competitive AKT inhibitorswhich have been clinically evaluated thus far.  In vitro and 
in vivo anticancer efficacy of MK-2206 was demonstrated in breast cancer cell lines and in the 
A2780 ovarian cancer xenograft model in nude mouse and rat, either as a single agent or in 
combination with erlotinib, trastuzumab, and docetaxel. 
Preclinical safety assessment studies in the most sensitive species, dogs, demonstrated NOAEL 
(no observed adverse effect level) at a 2.5 mg/kg dose (Cmax of 365 nM and AUC0-48h of 8.52 
μM∙h) and NOEL for cardiovascular effects at a 1 mg/kg dose (Cmax of 92 nM and AUC0-48h 
of 1.59 μM.  Based on these data, the human equivalent doses are 34 mg (NOEL) and 80 mg 
(NOAEL) for a 60-kg man. 
The projected human clearance for MK-2206 is 2-4 mL/min/kg with bioavailability in the range 
of 50%-75%.  Although preclinical safety/tolerability studies identified health risks of prolonged 
QTc interval and hyperglycemia associated with MK-2206, no significant hyperglycemia has 
been seen thus far on the phase I trial; and while Grades 1-2 QTc prolongation has been noted 
with MK-2206 in clinical trials, it has not been thought to be clinically significant.   
Merck is completing a phase 1 clinical trial with MK-2206 as a single agent in patients with solid 
tumors.  Preliminary data from this study suggest that the dosing regimen of 60 mg orally (PO) 
every other day (QOD) is well-tolerated and achieves target effects of AKT inhibition.  In 
addition, Merck has completed Phase I testing of a weekly schedule of MK-2206 and has 
recommended a Phase II dose of 200 mg orally (PO) weekly.  Pharmacokinetic data is available 
for this weekly regimen.  This schedule has demonstrated less toxicity than the 60 mg PO QOD 
schedule, appears to have at least equal antitumor activity, and is favored by Merck for 
subsequent trials. 
2.1.5 Background and rationale for the use of lapatinib in patients with ERBB2 mutations or 
amplification. 
HER2 (erbB-2/neu) is a member of the erbB receptor tyrosine kinase family that also includes 
EGFR (HER1/erbB-1), HER3 (erbB-3), and HER4 (erbB-4).  Whereas these family members 
usually dimerize upon ligand binding, HER2, for which no ligand is reported, exists mainly in its 
active conformation.  HER2 readily heterodimerizes with other erbB family members and is 
considered to be the preferred dimerization partner for EGFR, HER3, and HER4.  In addition to 
ligand binding, receptor dimerization can be induced by a high concentration of receptors at the 
plasma membrane or by kinase domain mutations, resulting in receptor activation by the 
transphosphorylation of tyrosine residues in the C terminus of the respective molecules.  The 
phosphorylated residues act as docking sites for an array of downstream signaling molecules 
activating several biochemical pathways such as the MAPK, the PI3K/Akt/mTOR, the 
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phospholipase C, and the Jak/Stat signaling pathways.  These signal transduction cascades in 
concert regulate cellular processes such as proliferation, apoptosis, angiogenesis, migration, 
adhesion, and differentiation(62).  
Mutations in the HER2 kinase domain have been reported in lung adenocarcinomas at a 
relatively low frequency of 2–4%.  Thus far, the majority of the HER2 mutations identified in 
non-small cell lung cancer (NSCLC) samples are in-frame duplications or insertions in a small 8-
codon region (codons 774–781 or 775–782) on exon 20.  These mutations are analogous to the 
duplications/insertions in the 9-codon region of exon 20 in EGFR, translating to the C terminus 
of the αC helix in the TK (tyrosine kinase) domain.  Based on this similarity, it has been 
postulated that mutations in HER2 cause a shift in the helical axis that narrows the ATP binding 
cleft, resulting in both increased TK activity and TK inhibitor sensitivity.  These HER2 
mutations are independent of HER2 receptor overexpression or KRAS, NRAS, BRAF, or EGFR 
mutations(63-65). 
Studies of ERBB2 expression in NSCLC have varied in use of antibodies and 
immunohistochemical technique as well as the definition of positive cases.  In general, positive 
immunostaining for ERBB2 (IHC ≥1+) in NSCLC has been reported in 2 to 60% of cases and 
overexpression has been associated with poor prognosis.  Discrepancies among the reported 
frequencies might be due to different factors, including distribution of histological types, tissue 
processing, criteria for the scoring and interpretation of the staining results.  However, strong 
overexpression defined by3+ IHC or gene amplification by FISH has been reported in less than 5 
% of NSCLC patients (62, 66).  
Molecular characterization of ERBB2 abnormalities in thymic carcinoma has shown a high rate 
of ERBB2 overexpression (45%) and gene amplification (50%) and a positive correlation (85%) 
was detected between ERBB2 protein expression and gene amplification (Kuhn E. et al. 1st 
International Conference on Thymic malignancies 2009).  
The clinical experience with anti-HER2 directed therapies in the thoracic malignancies such as 
NSCLC has been disappointing most likely as a result of poor patient selection.  The Cancer and 
Leukemia Group B (CALGB) initiated a trial in February 2000 to determine the single-agent 
efficacy of trastuzumab in patients with stage IIIB or IV NSCLC who had tumors that 
overexpressed ERBB2.  Of note is that ERBB2 overexpression was defined by 2 or 3 + positivity 
on immunohistochemistry analysis.  Among 209 screened patients, 24 patients (11%) had tumors 
with 2+ or 3+ expression of HER-2.  However, of the 22 patients that were treated, 21 had 2+ 
IHC and no FISH analysis was performed.  Only one patient achieved a partial response and the 
trial was stopped (67).  A randomized phase II trial examined the effect of adding trastuzumab to 
a standard chemotherapeutic combination (gemcitabine–cisplatin) in patients with HER2-
positive NSCLC defined by IHC ≥1.  Efficacy was similar in the trastuzumab and control arms 
with a response rate 36% versus 41%; median time to progression 6.3 versus 7.2 months; and 
median progression-free survival (PFS) 6.1 versus 7 months(68).  
Lapatinib (GW572016) is an oral reversible, dual tyrosine kinase inhibitor of EGFR (ERBB1) 
and HER2/neu (ERBB2).  A study conducted in chemotherapy naïve patients with NSCLC was 
stopped for futility after 131 patients were randomized.  Median age 66 (range 32–86); female 
56%; BAC 20%, No BAC 71%; previously untreated 98.5%; current/former smokers 70%, never 
smoker 30%.  There were no complete responses.  Of 56 patients in the target population, 1 (2%) 
achieved partial response (PR), 11 (20%) had stable disease (SD) of 24 wks; in the non-target 
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population, 1 patient had a PR (1.3%) and 12 (16%) had SD of 24 wks.  Three patients had 
ERBB1 mutations (G719S, S768I, KRAS G12S; L858R and T790M; L858R) but none of them 
responded.  Three of 77 patients evaluated had ERBB1 gene copy increase (none of whom 
responded) and 2 had ERBB2 gene copy increase (one had a 51% decrease in tumor size).  The 
most common adverse events were grade 1/2 diarrhea, nausea, rash, vomiting and fatigue, and 
were similar in both groups(69).  
Despite the lack of efficacy of lapatinib in an unselected population of patients with NSCLC, 
there is no prospective clinical data on the use of Lapatinib in patients with ERBB2 mutations or 
amplification.  As stated above, these mutations are analogous to the duplications/insertions in 
the 9-codon region of exon 20 in EGFR, translating to the C terminus of the αC helix in the TK 
domain.  Based on this similarity, it has been postulated that mutations in ERBB2 cause a shift in 
the helical axis that narrows the ATP binding cleft, resulting in both increased TK activity and 
TK inhibitor sensitivity(63-65, 70).  Furthermore, preclinical studies assessing the in vivo effect 
of a dual EGFR / ERBB2 TKI (BIBW2992) on HER2(YVMA) transgenic mice or H1781 
xenografts with documented tumor burden revealed that BIBW2992 has significant activity in 
regards to signaling and tumor shrinkage(63). 
Theoretically it might be predicted that the protein expression would be superior for assessing 
response to trastuzumab therapy because the antibody binds to the cell surface protein.  In breast 
cancer, however, FISH technique has been demonstrated to be a more accurate and reliable 
method for selecting patients eligible for treatment with anti-HER2 directed therapy(66).  In 
NSCLC HER2 status assessed by IHC has been has been shown to be a method that is not 
optimal.  On the other hand, anecdotal evidence supports the notion that FISH analysis would be 
a better method to predict the response to anti-HER2 therapies in NSCLC patients (66, 70).  
Moreover, in a phase II clinical trial of trastuzumab in combination with chemotherapy in 
NSCLC, the few patients whose tumors had HER2 gene amplification and who were treated with 
trastuzumab had a better response to trastuzumab compared to other patients.  Response rate 
(83%) and median PFS (8.5 months) are higher in trastuzumab-treated patients with HER2 3+ or 
fluorescence in situ hybridization (FISH)-positive NSCLC compared to patients without HER2 
overexpression (68). 
2.1.6 Background and rationale for the use of sunitinib in patients with PDGFR-A gene 
amplification or mutations or KIT mutations.  
The PDGFR/PDGF system includes two receptors (PDGFRA and PDGFRB) and four ligands 
(PDGFA, PDGFB, PDGFC, and PDGFD).  Ligand binding induces receptor dimerization, 
enabling autophosphorylation of specific tyrosine residues and subsequent recruitment of a 
variety of signal transduction molecules.  PDGFR regulates normal cellular growth and 
differentiation, and expression of activated PDGFR promotes oncogenic transformation 
Increased expression of PDGFR has also been associated with poor prognosis in NSCLC (71). 
Analysis of early stage (I and II) NSCLC samples by IHC revealed a high expression of PDGFR-
A in 51% of squamous cell carcinoma, 77% in large cell carcinoma, 73% in adenocarcinomas 
(73%), and 68% in  bronchioalveolar carcinoma (68%) (72).  However, a similar study 
performed in early stage NSCLC patient samples identified strong PDGFR-A staining by IHC in 
just 2 to 3% of cases (73).  In addition, mutations in the PDGFR-A gene have been identified in 
3.7% of cases of adenocarcinoma (3). 
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Sunitinib malate is an oral, selective multitargeted tyrosine kinase inhibitor with antiangiogenic 
and antitumor activities.  It inhibits VEGF receptor (VEGFR)-1, -2, and -3 and PDGFR-A and -B 
activity, as well as the activity of several related tyrosine kinases.  It is FDA approved for its use 
in previously untreated patients with advanced renal cell carcinoma and in imatinib-refractory 
gastrointestinal stromal tumors (GIST).  A recent phase II clinical study has revealed modest 
efficacy of single-agent sunitinib in advanced NSCLC patients with an ORR of 11.1% (95% CI, 
4.6% to 21.6%).  An additional 18 patients (28.6%) experienced stable disease of at least 8 
weeks in duration.  Median progression-free survival was 12.0 weeks (95% CI, 10.0 to 16.1 
weeks), median overall survival was 23.4 weeks (95% CI, 17.0 to 28.3 weeks), and therapy was 
generally well tolerated (74). 
However, sunitinib has not been tested in selected populations of NSCLC patients who have 
mutations or overexpression of PDGFR or VEGFR and there is no retrospective analysis 
correlating the levels of these receptors with clinical outcomes(74). Using a high-throughput 
cancer cell line screening platform, it has been found that a small fraction of human tumor-
derived cell lines show significant sensitivity to single-agent sunitinib exposure.  These two cell 
lines [a non–small-cell lung cancer (NSCLC) and a rhabdomyosarcoma] showed expression of 
highly phosphorylated PDGFRA.  In the sunitinib-sensitive adenosquamous NSCLC cell line, 
PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly 
detected in a small fraction of squamous cell NSCLC primary tumor specimens.  Moreover, in 
this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was 
also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited 
proliferation.  These findings suggest that, rare tumors that show PDGFRA activation may be 
more likely to be responsive to pharmacologic inhibition by sunitinib (75). 
The c-kit proto-oncogene encodes a Kit transmembrane tyrosine kinase receptor whose ligand is 
stem cell factor (SCF), a growth factor important in the stimulation and formation of various cell 
types.  Upon SCF binding, the Kit receptor dimerizes and autophosphorylates to in turn activate 
many downstream signal transduction components including PI3K, PKB/Akt, Src, Janus 
transcription pathway, and the Ras-Raf-MAPK cascade that all in some form promote cell 
survival and increase cellular proliferation.  Mutations in KIT lead to a constitutive activation of 
the receptor in a ligand independent fashion.  It has been shown through structural analyses of 
the KIT receptor and related tyrosine kinase receptors that the juxtamembrane domain of this 
receptor plays an inhibitory role on the regulation of this receptor.  Furthermore, this ability to 
suppress Kit receptor firing is compromised by mutations and deletions seen in the 
juxtamembrane domain. 
The presence of KIT mutations has been found in less than 4% of samples from thymic 
malignancies.  In contrast to other mutations, KIT mutations have been found exclusively in 
thymic carcinomas. One of these mutations is a V560 deletion in exon 11.  This mutation is 
associated with sensitivity to KIT inhibitors based upon multiple lines of evidence: (a) the 
growth of mutant-bearing Ba/F3 cells in vitro is readily inhibited by treatment with imatinib and 
sunitinib(7); (b) a patient whose tumor harbored this mutation responded to treatment with 
imatinib(8); and (c) this mutation has also been found in an imatinib-sensitive gastrointestinal 
stromal tumor (76). Another KIT-mutant case of thymic carcinoma reported in the literature 
harbored an L576P mutation in exon 11 (10).  This mutation has also previously been described 
in gastrointestinal stromal tumor and melanoma and has been biologically characterized as being 
sensitive to imatinib (76).  The third type of mutation reported is a D820E mutation in exon 17 
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exhibited by a thymic carcinoma responding to sorafenib(13).  Finally, the KIT H697Y mutation 
identified in exon 14 is associated in vitro with sensitivity to sunitinib and imatinib (7). 
2.1.7 Rationale for the non-otherwise (NOS) specified arm 
In order to accomplish the primary objective of identifying molecular profiles in patients with 
NSCLC, SCLC, and thymic malignancies and characterize their natural histories, clinical course 
and response to treatment, we will follow all patients that undergo molecular profiling from the 
time that they are enrolled in the trial until the time of death.  For this reason, we have created a 
study arm called the “non otherwise specified” (NOS) arm.  In this arm, we will include all 
patients that undergo molecular profiling under this protocol, but that are otherwise not eligible 
for any of the active treatment arms in the protocol.  This will allow us to link their clinical and 
mutational analyses, to determine the frequency of each mutation, its association with clinical 
features, response to treatment and outcome, and its association with other mutations.  As future 
therapeutic protocols specific for these mutations are developed, patients may be notified of their 
eligibility for these studies, if they consent.  Future translational studies may be used to: a) 
unravel the complex biology of lung cancer; b) identify prognostic markers; c) define predictive 
markers of response/resistance to new therapies; and d) identify new targets.  
2.1.8 Background and rationale for EGFR germline mutation testing in lung cancer families 
Lung cancer is the leading cause of cancer-related death worldwide, accounting for more than 
one million deaths every year (2, 77). Cigarette smoke accounts for approximately 85-90% of all 
lung cancers. Other etiological factors for lung cancer include radon (a radioactive gas produced 
by decay of radium 226), asbestos, lung inflammation and scarring (78).  
Although the etiological role of genetic factors in lung cancer is poorly understood, several lines 
of evidence suggest a role for these factors in lung carcinogenesis even after adjustment for age, 
gender and smoking habits. For example, in the Environment And Genetics in Lung cancer 
Etiology (EAGLE) study, the relative risk of lung cancer associated with a positive family 
history, adjusted for age, gender, residence, education, and smoking, was 1.57 (95% CI 1.25-
1.98) (79). Genome-wide association (GWA) studies have suggested lung cancer susceptibility 
loci at various locations (80). Other studies have identified single nucleotide polymorphisms 
(SNPs) in enzymes involved in DNA repair and detoxification of xenobiotics and environmental 
chemicals as well as germline mutations in pro-survival pathways (81-84). However, as cigarette 
smoking is such an overwhelming and preventable risk factor, the importance of family history 
and genetic susceptibility to lung cancer risk has often been overlooked and is difficult to 
discern.  
Germline testing for inherited predisposition is a well established part of care of individuals who 
may be at hereditary risk for cancers of the breast, ovary, colon, stomach, uterus, thyroid, and 
other primary sites(85, 86). In contrast to somatic genetic profiling of tumor tissue, germline 
testing involves analysis of DNA from blood or saliva for inherited mutations in specific genes 
that are associated with the type of cancer seen in the individual or family seeking assessment 
(86).  
High-penetrance germline mutations usually result in a significant alteration in the function of 
the corresponding gene product and are associated with large increases in cancer risk. For 
example, BRCA1 mutation, which is found at a frequency of 1 in 166 to 1000 in the general 
population, confers a relative risk for breast cancer of 32 in women aged between 40 and 49. 
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Other mutations are associated with less dramatic increases in risk. APC*I1307K and 
rs10505477 at 8q24 are associated with relative risks of 1.7 (intermediate-penetrance mutations) 
and 1.2 respectively for colon cancer (low-penetrance variants) (86). Germline testing of several 
high-penetrance germline mutations are now part of standard clinical practice and identification 
of these mutations often justifies an adjustment of clinical care through the modification of 
surveillance or through preventive surgery. Genetic tests for intermediate-penetrance mutations 
and low-penetrance variants are of uncertain clinical utility because the cancer risk associated 
with the mutation is generally too small to form an appropriate basis for clinical decision 
making.  
 
 
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Table 5. Previously reported germline mutations in lung cancer, clinico-pathologic features of the patients 
and their response to TKI 
Germline 
mutation 
Author, 
year 
Proband 
Ethnicity 
Smoking 
status 
Stage 
at 
presentation 
Histology 
Concurrent 
somatic  
mutations 
Response 
to EGFR 
TKI 
Family 
History 
Germline 
mutation in 
family members 
Follow 
up 
 
EGFR 
exon 20 
T790M 
 
Carmelo 
et al, 
2011 
72F 
European 
NS 
IV 
Adenocarcinoma 
EGFR 
E746-
A750 in 
exon 19 
PR/ 
PFS 9 
months 
Sister with 
LC 
(below) 
Absent in 2 
daughters 
OS 23 
months 
74F 
European 
NS 
IIIBwet 
Poorly 
differentiated 
carcinoma 
Negative 
PR/ 
PFS  45 
months 
 
Absent in 2 
sons 
NR 
Girard 
et al, 
2010 
66F 
Asian 
Indian 
 
NS 
IV 
Mixed 
adenocarcinoma  
(acinar 
and 
bronchioloalveolar) 
somatic 
EGFR 
L858R 
mutation 
NR 
2  family 
members 
with lung 
cancer  in 
2 
generations 
NR 
NR 
58M 
 
Eastern 
European 
NS 
IV 
Poorly 
differentiated 
adenocarcinoma 
(acinar and solid) 
EGFR 
L858R 
NR 
7  family 
members 
with lung 
cancer  in 
5 
generations 
NR 
NR 
Bell et 
al, 2005 
50M 
European 
Smoker 
IV 
BAC 
EGFR 
L858R, del 
L747-
T751 
PFS 9 
months 
6 family 
members 
with lung 
cancer, 
BAC or 
pulmonary 
nodules in 
3 
generations 
EGFRT790M 
in all 4 siblings 
NR 
55M 
European 
NR 
IV 
Adenocarcinoma 
EGFR 
G719A 
No 
response 
OS 6 
months 
Prudkin 
et al, 
2009 
72F 
NR 
NS 
NR 
Adenocarcinoma, 
BAC, LCNEC 
None 
NR 
2 family 
members 
with lung 
cancer in 2 
generations 
 
NR 
NR 
EGFR 
exon 21 
V843I 
 
Ikeda et 
al, 2008 
70F 
NR 
NR 
IIA, IA 
Adenocarcinoma, 
BAC, AAH 
EGFR 
L861Q 
 
EGFR 
L858R 
Not used 
3 family 
members 
with lung 
cancer in 2 
generations 
 
 
EGFRL861Q in 
3 siblings 
PFS 8 
months* 
Ohtsuka 
et al 
2010 
48F 
Japanese 
NR 
IV 
Adenocarcinoma 
NR 
No 
response 
4 
individuals 
with lung 
cancer in 3 
generations 
EGFRV843I in 
4 family 
members- 3 
with lung 
adenocarcinoma 
and 1 healthy 
person 
OS NR 
EGFR 
exon 21 
R831C 
Chung 
et al, 
2010 
76F 
NR 
NS 
IIIA 
Adenocarcinoma 
EGFR 
L861R 
PR 
PFS 14 
months 
Sister died 
of lung 
cancer at 
67 years 
NR 
 
EGFR 
exon 20 
R776G 
Centeno 
et al, 
2011 
47M 
European 
Smoker 
IIIA 
Adenocarcinoma 
EGFR 
exon 21 
L858R 
NR 
One 
sibling 
died of 
cancer 
NR 
OS 1 
year 
Abbreviations: EGFR: epidermal growth factor; PFS: progression free survival; NR: not reported; NS: never-smoker; BAC: 
bronchioalceolar carcinoma; AAH: atypical adenomatous hyperplasia; LCNEC: large cell neuroendocrine carcinoma; TKI: 
tyrosine kinase inhibitor OS: overall survival 
 
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No high penetrance mutations have been described for lung cancer. Germline mutations in EGFR 
and its association with familial lung cancer have been rarely described, but their penetrance and 
patterns of familial involvement are not known. Previously described germline mutations and 
clinico-pathologic features of lung cancer patients are shown in Table 5. EGFRT790M is the 
most extensively studied germline mutation in familial lung cancer. The T790M mutation occurs 
within exon 20, which encodes part of the kinase domain and results in an amino acid 
substitution at position 790 in EGFR, from a threonine (T) to a methionine (M). It is known to 
occur as a 'second-site mutation' in more than 50% of patients who develop acquired resistance 
(progressive disease while on therapy after an initial response) to EGFR tyrosine kinase inhibitor 
(TKI) therapy (87, 88).  
Bell et al reported a family with multiple cases of lung cancer associated with germline 
transmission of the EGFRT790M mutation (81). Four of the six tumors analyzed showed a 
secondary somatic activating EGFR mutation (either L858R, del L747-T751, or G719A) 
occurring in cis with the germ line T790M mutation. Although somatic EGFRT790M mutations 
are common in patients with acquired resistance to EGFR inhibitors, germline EGFRT790M 
mutations are rare. Two subsequent studies examined this germline mutation in a larger series of 
patients: Girard et al found EGFRT790M germline mutation in two of 369 cases of never 
smokers with NSCLC- both patients had a family history significant for lung cancer (89). 
However Vikis et al analyzed genomic DNA from 237 probands representing lung cancer 
families with more than three affected individuals for EGFRT790M mutation (90). No mutation 
was observed in any of the family probands analyzed and in any of 60 random fresh-frozen 
resected lung tumors suggesting that it may be a minor contributor to genetic susceptibility in 
familial lung cancers. Furthermore, in the Genetic Epidemiology of Lung Cancer Consortium 
(GELCC) linkage study, the analysis of 52 families (and family subsets within) did not reveal a 
significant logarithm of odds (LOD) score on or near 7p11, where the EGFR gene is located, 
which also suggests that the mutation may not be a major contributor to familial predisposition to 
lung cancer. Prudkin et al identified one germ line EGFRT790M mutation in a cohort of 240 
patients with previously untreated lung adenocarcinoma (91).  
EGFR exon 21V843I is an additional germline mutation which has been described in two 
reports, in association with a significant family history of lung cancer (92, 93). One subsequent 
study found no V843I mutations in 285 NSCLC patients with family history of lung cancer (94).   
The role if any of these mutations in inherited susceptibility to lung cancer in families with 
clustering of germline mutation and lung cancer is not completely clear. However early evidence 
suggests that EGFRT790M may provide a proliferative advantage with respect to wild-type 
(WT) EGFR, possibly due to the enhanced kinase activity of the mutant (90, 95-97). In a human 
bronchial epithelial cell line, overexpression of EGFRT790M displayed a growth advantage over 
WT EGFR (90). Moreover, presence of a concurrent L858R mutation, i.e. T790M/L858R double 
mutation resulted in a substantial increase in phosphorylation, compared with the L858R alone 
(95). Additionally, even in the absence of additional kinase domain mutations, EGFR T790M 
mice developed tumors, albeit with longer latency than EGFR L858R/T790M mice. Enhanced 
tyrosine autophosphorylation was also observed in cells transfected with the plasmid containing 
EGFRR776G (a germline EGFR mutation identified in Case 3 of Table 5) when compared to 
those transfected with WT EGFR (94).  
At this time, the clinical utility of identification of these germline mutations in lung cancer is not 
known. It is likely that these and other intrinsic genetic factors controlling susceptibility to lung 
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cancer might be hidden by strong environmental factors like cigarette smoking and air pollution 
which have been implicated in the mutagenesis of many other genes controlling pathways 
involved in the development lung cancers (3, 98). However, identification of these germline 
mutations may benefit individuals by providing deeper self-knowledge and motivation to pursue 
healthy behaviors (e.g., quit smoking), even if the results may not inform clinical decision 
making (99).  
With Amendment F, we will begin testing selected individuals (see Section 3.4) for the presence 
of EGFR germline mutations known to be associated with susceptibility to lung cancer. Only 
patients who enroll at the NCI will be eligible for this testing.  
2.2 
CTEP-Supplied Investigational Agent(s) 
See Section 18.1.1 
2.3 
Other agents 
See Section 18.1.2 
2.4 
Hypothesis 
A better understanding of the genetic make-up of the individual tumor may offer potentially 
improved therapies.  This approach may also give rapid access to response data in patients with 
sometimes rare genetic abnormalities.  In addition, it will allow us to test targeted therapies in a 
select population of patients that is more likely to have a favorable response based on their 
molecular profile and the specific mechanism of action of the drug being tested.  This approach 
will also speed up drug development and potentially approval, and rescue an otherwise 
ineffective drug candidate for the specific subgroup that can benefit. 
3 
PATIENT SELECTION 
3.1 
Eligibility criteria for initial enrollment 
3.1.1 Patients with histologically confirmed advanced NSCLC, SCLC and thymic malignancies 
for whom surgical resection or multimodality therapy with curative intent is not feasible.  
For patients with Stage III NSCLC, who can be encompassed by a radiation port, 
definitive XRT should have been performed first when possible. 
3.1.2 Individuals who meet the eligibility criteria for EGFR germline mutation testing (Section 
3.4) but who do not have advanced cancer as defined in 3.1.1 may enroll for EGFR 
germline mutation testing only and will not be eligible for the treatment or NOS arms. 
3.1.3 Patients with advanced cancer must meet one of the following criteria (does not apply to 
first-degree relatives or individuals with pre-invasive histology enrolling only for EGFR 
germline mutation testing): 
• Patients must have biopsiable disease and be willing to undergo biopsy for 
molecular profiling 
or 
• Patients must have enough and adequate archival material from a previous biopsy 
to perform molecular profiling analyses.  The adequacy of the material provided 
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will be determined by the principal investigator in conjunction with the 
laboratories performing the molecular profiling analyses. 
or 
• Patients must have previously undergone a successful molecular profiling of their 
tumor with mutation analysis of any of the genes described in section 5.2 or ALK 
break apart fluorescence in situ hybridization, as part of this protocol (crossover 
patients) or other molecular profiling protocols such as the Lung Cancer Mutation 
Consortium protocol among others.  
3.1.4 Age ≥18 years. 
3.2 
Eligibility criteria for enrollment into the Treatment arms (Treatment arms are no 
longer recruiting as of 3/22/16) 
Please refer to section 3.3 for eligibility criteria for enrollment in the specific molecular profile / 
treatment arms of this protocol.  
3.2.1 Inclusion Criteria 
3.2.1.1 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as >20 
mm with conventional techniques or as >10 mm with spiral CT scan.  See Section 13 
for the evaluation of measurable disease.  
Target lesions cannot be selected within previously irradiated areas, if not newly 
arising or clearly progressing after irradiation as proven by repeat scanning. 
3.2.1.2 Life expectancy of greater than 3 months. 
3.2.1.3 Performance status (ECOG) ≤ 2 (See Appendix C: Performance Status Criteria). 
3.2.1.4 Patients must have normal organ and marrow function as defined below: 
• leukocytes 
 
 
>1,500/mcL 
• absolute neutrophil count 
>1,000/mcL 
• platelets 
 
 
>100,000/mcL 
• total bilirubin* 
 
< 1.5 X institutional upper limit of normal 
For patients with Gilbert’s syndrome or levels of 
indirect bilirubin above the upper limit of normal, 
direct bilirubin will be used for eligibility and 
should be < 1.5 X institutional upper limit of 
normal. 
• AST(SGOT)/ALT(SGPT) 
< 3 X institutional upper limit of normal 
• creatinine 
 
 
≤1.5 X institutional upper limits of normal 
OR creatinine clearance >50 mL/min/1.73 m2 for 
patients with creatinine levels above 1.5 X 
institutional normal.  
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3.2.1.5 Patients must have recovered from toxicity related to prior therapy (chemotherapy, 
surgery or radiation) to grade ≤ 1 (defined by CTCAE: The NCI Common Terminology 
Criteria for Adverse Events Version 4 (CTCAE) will be used for toxicity and adverse 
event reporting. All appropriate treatment areas have access to a copy of the CTCAE 
version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site (http://ctep.cancer.gov). 
3.2.1.6 The effects of most of the therapeutic agents used in this trial on the developing human 
fetus at the recommended therapeutic doses are unknown.  For this reason and because 
some agents are known to be teratogenic, women of child-bearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation, and continue 
for at least 16 weeks after completing the study to avoid pregnancy and/or potential 
adverse effects on the developing embryo.  Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she should inform her treating 
physician immediately.  Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with targeted therapies, 
breastfeeding should be discontinued if the mother is treated with targeted therapies. 
3.2.1.7 Ability to understand and the willingness to sign a written informed consent document. 
3.2.2 Exclusion Criteria 
3.2.2.1 Patients who have had major surgery, chemotherapy or radiotherapy within 2 weeks prior 
to entering the study or those who have not recovered from adverse events due to agents 
administered more than 2 weeks earlier. 
3.2.2.2 Patients may not be receiving any other investigational agents or other medications for 
the treatment of their malignancy. 
3.2.2.3 Patients with symptomatic brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events.  
However, patients who have had treatment for their brain metastases and whose brain 
metastatic disease status has remained stable for at least 1 week after the end of brain 
radiation may be enrolled to undergo molecular profiling at the discretion of the 
principal investigator. In addition, brain metastatic disease should be stable for at least 4 
weeks, before the patients can be enrolled in any of the experimental treatment arms.  
3.2.2.4 Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to 
take oral medication or a requirement for IV alimentation, prior surgical procedures 
affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow 
and retain tablets are excluded. 
3.2.2.5 Any uncontrolled medical illness that precludes the patient from undergoing a biopsy for 
molecular profiling and / or receiving treatment under one of the experimental arms of 
the study should be excluded.  These conditions include but are not limited to: 
• Ongoing or uncontrolled, symptomatic congestive heart failure (Class III or IV as 
defined by the NYHA functional classification system (see Appendix D). 
• Uncontrolled hypertension 
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• Unstable angina pectoris 
• Cardiac arrhythmia 
• Uncontrolled diabetes 
• Uncontrolled psychiatric illness/social situations that would limit compliance with 
study requirements.  
3.2.2.6 Patients with QTc prolongation (defined as a QTc interval equal to or greater than 500 
msec) or other significant ECG abnormalities are excluded. 
3.2.2.7 Caution should be used if patients are required to use a concomitant medication that can 
prolong the QT interval and efforts should be made to switch to a different medication 
before the patient begins treatment under an experimental arm.  See Appendix E for a 
table of medications with the potential to prolong the QTc interval.  A comprehensive 
list of agents with the potential to cause QTc prolongation can be found at: 
http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm 
 
3.2.2.8 The eligibility of patients taking medications that are potent inducers or inhibitors of that 
enzyme will be determined following a review of their case by the Principal 
Investigator.  (A list of potent CYP3A4 inducers or inhibitors can be found in Appendix 
F).  Every effort should be made to switch patients taking such agents or substances to 
other medications before they begin treatment with one of the experimental drug 
included in this protocol, particularly patients with gliomas or brain metastases who are 
taking enzyme-inducing anticonvulsant agents.  A comprehensive list of medications 
and substances known or with the potential to alter the pharmacokinetics of sunitinib 
through CYP3A4 is provided in Appendix F. 
3.2.2.9 Patients with tumor amenable to potentially curative therapy as assessed by the 
investigator. 
3.2.2.10 Pregnant women are excluded from this study because many of the FDA approved 
agents and investigational agents in this trial have the potential for teratogenic or 
abortifacient effects.  Because there is an unknown but potential risk for adverse events 
in nursing infants secondary to treatment of the mother with these agents, breastfeeding 
should be discontinued if the mother is treated in this protocol.  These potential risks 
may also apply to other agents used in this study. 
3.3 
Specific eligibility criteria for enrollment in treatment arms (Treatment arms are no 
longer recruiting as of 3/22/16) 
The following is a description of the eligibility criteria required to be enrolled in the specific 
molecular profile-based treatment arms of this study which include: Erlotinib, AZD6244, MK-
2206, Lapatinib and Sunitinib arms.  This is in addition to the general eligibility and exclusion 
criteria described in sections 3.1 and 3.2. 
3.3.1 Erlotinib arm 
3.3.1.1 Inclusion criteria 
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3.3.1.1.1 Patients must have an EGFR TKI sensitizing mutation as determined by analysis of 
the primary tumor or a metastatic site in a CLIA certified laboratory. 
3.3.1.1.2  Patients with SCLC or thymic malignancies must have been treated with at least 1 
previous standard of care chemotherapy regimen or refuse to be treated with 
conventional chemotherapy agents. 
3.3.1.2 Exclusion criteria 
3.3.1.2.1 Previous anti-EGFR TKI therapy 
3.3.1.2.2 Patients with a known EGFR TKI resistant mutation. 
3.3.1.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Erlotinib. 
3.3.2 AZD6244 arm 
3.3.2.1 Inclusion criteria 
3.3.2.1.1 Patients must have one of the following as determined by analysis of the primary 
tumor or a metastatic site in a CLIA certified laboratory:  
• KRAS mutation or 
• NRAS mutation or 
• HRAS mutation or 
• BRAF mutation 
3.3.2.1.2 Patients must have been treated with at least 1 previous standard of care chemotherapy 
regimen or refuse to be treated with conventional chemotherapy agents.  
3.3.2.2 Exclusion criteria 
3.3.2.2.1 Any prior exposure to MEK, Ras, or Raf inhibitors. 
3.3.2.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to AZD6244. 
3.3.2.2.3 Cardiac conditions as follows: 
• 
Uncontrolled hypertension (BP ≥150/95 despite optimal therapy)  
• 
Heart failure NYHA Class II or above (See Appendix D: New York Heart 
Association Classifications) 
• 
Prior or current cardiomyopathy  
• 
Baseline LVEF ≤ 50%. 
• 
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).  
3.3.2.2.4 Laboratory values as listed below (SI units): 
• 
Absolute Neutrophil Count (ANC) <1.5x109/L (1500 per mm3)  
• 
Platelets <100x109/L (100,000 per mm3)  
• 
Hemoglobin (Hgb) <9.0 g/dL  
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• 
Serum bilirubin >1.5 x upper limit of normal (ULN)  
• 
Aspartate aminotransferase (AST/SGOT) or alanine aminotransferase 
(ALT/SGPT) >2.5 x ULN (≥5 ULN in presence of liver metastases).  
3.3.3 MK2206 arm 
3.3.3.1 Inclusion criteria 
3.3.3.1.1 Patients must have one of the following as determined by analysis of the primary 
tumor or a metastatic site in a CLIA certified laboratory:  
• PI3KCA mutation or 
• PI3KCA gene amplification by FISH (gene to chromosome ration >2) or 
• AKT mutation or 
• PTEN mutation 
3.3.3.1.2 Patients must have been treated with at least 1 previous standard of care chemotherapy 
regimen or refuse to be treated with conventional chemotherapy agents.   
3.3.3.2 Exclusion criteria 
3.3.3.2.1 Previous AKT inhibitor therapy.  
3.3.3.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MK-2206. 
3.2.3.2.3   Preclinical studies demonstrated the potential of MK-2206 for induction of 
hyperglycemia in all preclinical species tested.  Patients with diabetes or in risk for 
hyperglycemia should not be excluded from trials with MK-2206, but the 
hyperglycemia should be well controlled on oral agents before the patient enters the 
trial. 
3.3.4 Lapatinib arm 
3.3.4.1 Inclusion criteria 
3.3.4.1.1 Patients must have one of the following as determined by analysis of the primary 
tumor or a metastatic site in a CLIA certified laboratory:  
• ERBB2 mutation or 
• ERBB2 gene amplification by FISH (gene to chromosome ration >2) 
3.3.4.1.2 Patients must have been treated with at least 1 previous standard of care chemotherapy 
regimen or refuse to be treated with conventional chemotherapy agents.  
3.3.4.2 Exclusion criteria 
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3.3.4.2.1 Previous Lapatinib therapy.  
3.3.4.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to lapatinib. 
3.3.4.2.3 LVEF < 50%  
3.3.5 Sunitinib arm 
3.3.5.1 Inclusion criteria 
3.3.5.1.1 Patients must have one of the following as determined by analysis of the primary 
tumor or a metastatic site in a CLIA certified laboratory:  
• PDGFR-A mutation or 
• PDGFR-A gene amplification by FISH (gene to chromosome ratio >2) or 
• KIT mutation 
3.3.5.1.2 Patients must have been treated with at least 1 previous standard of care chemotherapy 
regimen or refuse to be treated with conventional chemotherapy agents.  
3.3.5.2 Exclusion criteria 
3.3.5.2.1 Previous sunitinib therapy 
3.3.5.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to sunitinib. 
3.3.5.2.3 Patients who require use of therapeutic doses of coumarin-derivative anticoagulants 
such as warfarin are excluded. Note: Low molecular weight heparin is permitted 
provided the patient’s PT INR is <1.5.  
3.3.5.2.4 Patients with any of the following conditions are excluded: 
• Serious or non-healing wound, ulcer, or bone fracture. 
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within 28 days of treatment. 
• Any history of cerebrovascular accident (CVA) or transient ischemic attack 
within 12 months prior to study entry. 
• History of myocardial infarction, cardiac arrhythmia, stable/unstable angina, 
symptomatic congestive heart failure, or coronary/peripheral artery bypass graft 
or stenting within 12 months prior to study entry. 
• History of pulmonary embolism within the past 12 months. 
3.3.5.2.5 Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid 
function in the normal range with medication are ineligible. 
3.4 
Eligibility criteria for EGFR germline mutation testing (NCI site only) 
3.4.1 Age ≥ 18 years with one of the following criteria: 
3.4.2 Personal history of invasive lung cancer or one of the pre-invasive histologies associated 
with the development of lung cancer [adenocarcinoma in situ (AIS), minimally invasive 
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adenocarcinomas (MIA) or atypical adenomatous hyperplasia (AAH)] and more than two 
affected family members with invasive lung cancer or one of the pre-invasive histologies 
associated with the development of lung cancer; OR 
3.4.3 First-degree relatives of an individual enrolled in the study with a known EGFR germline 
mutation; OR 
3.4.4 Detection of de-novo (prior to any treatment with TKI) T790M mutation in the tumor 
specimen of a lung cancer patient; OR 
3.4.5 A family history of lung cancer not possibly related to smoking history, defined as at 
least one family member within the 3rd degree of consanguinity with lung cancer who 
was a never or oligo-smoker* or at least two family members in either the maternal or 
paternal side with a history of lung cancer; OR 
3.4.6 Documented germline lung cancer associated mutation (such as EGFR T790M) tested 
elsewhere. 
*An oligo-smoker is defined as an individual with ≤ 15 pack-year history of smoking.  
3.5 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.  The following are 
our accrual targets based on race and gender for allhistology groups combined (i.e. NSCLC, 
SCLC, and thymic malignancies): 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 Males 
 Total 
Hispanic or Latino 
42 
+ 
42 
= 
84 
Not Hispanic or Latino 
258 
+ 
258 
= 
516 
Ethnic Category: Total of all subjects 
300 
+ 
300 
= 
600 
 
Racial Category 
 
American Indian or Alaskan Native 
12 
+ 
12 
= 
24 
Asian 
90 
+ 
90 
= 
180 
Black or African American 
42 
+ 
42 
= 
84 
Native Hawaiian or other Pacific 
Islander 
12 
+ 
12 
= 
24 
White 
144 
+ 
144 
= 
288 
Racial Category: Total of all subjects 
300 
+ 
300 
= 
600 
Accrual Rate: 10 patients/month 
Total Expected Accrual:  600 patients from all participating sites and in all diseases combined. 
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4 
PATIENT REGISTRATION 
4.1 
 Registration Process 
4.1.1 NCI Patient Registration 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov . After confirmation of eligibility at Central Registration Office, CRO staff will 
call pharmacy to advise them of the acceptance of the treatment-eligible patient on the protocol 
prior to the release of any investigational agents.  Verification of Registration will be forwarded 
electronically via e-mail to the research team.  Please note, it is very important for all registrars 
to acquire encrypted e-mail from NIH Help Desk, since the verification of registration includes 
patient’s information.  A recorder is available during non-working hours.  
Patients will retain their number throughout their time on the protocol but will be given a letter 
designation to identify which arm they have been enrolled to, or re-enrolled to in accordance 
with Section 5.4.  The letters that correspond to the treatment arms are as follows: 
A – Arm A (Erlotinib) 
B – Arm B (AZD6244) 
C – Arm C (MK-2206) 
D – Arm D (Lapatinib) 
E – Arm E (Sunitinib) 
F – Arm F (NOS) 
Version M 04/08/14 NOTE: The treatment arms are closed to accrual, but patients are still being 
accrued for germline testing. 
4.1.2 For Participating Site Registration 
NOTE:  The participating site closed on 02/05/2015. This section is no longer applicable, but is 
being retained for historical purposes.  
All patients must be registered through the NCI Central Registration Office (CRO).  The CRO is 
open from 8:30am to 5:30pm EST Monday through Friday, excluding federal holidays.  The 
protocol registration form and cover memo will be supplied by the Coordinating Center, NCI 
CCR, and updates will be provided as needed.  Subject eligibility and demographic information 
is required for registration.  To initially register a subject after the participant has signed consent, 
complete the top portion of the form and fax to the CRO at 301-480-0757. Once eligibility is 
confirmed, complete the remainder of the form which is the eligibility checklist and, fax the 
completed registration checklist and cover memo to the CRO at 301-480-0757.    
The CRO will notify the registering site personnel either by e-mail or fax that the protocol 
registration form has been received.  The CRO will assign a unique patient/subject ID number 
for each subject that will be used to enter data into the C3D database.  Questions about eligibility 
should be directed to the Coordinating Center’s Research Nurse: 
Arlene Berman, RN 
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9000 Rockville Pike 
Bldg 10, Rm 12N226 
Bethesda, MD 20892 
Telephone: 301.435.5609 
Fax: 301.480.2590 
Email: arleneb@mail.nih.gov 
Technical questions about the form should be directed to the Central Registration: Office (301-
402-1732). 
4.2 
On-Study Research Evaluation  
This section applies only to patients enrolled into any of the treatment arms of the protocol. 
4.2.1 Complete history and physical examination (including height, weight, vital signs and 
ECOG performance score) with documentation of 1) measurable disease, 2) narcotic use 
and pain assessment, and 3) prior therapies (surgical, radio therapeutic and cytotoxic) will 
be conducted prior to on-study.  A complete medication history will be obtained prior to 
starting, including medications at base line, over the counter medications, homeopathic 
remedies, vitamins, and alternative therapies.   
4.2.2 Imaging Studies (Baseline) - Every patient should have a baseline clinical evaluation with 
CT scan of chest, abdomen and/or pelvis for areas of known or suspected disease 
involvement prior to receiving treatment.  In some patients an MRI may be more 
appropriate.  FDG-PET scans are recommended but not mandatory. Baseline scans must 
be completed within 28 days prior to enrollment.  
4.2.3 Laboratory Evaluation [baseline labs must be obtained within one week prior to 
enrollment]. 
4.2.4 Hematological Profile: CBC with differential and platelet count, prothrombin time, 
activated partial thromboplastin time.  
4.2.5 Biochemical Profile: Sodium, potassium, chloride, CO2, BUN, creatinine, glucose, AST, 
ALT, alkaline phosphatase, bilirubin, albumin, total protein, LDH, calcium, phosphorous, 
magnesium, and urinalysis. 
4.2.6 PT and PTT 
4.2.7 EKG (baseline) 
4.2.8 Pregnancy test for female patients of childbearing age and anatomic ability. 
5 
STUDY DESIGN / TREATMENT PLAN 
The purpose of this trial is to perform molecular profiling analysis in patients with advanced 
NSCLC, SCLC and thymic malignancies and offer enrollment into targeted therapy arms based 
on their molecular profiles. We will also be studying the frequency of EGFR germline mutations 
by enrolling patients from families with high susceptibility to lung cancer and their first-degree 
relatives (at the NCI only). 
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5.1 
Specimen Collection 
Individuals who meet the eligibility criteria for EGFR germline mutation testing but who do not 
have advanced cancer as defined in Section 3.1.1 will not undergo tumor biopsy for molecular 
profiling. 
Patients with advanced cancer (as defined in Section 3.1.1) who meet eligibility criteria will 
undergo biopsy of the primary tumor or any metastatic site for molecular profiling analyses (with 
the exception of patients who have available archival material or patients that have previously 
undergone successful molecular profiling).  All attempts will be made to obtain fresh tissue 
biopsies but if this is not feasible, archived paraffin blocks will be acceptable as long as there is 
enough and adequate material to perform the molecular profiling analyses described below.  The 
adequacy of the archival tissue provided by the patient will be determined by the principal 
investigator at each participating institution in conjunction with the molecular pathology 
laboratories performing the molecular analyses. The following techniques will be used to obtain 
tissue samples for molecular profiling according to the location and size of the lesions: 
• Core needle biopsy 
• Excisional biopsies 
Sample collection will be performed either by the interventional radiology or the surgery 
departments at the participating institution.  Biopsies will be performed according to the standard 
operating procedures in place at the performing institution.  Samples will be formalin fixed and 
sent to the local pathology department for further processing and confirmation of the histologic 
diagnosis.  If possible, one of the samples will be immediately frozen to perform some of the 
correlative analyses described in Section 10. 
5.2 
Molecular Profiling 
After the tumor samples are obtained, molecular profiling analyses will be performed to 
determine enrollment in specific treatment arms (with the exception of patients who have 
previously undergone successful molecular profiling).  Since these analyses will be used for 
treatment decisions, they will be performed in a CLIA certified laboratory at the participating 
institutions.  The following is a list of the molecular profiling analyses to be performed: 
5.2.1 Gene mutation analyses for treatment decisions 
Approved 
Gene 
Symbol 
Approved Gene Name 
Location 
Sequence 
Accession 
IDs 
Previous 
Symbols 
Aliases 
AKT1 
v-akt murine thymoma viral 
oncogene homolog 1 
14q32.32-
q32.33 
M63167 
NM_005163 
  
RAC, PKB, 
PRKBA, AKT 
AKT2 
v-akt murine thymoma viral 
oncogene homolog 2 
19q13.1-
q13.2 
NM_001626 
 
 
BRAF 
v-raf murine sarcoma viral 
oncogene homolog B1 
7q34 
M95712 
NM_004333 
  
BRAF1 
EGFR 
epidermal growth factor 
receptor (erythroblastic 
leukemia viral (v-erb-b) 
oncogene homolog, avian) 
7p12 
NM_005228 
ERBB 
ERBB1 
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ERBB2 
v-erb-b2 erythroblastic leukemia 
viral oncogene homolog 2, 
neuro/glioblastoma derived 
oncogene homolog (avian) 
17q11.2-
q12 
X03363 
NGL 
NEU, HER-2, 
CD340, HER2 
HRAS 
v-Ha-ras Harvey rat sarcoma 
viral oncogene homolog 
11p15.5 
AJ437024 
NM_176795 
HRAS1 
 
KIT 
v-kit Hardy-Zuckerman 4 feline 
sarcoma viral oncogene 
homolog 
4q11-q12 
S67773 
PBT 
CD117, SCFR, C-
Kit 
KRAS 
v-Ki-ras2 Kirsten rat sarcoma 
viral oncogene homolog 
12p12.1 
BC010502 
NM_033360 
KRAS2 
KRAS1 
NRAS 
neuroblastoma RAS viral (v-ras) 
oncogene homolog 
1p13.2 
BC005219 
NM_002524     
 
 
PDGFRA 
platelet-derived growth factor 
receptor, alpha polypeptide 
4q12 
D50001 
NM_006206 
  
CD140a, 
PDGFR2 
PIK3CA 
phosphoinositide-3-kinase, 
catalytic, alpha polypeptide 
3q26.3 
  NM_006218 
  
p110-alpha, 
MGC142161, 
PI3K, 
MGC142163 
PTEN 
phosphatase and tensin homolog 
10q23 
U92436 
NM_000314   
BZS, 
MHAM 
MMAC1, TEP1, 
PTEN1 
5.2.2 ERBB2 amplification by FISH 
5.2.3 PDGFRA amplification by FISH 
5.3 
Enrollment in treatment arms  
Treatment arms are no longer recruiting as of 3/22/16. 
Due to the rapidly progressing course of the thoracic malignancies in this study, treatment 
decisions will be made in approximately 2 weeks from the time that the tumor samples were 
obtained. Based on the molecular profiling results, the patients will be offered enrollment into a 
specific treatment arm according to the decision tree shown in Figure 2 and the eligibility criteria 
described in Section 3.  
Individuals who meet the eligibility criteria for EGFR germline mutation testing (Section 3.4) 
but who do not have advanced cancer as defined in Section 3.1.1 are not eligible for the 
treatment arms. 
 
 
 
 
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Figure 2. Schema 
 
Each study arm is independent from the other arms; it has its own eligibility criteria (Section 3) 
and statistical considerations (Section 15), and will be analyzed independently.  Additionally, it 
is not our intention to compare the outcomes among treatment arms since the patients enrolled in 
each arm will have different molecular characteristics. 
Patients enrolled in one of the treatment arms of this protocol, with the exception of the NOS 
arm and individuals enrolled for EGFR germline mutation testing only, will be treated and 
EGFR germline 
mutation testing in 
eligible patients† 
A 
Biopsy and 
molecular  
profiling 
EGFR  
Mutation* 
KRAS,  HRAS 
NRAS, or 
BRAF, 
 Mutation* 
PTEN 
Akt  or PI3K 
Mutation or 
PI3K Amp* 
ERBB2 
Mutation 
or  
Amp* 
KIT, 
PDGFR-A  
Mutation 
or 
Amp* 
Other* 
Erlotinib 
AZD6244 
MK2206 
Lapatinib 
Sunitinib 
NOS 
Disease 
Progression 
A 
Yes 
Yes 
Yes 
Yes 
Yes 
No 
No 
No 
No 
No 
* See Sections 3.2 and 3.3 for eligibility criteria for the treatment arms.  Patients will be 
allowed to crossover to different treatment arms as long as they meet eligibility criteria. 
† See separate eligibility criteria (Section 3.4) and schema for EGFR germline mutation 
testing. 
No = No or not available 
Amp = gene amplification by FISH 
NOS = non-otherwise specified arm 
         = optional re-biopsy for patients that responded to previous line of therapy 
A 
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followed with clinical visits at least every 3, 4, or 6 weeks, as defined for each treatment arm; 
i.e., every 3 weeks for the Erlotinib, AZD6244, and Lapatinib arms; every 4 weeks for the MK-
2206 arm; and every 6 weeks for the Sunitinib arm.  The time between clinic visits may be 
extended at the PI’s discretion by up to 1 full cycle, for a maximum of 2 cycles between clinic 
visits (i.e., clinic visits may be extended to every 6 weeks for the Erlotinib, AZD6244, and 
Lapatinib arms; every 8 weeks for the MK-2206 arm; and every 12 weeks for the Sunitinib arm).  
If the frequency of clinic visits is extended, laboratory tests will not be required nor samples 
collected until the next clinic visit.  Re-staging imaging will be performed at the end of every 
two cycles as defined for each treatment arm; i.e., every 6, 8, or 12 weeks +/- 1 week.  See 
Section 5.9.2 for details.  The patients will continue on the selected arms until disease 
progression.    
5.4 
Treatment after disease progression  
Patients who initially had a response to treatment or a prolongued stabilization of the tumor (>6 
months) but that eventually develop progressive disease, will be offered the option to have a 
repeat biopsy for molecular profiling analyses. This biopsy will have the intention to study 
potential mechanisms of resistance to specific targeted therapies. This will also be potentially 
used for treatment decisions or enrollment in other molecularly targeted protocols.  However, if 
the patient refuses this option, we will use the most recent results of the molecular profiling 
analyses to verify eligibility for enrollment in an alternative treatment arm on this study 
(crossover). 
At the time of disease progression, the patients will be allowed to re-register onto another 
treatment arm that is available in this protocol, according to the schema, and as long as they still 
meet the eligibility criteria described in Section 3. In this case, patients will be re-registered onto 
the treatment arm, but not re-consented.   The patient will count as a new patient to that specific 
arm, keeping their original patient ID number. 
5.5 
The NOS arm 
All patients that undergo molecular profiling but that are not enrolled into any of the 
investigational treatment arms will be enrolled into the NOS arm, which is considered to be a 
natural history arm.  These patients do not have to meet any particular eligibility criteria. 
Individuals who meet the eligibility criteria for EGFR germline mutation testing (Section 3.4) 
but who do not have advanced cancer as defined in Section 3.1.1 are not eligible for the NOS 
arm. 
This will allow data collection on these patients, linking their clinical information with their 
molecular profiling analyses.  Frequency determination of each mutation, its association with 
clinical features, response to other standard and experimental treatments and overall outcome 
data will be collected.  As future therapeutic protocols or treatment arms specific for their 
molecular profiles are developed at NIH or elsewhere, patients may be notified of their eligibility 
for these studies. 
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The NOS arm will consist of the following mixture of patients: 
• Patients that do not meet the eligibility criteria for enrollment in the available treatment 
arms of this protocol.  
• Patients that meet eligibility criteria for a particular arm but cannot be enrolled on it 
because of other reasons such as patient preference or drug availability issues, among 
others. 
The NOS arm is considered a natural history arm in which the patients are allowed to receive a 
standard of care or experimental therapy of their choice, including but not limited to the 
following modalities: 
• Patients will be allowed to participate on any available treatment clinical trial at NIH or 
elsewhere. 
• Patients will be allowed to receive standard of care treatment at NIH under protocol 04-
C-0165 (“Care of the Adult Oncology Patient, Center for Cancer Research, NCI;” 
Principal Investigator: James Gulley, M.D.) or elsewhere. 
• Patients will be allowed to receive best supportive care at NIH or elsewhere. 
Patients on this arm will be followed either with clinic visits, phone interviews, or medical 
records review every 4 months (+/- 2 months).  The patients will continue to be followed in this 
arm indefinitely, until death or until the patient decides to withdraw from the protocol. 
5.6 
EGFR germline mutation testing 
Patients at the NCI site meeting the eligibility criteria in Section 3.4 will be enrolled in EGFR 
germline mutation arm of the study (100, 101). Guidelines set forth by American Society of 
Clinical Oncology (ASCO) in 2003 and updated in 2010 will be followed in obtaining consent, 
genetic counseling, testing and follow up (86, 102).  
 
Evaluation and follow-up of eligible patients and family members are outlined in Figure 3 and 
Figure 4.  
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Figure 3. Flow chart depicting evaluation and follow-up of eligible patients who undergo EGFR 
germline mutation testing. 
 
 
1  Consent II: Informed consent for testing for EGFR germline mutations.  
2  EGFR germline mutation panel: EGFR exon 20 T790M, exon 21 V843I, exon 21 R831C and 
exon 20 R776G. 
 
Eligible patients for EGFR 
germline mutation testing 
History and Physical exam 
Pre-test genetic counseling
1Consent II
2EGFR germline mutation 
panel testing
No EGFR germline mutations 
Result disclosure and post-test genetic counseling 
Mangement of invasive carcinoma/pre-invasive 
histology per standard guidelines
EGFR germline mutation/s 
positive 
Result disclosure and post-test genetic counseling
Mangement of invasive carcinoma/pre-invasive histology per 
standard guidelines
All first-degree relatives invited to participate in the study 
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Figure 4. Flow chart depicting evaluation and follow-up of first-degree relatives who undergo 
EGFR germline mutation testing. 
5.6.1 Consent 
1 Between 55 and 74 years of age at enrollment with a history of cigarette smoking of at least 30 pack-years, and, if former 
smokers, those who quit within the previous 15 years.  
2 Age ≥ 45 years at enrollment with ≥ 20 pack-year smoking history or age within 5 years before the youngest family 
member was diagnosed with lung cancer. 
3 For lung nodules and incidental lesions detected on CT, follow up is per standard guidelines. 
Consent III: Informed consent for testing for EGFR germline mutations in first-degree relatives of individuals with known 
EGFR germline mutations.  
Abbreviation: LDCT, low-dose screening computed tomography scan. 
Follow-up of lung nodules recommended by Fleischner Society (1) and National Comprehensive Cancer Network(2)(2)(2).  
History and Physical Exam 
Pre-test genetic counseling 
Consent III 
EGFR germline testing of index mutation found in proband 
Mutation negative 
Result disclosure and post-
test genetic counseling  
1High risk  
Annual LDCT 
screening for at 
least 3 years and 
until age 74 
Mutation positive 
Result disclosure and post-
test genetic counseling  
2High risk 
3Baseline CT 
followed by 
annual LDCT 
screening for at 
least 3 years 
and until age 74 
Not high risk 
≥ 20 pack-year smoking history 
< 20 pack-year smoking history 
LDCT at 1 year intervals for  
3 years starting 5 years before 
the youngest family member was 
diagnosed with lung cancer or 
age 45 (whichever one earlier) 
No baseline CT  
Baseline CT followed by LDCT 
at 1 year intervals for 3 years 
starting 5 years before the 
youngest family member was 
diagnosed with lung cancer or 
age 45 (whichever one earlier) 
Not high risk  
No further 
intervention 
First-degree relatives of patient with EGFR germline 
mutation (proband) 
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The proband as well as all family members undergoing germline genetic testing will sign 
informed consent after undergoing genetic counseling and prior to any germline genetic testing. 
Consents I, II and III will be used as follows:  
Consent I: Patients who are eligible for the molecular profiling protocol will sign the standard 
consent for molecular profiling protocol. 
Consent II: Individuals with lung cancer or a pre-invasive histology who meet the eligibility 
criteria for EGFR germline mutation testing (i.e., meets criteria 3.4.1 and 3.4.2) will sign consent 
II (i.e., consent for germline mutation testing of proband). Consent II will be obtained from the 
next of kin for deceased family members of the proband with a history of lung cancer for whom 
tissue is available. 
Consent III: First-degree relatives of individuals with EGFR germline mutations (with no known 
lung cancer and/or germline mutations, i.e., meets criteria 3.4.1 and 3.4.3) will sign consent III 
(i.e., consent for germline mutation testing of unaffected family member).  
5.6.2  Pre-test genetic counseling 
Genetic counseling will be provided for the individual and family members both before and after 
germline mutation analysis as detailed below: The proband and family members who undergo 
genetic testing will meet a genetics healthcare provider (GHP) (either in clinic or via phone 
conference) prior to signing consent for germline testing and undergoing germline genetic 
testing. The GHP will explain the specific testing to be performed, the timeframe for analysis, 
follow-up testing that may be required, and the types of information that may be obtained and 
potential healthcare recommendations which could result based on potential results. Ample time 
will be given to ensure that all questions are answered. At each step in the process the GHP will 
be available to answer questions and assist the individual in the decision process regarding 
testing and results.  
5.6.3 Genetic testing 
Step 1: The proband (patient who presents to our clinic with lung cancer or a pre-invasive 
histology with more than two affected family members with invasive lung cancer or one of the 
pre-invasive histologies associated with the development of lung cancer) will be tested for EGFR 
germline mutations (on peripheral blood mononuclear cells) that have been associated with 
familial clustering of lung cancer (EGFR exon 20 T790M, exon 21 V843I, exon 21 R831C and 
exon 20 R776G). The following information will be documented for the proband: mutational 
status of the tumor, treatment history and response to EGFR TKI, age, sex, ethnicity, detailed 
family history with documentation of any malignencies in the family, smoking survey based on 
the Centers for Disease Control and Prevention Behavioral Risk Factor Surveillance System 
Survey Questionnaire (Appendix K: Tobbacco Use History Questionnaire), environmental 
exposure and previous malignancies. Once a specific mutation is confirmed in the proband, all 
adult first-degree relatives (parents, offspring, and siblings) will be invited to participate in this 
study.  
Step 2: Recruitment of first-degree relatives  
If the proband consents to do so, all first-degree relatives (of the proband) will be contacted by a 
letter followed by phone call. 
Step 3: Consenting family members of the proband will be asked to undergo germline mutation 
testing of the index mutation, which was identified in the proband.  For all family members, a 
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history and physical exam will be performed and the following information documented: age, 
sex, ethnicity, detailed family history with documentation of any malignencies, smoking survey 
based on the Centers for Disease Control and Prevention Behavioral Health Factor Surveillance 
System Survey Questionnaire (Appendix K: Tobbacco Use History Questionnaire), 
environmental exposure and previous malignancies.  
In many cases, due to the high case-fatality rate of lung cancer, the family member with lung 
cancer may be deceased. In these cases, archived FFPE tissue may be used for germline mutation 
testing (after genetic counseling and obtaining consent from next of kin), if normal tissue can be 
isolated using laser capture microdissection.  
5.6.4 Result disclosure and post-test counseling  
Results of EGFR germline mutation testing will be available in Clinical Research Information 
System (CRIS) in ≤ 2 weeks after date of sample collection. Disclosure of test results will be 
performed by a study investigator and GHP, who will provide any management 
recommendations as well as recommendations for testing family members as applicable. Study 
participants and their designated local health care provider(s) will also receive these 
recommendations in writing as a counseling letter.  
5.6.5 Follow-up 
The follow up of individuals who undergo germline mutation testing will follow the schema in 
Figure 3. After result disclosure and post-test counseling, whether an EGFR germline mutation is 
found or not, mangement of invasive carcinoma/pre-invasive histology will follow standard 
guidelines.   
The follow up of first-degree relatives of the proband who undergo germline mutation testing 
will follow the schema in Figure 4.  
Mutation negative individual: These individuals will be will be risk stratified based on smoking 
history into "high-risk" (individuals between 55 and 74 years of age at enrollment with a history 
of cigarette smoking of at least 30 pack-years, and, if former smokers, those who quit within the 
previous 15 years) and "not high-risk" (individuals not meeting the high-risk criteria) groups 
(103). In the high-risk group, annual low-dose computed tomography (LDCT) screening (CT 
screening techniques will follow NCCN guidelines; an example of the latest guideline is in 
Appendix L) will be rcommended for at least 3 years and until age 74 (103). No further 
intervention will be recommended for the not high-risk group.  
Mutation positive individual: These individuals will be will be risk stratified based on smoking 
history and age of youngest family member with lung cancer into "high-risk" (age ≥ 45 at 
enrollment with ≥ 20 pack-year smoking history or age within 5 years before the youngest family 
member was diagnosed with lung cancer) and "not high-risk" (individuals not meeting the high-
risk criteria) groups. In the high-risk group, annual LDCT screening will be rcommended for at 
least 3 years and until age 74 (103). The not-high risk individuals will be further risk-stratified 
based on smoking history into 2 groups and followed as described: ≥ 20 pack-year history of 
smoking [Baseline CT followed by LDCT at 1 year intervals for 3 years starting 5 years before 
the youngest family member was diagnosed with lung cancer or age 45 (whichever one earlier)] 
and ≤20 pack year history of smoking [LDCT at 1 year intervals for 3 years starting 5 years 
before the youngest family member was diagnosed with lung cancer or age 45 (whichever one 
earlier)].  
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All probands as well as family members who are enrolled in the protocol will be counseled 
regarding smoking cessation and will be offered pharmacologic assistance if needed at NIH. All 
consented individuals (probands and first-degree relatives) will remain on study until death or 
withdrawal of consent to participate. Survival data, adherence to screening recommendations and 
details of incident cancers (date of diagnosis, stage at diagnosis) will be documented in first-
degree relatives using a phone call once a year. The proband will be followed using a phone call 
once a year to collect survival data.  
5.6.6 Laboratory and specimen information 
Peripheral blood samples (3-5 mL) will be submitted in sodium citrate anticoagulated “light blue 
top” tubes to the Molecular Diagnostics Laboratory of the Laboratory of Pathology, NCI for 
analysis of the following germline mutations affecting the EGFR gene: exon 20 T790M, exon 21 
V843I, exon 21 R831C and exon 20 R776G. DNA extraction is performed on a PSS Biosystems 
(Pleasanton, CA) robotic device using the company’s proprietary bead-based DNA extraction 
kit. Targeted analysis for potential germline EGFR mutations will be performed by 
pyrosequencing on a PyroMark Q24 instrument (Qiagen, Valencia, CA) after initial PCR of the 
targeted regions. Primers for all PCR and pyrosequencing reactions are designed and validated 
by the Molecular Diagnostics Laboratory (MDU) of the Laboratory of Pathology, Center for 
Cancer Research, NCI, NIH, and are available upon request.  The MDU is a CLIA-regulated and 
CAP-inspected high-complexity clinical molecular diagnostics laboratory (CLIA# 21D0716664; 
Exp. 7/16/2012). The report will be issued within 2 weeks from the date of collection and will be 
available in Clinical Research Information System (CRIS).  
5.6.7 Data collection 
A full pedigree will be collected on each family enrolled in this aspect of the study. This study 
will utilize the genetic database Progeny for collection and storage of pedigree data. Progeny is 
an online multi-user clinical data management system used to track family history, phenotype, 
and genotype data. The Progeny database is stored on a secure NCI server that is password 
protected. The database itself is also password protected with the options to restrict each class of 
users to specifically defined access and read/write privileges based on their role on the 
study. The database also has the capability to track passwords, logins, previous entry, new entry 
and user information with a date/time stamp.  Families and individual subjects within families 
are tracked by distinct identification labels that include a unique numeric family and individual 
identifier. 
5.6.8 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
Biospecimens will be collected and processed using validated SOPs that will ensure both 
specimen quality and patient confidentiality pursuant to informed consent provisions.  
Using a computerized inventory system and a backup hardcopy process, all specimen collection 
and processing steps will be documented and the specific location of each specimen will be 
tracked.  Each new specimen collected will be assigned a unique barcode identifier that can be 
linked to the original specimen collected and other relevant information within the inventory 
system.  To ensure patient confidentiality, only containers used for the initial specimen 
collections will be labeled with patient identifiers.  Coded, linked labels will be applied to all 
subsequent specimen containers.  When specimens are processed and aliquoted, no patient 
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information will be included on the new containers.  Original specimen containers will be 
discarded.  Only de-linked specimens will be shipped for analysis and/or storage.  Coded, linked 
specimen labels will indicate: protocol number, order in which the patient was enrolled in the 
trial, type of sample, collection time, and total volume collected, as appropriate.  
The inventory process contains other security provisions sufficient to safeguard patient privacy 
and confidentiality.  Access to the inventory system and associated documents will be restricted 
to appropriate personnel only.  The only patient information available in the inventory system 
will be the patient sex, diagnosis, and level of informed consent provided.  SOPs ensure that any 
changes in the informed consent made by a patient and relayed to the PI will be reflected in the 
inventory system to ensure that specimens are destroyed as appropriate.  All laboratory personnel 
will be trained to adhere to SOPs and will be monitored for high-quality performance. 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request.  Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested).   
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will 
be made per the requirements of section 8.2. 
A Certificate of Confidentiality will be obtained from the Department of Health and Human 
Services before germline mutation testing begins. The investigators will use the Certificate to 
protect against the compelled disclosure of personally identifiable information and to support 
and defend the authority of the Certificate against legal challenges. Personnel involved in the 
conduct of the research will comply with all the requirements of 45 CFR Part 46 "Protection of 
Human Subjects." All research participants will be informed that a Certificate has been issued, 
and they will be given a description of the protection provided by the Certificate.  
5.7 
Agent Administration 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks from the agents used in this protocol are described in Section 7.  Appropriate dose 
modifications for these agents are described in Section 6.  No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the patient's malignancy. 
Patients in all treatment arms (Erlotinib, AZD6244, MK2206, Lapatinib and Sunitinib) will be 
provided with a Medication Diary (Appendix B). They will be instructed in its use and asked to 
bring the diary with them to each appointment.  A new copy of the Medication Diary will be 
given to patients whose dose is reduced due to adverse events.  Patients should log in their daily 
dose onto the diary, including missed, skipped, or vomited doses.  If the patient vomits after 
taking the tablets, the dose is replaced only if the tablets can actually be seen and counted.  If a 
patient misses a dose, he or she should be instructed to resume dosing with the next scheduled 
dose.  
5.7.1 CTEP agents 
5.7.1.1 Erlotinib 
1) Erlotinib will be administered at a dose of 150 mg once daily every three 
weeks. 
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2) Tablets should be taken once daily preferably in the morning with up to 200 
mL of water 1 hour before or 2 hours after food. 
3) Patients should wear sunscreen protection, hat, and long sleeves to avoid sun 
as it can exacerbate skin rash. 
4) Patients should be instructed to store Erlotinib at room temperature. 
5) Patients should be advised to drink plenty of water or take rehydration fluids 
to avoid dehydration if diarrhea occurs.   
5.7.1.2 AZD6244 Hydrogen Sulfate  
1) AZD6244 hydrogen sulfate will be administered at a dose of 75 mg twice 
daily (BID), approximately 12 hours apart, every three weeks. 
2) Advise the patient to take AZD6244 doses on an empty stomach (no food or 
drink other than water for 1 hour before or 2 hours after dosing).  
3) Patients should be instructed to store AZD6244 at room temperature. 
4) Patients should be advised to drink plenty of water or take rehydration fluids 
to avoid dehydration if diarrhea occurs. 
5) Patients should avoid excessive sun exposure and use adequate sunscreen 
protection if sun exposure is anticipated. 
5.7.1.3 MK-2206 
1) MK-2206 will be administered orally at a dose of 200 mg weekly every four 
weeks. 
2) Patients should take MK-2206 - 2 hours before or after a meal.    
3) Patients should be instructed to store MK-2206 at room temperature. 
4) Patients should be advised to drink plenty of water or take rehydration fluids 
to avoid dehydration if diarrhea occurs.   
5.7.1.4 Lapatinib 
1) Lapatinib will be administered orally at a dose of 1500 mg daily every three 
weeks. 
2) Patients should take Lapatinib - 1 hour before or after a meal.    
3) Patients should be instructed to store Lapatinib at room temperature. 
4) Patients should be advised to drink plenty of water or take rehydration fluids 
to avoid dehydration if diarrhea occurs.   
5) Routine monitoring for cardiac function (ECHO/MUGA) should be performed 
at baseline and every other cycle of treatment. 
5.7.2 Other agents 
5.7.2.1 Sunitinib 
1) Sunitinib will be administered orally at a dose of 50 mg daily for 4 consecutive weeks 
followed by 2 weeks of rest (drug holiday) with no sunitinib every 6 weeks. 
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2) Patients will take sunitinib once daily in the morning, with or without food, as desired. 
3) Patients should be instructed to store Sunitinib at room temperature. 
4) Patients should be advised to drink plenty of water or take rehydration fluids to avoid 
dehydration if diarrhea occurs.   
5) Because hypertension is a known and potentially serious but rare adverse event 
associated with sunitinib malate treatment, patients will have their blood pressure 
monitored and recorded weekly during the first cycle of therapy, either at the doctor’s 
office or using any calibrated electronic device (such as those found at a local drug store 
or pharmacy).  (See Section 6 for hypertension management and dose reduction 
guidelines.) 
6) Routine monitoring for cardiac function (ECHO/MUGA) should be performed at baseline 
and then every other cycle of treatment in the following groups of patients:  (1) those 
entering the trial with NYHA Class II cardiac dysfunction (see Appendix D), (2) those 
with a history of Class II heart failure who are asymptomatic on treatment, and (3) in 
those previously exposed to anthracyclines or thoracic irradiation if the heart was 
included in the radiotherapy port.  Routine cardiac monitoring is not required in patients 
with no known cardiac dysfunction at entry or in the absence of clinically observed 
adverse cardiac events. 
7) Although adrenal gland insufficiency is rarely seen with sunitinib treatment, patients 
should be clinically followed for the signs and symptoms of this complication, especially 
(1) patients with comorbidities associated with adrenal dysfunction, (2) patients with pre-
existing adrenal insufficiency (primary or secondary), and (3) patients with concomitant 
stress (e.g., fever, infection, bleeding, serious accident, surgery) that may precipitate 
overt adrenal insufficiency in the presence of subclinical sunitinib-induced adrenal 
toxicity.  If clinically indicated, objective testing for adrenal gland function should be 
conducted. 
8) Patients with bulky solid tumors should be monitored closely for pneumothorax, 
intestinal fistulae, or intestinal perforation in the event of rapid tumor destruction. 
9) Patients should be alerted to the possibility that sunitinib capsules can cause a yellow 
discoloration of the skin on direct contact.  If this happens, the patient should wash 
immediately with soap and water. 
5.8 
General Concomitant Medication and Supportive Care Guidelines 
5.8.1 General Guidelines:  Concomitant Medications 
A concomitant medication is any medication a patient entering the trial is using and is expected 
to continue using for some portion of the trial as well as any medication the patient uses during 
the course of the trial.  Study drugs are not considered concomitant medication. 
All concomitant medications recorded at trial entry must have a related, ongoing concomitant 
illness listed under the medical history at the time of patient entry into the trial unless the 
medication is used for prophylaxis.  Patients may continue to use any ongoing medications not 
prohibited by the protocol. All prescription and over-the-counter medications at trial entry as 
well as any new medications started during the trial must be documented.  The documentation 
should continue until 30 days from the end of the last study drug treatment. 
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No other anti-cancer therapy including chemotherapy, radiation therapy, hormonal cancer 
therapy and immunotherapy, or experimental medications are permitted while the patients are 
receiving treatment under one of the targeted therapy arms of this trial.  Any disease progression 
that requires other specific anti-tumor therapy will be cause for discontinuation from study 
medication.  Patients who are receiving steroids for complications of their primary malignancy 
may enroll on the study and continue receiving steroids as long as needed. Because there is a 
potential for interaction of all of the medications used in the experimental arms, with other 
concomitantly administered drugs through the cytochrome P450 system, the case report form 
(CRF) must capture the concurrent use of all other drugs, over-the-counter medications, or 
alternative therapies.  The Principal Investigator should be alerted if the patient is taking any 
agent known to affect or with the potential to affect selected CYP450 isoenzymes.  A 
comprehensive list of CYP3A4 inhibitors, inducers, and substrates is provided (see Appendix 
F).  In addition, patients and their caregivers should be provided the patient information sheet 
(see Appendix G) describing potential interactions of the study agents with other drugs, 
remedies, and medications. 
Additionally, the patient’s smoking history should be documented in the CRF, including the 
number of packs smoked/day (if a current smoker). 
5.8.1.1 Diarrhea 
Diarrhea should be treated with the following regimen:  loperamide (4 mg PO) at onset of 
symptoms, followed by 2 mg loperamide every 2 hours while awake (or 4 mg PO every 4 
hours while sleeping) up to a maximum of 16 mg loperamide per day. 
5.8.1.2 Nausea and vomiting 
The nausea and vomiting that may occur with investigational agents should be managed 
through the use of appropriate simple supportive measures (e.g., prochlorperazine or 
metoclopramide).   
5.8.1.3 Hand-foot syndrome  
This may be treated with topical emollients (such as Aquaphor), topical or systemic 
steroids, and/or antihistamine agents.  Vitamin B6 (pyridoxine; 50-150 mg orally each 
day) may also be used.  Avoid exposure to heat, hot water, pressure, or friction. Use of 
soft, well-fitting shoes may help, as may use of acetaminophen if needed for analgesia. 
5.8.1.4 Rash 
Rash should be treated with standard acne therapies, including topical and oral antibiotics 
used to treat acne such as the following: minocycline, topical tetracycline, topical 
clindamycin, topical silver sulfadiazine, diphenhydramine, or oral prednisone (short 
course).  
5.8.1.5 Other protective / preventative measures 
Patients on Erlotinib should wear sunscreen protection, hat, and long sleeves to avoid sun 
as it can exacerbate skin rash. 
5.8.1.5.1 Myelossupression related complications 
Patients with neutropenic fever or infection should be evaluated promptly and treated 
with IV antibiotic therapy or therapeutic colony-stimulating factors as appropriate 
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following the ASCO guidelines [J Clin Oncol 18(20):3558-85, 2000].  Packed red blood 
cell and platelet transfusion should be administered as clinically indicated.  
Erythropoietic agents may be used at the discretion of the treating physician. 
5.8.1.5.2 Additional recommendations for patients in Sunitinib arm 
• Use of agents with proarrhythmic potential (terfenadine, quinidine, procainamide, 
disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, and 
flecainide) is not permitted during treatment with this drug.  A comprehensive list of 
agents with proarrhythmic potential can be found at http://torsade.org . 
• Sunitinib is primarily metabolized by liver enzymes, particularly CYP3A4.  Co-
administration of potent inhibitors or inducers of this enzyme can result in significant 
changes in exposure to sunitinib (e.g., a mean 1.8-fold increased exposure with 
ketoconazole and a mean 4-fold decrease with rifampin).  For this reason, use of the 
following agents is not permitted before or during enrollment in this arm of the study: 
Inhibitors – prohibited 7 days before dosing and during study. 
azole antifungals (ketoconazole, 
itraconazole) 
Verapamil 
clarithromycin 
HIV protease inhibitors (indinavir, 
saquinavir, ritonavir, atazanavir, 
nelfinavir) 
erythromycin 
Delavirdine 
diltiazem 
 
Inducers – prohibited 12 days before dosing and during study. 
rifampin  
Phenytoin 
rifabutin 
St. John’s wort 
carbamazepine 
Efavirenz 
phenobarbital 
Tipranavir 
• Steroid use is not recommended during sunitinib treatment unless absolutely 
necessary (e.g., for treatment of adverse events or protocol-required premedication) 
because many steroids (e.g., prednisone, prednisolone, dexamethasone, etc.) 
effectively lower sunitinib exposure through CYP3A4 interactions. 
• The use of coumarin-derivative anticoagulants such as warfarin (Coumadin®) is not 
recommended, although doses of up to 2 mg daily are permitted for prophylaxis of 
thrombosis. 
5.8.1.5.3 Additional recommendations for patients in AZD6244 arm 
• Ophthalmologic exam (including slit-lamp) – to be performed in patients 
experiencing visual disturbances while in the trial.   
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• Echocardiogram or MUGA scan (measurement of LVEF) – to be performed in 
patients with symptoms (AEs) suggestive of cardiac impairment (congestive heart 
failure, oedema, dyspnea).  
• Decreases in LVEF from baseline (if known) may be investigated according to the 
algorithm (note- this appears as a word doc in the in AZD6244 ISS study guide)    
• All new dyspnea AEs or worsening of pre-existing dyspnea AEs should be followed 
according to the dyspnea algorithm (note this appears in the AZD6244 ISS study 
guide)  
5.9 
Protocol Evaluation 
5.9.1 Prior to each treatment cycle (please refer to Section 5.3 for definition of a cycle): 
5.9.1.1 SOAP progress note. 
5.9.1.2 Laboratory examination: 
5.9.1.2.1 Hematological Profile: CBC with differential and platelet count.  
5.9.1.2.2 Biochemical Profile: Sodium, potassium, chloride, CO2, BUN, creatinine, glucose, 
AST, ALT, alkaline phosphatase, bilirubin, albumin, total protein, LDH, calcium, 
phosphorous and magnesium. 
5.9.1.3 Vital signs including weight. 
5.9.2 Restaging and Imaging: 
Restaging will be performed at the end of every two cycles, +/- 1 week, as defined for 
each treatment arm.  Therefore, restaging will be performed every 6 weeks +/- 1 week for 
the Erlotinib, AZD6244, and Lapatinib arms; every 8 weeks +/- 1 week for the MK-2206 
arm, and every 12 weeks +/- 1 week for the Sunitinib arm.  Imaging modalities will 
consist of CT or MRI, as appropriate for disease evaluation.  The use of FDG-PET will 
be allowed but it would be considered exploratory and its results will not be used for 
treatment decisions. 
5.10 Duration of therapy / off treatment criteria 
In the absence of treatment delays due to adverse events, treatment under any of the 
investigational arms (Erlotinib, AZD6244, MK2206, Lapatinib and Sunitinib) may continue until 
one of the following criteria applies: 
• Disease progression as defined by Section 13. 
• Intercurrent illness that prevents further administration of treatment. 
• Delay of treatment due to toxicity of ≥3 weeks. 
• Unacceptable adverse event(s)*.  
• Non-compliance to therapy regimen. 
• Pregnancy 
• Patient decides to withdraw from the study arm or stop therapy. 
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• Deterioration of the patient’s condition that render further treatment unacceptable in the 
judgment of the investigator. 
* Patients removed from study arm due to unacceptable adverse events, will continue to be 
followed in clinic, at least every 4 weeks until all adverse events have resolve to grade I or less. 
5.11 Duration of follow up 
All patients that are not receiving active investigational treatment (Erlotinib, AZD6244, 
MK2206, Lapatinib and Sunitinib), including those on the NOS arm and those deemed as 
“Screen Failures,” will continue to be followed until death or the patient decides to withdraw 
from the study. These patients will be followed either with clinic visits or phone interviews every 
4 months (+/- 2 months).  If patient is receiving treatment at an outside facility, pertinent medical 
records should be sent to the PI at the participating institution for data collection.  The following 
information will be collected: 
• Date of follow up 
• Is patient dead or alive?  
• If dead, document exact date of death. 
• Further chemotherapy / biotherapy treatment(s) 
o Drug name(s) 
o Date(s) of administration (month/year) 
o Response to treatment 
• Document date of disease progression 
• Document ECOG PS 
* No toxicity information will be collected for patients being followed in the NOS arm. 
5.12 Off Study Criteria 
Patients will be removed from study for: 
• 
Screening failure 
• 
Death 
• 
Patient decides to withdraw from the study 
• 
At the investigator’s discretion 
• 
Lost to follow-up 
 The reason for study removal and the date the patient was removed will be documented in the 
Case Report Form. 
5.13 Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. A Participant Status Updates Form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
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sent via encrypted email to:  NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov. 
6 
DOSING DELAYS/DOSE MODIFICATIONS 
Patients enrolled in one of the experimental study arms may continue to receive additional cycles 
of therapy provided that the patient meets the following criteria on Day 1 of each cycle: 
• 
ANC > 1,000/mcL 
• 
Platelets > 100,000/mcL 
• 
Non-hematologic toxicity recovered to < grade 2 (or tolerable grade 2 or baseline) 
• 
No evidence of progressive disease 
In the event of an adverse event at least possibly related to the agent, the doses of such agent 
should be adjusted according to the guidelines shown in the Dose Delays / Dose Modifications 
tables shown below (Sections 6.1 and 6.2).  If an adverse event is not covered in such tables, 
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).   
Subjects will be withdrawn from the study arm if they fail to recover to CTC Grade 0-1 or 
tolerable grade 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) 
from a treatment-related adverse event within 21 days OR  they experience agent related adverse 
events requiring dose modification despite two previous dose reductions (i.e. would require a 3rd 
dose reduction) unless the investigator and CTEP monitor agree that the subject should remain in 
the study arm because of evidence that the patient is/may continue deriving benefit from 
continuing study treatment (i.e. patient has PR, CR, SD > 3 months).  The appropriate reduced 
dose will be determined after discussion between the principal investigator and CTEP monitor. 
6.1 
CTEP agents 
6.1.1 Erlotinib 
Table 6. Erlotinib Monotherapy Dose Level Reductions 
 
Dose Level 
Erlotinib Dose 
 Starting Dose 
150 mg/day 
 First Dose Reduction 
100 mg/day 
 Second Dose Reduction 
75 mg/day 
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Table 7. Dosage Modification Criteria for Erlotinib–related Toxicities 
Toxicity 
Grade 
Erlotinib dosage 
modification* 
Guideline for management 
Keratitis 
1 
None 
No intervention 
2 (if < 14 
days) 
None 
Preservative-free artificial tears, 
ointments, and/or other therapies 
as clinically indicated, with a 
follow-up examination within 
2 weeks 
2 (if >14 
days) 
Hold until recovery to ≤ grade 1 
And then 
Reduce 1 dose level 
≥3 
Hold until recovery to ≤ grade 1 
And then 
Reduce 1 dose level* 
Diarrhea  
1 
None 
No intervention 
2 
None if tolerable 
If not tolerable, hold until 
resolution to grade ≤ 1, then 
resume at the same dose.  
If intolerable grade 2 recurs 
after resumption, hold until 
resolution to grade ≤ 1 and 
resume with 1 dose reduction.  
Loperamide (4 mg at first onset, 
followed by 2 mg every 2–4 hrs 
until diarrhea free for 12 hrs) 
≥ 3 
(despite 
optimal 
loperamide 
use) 
Hold until recovery to ≤ grade 1  
And then 
Reduce 1 dose level* 
Rash 
1 
None 
No intervention 
2 
None if tolerable 
If not tolerable, hold until 
resolution to grade ≤ 1, then 
resume at the same dose.  
If intolerable grade 2 recurs 
after resumption, hold until 
resolution to grade ≤ 1 and 
resume with 1 dose reduction.  
Any of the following: 
minocycline, topical tetracycline 
or clindamycin, topical silver 
sulfadiazine, diphenhydramine, 
oral prednisone (short course) 
≥ 3 
Hold until recovery to ≤ grade 1 
And then 
Reduce 1 dose level 
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Bilirubin 
 
≥3 x ULN 
 
Hold until grade ≤2  
And then 
Reduce 1 dose level 
 
Liver 
transamin
ase 
> 5 x ULN 
Hold until grade ≤2  
And then 
Reduce 1 dose level 
 
Signs and symptoms of 
interstitial pneumonitis 
Hold pending diagnosis 
Permanently discontinue if 
diagnosis is confirmed and 
considered possibly related to 
erlotinib 
Patient should be thoroughly 
evaluated, closely monitored, and 
supported as clinically indicated 
Other 
toxicity 
≥ 2 prolonged 
clinically 
significant 
toxicity 
Hold until recovery to ≤ grade 1 
And then 
Reduce 1 dose level* 
Treatment as appropriate 
*if dose has been previously held for grade 2 rash or diarrhea, and grade 2 symptoms recur, OR if 
the patient finds the symptoms unacceptable, hold dose until recovery to ≤ grade 1 and then reduce 
dose one level  
 
6.1.2 AZD6244 Hyd-Sulfate  
Table 8:  AZD6244 Monotherapy Dose Level Reductions 
Dose Level 
AZD6244 Dose 
 Starting Dose 
75 mg BID  
 First Dose Reduction 
50 mg BID 
 Second Dose Reduction 
50 mg once daily 
Table 9:  Dosage Modification Criteria for AZD6244–related Toxicities 
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 1.  
Recurrent 
Grade 3  
Hold AZD6244 until < tolerable grade 2, 
then reduce 1 additional dose level and 
resume treatment 1.  
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Recurrent 
Grade 3 after 2 dose 
reductions 
 
Remove patient from study arm. 
Grade 4 
Patients with grade 4 rash (i.e. life 
threatening generalized exfoliative 
ulceration; erythemia multiforme/toxic 
epidermal necrolysis should be removed 
from study arm. 
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) 
Grade 3 or 4 
Hold AZD6244 until < tolerable grade 2, 
loperamide; reduce 1 dose level and resume 
treatment 1.  
Recurrent 
Grade 3 or 4  
Hold AZD6244 until < tolerable grade 2, 
loperamide; reduce 1 additional dose level 
and resume treatment 1.  
Recurrent 
Grade 3 or 4 after 2 dose 
reductions 
 
Remove patient from study arm. 
Hematologic 
 
(neutrophils, 
platelets, 
hemoglobin) 
Grade 1 or 2 
Maintain dose 
Grade 3 or 4 
Hold AZD6244 until < grade 2, then reduce 
1 dose level and resume treatment.  
Recurrent 
Grade 3 or 4  
Hold AZD6244 until < grade 2, then reduce 
1 additional dose level and resume 
treatment.  
Recurrent 
Grade 3 or 4 after 2 dose 
reductions 
 
Remove patient from study arm. 
Liver Function 
 
(serum bilirubin, 
AST, or ALT) 
 
Grade 1 or 2 
Maintain dose 
Grade 3 or 4 
Hold AZD6244 until < grade 2, then reduce 
1 dose level and resume treatment   
Recurrent 
Grade 3 or 4  
Hold AZD6244 until < grade 2, then reduce 
1 additional dose level and resume 
treatment  
Recurrent 
Grade 3 or 4 after 2 dose 
reductions 
 
Remove patient from study arm. 
Other non-
Grade 1 or 2 
Maintain dose 
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hematological 
toxicity 
Any Grade 2 of concern 
(e.g., prolonged cardiac, 
pulmonary, or 
neurotoxicity, intolerable 
stomatitis) 
Hold AZD6244 until < grade 1, then reduce 
1 dose level and resume treatment  
Grade 3 or 4 
Hold AZD6244 until < tolerable grade 2, 
then reduce 1 dose level and resume 
treatment 2 
Recurrent 
Grade 3 or 4  
Hold AZD6244 until < tolerable grade 2, 
then reduce 1 additional dose level and 
resume treatment 2 
1 
If event has not improved to < tolerable grade 2 or baseline within < 21 days, patient 
should be removed from the study. 
2 
Patients with medically concerning grade 3 or 4 AEs related to AZD 6244 may be 
taken off study at investigator’s discretion. 
6.1.2 MK2206 
Table 10: MK2206 Monotherapy Dose Level Reductions 
Dose Level 
MK2206 Dose 
 Starting Dose 
200 mg QW 
 First Dose Reduction 
135 mg QW 
 Second Dose Reduction 
90 mg QW 
 
Table 11:  Dosage Modification Criteria for MK2206–related Toxicities 
Event 
AE Grade or 
Observation 
Dose modification 
Dermatology/Skin 
Grade 1 or 2 
Maintain dose 
Grade 3 or 4 or intolerable 
grade 2 
Hold MK2206 until < tolerable grade 2, then 
reduce 1 dose level and resume treatment 1.  
Recurrent 
Grade 3  
Hold MK2206 until < tolerable grade 2, then 
reduce 1 additional dose level and resume 
treatment 1.  
Recurrent 
Grade 3 after 2 dose 
reductions 
 
Remove patient from study arm. 
Grade 4 
Patients with grade 4 rash (i.e. life threatening 
generalized exfoliative ulceration; erythemia 
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multiforme/toxic epidermal necrolysis should 
be removed from study arm. 
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) 
Grade 3 or 4 
Hold MK2206 until < tolerable grade 2, 
loperamide; reduce 1 dose level and resume 
treatment 1.  
Recurrent 
Grade 3 or 4  
Hold MK2206 until < tolerable grade 2, 
loperamide; reduce 1 additional dose level and 
resume treatment 1.  
Recurrent 
Grade 3 or 4 after 2 dose 
reductions 
 
Remove patient from study arm. 
Hematologic 
 
(neutrophils, 
platelets, 
hemoglobin) 
Grade 1 or 2 
Maintain dose 
Grade 3 or 4 
Hold MK2206 until < grade 2, then reduce 1 
dose level and resume treatment.  
Recurrent 
Grade 3 or 4  
Hold MK2206 until < grade 2, then reduce 1 
additional dose level and resume treatment.  
Recurrent 
Grade 3 or 4 after 2 dose 
reductions 
 
Remove patient from study arm. 
Liver Function 
 
(serum bilirubin, 
AST, or ALT) 
 
Grade 1 or 2 
Maintain dose 
Grade 3 or 4 
Hold MK2206 until < grade 2, then reduce 1 
dose level and resume treatment   
Recurrent 
Grade 3 or 4  
Hold MK2206 until < grade 2, then reduce 1 
additional dose level and resume treatment  
Recurrent 
Grade 3 or 4 after 2 dose 
reductions 
 
Remove patient from study arm. 
Other non-
hematological 
toxicity 
Grade 1 or 2 
Maintain dose 
Any Grade 2 of concern 
(e.g., prolonged cardiac, 
pulmonary, or 
neurotoxicity, intolerable 
stomatitis) 
Hold MK2206 until < grade 1, then reduce 1 
dose level and resume treatment  
Grade 3 or 4 
Hold MK2206 until < tolerable grade 2, then 
reduce 1 dose level and resume treatment 2 
Recurrent 
Hold MK2206 until < tolerable grade 2, then 
reduce 1 additional dose level and resume 
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Grade 3 or 4  
treatment 2 
1 
If event has not improved to < tolerable grade 2 or baseline within < 21 days, patient 
should be removed from the study. 
2 
Patients with medically concerning grade 3 or 4 AEs related to MK2206 may be taken off 
study at investigator’s discretion. 
In the event of Grade 3 hyperglycemic events (>250 mg/dL) consult with an endocrinologist or 
other specialist.  If glucose levels do not return to grade 1 or lower within one week of 
appropriate therapy, patients should be considered to have a DLT (dose modification, etc.).  
Appropriate therapy will usually involve oral antihyperglycemic agents, since the inhibition of 
glucose transport into the cell by AKT/mTOR inhibitors may render insulin ineffective.  The 
goal of therapy is to keep fasting glucose <150 mg/dL, random blood glucose levels <180 
mg/dL, and Hemoglobin A1c <8%.  Glucose monitoring should be performed weekly, during the 
first cycle of therapy, and on day 1 of subsequent cycles, prior to drug administration.  
Hemoglobin A1c monitoring, for patients requiring treatment of hyperglycemia, should be 
performed with each cycle of MK-2206 therapy. 
6.1.3 Lapatinib 
Table 12: Lapatinib Monotherapy Dose Level Reductions 
Dose Level 
Lapatinib Dose 
 Starting Dose 
1500 mg daily  
 First Dose Reduction 
1250 mg daily 
 Second Dose Reduction 
1000 mg daily 
 
Table 13:  Dosage Modification Criteria for Lapatinib –related Toxicities 
Event 
AE Grade or Observation Dose modification 
Dermatology/Skin 
Grade 1 or 2 
Maintain dose 
Grade 3 or 4 or intolerable 
grade 2 
Hold Lapatinib until < tolerable grade 2, then 
reduce 1 dose level and resume treatment 1.  
Recurrent 
Grade 3  
Hold Lapatinib until < tolerable grade 2, then 
reduce 1 additional dose level and resume 
treatment 1.  
Recurrent 
Grade 3 after 2 dose 
reductions 
 
Remove patient from study arm. 
Grade 4 
Patients with grade 4 rash (i.e. life threatening 
generalized exfoliative ulceration; erythemia 
multiforme/toxic epidermal necrolysis should 
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be removed from study arm. 
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) 
Grade 3 or 4 
Hold Lapatinib until < tolerable grade 2, 
loperamide; reduce 1 dose level and resume 
treatment 1.  
Recurrent 
Grade 3 or 4  
Hold Lapatinib until < tolerable grade 2, 
loperamide; reduce 1 additional dose level 
and resume treatment 1.  
Recurrent 
Grade 3 or 4 after 2 dose 
reductions 
 
Remove patient from study arm. 
Hematologic 
 
(neutrophils, 
platelets, 
hemoglobin) 
Grade 1 or 2 
Maintain dose 
Grade 3 or 4 
Hold Lapatinib until < grade 2, then reduce 1 
dose level and resume treatment.  
Recurrent 
Grade 3 or 4  
Hold Lapatinib until < grade 2, then reduce 1 
additional dose level and resume treatment.  
Recurrent 
Grade 3 or 4 after 2 dose 
reductions 
 
Remove patient from study arm. 
Liver Function 
 
(serum bilirubin, 
AST, or ALT) 
 
Grade 1 or 2 
Maintain dose 
Grade 3 or 4 
Hold Lapatinib until < grade 2, then reduce 1 
dose level and resume treatment   
Recurrent 
Grade 3 or 4  
Hold Lapatinib until < grade 2, then reduce 1 
additional dose level and resume treatment  
Recurrent 
Grade 3 or 4 after 2 dose 
reductions 
 
Remove patient from study arm. 
Other non-
hematological 
toxicity 
Grade 1 or 2 
Maintain dose 
Any Grade 2 of concern 
(e.g., prolonged cardiac, 
pulmonary, or 
neurotoxicity, intolerable 
stomatitis) 
Hold Lapatinib until < grade 1, then reduce 1 
dose level and resume treatment  
Grade 3 or 4 
Hold Lapatinib until < tolerable grade 2, then 
reduce 1 dose level and resume treatment 2 
Recurrent 
Grade 3 or 4  
Hold Lapatinib until < tolerable grade 2, then 
reduce 1 additional dose level and resume 
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treatment 2 
1 
If event has not improved to < tolerable grade 2 or baseline within < 21 days, patient 
should be removed from the study. 
2 
Patients with medically concerning grade 3 or 4 AEs related to Lapatinib may be taken 
off study at investigator’s discretion. 
 
6.1.4 Criteria for Evaluating Cardiac and Respiratory Events 
A patient who has a >20% decrease in the left ventricular cardiac ejection fraction (as a 
% of baseline) that is asymptomatic, and the ejection fraction is below the institution’s 
lower limit of normal, should have a repeat evaluation of ejection fraction 1-2 weeks later 
while still receiving therapy with lapatinib.  If the repeat ejection fraction evaluation 
confirms a > 20% decrease in left ventricular cardiac ejection fraction (as a % of 
baseline), and the ejection fraction is below the institution’s lower limit of normal, then 
the CTEP medical monitor should be consulted to help determine if therapy should be 
temporarily discontinued.  If therapy is interrupted and the left ventricular ejection 
fraction recovers during the next 3 weeks, in consultation with the CTEP medical 
monitor, the patient may be restarted on therapy with lapatinib at a reduced dose.  For 
such patients, monitoring of left ventricular ejection fraction will then be performed 2 
weeks and 4 weeks after re-challenge and then every 4 weeks therafter for at least 16 
weeks or until resolution.  If repeat ejection fraction evaluation still shows a decrease 
>20% in left ventricular ejection fraction (as a % of baseline), and the value is below the 
insitution’s lower limit of normal, then the patient should be withdrawn from therapy 
with lapatinib. 
Patients with and NCI-CTCAE grade 3 (LVEF less than 40% and symptomatic) or grade 
4 (LVEF less than 20%) left ventricular systolic dysfunction or interstitial pneumonitis 
must be withdrawn from lapatinib therapy. 
6.2 
Other agents 
6.2.1 Sunitinib 
Table 14: Sunitinib Monotherapy Dose Level Reductions 
Dose Level 
Sunitinib Dose 
 Starting Dose 
50 mg daily  
 First Dose Reduction 
37.5 mg daily 
 Second Dose Reduction 
25 mg daily 
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Table 15. Management of Treatment-Emergent Hypertension 
Recommended Hypertension Monitoring and Management 
(BP in mmHg) 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sunitinib 
Dose Modification 
Persistent Grade 1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-90  
 
 
Standard       
 
No change 
Persistent Grade 2- 
Moderate 
Systolic 140-159  
Diastolic 90-99  
   
Protocol-specific 
guidance 
supersedes any 
other management 
guidelines, 
including CTCAE 
v4  
Step 1) Initiate LA DHP CCB 
treatment and if needed, after 
24-48 hr Rx, increase dose in 
stepwise  fashion every 24-48 
hours  until BP is controlled or 
at max dose of Rx 
Step 2) If BP still not 
controlled, add another 
antihypertensive Rx, a BB, 
ACE1, ARB, or ABB; 
increase dose of this drug as 
described in step 1   
Step 3) If BP still not 
controlled, add 3rd drug from 
the list of antihypertensives in 
step 2; increase dose of this 
drug as described in step 1 
Step 4) If BP still not 
controlled, consider either 1 
dose reduction of sunitinib or 
stopping sunitinib  
NOTE: Stopping or reducing 
the dose of sunitinib is 
expected to cause a decrease 
in BP. The treating physician 
should monitor the patient for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly. 
BP should be 
monitored as 
recommended by 
the treating 
physician  
No change except as 
described in step 4 
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Persistent Grade 3 
Severe  
Systolic >160 
Diastolic >100  
 
Protocol-specific 
guidance 
supersedes any 
other management 
guidelines, 
including CTCAE 
v4 
HOLD sunitinib until systolic 
BP <159 and diastolic BP 
<99.  
 
BP management is identical to 
that for Grade 2 (see steps 1-4 
above) with 2 major 
exceptions:  
1)  If systolic BP >180 or 
diastolic BP >110 and the 
patient is symptomatic: 
optimal management with 
intensive IV support in ICU; 
STOP sunitinib and notify 
hospital staff that stopping 
sunitinib may result in a 
decrease in BP 
 and  
2) If systolic BP >180 or 
diastolic BP >110 and the 
patient is asymptomatic, 
2 new anti-hypertensives must 
be given together in step 1 
(and dose escalated 
appropriately as in step 1). 
NOTE: Stopping or reducing 
the dose of sunitinib is 
expected to cause a decrease 
in BP. The treating physician 
should monitor the patient for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly 
BP should be 
monitored as 
recommended by 
the treating 
physician unless 
the patient is 
symptomatic with  
systolic BP >180 
or diastolic BP 
>110 in which 
case, monitoring 
should be 
intensive. 
HOLD sunitinib until 
systolic BP <159 and 
diastolic BP  
<99. 
In most circumstances, 
if BP cannot be 
controlled after an 
optimal trial of anti-
hypertensive 
medications, consider 
either 1 dose reduction 
of sunitinib or 
stopping sunitinib. 
HOWEVER, 
if the patient requires 
hospitalization for 
management of 
symptomatic systolic 
BP >180 or diastolic 
BP >110,permanently 
discontinue sunitinib 
or if BP is controlled, 
re-start sunitinib at 1 
lower dose level after 
consultation with the 
study Principal 
Investigator 
Grade 4 
Life-threatening 
consequences of 
hypertension 
 
Optimal management with 
intensive IV support in ICU; 
STOP sunitinib and notify 
hospital staff that stopping 
sunitinib may result in a 
decrease in BP 
Intensive 
Permanently 
discontinue sunitinib 
or if BP is controlled, 
re-start sunitinib at 1 
lower dose level after 
consultation with the 
study Principal 
Investigator 
Abbreviations: dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers 
(BB), angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), 
alpha beta blocker (ABB) 
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If patients require a delay of >2 weeks for management of hypertension, discontinue protocol 
therapy 
If patients require >2 dose reductions, discontinue protocol therapy 
Patients may have up to 2 drugs for management of hypertension prior to any dose reduction in 
sunitinib 
24-48 hours should elapse between modifications of anti-hypertensive therapy 
Hypertension should be graded using CTCAE v4. 
Increases in blood pressure (BP) and cases of hypertension have been associated with many drugs 
acting on the VEGF pathway.  The proposed mechanism for this increase is through inhibition of 
VEGF-induced peripheral vasodilation.  Hypertension following sunitinib treatment has rarely 
been seen in animal studies or clinical trials.  Specific guidelines for management of this adverse 
event and a table of various antihypertensive medications are provided in Appendix H.  In 
addition, guidance on the collection and recording of BP information is also provided.  
 
Table 16. Dosage Modification Criteria for Sunitinib –related Toxicities 
Event 
AE Grade or Observation 
Dose modification 
Neutropenia 
Grades 1 and 2 
Maintain dose 
Grade 3* 
Hold sunitinib until < grade 2, then resume 
at same dose level 
Grade 4 
Hold sunitinib until < grade 2, then reduce 
1 dose level and resume treatment 
Thrombocytopenia 
Grades 1 and 2 
Maintain dose 
Grade 3*  
Hold sunitinib until < grade 2, then reduce 
1 dose level and resume treatment 
Grade 4 
Hold sunitinib until < grade 2, then reduce 
1 dose level and resume treatment 
Fever or flu-like 
symptoms 
Grades 1-4 
Maintain dose 
Fatigue (lethargy, 
malaise, asthenia) 
Grades 1 and 2 
Maintain dose 
Grade 3*  
Hold sunitinib until < grade 2, then reduce 
1 dose level and resume treatment 
 
 
 
>450 but 
 < 550 msec 
Review patient’s concomitant medications 
for QT interval-prolonging agents.  Correct 
any electrolyte abnormalities. 
Continue sunitinib at current dose level. 
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QTc prolongation 
Do not use 
CTCAE v4 grades 
> 550 msec 
Stop sunitinib and any other QT-interval 
prolonging agents immediately.  Correct 
any electrolyte abnormalities, then 
If there is a plausible explanation for AE 
other than sunitinib treatment, resume 
sunitinib at current dose level. 
If sunitinib may have contributed to the 
AE: 
Reduce 2 dose levels and restart sunitinib. 
If QTc remains <500 msec after 14 days at 
reduced dose, increase one dose level and 
continue sunitinib. 
If QTc remains <500 msec after 14 days, 
original dose of sunitinib may be resumed. 
Hand-foot 
syndrome 
Grades 1 and 2 
Maintain dose 
Grade 3* 
Hold sunitinib until < grade 1, then resume 
treatment at same dose or reduce 1 dose 
level 
AST and/or ALT 
elevation 
(SGOT, SGPT) 
Grades 1-4 
Maintain dose * 
 
      *Recurrent grade 3 events require dose reduction. 
 
Table 17. Management of Other Clinically Significant Sunitinib-related AEs 
(not specifically addressed above) 
Observation 
Action 
AE resolves promptly with supportive care 
Maintain dose level 
1. 
Grade 3 or higher (non-hematologic or grade 4 
(hematologic) AE related to sunitinib and lasting >5 
days that does not resolve to grade 2 or below despite 
maximum supportive care for < 48 hours. 
2. 
Lower grade but related AEs (e.g., creatinine) 
 
 
 
Reduce one dose level 
AE does not resolve to grade 2 or below after treating 
patient at the lowest (i.e., 25* mg or 12.5* daily) 
reduced dose level. 
In general, remove patient from study** 
*     25 mg if the patients start dosing at 50 mg on a 4/2 schedule (solid tumors) or 12.5 mg if 
patients start dosing at 37.5 mg  
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considered for patients on study > 3 months who are benefiting from the agent.  
6.3 
Treatment delays and modifications for administrative needs 
Brief interruptions and delays may occasionally be required due to travel delays, airport closure, 
inclement weather, family responsibilities, security alerts, and government holidays, etc.  These 
delays will not be considered protocol deviations, and will not be separately reported. A patient 
that interrupts therapy for more than 21 days will be taken off treatment. 
6.4 
Treatment delays and modifications for medical needs 
Patients experiencing complications of their disease or other medical illness not attributable to 
disease progression, or protocol therapy may also require brief interruptions and delays that will 
not be considered protocol deviations, and will not be separately reported. A patient that 
interrupts therapy for more than 21 days will be taken off treatment. 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event monitoring and reporting is a routine part of every clinical trial.  The following 
list of adverse events (Section 7.3) and the characteristics of an observed adverse event (Section 
7.4) will determine whether the event requires expedited (via CTEP-AERS; Section 7.5) or 
routine (via CTMS or CDUS; Section 7.6) reporting.   
The following sections related to adverse event monitoring and reporting apply only to patients 
receiving treatment under one of the experimental arms (Erlotinib, AZD6244, MK2206, 
Lapatinib and Sunitinib).  No toxicity data will be reported to CTEP for patients being followed 
under the NOS arm or individuals enrolled for germline mutation testing and follow-up only; 
applicable side effects occurring in these participants will be reported to the IRB. 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) was developed to provide 
a single, complete list of reported and/or potential adverse events associated with an agent using 
a uniform presentation of adverse events by body system.  In addition to the comprehensive list, 
the subset of those events that are “expected” [i.e., the Agent Specific Adverse Event List 
(ASAEL)] is presented in a separate column and identified with bold and italicized text.  This 
subset is used to guide expedited reporting requirements. 
7.1.1 CAEPRs for CTEP-Supplied Investigational Agent(s) 
7.1.1.1 Erlotinib (OSI-774, NSC 718781) 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Erlotinib (Tarceva®, NSC 718781) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
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text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3622 patients. Below is the CAEPR for erlotinib 
(Tarceva®). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
Version 2.5, March 25, 
2015(77) 
 Adverse Events with Possible  
 Relationship to Erlotinib (Tarceva®) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Disseminated intravascular 
coagulation(104) 
  
 
 
Hemolytic uremic syndrome(104)   
 
 
Thrombotic thrombocytopenic 
purpura(104) 
  
CARDIAC DISORDERS 
  
 
 
Myocardial infarction(104) 
  
EYE DISORDERS 
  
 
Conjunctivitis 
 
 Conjunctivitis (Gr 2) 
 
Dry eye 
 
 Dry eye (Gr 2) 
 
 
Eye disorders - Other (corneal 
perforation) 
  
 
Eye disorders - Other (eyelash in-
growth and/or thickening) 
 
  
 
 
Keratitis 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Gastrointestinal hemorrhage(105) 
 
  
 
 
Gastrointestinal perforation(106)   
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
Skin infection(107) 
 
 Skin infection(107) (Gr 2) 
INVESTIGATIONS 
  
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 Adverse Events with Possible  
 Relationship to Erlotinib (Tarceva®) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Alanine aminotransferase increased  
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 
3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
NERVOUS SYSTEM DISORDERS 
   
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
 
Intracranial hemorrhage 
  
 
 
Ischemia cerebrovascular(104) 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
Pneumonitis 
 
 Pneumonitis (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
 
Nail loss 
 
 Nail loss (Gr 2) 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2) 
Rash maculo-papular  
 
 Rash maculo-papular (Gr 3) 
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2The risk of myocardial infarction, cerebrovascular accident, and microangiopathic hemolytic anemia is 
increased in patients with pancreatic cancer who were treated concomitantly with gemcitabine. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
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4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
5Includes infection of the skin (folliculitis or cellulitis) as complications of rash. 
 
Adverse events reported on erlotinib (Tarceva®) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that erlotinib (Tarceva®) caused the adverse 
event: 
 
EYE DISORDERS - Blurred vision; Eye disorders - Other (orbital cellulitis); Uveitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Colitis; Constipation; Duodenal ulcer; Dysphagia; Esophagitis; 
Gastric ulcer; Gastritis; Gastrointestinal disorders - Other (pneumatosis intestinalis); Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs 
HEPATOBILIARY DISORDERS - Cholecystitis 
INVESTIGATIONS - Creatinine increased; INR increased (in patients taking Coumadin); Lymphocyte 
count decreased; Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; Hypocalcemia; 
Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle weakness 
NERVOUS SYSTEM DISORDERS - Dizziness; Peripheral sensory neuropathy 
PSYCHIATRIC DISORDERS - Confusion 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Pharyngolaryngeal pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Urticaria 
VASCULAR DISORDERS - Thromboembolic event 
 
 
Note: Erlotinib (Tarceva®) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
Note:  Erlotinib (Tarceva®)-induced diarrhea and/or vomiting has been associated with dehydration, 
hyperkalemia; hypocalcemia; hypokalemia; hypomagnesemia; hyponatremia; hypophosphatemia, 
increased creatinine, and renal failure. 
 
Note:  Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during 
use of erlotinib (Tarceva®) in patients with or without baseline hepatic impairment. 
 
7.1.1.2 Comprehensive Adverse Events and Potential Risks list (CAEPR) for Selumetinib 
(AZD6244 Free base [NSC 741078], AZD6244 Hydrogen sulfate [NSC 748727]) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
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further clarification. Frequency is provided based on 665 patients. Below is the CAEPR for 
Selumetinib (AZD6244). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
Version 2.4, February 26, 20131 
 Adverse Events with Possible  
 Relationship to Selumetinib (AZD6244)  
 (CTCAE 4.0 Term) 
[n= 665] 
  Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 (formerly known as ASAEL) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Febrile neutropenia2 
  
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
 Left ventricular systolic 
dysfunction (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea3 
 
 
 Diarrhea3 (Gr 3) 
 
Dry mouth 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema face 
 
 Edema face (Gr 2) 
Edema limbs 
 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Platelet count decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hypoalbuminemia 
 
  
 
Hypomagnesemia 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
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Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Pruritus 
 
  
Rash acneiform 
 
 
 Rash acneiform (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
2Febrile neutropenia/neutropenic infection has been observed primarily in trials combining Selumetinib (AZD6244) 
and docetaxel. 
3SBE-CD (Captisol®, vehicle) in the mix and drink formulation is known to cause soft stools and/or diarrhea in rats 
and dogs; however, it is possible that some of these findings might be related to exacerbation of the vehicle effect by 
Selumetinib (AZD6244). 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
Also reported on Selumetinib (AZD6244) trials but with the relationship to Selumetinib (AZD6244) still 
undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(hemorrhagic anemia) 
CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (Takatsubo cardiomyopathy 
syndrome); Chest pain - cardiac; Heart failure; Palpitations; Right ventricular dysfunction; Sinus bradycardia 
EYE DISORDERS - Blurred vision; Extraocular muscle paresis; Eye disorders - Other (bilateral macular edema); 
Eye disorders - Other (black haze in line of vision); Eye disorders - Other (elevated intraocular pressure); Flashing 
lights; Glaucoma; Retinopathy 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Dyspepsia; Esophagitis; 
Flatulence; Gastric hemorrhage; Gastroesophageal reflux disease; Ileal stenosis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac 
chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (cholangitis) 
INFECTIONS AND INFESTATIONS - Infection4 
INVESTIGATIONS - CPK increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; 
Neutrophil count decreased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder -  Other (joint swelling); Musculoskeletal and 
connective tissue disorder -  Other (rhabdomyolysis); Myalgia; Myositis; Pain in extremity 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Depressed level of consciousness; Dysgeusia; 
Dysphasia; Ischemia cerebrovascular; Leukoencephalopathy; Memory impairment; Nervous system disorders - 
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Other (numbness); Nervous system disorders - Other (spinal cord compression); Oculomotor nerve disorder; 
Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy syndrome; Seizure 
PSYCHIATRIC DISORDERS - Confusion; Depression 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Epistaxis; Hypoxia; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Sore throat; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Pain of skin; Palmar-plantar 
erythrodysesthesia syndrome; Photosensitivity; Scalp pain; Skin and subcutaneous tissue disorders - Other (angular 
cheilitis, unilateral); Skin and subcutaneous tissue disorders - Other (skin fissures) 
VASCULAR DISORDERS - Hypotension; Thromboembolic event 
Note:  Selumetinib (AZD6244) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
7.1.1.3 Comprehensive Adverse Event and Potential Risks list (CAEPR) for MK-2206 (NSC 
749607) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 245 patients. Below is the CAEPR for MK-
2206. 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
Version 2.2, June 16, 2015(77) 
 
 Adverse Events with Possible  
 Relationship to MK-2206 
 (CTCAE 4.0 Term) 
[n= 245] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
CARDIAC DISORDERS 
  
 
Sinus bradycardia 
 
 Sinus bradycardia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
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 Adverse Events with Possible  
 Relationship to MK-2206 
 (CTCAE 4.0 Term) 
[n= 245] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
 
Creatinine increased 
 
  
 
Electrocardiogram QT corrected 
interval prolonged 
 
 Electrocardiogram QT corrected 
interval prolonged (Gr 2) 
 
Hemoglobin increased 
 
  
 
Investigations - Other 
(eosinophilia) 
 
 Investigations - Other 
(eosinophilia) (Gr 2) 
 
Investigations - Other (insulin c-
peptide increased) 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 
4) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
 
Platelet count decreased 
 
  
 
Weight loss 
 
  
 
White blood cell decreased 
 
 White blood cell decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
Hyperglycemia 
 
 
 Hyperglycemia (Gr 3) 
 
Hypocalcemia 
 
  
 
Hyponatremia 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. 
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
Adverse events reported on MK-2206 trials, but for which there is insufficient evidence to suggest that there 
was a reasonable possibility that MK-2206 caused the adverse event: 
 
Blood and lymphatic system disorders - Febrile neutropenia; Hemolysis; Hemolytic uremic syndrome; 
Leukocytosis 
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Cardiac disorders - Atrioventricular block complete; Left ventricular systolic dysfunction; Myocardial infarction; 
Palpitations; Ventricular arrhythmia 
Ear and labyrinth disorders - Vertigo 
Endocrine disorders - Hypothyroidism 
Eye disorders - Blurred vision; Conjunctivitis; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(blepharitis); Eye disorders - Other (eye swelling); Eye disorders - Other (foreign body sensation in eyes); Eye 
disorders - Other (iritis); Eye disorders - Other (mydriasis); Eye disorders - Other (visual acuity reduced); Eye pain; 
Floaters; Keratitis; Photophobia; Retinal detachment; Uveitis 
Gastrointestinal disorders - Abdominal distension; Abdominal pain; Ascites; Cheilitis; Colonic perforation; 
Constipation; Dry mouth; Dyspepsia; Dysphagia; Gastritis; Gastrointestinal disorders - Other (oropharyngeal pain); 
Lip pain; Toothache 
General disorders and administration site conditions - Chills; Edema face; Edema limbs; Flu like symptoms; 
General disorders and administration site conditions - Other (throat tightness); Injection site reaction; Irritability; 
Localized edema; Non-cardiac chest pain; Pain 
Immune system disorders - Allergic reaction 
Infections and infestations - Infections and infestations - Other (herpetic vesicular rash [due to herpes zoster 
infection]); Infections and infestations - Other (oral herpes); Lung infection; Nail infection; Paronychia; Pharyngitis; 
Rhinitis infective; Sepsis; Sinusitis; Skin infection; Urinary tract infection 
Injury, poisoning and procedural complications - Fall 
Investigations - Activated partial thromboplastin time prolonged; Blood bilirubin increased; INR increased; 
Investigations - Other (blood LDH increased); Investigations - Other (hyperinsulinemia); Lipase increased; Serum 
amylase increased; Weight gain 
Metabolism and nutrition disorders - Dehydration; Hypercalcemia; Hyperkalemia; Hypermagnesemia; 
Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hypophosphatemia 
Musculoskeletal and connective tissue disorders - Arthralgia; Back pain; Bone pain; Generalized muscle 
weakness; Myalgia; Neck pain; Pain in extremity 
Nervous system disorders - Akathisia; Dizziness; Encephalopathy; Lethargy; Presyncope; Reversible posterior 
leukoencephalopathy syndrome; Seizure; Syncope; Tremor 
Psychiatric disorders - Anxiety; Confusion; Depression; Insomnia 
Renal and urinary disorders - Acute kidney injury; Proteinuria; Renal and urinary disorders - Other (renal tubular 
necrosis); Renal and urinary disorders - Other (glucose urine present); Urinary incontinence; Urinary tract pain 
Reproductive system and breast disorders - Gynecomastia; Vaginal hemorrhage; Vaginal perforation 
Respiratory, thoracic and mediastinal disorders - Bronchial obstruction; Cough; Dyspnea; Epistaxis; Hypoxia; 
Pneumonitis; Pulmonary edema; Respiratory failure; Sore throat 
Skin and subcutaneous tissue disorders - Alopecia; Erythema multiforme; Erythroderma; Hyperhidrosis; Palmar-
plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; Rash acneiform; Skin and subcutaneous tissue 
disorders - Other (skin irritation); Stevens-Johnson syndrome; Urticaria 
Vascular disorders - Hematoma; Hypertension; Hypotension; Thromboembolic event 
Note: MK-2206 in combination with other agents could cause an exacerbation of any adverse event currently known 
to be caused by the other agent, or the combination may result in events never previously associated with either 
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7.1.1.4 Comprehensive Adverse Event and Potential Risks list (CAEPR) for GW572016 
(Lapatinib, Tykerb, NSC 727989) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 1890 patients. Below is the CAEPR for 
GW572016 (lapatinib, Tykerb). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
Version 2.6, February 28, 20131 
 Adverse Events with Possible  
 Relationship to GW572016 (lapatinib, Tykerb) 
 (CTCAE 4.0 Term) 
[n= 1890] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
 Left ventricular systolic 
dysfunction (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension (Gr 2) 
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Flatulence 
 
 Flatulence (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
 
 Rectal mucositis 
 
 Rectal mucositis (Gr 2)  
 
 Small intestinal mucositis 
 
 Small intestinal mucositis 
(Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Flu like symptoms 
 
 Flu like symptoms (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
 Hepatic failure (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
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INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 
2) 
 
 
 
Electrocardiogram QT 
corrected interval prolonged 
 Electrocardiogram QT 
corrected interval prolonged 
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 Laryngeal mucositis 
 
 Laryngeal mucositis (Gr 2) 
 
 Pharyngeal mucositis 
 
 Pharyngeal  mucositis (Gr 2) 
 
 
Pneumonitis 
  
 
 Tracheal mucositis 
 
 Tracheal mucositis (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Nail loss 
 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
3Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal 
obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal obstruction under the 
GASTROINTESTINAL DISORDERS SOC. 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Also reported on GW572016 (lapatinib, Tykerb) trials but with the relationship to GW572016 (lapatinib, 
Tykerb) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Restrictive cardiomyopathy 
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EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Constipation; Dysphagia; Gastritis; Gastrointestinal hemorrhage2; 
Gastrointestinal obstruction3 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Fever; Pain 
INFECTIONS AND INFESTATIONS – Infection4 
INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; Lymphocyte count decreased; 
Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypoalbuminemia; Hypoglycemia; 
Hypokalemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Myalgia 
NERVOUS SYSTEM DISORDERS - Cerebrospinal fluid leakage; Depressed level of consciousness; Dizziness; 
Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Pleural 
effusion 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Palmar-plantar erythrodysesthesia 
syndrome; Skin and subcutaneous tissue disorders - Other (seborrheic dermatitis); Urticaria 
VASCULAR DISORDERS - Hypotension; Thromboembolic event; Vascular disorders - Other (hypovolemia) 
 
Note: GW572016 (lapatinib, Tykerb) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
7.1.2 Adverse Event List(s) for Commercial Agent(s) 
 
7.1.2.1 Sunitinib Malate (SU011248 L-malate, NSC 736511) 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Sunitinib malate (SU011248 L-malate, NSC 736511) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for 
further clarification. Frequency is provided based on 7115 patients. Below is the CAEPR for 
Sunitinib malate (SU011248 L-malate). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
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investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.12, January 14, 
2016(108) 
 
Adverse Events with Possible 
Relationship to Sunitinib malate (SU011248 L-malate) 
(CTCAE 4.0 Term) 
[n= 7115] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Hemolytic uremic 
syndrome 
  
 
 
Thrombotic 
thrombocytopenic purpura 
  
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
ENDOCRINE DISORDERS 
  
 
 
Endocrine disorders - Other 
(thyroiditis) 
  
 
 
 Hyperthyroidism 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
EYE DISORDERS 
  
 
 
Eye disorders - Other 
(macular edema) 
 Eye disorders - Other 
(macular edema) (Gr 2) 
 
 
Eye disorders - Other 
(vision deterioration) 
 Eye disorders - Other (vision 
deterioration) (Gr 2) 
 
Papilledema 
 
 Papilledema (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension (Gr 2) 
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
Anal mucositis 
 
 
 Anal mucositis (Gr 2) 
Constipation 
 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
Dyspepsia 
 
 
 Dyspepsia (Gr 2) 
 
 
 Esophagitis 
  
 
Flatulence 
 
 Flatulence (Gr 2) 
 
Gastritis 
 
 Gastritis (Gr 2) 
 
Gastroesophageal reflux 
disease 
 
  
 
 
Gastrointestinal 
perforation(109) 
  
Mucositis oral 
 
 
 Mucositis oral (Gr 3) 
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Adverse Events with Possible 
Relationship to Sunitinib malate (SU011248 L-malate) 
(CTCAE 4.0 Term) 
[n= 7115] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Oral pain 
 
 Oral pain (Gr 2) 
 
 
 Pancreatitis 
  
Rectal mucositis 
 
 
 Rectal mucositis (Gr 2) 
Small intestinal 
mucositis 
 
 
 Small intestinal mucositis (Gr 
2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Cholecystitis 
  
 
 
Hepatic failure 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction(110) 
  
INFECTIONS AND INFESTATIONS 
  
 
 
Infection and infestations - 
Other (necrotizing fasciitis) 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase 
increased  
(Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 
2) 
 
CPK increased 
 
  
 
Creatinine increased 
 
 Creatinine increased (Gr 3) 
 
 
Electrocardiogram QT 
corrected interval prolonged 
  
 
Lipase increased 
 
 Lipase increased (Gr 4) 
 
Lymphocyte count decreased  
 Lymphocyte count decreased 
(Gr 2) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased 
(Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 
4) 
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Adverse Events with Possible 
Relationship to Sunitinib malate (SU011248 L-malate) 
(CTCAE 4.0 Term) 
[n= 7115] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
 
Serum amylase increased 
 
 Serum amylase increased (Gr 
2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased 
(Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hyperuricemia 
 
 Hyperuricemia (Gr 2) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
 
Hypoglycemia 
  
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 2) 
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
 
Musculoskeletal and 
connective tissue disorder - 
Other (rhabdomyolysis) 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Leukoencephalopathy 
  
 
 
Nervous system disorders - 
Other (cerebral infarction) 
  
 
 Paresthesia 
 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
 
 
Transient ischemic attacks   
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
 Acute kidney injury 
  
 
 
 Proteinuria 
  
 
 
 Renal and urinary disorders 
- Other (nephrotic 
syndrome) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
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Adverse Events with Possible 
Relationship to Sunitinib malate (SU011248 L-malate) 
(CTCAE 4.0 Term) 
[n= 7115] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
 Epistaxis Gr 2) 
Laryngeal mucositis 
 
 
 Laryngeal mucositis (Gr 2) 
Pharyngeal mucositis  
 
 Pharyngeal mucositis (Gr 2) 
Tracheal mucositis 
 
 
 Tracheal mucositis (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 3) 
 
Pruritus 
 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous tissue 
disorders - Other (hair color 
change) 
 
 Skin and subcutaneous tissue 
disorders - Other (hair color 
change) (Gr 2) 
 
 
 Skin and subcutaneous 
tissue disorders - Other 
(pyoderma gangrenosum) 
  
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
 
 
Stevens-Johnson syndrome   
 
 
Toxic epidermal necrolysis   
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
Vascular disorders - Other 
(hemorrhage)(111) 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
2Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC. 
3Allergic reactions observed include anaphylaxis and angioedema. 
4The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a critical area or 
organ (e.g., eye, GI tract, GU system, respiratory tract, nervous system [including fatal intracranial hemorrhage, and 
cerebrovascular accident], and tumor site) have been reported. 
Adverse events reported on Sunitinib malate (SU011248 L-malate) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that Sunitinib malate (SU011248 L-malate) caused 
the adverse event: 
 
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BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Pericardial effusion 
GASTROINTESTINAL DISORDERS - Ascites; Dysphagia; Gastrointestinal disorders - Other (enteritis); 
Hemorrhoids; Ileus; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Pain 
INVESTIGATIONS - GGT increased; INR increased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; Hyperkalemia; 
Hypocalcemia; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Nervous system disorders - Other (spinal cord 
compression); Peripheral sensory neuropathy; Seizure; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion 
Renal and urinary disorders - Hematuria; Urinary retention 
REPRODUCTIVE SYSTEMS AND BREAST DISORDERS - Hematosalpinx 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pharyngolaryngeal pain; Pleural effusion; 
Pneumothorax 
VASCULAR DISORDERS - Flushing; Hypotension; Thromboembolic event 
 
Note: Sunitinib malate (SU011248 L-malate) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
7.2 
Adverse Event Characteristics 
7.2.1 CTCAE term (Adverse event description) and grade:   
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
“Expectedness”:   
Adverse events can be “Expected” (see Section 7.1) or unexpected.  Bold and italicized terms in 
Section 7.1 identify expected events.  See Section 7.5 for guidelines for reporting both types of 
events. 
7.2.2 Attribution of the adverse event: 
Definite – The adverse event is clearly related to the study treatment. 
Probable – The adverse event is likely related to the study treatment. 
Possible – The adverse event may be related to the study treatment. 
Unlikely – The adverse event is doubtfully related to the study treatment. 
Unrelated – The adverse event is clearly NOT related to the study treatment. 
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7.3 
Expedited Adverse Event Reporting 
Expedited adverse event reporting for this study is via CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the secure CTEP web site https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1397144505895).  The reporting procedures to be 
followed are presented in the “NCI Guidelines: Expedited Adverse Event Reporting 
Requirements for NCI Investigational Agents” which can be downloaded from the CTEP web 
site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf).  
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497, only when Internet connectivity is disrupted.  Once 
Internet connectivity is restored, a 24-hour notification phoned in must be entered electronically 
into CTEP-AERS by the original submitter at the site. 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Study Coordinator of the Lead Organization, Principal Investigator, and the local 
treating physician.  CTEP-AERS provides a copy feature for other e-mail recipients. 
7.3.1 Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
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NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  Attribution 
to treatment or other cause must be provided. 
 
• Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE 
via CTEP-AERS within 24 hours of learning of the event followed by a 
complete CTEP-AERS report within 5 calendar days of the initial 24-hour 
report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the 
event.  
 
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse 
event reporting exclusions.   
 
• Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND. 
 
• Use the NCI protocol number and the protocol-specific patient ID assigned 
during trial registration on all reports. 
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7.3.2 Expedited AE reporting timelines defined: 
• 
“24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 5 calendar days of the initial 24-hour report. 
• 
“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted within 
10 calendar days of the investigator learning of the event.  
The Worldwide Product Safety (WPS) department at Merck will receive Adverse Experience 
reports, which are entered into the CTEP-AERS database, from the CTEP Contractor CTIS at the 
same time that they are forwarded to the NCI/CTEP. 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions.   
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via CTEP-AERS if the event occurs following treatment with 
an agent under a CTEP IND. 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
7.3.3 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
For this protocol only, certain adverse events/grades are exceptions to the Expedited Reporting 
guidelines and do not require expedited reporting.  The following adverse events should be 
reported through the routine reporting mechanism (Section 7.4): 
 
 
CTCAE Category 
 
Adverse Event 
 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
 
Comments 
GI disorders 
Nausea 
2 to 3 
 
 
 
Diarrhea 
2 to 3 
 
 
 
Constipation 
2 to 3 
 
 
 
Vomiting 
2 to 3 
 
 
Metabolism and 
nutrition disorders 
Electrolyte 
abnormalities 
2 to 4 
 
 
Nervous system 
disorders 
Disguesia 
2 
 
 
Dermatology/Skin 
Rash 
Acne/Acneiform 
2 to 3 
 
 
Events that are clearly consequences of the “main” event (e.g., hypokalemia associated with 
diarrhea or the arrhythmias, hypotension, hypoxia, etc. that are known to occur concurrently with 
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sepsis) may be noted in the Description of Event in the CTEP-AERS report and do not require 
separate CTEP-AERS reports. 
The possibility of the contribution of comorbid conditions to the event should be considered 
when reporting adverse events.  Examples include hyperglycemia in patients with diabetes or 
headaches and seizures in patients with brain tumors. 
7.4 
Routine Adverse Event Reporting 
Those adverse events that do not require expedited reporting must be reported in routine (CTMS 
or CDUS; see Section 14.1) study data submissions.  Adverse events reported through CTEP-
AERS must also be reported in routine study data submissions. 
NOTE:  Grade 1 events are not required to be reported or collected. 
8 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 
8.1 
Definitions 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
8.2 
OHSRP Office of Compliance and Training / IRB Reporting 
8.2.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here.  
8.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
8.3 
NCI Clinical Director Reporting  
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI 
Clinical Director.  A separate submission is not necessary as reports in iRIS will be available to 
the Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.NIH 
Required Data and Safety Monitoring Plan 
8.3.1 Principal Investigator/Research Team  
The clinical research team will meet on a weekly basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 8.2.1 will be submitted within the appropriate timelines.   
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The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
9 PHARMACEUTICAL INFORMATION 
 
9.1 
CTEP-Supplied Investigational Agent(s) 
9.1.1 Erlotinib 
OSI-774 (NSC 718781) 
9.1.1.1 Chemical Name:  
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, monohydrochloride 
9.1.1.2 Other Names:   
 
Erlotinib hydrochloride, Tarceva™ 
9.1.1.3 Classification:  
 
Tyrosine kinase Inhibitor (EGFR) 
9.1.1.4 Molecular Formula:  
C22H23N3O4 HCl 
 
 
M.W.: 393.4 (free base) 
429.9 (hydrochloride salt) 
9.1.1.5 Mode of Action:  
Direct inhibition of EGFR tyrosine kinase 
9.1.1.6 How Supplied:  
Erlotinib tablets are provided by Astellas Pharma and distributed by the Pharmaceutical 
Management Branch, DCTD/NCI as 25 mg, 100 mg, and 150 mg white film-coated 
immediate-release tablets packaged in high-density polyethylene (HDPE) bottle.  Each 
bottle contains 30 tablets.  
The tablets are round and convex without markings.  The 25 mg tablets are 1/4 inches (6 
mm); the 100 mg tablets are 11/32 inches (9 mm); and the 150 mg tablets are 13/32 
inches (10 mm). Erlotinib excipients include lactose monohydrate, hypromellose, 
hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch 
glycolate, sodium lauryl sulfate, and titanium dioxide.  The tablets also contain trace 
amounts of color additives, including FD&C Yellow No. 6 (25 mg only) for product 
identification. 
9.1.1.7 Storage:   
Store at 25○C (77○F) in the original container; excursions permitted to 15○ - 30○C (59○ - 
86○F). 
9.1.1.8 Stability:  
Current data indicates erlotinib is stable for at least 3 years at room temperature. 
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9.1.1.9 Route of Administration:   
Oral. 
9.1.1.10 Method of Administration:  
• Tablets should be taken once daily preferably in the morning with up to 200 mL of 
water one hour before or two hours after food. 
• Administration through G-tube: Dissolve the dose in 100 mL of sterile water, and 
shake it vigorously to form a uniform suspension.  Draw suspension into a syringe 
and administer through the G-tube port.  Repeat the transfer until the entire volume 
has been administered.  Add small volume (40 mL) of sterile water to the container 
used to dissolve the tablets.  Shake the residual suspension, aspirate it into a syringe, 
and administer.  Repeat this last step to ensure the entire dose is administered.  The 
total volume of delivery/rinse is ~180 mL.  
9.1.1.11 Potential Drug Interaction:  
Erlotinib is highly protein bound (92% to 95% in humans) and metabolizes primarily via 
CYP3A4 enzymes.  Dose erlotinib cautiously with agents that are highly protein bound or 
potent CYP3A4 inhibitors/inducers enzymes. 
CYP Iso-Enzymes Inhibitors/Inducers: 
o Potent CYP3A4 Inhibitors:  Use alternative drug.  Alternatively, reduce erlotinib 
dose in the event of drug interaction (if permitted by the protocol).  
o Potent CYP3A4 inducers:  Use alternative drug.  If an alternative treatment is 
contraindicated, consider increasing the erlotinib dose (if permitted by the 
protocol).  
o Food-drug interaction: Avoid grapefruit /grapefruit juice (potent CYP3A4) while 
taking erlotinib. 
o Smoking:  Advise smokers to stop smoking while taking erlotinib.  Smoking 
induces CYP1A2 enzymes and alters Erlotinib exposure by 64%. 
Anticoagulant:  Concomitant NSAIDs, warfarin or warfarin-derivatives may increase 
bleeding and prothrombin time (PT) / international normalized ratio (INR). Dose 
adjustment may be needed.  
Patients receiving warfarin: Severe and fatal hemorrhage associated with elevated 
INRs can occur when OSI-774 and warfarin are administered concurrently. Patients 
taking warfarin or other coumarin-derivative anticoagulants should have more 
frequent INR/PT determinations (e.g., weekly for the first month and weekly for a 
minimum of 2 weeks following discontinuation of Erlotinib). 
Statin:  The combination of Erlotinib and a statin may increase the potential for statin-
induced myopathy, including rhabdomyolysis, which was observed rarely. 
Proton Pump Inhibitor:  Erlotinib’s solubility decreases as the pH increases. Co-
administration of omeprazole with Erlotinib will increase the AUC and Cmax by 46% 
and 61%, respectively.  
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H2-antagonist: Avoid concomitant use of Erlotinib with gastric acid reducing agents if 
possible.  When ranitidine 300 mg is given with Erlotinib, Erlotinib AUC and Cmax 
decrease by 33% and 54%, respectively.  Increasing the dose of Erlotinib will not 
compensate the loss of exposure.  However, if an H2-antagonist receptor is needed, 
take Erlotinib at least 2 hours before or 10 hours following the H2-antagonist 
administration.  Dosing such, Erlotinib loss of exposure is minimized to AUC of 
15% and Cmax of 17%.   
Gastrointestinal perforation:  Concomitant use of anti-angiogenic agents, 
corticosteroids, NSAIDs, and/or taxane based chemotherapy, or patients with prior 
medical history with peptic ulcers or diverticular disease are at high risk of GI 
perforation while on Erlotinib treatment.  Discontinue Erlotinib if GI perforation 
manifests. 
Patient Care Implications: If patient vomits after taking the tablets, readminister the dose only 
if the tablets can actually be seen and counted. 
Recommend patients use sunscreen protection, and wear hat and long sleeve shirts as sunlight 
can exacerbate skin reactions. 
9.1.1.12 Availability 
Erlotinib is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), National Cancer Institute (NCI). 
Erlotinib is provided to the NCI under a Clinical Trials Agreement (CTA) between Astellas 
Pharma and the DCTD, NCI. 
9.1.2 AZD6244 
AZD6244 hydrogen sulfate (NSC 748727) 
9.1.2.1  Chemical Name:   
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-
hydroxy-ethoxy)-amide hydrogen sulfate 
Other Names:  ARRY-142886; AR00142866; AR-142886-01, AZD6244, AZD6244 Hyd-
Sulfate,  
9.1.2.2 Classification:   
Mitogen-activated protein kinase (MEK) inhibitor 
CAS Registry Number:   943332-08-9 
9.1.2.3 Molecular Formula:    
C17H15BrClFN4O3 ·  H2SO4 
 
 
M.W.:  555.7 
9.1.2.4 Mode of Action:   
The RAS/RAF/MEK/ERK pathway is an important mediator of many cellular processes 
including proliferation, survival, differentiation, apoptosis, motility, and metabolism.  This 
pathway is often aberrantly activated in human tumors due to the overexpression of mutant 
KRAS, mutant BRAF, or other growth factor receptors.  AZD6244 is a selective mitogen-
activated protein kinase (MEK) inhibitor.  By inhibiting MEK, AZD6244 inhibits ERK 
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phosphorylation.  Thus, AZD6244 may inhibit oncogenic growth signaling in tumor cells by 
targeting the RAS/RAF/MEK/ERK pathway. 
9.1.2.5 How Supplied:   
AZD6244 hydrogen sulfate is supplied as a 25 mg, size 4, plain, white, hydroxypropyl-
methylcellulose (HPMC) capsule in white high density polyethylene (HDPE) containers with 
foil-lined, induction-sealed, child-resistant closures.  Each bottle contains 60 capsules.  
Each capsule contains a dispersion of AZD6244 hydrogen sulfate in d-α-tocopheryl polyethylene 
glycol 1000 succinate (TPGS; a water soluble form of vitamin E).   
9.1.2.6 Storage:   
Store the AZD6244 hydrogen sulfate capsules at room temperature (20°C-25°C). Brief 
excursions are permitted between 15°C and 30°C.    
9.1.2.7 Stability:   
Stability studies are ongoing.   
9.1.2.8 Route of Administration:    
Oral.  Take AZD6244 on an empty stomach (either 1 hour before or 2 hours after meals).  
AZD6244 capsules should be taken with water only.        
9.1.2.9 Potential Drug Interactions:   
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.    
High vitamin E doses may potentiate warfarin’s anticoagulant activity.  Monitor PT/INR more 
frequently in patients receiving both warfarin and AZD6244 hydrogen sulfate capsules.   
Avoid concomitant intake of Vitamin E in excess of 100% of the recommended daily dose.  
9.1.2.10 Availability:    
AZD6244 is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. AZD6244 is provided to the NCI under a Collaborative 
Agreement between AstraZeneca and the DCTD, NCI (see Section 14.3). 
9.1.3 MK-2206 
MK-2206 (NSC 749607) 
9.1.3.1 Chemical Name or Amino Acid Sequence:  
8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-ƒ]-1,6-naphthyridin-3(2H)-one 
mono-hydrochloride salt 
9.1.3.2 Classification: Akt inhibitor 
9.1.3.3 Molecular Formula:  
C25H22N5OCl 
 
M.W.:  443.93  
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Approximate Solubility:  Soluble in water (7.54 mg/mL; pH = 6.13) but less soluble in 
acetonitrile (1.4 mg/mL) and ethanol (2 mg/mL). Its mono-hydrochloride salt is slightly 
hygroscopic (absorbs 1.9 wt% water up to 95% relative humidity).   
9.1.3.4 Mode of Action:   
The PI3K-Akt pathway is activated downstream of EGFR, HER2, IGF1R, and cMet, and is a 
suspected driver of tumor progression in most cancers.  Overexpression or activating mutations 
in receptor tyrosine kinases, PI3K and Ras, inactivation of the tumor suppressor PTEN, or 
amplification or mutation of Akt can activate Akt protein kinase in most carcinomas.  It is 
believed that Akt inhibitors that target the pathway downstream of the most common mutations 
have broader utility and provide less resistance in the clinic.   
9.1.3.5 Description:   
A highly selective non-ATP competitive allosteric Akt inhibitor. 
9.1.3.6 How Supplied:  
MK-2206 tablets are supplied by Merck and distributed by the DCTD, NCI.  The 5 mg, 25 mg, 
and 200 mg tablets are film coated, packaged in HDPE bottles.  The 5 mg and 25 mg bottles 
contain 10 and 20 tablets, respectively.  When inventory allows, the 5 mg and 25 mg bottles also 
contain 30 tablets each.  The 200 mg bottles contain 5 tablets each.  The pharmaceutical 
collaborator does not have stability data to support repackaging MK-2206 tablets in any 
container other than what is provided. 
The white film (Opadry® 20A18273) coating consists of hydroxypropyl cellulose, 
hydroxypropyl methylcellulose and titanium dioxide.  
Inactive ingredients consist of microcrystalline cellulose (Avicel PH102®), calcium phosphate 
dibasic anhydrous (ATAB®), croscarmellose sodium, and magnesium stearate.  
9.1.3.7 Storage:  
Store intact bottles at room temperature, not to exceed 30°C. 
9.1.3.8 Stability:   
Shelf life studies of MK-2206 are on going. 
9.1.3.9 Route(s) of Administration: Oral 
9.1.3.10 Method of Administration:  
Take tablets 2 hours before or after food. 
9.1.3.11 Potential Drug Interactions:   
No clinical drug interaction studies have been performed with MK-2206; MK-2206 is not an 
inducer or inhibitor of major human P450 enzymes (CYP3A4, 2C9 and 2D6). In human 
hepatocytes, its metabolism involves both oxidation mainly by CYP3A4 and direct 
glucuronidation. MK-2206 is a substrate for P-glycoprotein (P-gp) mediated transport. 
Patient Care Implications:  In acute overdose, use activated charcoal to reduce the absorption of 
MK-2206.  If additional measures are needed, consider emptying the stomach.  Administer 
specific medical therapy as clinically appropriate. 
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9.1.4 Lapatinib 
Lapatinib (NSC 727989) 
9.1.4.1 Chemical Name:   
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2 
furyl]-4-quinazolinamine 
Other Names:         GW572016, Tykerb® 
9.1.4.2 Molecular Formula:  
C29H26ClFN4O4S(C7H8O3S)2H2O 
Molecular Weight:   943.48 
Approximate solubility:    0.007 mg/mL in water and  0.001 mg/mL in 0.1 N HCl at 25°C.   
9.1.4.3 Mode of Action:    
Dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 tyrosine 
kinases.  
9.1.4.4 How Supplied:     
Lapatinib is supplied by the NCI/DCTD as 250 mg oval, biconvex, orange film-coated tablets 
with one side plain and the opposite side debossed with either FG HLS or GS XJG. The tablets 
contain 405 mg of lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib free base per 
tablet. The tablets are packaged into HDPE bottles with child-resistant closures containing 90 
tablets per container.  
Excipients present in the tablet include: Microcrystalline cellulose, povidone, sodium starch 
glycolate, and magnesium stearate. 
The film-coat contains:  Hydroxypropyl methylcellulose, titanium dioxide, macrogel/PEG 400, 
Polysorbate 80, FD&C Yellow No. 6, and FCF aluminum lake. 
9.1.4.5  Storage:        
Store intact bottles at controlled room temperature (15°C-30°C).  Protect from light. 
9.1.4.6 Stability:        
Shelf life surveillance studies of the intact bottle are on-going.  Current data indicates lapatinib is 
stable for at least 36 months at controlled room temperature (15°C - 30°C). 
9.1.4.7 Route of Administration:   
Oral on an empty stomach (either 1 hour before or 1 hour after meals).  
9.1.4.8 Method of Administration:  
Administer whole tablets.  Tablet crushing is not recommended.  
9.1.4.9 Potential Drug Interactions:   
In vitro studies with human liver microsomes indicate that lapatinib is metabolized by CYP3A4 
and CYP3A5, and to a lesser extent CYP2C19 and CYP2C8.   Co-administration of lapatinib 
with potent or moderate CYP3A4 inhibitors (including grapefruit juice) and all CYP3A4 
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inducers is prohibited.  Assess risk/benefit before co-administering lapatinib with weak CYP3A4 
inhibitors.  CYP3A4 inhibitors may decrease lapatinib metabolism (increasing levels); while 
CYP3A4 inducers may increase lapatinib metabolism (decreasing levels).   
In human subjects, lapatinib inhibited CYP3A4 and CYP2C8 at clinically relevant 
concentrations. Avoid co-administration of lapatinib with drugs that are substrates of CYP3A4 or 
CYP2C8 and have narrow therapeutic windows.    
Lapatinib potentially interacts with warfarin and quinazoline derivatives to increase INR and 
bleeding.  Collect INR/PT determinations more frequently (e.g. weekly for the first month and 
weekly for a minimum of 2 weeks following lapatinib discontinuation). 
9.2 
Other Agent(s) 
9.2.1 Sunitinib 
Sunitinib malate (NSC 736511) 
9.2.1.1 Chemical Name:  
5-(5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic 
acid(2-diethylamino-ethyl)-amide; compound with (S)-2-hydroxy-succinic acid. 
Other names:   SU011248 L-Malate salt; SU010398; PHA-290940AD; Sutent; SU011248 
9.2.1.2 Classification:   
Receptor tyrosine kinase inhibitor (RTK) 
9.2.1.3  Molecular formula:   
C22H27FN4O2.C4H6O5                  M.W.: 532.56 Daltons 
9.2.1.4 Physical description:   
Yellow to orange powder 
Cas registry number:  341031-54-7 
Aqueous solubility:                                 
Solvent 
Solubility (mg/mL) 
0.1 M HCl 
59.1  
pH 4.5 buffer 
25.4  
pH 6.8 buffer 
37.8 
pH 7.5 buffer 
0.05  
  in water                               
1.6 
Solubility in various solvents: 
Solvent 
Solubility (mg/mL) 
Acetonitrile 
0.1 
Dimethyl sulfoxide 
92.9 
Tetrahydrofuran 
0.2 
Methanol 
1.5 
Ethanol 
0.3 
1-Butanol 
0.1 
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1-Butano:Water (80/20 v/v) 
6.2 
N,N-Dimethylacetamide 
37 
N,N-Dimethylformamide 
18.4 
9.2.1.5 Mode of Action:  
Sunitinib malate is a receptor tyrosine kinase inhibitor involved in tumor proliferation and 
angiogenesis, specifically inhibiting platelet derived growth factor receptor, vascular endothelial 
growth factor receptor, stem cell factor receptor, Fms-like tyrosine kinase-3 receptor, and ret 
proto-oncogene. 
9.2.1.6 How Supplied:  
Sunitinib malate capsule is commercially available through Pfizer, Inc. and will be purchased by 
the participating institutions in the following strengths:  
Capsules: 12.5 mg, 25 mg, and 50 mg capsules with mannitol, croscarmellose sodium, povidone, 
and magnesium stearate.  Each opaque plastic bottle contains 30 capsules.                                    
Capsule strength 
              Description 
12.5 mg 
Swedish Orange, Size 4 hard gelatin capsule 
25 mg 
Swedish Orange/Caramel, Size 3 hard gelatin 
capsule. 
50 mg 
Caramel, Size 2 hard gelatin capsule 
9.2.1.7 Storage:   
Store at controlled room temperature (15 to 30°C), and protect from light.  
9.2.1.8 Stability:  
The expiration date can be found on the commercially available supplies.   
9.2.1.9 Route of Administration:  
Oral.  Sunitinib malate may be administered without regard to meals.  
9.2.1.10 Potential Drug Interaction:   
Sunitinib malate is metabolized primarily by liver enzymes, particularly CYP3A4.  Dose 
reduction with the CYP3A4 inhibitors is recommended, based on clinical symptoms. 
Concomitant treatment with dysrhythmic drugs, i.e., terfenadine, quinidine, procainamide, 
sotalol, probucol, bepridil, haloperidol, risperidone, and indapamide, is not recommended. 
Patients Care Implications:    A yellow discoloration of the skin area may result following direct 
contact with the capsules.  Wash the exposed area with soap and water immediately. 
9.3 
Agent Ordering 
NCI supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained.)  The CTEP assigned protocol number must be used for ordering all CTEP supplied 
investigational agents.  The responsible investigator at each participating institution must be 
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registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial 
Disclosure Form (FDF).  If there are several participating investigators at one institution, CTEP 
supplied investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx >. Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account < 
https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance of an “active” account status and a 
“current” password. For questions about drug orders, transfers, returns, or accountability, call 
(240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
9.4 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See the CTEP 
home page at http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage and 
to obtain a copy of the DARF and Clinical Drug Request form.) 
10 CORRELATIVE / SPECIAL STUDIES 
If enough material is available (after the molecular profiling analyses described in Section 5 have 
been performed), and the patient provides consent, the remainder paraffin embedded tissue and / 
or frozen samples or tumor DNA will be used for further molecular analysis.  
10.1 Sample Storage, Tracking and Disposition 
All research samples will be numerically coded prior to storage to maintain patient 
confidentiality.  Subject identity is not provided to research laboratory personnel; i.e., samples 
are analyzed in a blinded fashion.  Subjects will be given the option of consenting to future use 
of their research samples per the informed consent process with their option declared in the 
consent document.  Biospecimens will be collected and processed using validated SOPs that will 
ensure both specimen quality and patient confidentiality pursuant to informed consent 
provisions.  
Using a computerized inventory system and a backup hardcopy process, all specimen collection 
and processing steps will be documented and the specific location of each specimen will be 
tracked.  Each new specimen collected will be assigned a unique barcode identifier that can be 
linked to the original specimen collected and other relevant information within the inventory 
system.  To ensure patient confidentiality, only containers used for the initial specimen 
collections will be labeled with patient identifiers.  Coded, linked labels will be applied to all 
subsequent specimen containers.  When specimens are processed and aliquoted, no patient 
information will be included on the new containers.  Original specimen containers will be 
discarded.  Only de-linked specimens will be shipped for analysis and/or storage.  De-linked 
specimen labels will indicate: protocol number, order in which the patient was enrolled in the 
trial, type of sample, collection time, and total volume collected, as appropriate.  
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The inventory process contains other security provisions sufficient to safeguard patient privacy 
and confidentiality.  Access to the inventory system and associated documents will be restricted 
to appropriate personnel only.  The only patient information available in the inventory system 
will be the patient sex, diagnosis, and level of informed consent provided.  SOPs ensure that any 
changes in the informed consent made by a patient and relayed to the PI will be reflected in the 
inventory system to ensure that specimens are destroyed as appropriate.  All laboratory personnel 
will be trained to adhere to SOPs and will be monitored for high-quality performance. 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request.  Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested). The PI will record any loss 
or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of 
section 8.2. 
10.2 Large Scale Detection of Mutations in Candidate Genes  
The remainder paraffin embedded tissue and / or frozen samples or tumor DNA, will be sent to 
one of the two following laboratories for large scale detection of mutations in candidate genes 
using next generation sequencing technologies:  
Dr. Paul Meltzer 
Attn. Dr. Keith Killian 
Clinical Molecular Profiling Core lab 
National Cancer Institute 
Building 37, Room 6144 
37 Convent Drive 
Bethesda, MD 20892  
Phone:   301-496-0999  
E-Mail:   killianj@mail.nih.gov 
 
Dr. Robert Searless 
Massively Parallel Sequencing Shared Resource 
Oregon Health & Science University 
Mailcode CH14G 
3303 SW Bond Ave 
Portland, OR 97239 
 
10.2.1 Sample processing 
Genomic DNA from histologically characterized tissue will be sequenced at loci encoding each 
candidate gene.  DNA will be amplified using a PCR device and using exon specific primers.  
The PCR products will then be pooled and sequenced directly using a next generation 
sequencing device (i.e. Illumina Genome Analyzer).  This will allow the parallel sequencing of 
the entire panel of candidate genes with rapid turnaround.  
10.2.2  Gene sequencing 
Somatic gene mutation analysis including but not limited to the following list of genes will be 
performed in the available tumor samples: 
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Approved 
Gene 
Approved Gene 
Name 
Symbol 
Location 
Sequence 
Accession IDs 
Previous 
Symbols 
Aliases 
AKT1 
v-akt murine thymoma 
viral oncogene homolog 
1 
14q32.32-
q32.33 
M63167 
NM_005163 
  
RAC, PKB, 
PRKBA, AKT 
AKT2 
v-akt murine thymoma 
viral oncogene homolog 
2 
19q13.1-
q13.2 
NM_001626 
 
 
ALK 
anaplastic lymphoma 
receptor tyrosine kinase 
2q23 
D45915 
NM_004304 
  
CD246 
APC 
adenomatous polyposis 
coli 
5q21-q22 
M74088 
NM_000038 
  
DP2, DP3, DP2.5 
ART 
anaplastic lymphoma 
receptor tyrosine kinase 
2p23 
D45915 
NM_004304 
  
CD246  
ATM 
ataxia telangiectasia 
mutated 
11q22-q23 
AB209133 
NM_000051 
ATA, ATDC, 
ATC, ATD 
TEL1, TELO1 
BCL2 
B-cell CLL/lymphoma 
2 
18q21.3 
M14745 
NM_000633, 
NM_000657 
  
Bcl-2 
BMPR1A 
bone morphogenetic 
protein receptor, type 
IA 
10q22.3 
BC028383 
NM_004329 
ACVRLK3 
ALK3, CD292 
BMPR1B 
bone morphogenetic 
protein receptor, type 
IB 
4q23-q24 
D89675 
NM_001203 
  
ALK6, CDw293 
BMPR2 
bone morphogenetic 
protein receptor, type II 
(serine/threonine 
kinase) 
2q33-q34 
Z48923 
PPH1 
BRK-3, T-ALK, 
BMPR3, BMPR-II 
BRAF 
v-raf murine sarcoma 
viral oncogene homolog 
B1 
7q34 
M95712 
NM_004333 
  
BRAF1 
CDKN2A 
cyclin-dependent kinase 
inhibitor 2A 
(melanoma, p16, 
inhibits CDK4) 
9p21 
L27211 
NM_000077 
CDKN2, 
MLM 
CDK4I, p16, 
INK4a, MTS1, 
CMM2, ARF, p19, 
p14, INK4, 
p16INK4a 
CDKN2B 
cyclin-dependent kinase 
inhibitor 2B (p15, 
inhibits CDK4) 
9p21 
AB060808 
NM_004936 
  
P15, MTS2, 
INK4B, TP15, 
CDK4I, p15INK4b 
CDKN2C 
cyclin-dependent kinase 
inhibitor 2C (p18, 
inhibits CDK4)   
1p32.3 
BC000598 
NM_001262 
  
  INK4C, p18 
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CDH1 
cadherin 1, type 1, E-
cadherin (epithelial) 
16q22.1 
L08599 
NM_004360 
UVO 
uvomorulin, CD324 
CTNNB1 
catenin (cadherin-
associated protein), beta 
1, 88kDa 
3p21 
X87838  
NM_001098210 
CTNNB 
beta-catenin  
EGFR 
epidermal growth factor 
receptor (erythroblastic 
leukemia viral (v-erb-b) 
oncogene homolog, 
avian) 
7p12 
NM_005228 
ERBB 
ERBB1 
EML4 
echinoderm microtubule 
associated protein like 4 
2p21 
 AF177377 
NM_019063 
C2orf2 
ROPP120, ELP120 
EPHA3 
EPH receptor A3 
3p11.2 
M83941 
NM_005233 
ETK, ETK1, 
TYRO4 
HEK, HEK4 
EPHA5 
EPH receptor A5 
4q13.1 
L36644 
NM_004439 
 
Hek7, TYRO4, 
CEK7, EHK1 
EPHA7 
EPH receptor A7 
6q16.3 
L36642 
  
Hek11 
ERBB2 
v-erb-b2 erythroblastic 
leukemia viral 
oncogene homolog 2, 
neuro/glioblastoma 
derived oncogene 
homolog (avian) 
17q11.2-
q12 
X03363 
NGL 
NEU, HER-2, 
CD340, HER2 
ERBB3 
v-erb-b2 erythroblastic 
leukemia viral 
oncogene homolog 3 
(avian) 
12q13 
M34309 
LCCS2 
HER3 
ERBB4 
v-erb-a erythroblastic 
leukemia viral 
oncogene homolog 4 
(avian) 
2q33.3-q34 
L07868 
NM_001042599 
  
  
FAS 
Fas (TNF receptor 
superfamily, member 6) 
10q24.1 
M67454 
FAS1, APT1, 
TNFRSF6 
CD95, APO-1 
FGFR1 
fibroblast growth factor 
receptor 1 
8p12 
M34185 
FLT2, KAL2 
H2, H3, H4, H5, 
CEK, FLG, 
BFGFR, N-SAM, 
CD331 
FGFR2 
fibroblast growth factor 
receptor 2 
10q25.3-
q26 
AK026508 
NM_022976, 
NM_000141 
KGFR, BEK, 
CFD1, JWS 
CEK3, TK14, 
TK25, ECT1, K-
SAM, CD332 
FGFR3 
fibroblast growth factor 
receptor 3 
4p16.3 
M64347 
ACH 
CEK2, JTK4, 
CD333 
FGFR4 
fibroblast growth factor 
receptor 4 
5q33-qter 
AF202063 
  
JTK2, CD334 
FLT4 
fms-related tyrosine 
kinase 4 
5q34-q35 
X68203 
  
VEGFR3, PCL 
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FZD1 
frizzled homolog 1 
(Drosophila) 
7q21 
AB017363 
NM_003505 
  
DKFZp564G072 
GNAS 
GNAS complex locus 
20q13.2-
q13.3 
M21142 
NM_000516 
GNAS1 
NESP55, NESP, 
GNASXL, GPSA, 
SCG6 
GSK3B 
glycogen synthase 
kinase 3 beta 
3q13.3 
BC012760 
  
  
HIF1A 
hypoxia inducible factor 
1, alpha subunit (basic 
helix-loop-helix 
transcription factor) 
14q23.2 
U22431 
NM_001530 
  
MOP1, HIF-1alpha, 
PASD8, HIF1, 
bHLHe78 
HRAS 
v-Ha-ras Harvey rat 
sarcoma viral oncogene 
homolog 
11p15.5 
AJ437024 
NM_176795 
HRAS1 
 
IGF1R 
insulin-like growth 
factor 1 receptor 
15q26.3 
M69229 
NM_000875 
  
JTK13, CD221, 
IGFIR, MGC18216, 
IGFR 
INHBA 
inhibin, beta A 
7p15-p13 
  
  
  
KDR 
kinase insert domain 
receptor (a type III 
receptor tyrosine 
kinase) 
4q11-q12 
AF035121 
  
FLK1, VEGFR, 
VEGFR2, CD309 
KIT 
v-kit Hardy-Zuckerman 
4 feline sarcoma viral 
oncogene homolog 
4q11-q12 
S67773 
PBT 
CD117, SCFR, C-
Kit 
KRAS 
v-Ki-ras2 Kirsten rat 
sarcoma viral oncogene 
homolog 
12p12.1 
BC010502 
NM_033360 
KRAS2 
KRAS1 
LRP1B 
low density lipoprotein-
related protein 1B 
(deleted in tumors) 
2q21.2 
AF176832 
NM_018557 
  
LRP-DIT 
LTK 
leukocyte receptor 
tyrosine kinase 
15q15.1-
q21.1 
D16105 
 
TYK1 
MAPK1 
mitogen-activated 
protein kinase 1 
22q11.2 
M84489 
PRKM2, 
PRKM1  
ERK, ERK2, 
p41mapk, MAPK2  
MAPK3 
mitogen-activated 
protein kinase 3 
16p11.2  
M84490 
PRKM3 
ERK1, p44mapk, 
p44erk1 
MAP2K1 
mitogen-activated 
protein kinase kinase 1 
15q22.1-
q22.33 
L11284 
PRKMK1 
MEK1, MAPKK1 
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MAP2K2 
mitogen-activated 
protein kinase kinase 2 
19p13.3 
L11285 
PRKMK2 
MEK2 
MET 
met proto-oncogene 
(hepatocyte growth 
factor receptor) 
7q31 
M35073 
  
HGFR, RCCP2 
mTOR 
mechanistic target of 
rapamycin 
(serine/threonine 
kinase) 
1p36 
L34075  
NM_004958 
FRAP, 
FRAP2, 
FRAP1 
RAFT1, RAPT1, 
FLJ44809 
NF1 
neurofibromin 1 
17q11.2 
NM_000267 
  
  
NOTCH1 
Notch homolog 1, 
translocation-associated 
(Drosophila) 
9q34.3 
AF308602 
NM_017617 
TAN1 
  
NRAS 
neuroblastoma RAS 
viral (v-ras) oncogene 
homolog 
1p13.2 
BC005219 
NM_002524     
 
 
NTRK1 
neurotrophic tyrosine 
kinase, receptor, type 1 
1q21-q22 
Y09028 
NM_002529 
  
TRK, TRKA, MTC 
NTRK2 
neurotrophic tyrosine 
kinase, receptor, type 2 
9q22.1 
AF410902 
  
TRKB 
NTRK3 
neurotrophic tyrosine 
kinase, receptor, type 3 
15q24-q25 
U05012 
 
TRKC 
PAK3 
p21 protein 
(Cdc42/Rac)-activated 
kinase 3 
Xq22.3 
AF068864 
NM_002578 
MRX30, 
MRX47 
hPAK3, bPAK 
PDGFRA 
platelet-derived growth 
factor receptor, alpha 
polypeptide 
4q12 
D50001 
NM_006206 
  
CD140a, PDGFR2 
PIK3CA 
phosphoinositide-3-
kinase, catalytic, alpha 
polypeptide 
3q26.3 
  NM_006218 
  
p110-alpha, 
MGC142161, PI3K, 
MGC142163 
PLK1 
polo-like kinase 1 
(Drosophila) 
16p 
NM_005030 
PLK 
  
PRKDC 
protein kinase, DNA-
activated, catalytic 
polypeptide 
8q11 
NM_001081640 
HYRC, 
HYRC1 
DNPK1, p350, 
DNAPK, XRCC7, 
DNA-PKcs 
PRKCG 
protein kinase C, 
gamma 
19q13.4 
M13977 
NM_002739 
PKCG, 
SCA14 
PKCC, MGC57564 
PTCH1 
patched homolog 1 
(Drosophila) 
9q22.1-q31 
AI494442 
NM_000264 
NBCCS, 
PTCH 
BCNS 
PTEN 
phosphatase and tensin 
homolog 
10q23 
U92436 
NM_000314   
BZS, 
MHAM 
MMAC1, TEP1, 
PTEN1 
PTPRD 
protein tyrosine 
phosphatase, receptor 
type, D 
9p24.1-p23 
X54133 
  
PTPD, HPTP 
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RB1 
retinoblastoma 1 
13q14.2 
M15400 
OSRC 
RB 
RHOA 
ras homolog gene 
family, member A 
3p21.3 
BC001360 
NM_001664 
ARH12, 
ARHA 
RhoA, Rho12, 
RHOH12 
SMAD2 
SMAD family member 
2 
18q21 
U65019 
NM_005901 
MADH2 
MADR2, JV18-1 
SMAD4 
SMAD family member 
4 
18q21.1 
U44378 
NM_005359 
MADH4 
 DPC4  
SLC38A3 
solute carrier family 38, 
member 3 
3p21.3 
U49082 
NM_006841 
 
G17, SN1   
 
SMG1 
SMG1 homolog, 
phosphatidylinositol 3-
kinase-related kinase 
(C. elegans) 
16p12.3 
AB061371 
NM_015092 
  
LIP, KIAA0421, 
ATX 
SMO 
smoothened homolog 
(Drosophila) 
7q32.1 
U84401 
NM_005631 
SMOH 
 
STK11 
serine/threonine kinase 
11 
19p13.3 
U63333 
NM_000455 
  
PJS, LKB1 
STK33 
serine/threonine kinase 
33 
11p15.3 
AJ303380 
NM_030906 
  
  
TGFB1 
transforming growth 
factor, beta 1 
19q13.1 
X02812 
TGFB, 
DPD1 
CED, TGFbeta 
TGFB2 
transforming growth 
factor, beta 2 
1q41 
M19154 
NM_003238 
  
  
TP53 
tumor protein p53 
17p13.1  
AF307851 
NM_000546 
  
p53, LFS1 
TSC1 
tuberous sclerosis 1 
9q34 
AF013168 
TSC 
KIAA0243, LAM, 
hamartin 
TSC2 
tuberous sclerosis 2 
16p13.3 
AB014460 
NM_000548 
TSC4 
tuberin, LAM 
Wnt 
wingless-type MMTV 
integration site family, 
member 1  
12q13 
X03072 
INT1 
  
ZMYND10 
zinc finger, MYND-
type containing 10 
3p21.3 
U70824 
NM_015896 
 
BLU 
 
 
 
 
 
 
 
10.3  Other molecular profiling analyses in tumor samples  
If enough material is available, other molecular profiling analyses including but not limited to 
the following will be performed: 
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1) Comparative genomic hybridization (CGH)  
2) FISH analysis of candidate genes 
3) Methylation analysis 
4) MicroRNAs 
5) Gene expression arrays 
6) Full tumor genome sequencing 
10.4 Non-invasive biomarkers studies (Only for patients enrolled at the NCI intramural 
program) 
Biomarkers, including prognostic and predictive factors, are widely studied in oncology and are 
important in anticancer drug development (112).  As mentioned above, recurrent somatic gene 
mutations, such as EGFR, KRAS, p53, and LKB-1, have been detected in lung cancers (113).  
Some are important prognostic or predictive factors for treatment (18).  With the emergence and 
progress of molecular targeted therapies, it is appealing to assess systematically the genetic 
background of lung cancer patients. Comprehensive evaluation of mutations, however, is often 
hampered by the small sample size of bioptic material or availability of cytologic material only.  
Also, repeat biopsy at relapse to study potential resistant mutations (e.g. EGFR T790M mutation) 
is technically challenging and potentially dangerous.  Detecting mutant tumor genes from 
peripheral blood circulation represents a potential alternative (114). Besides the detection of 
circulating tumor cells (115), a technique that still needs optimization, tumor DNA in the 
circulation is potentially a simpler and more attractive source of information (116). 
Techniques used nowadays for mutation detection, however, have several limitations.  
Traditional Sanger’s method has relatively low sensitivity and specificity, especially when the 
tumor cells are contaminated with normal cells.  Several real-time PCR based applications, such 
as scorpions-amplification refractory mutation system, are more sensitive (17, 18).  The real-time 
PCR based applications, however, need designed primers or probes and can only detect pre-
specified known mutations.  On the other hand, none of these techniques can quantify the 
presence of mutations, which can be important to evaluate the dynamics of tumor burden after 
treatment or evaluate gene copy number changes (e.g. MET).  
Invented initially for faster and more accurate genomic sequencing, next-generation sequencing 
(NGS) techniques, such as the Illumina genome analyzer, are applied to mutation discovery, 
DNA-protein interaction, mRNA expression, noncoding RNAs study, and metagenomics studies 
(113, 117).  Through high-throughput sequence analysis and high coverage of depth, NGS may 
overcome the disadvantages mentioned above. NGS has been applied to sequence the cancer and 
leukemia genomes(118).  NGS-based applications, RNA-seq and ChIP-seq, are superior to 
mRNA microarray and ChIP-on-chip technique, respectively, because they do not require prior 
knowledge of RNA and DNA sequences.  It has been reported that NGS can detect EGFR 
mutations in malignant pleural effusion specimens with low tumor content and can measure the 
proportion of DNA molecules carrying the mutation as well (119).  In summary, NGS could be 
an ideal platform to study genetic biomarkers of lung cancer in the circulation. 
In addition, urine samples are also ideal sources of biomarker researching.  Urine samples have 
been evaluated for diagnosis of bladder cancer (120, 121).  Giving that nucleic acids fragments 
can pass glomerulus and enter urine(122), it has been reported to be feasible to detect mutant 
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genes from urine in patients with non-genitourinary origin solid tumors(123).  Because 
microRNAs are potential important biomarkers of lung cancer(124, 125), are small in size (22-
26bp) to pass glomerulus, and are reported to be detectable in urine(126), it is interesting and 
reasonable to assess the role of urinary microRNA expression in lung cancer patients.  
10.4.1 Blood sample analyses. 
If possible, blood will be collected in one EDTA tube (5ml purple top) and one Sodium Heparin 
Tube (10ml green top) upon enrollment in the trial.  The samples will be stored at 4°C and sent 
to the following laboratory(s) for analyses: 
Dr. Udayan Guha 
Attn. Dr. Steven Lee 
National Cancer Institute 
Building 10, Room 8N258 
10 Center Drive 
Bethesda, MD 20892  
Phone:   301.402.0082 
The blood will be centrifuged at 820g for 10 minutes.  The plasma will be collected and stored in 
-80°C for further analyses that will include but are not limited to the following: 
Circulating DNA mutation detection. The buffy coat, in which white blood cells and 
circulating tumor cells are located, will be isolated for possible circulating tumor cells analysis.  
DNA in the buffy coat will be extracted within 24 hours of blood sampling if no more analysis of 
circulating cells will be conducted.  
DNA will be extracted from 1 ml of plasma.  A pilot study, which will enroll around 10 patients, 
will be conducted to evaluate the feasibility of detecting mutant genes in circulating tumor DNA. 
In the pilot study, mutant genes confirmed in tumor samples will be analyzed in the plasma by an 
Ilumina Genome Analyzer.  If mutant genes are detected, the amount of mutant gene will be 
represented by the ratio of mutant gene over wild-type gene, adjusted by the copy number of a 
reference gene, such as LINE-1 or hTERT gene.  
After the pilot study and adjustment of experiments’ conditions, circulating mutant genes will be 
measured regularly and their levels will be correlated with clinical treatment outcome.  Screening 
of new mutations will be conducted if disease progression develops and its result will be 
compared with the result of tumor re-biopsy, if any.  
10.4.2 Urine sample analyses. 
If possible, 5 ml of urine will be collected in a yellow top urine tube upon enrollment in the trial. 
The container will be stored at 4°C and sent to the following laboratory(s) for analyses: 
Dr. Udayan Guha 
Attn. Dr. Steven Lee 
National Cancer Institute 
Building 10, Room 8N258 
10 Center Drive 
Bethesda, MD 20892  
Phone:   301.402.0082 
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The urine will be used for further analyses that will include but are not limited to the following: 
Urine micro RNA detection. Urine will be stored at 4°C and processed within 4 hours of 
collection.  Urine will be mixed 1:1 with lysis buffer and frozen at -80°C for later DNA and 
RNA extraction.  Urine RNA will be extracted.  A panel of microRNA will be analyzed by real-
time PCR, including let7a, mir21, mir29b, mir34a, mir34b, mir34c, and mir155. U6 snRNA will 
be measured as internal control. The association of microRNA results with patients' clinical 
characteristics and treatment outcomes will be examined.  
10.4.3 Genomic Analysis 
Whole exome, transcriptome, and whole genome (only on a subset of patients) sequencing will 
be performed to identify somatic changes in tumor tissue if tissue is available after the other 
studies mentioned above are performed. Comparative genomic hybridization (CGH) analyses 
will be performed to interrogate the copy number gains and losses. DNA and RNA will be 
extracted from tumor samples and germ line DNA and RNA will be extracted from peripheral 
blood mononuclear cells from whole blood. 
DNA isolated from blood will be analyzed to identify the somatic and germline variants. 
Transcriptome sequencing will reveal expression at the RNA-level. The genomic analyses will 
be performed in ATC genome core facility, and in the laboratories of Drs. Meltzer, Raffeld and 
Guha. 
10.4.3.1.1 DNA Sequencing 
Whole-exome multiregion spatial sequencing of DNA will be performed using a next-generation 
sequencing device and somatic mutations identified will be validated and verified using Sanger 
sequencing (NCI Frederick sequencing facility). Whole genome sequencing will be performed 
on a subset of samples based on the results of whole-exome and transcriptome sequencing.  
10.4.3.1.2 RNA Sequencing 
Transcriptome profiling will be performed using RNA-Seq approach to study transcriptome 
complexity, and for identification of genes, structure of transcripts, alternative splicing, non-
coding RNAs, and new transcription units (NCI Frederick sequencing facility). RNA-seq will 
also reveal expression of individual genes at the transcript-level. This will be correlated with 
quantitative protein expression by mass spectrometry. 
10.5 Samples for Genetic/Genomic Analysis 
10.5.1 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
Tissue and blood samples will be coded. DNA, RNA and protein isolated from these tissues and 
cell lines and xenografts generated will all be similarly coded. Only personnel involved in this 
study will have access to both the code and the name of the patient. To help protect privacy, a 
Certificate of Confidentiality has been obtained from the National Institutes of Health. To 
facilitate genetic research, and for the purpose of publication of research work, data from 
genomic and proteomic studies may be deposited in appropriate public databases. Coded data 
will be deposited in a manner that the patient’s identity cannot be traced.  
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10.5.2 Management of Results 
Participants will be given the choice of whether or not they would like the Durable Power of 
Attorney (DPA) to receive notification if a gene variant known to cause or contribute to disease 
is identified.  In cases where in the opinion of the principal investigator there is a finding of 
urgent importance to the health of the family members of the participants, the investigator will 
consult with an interdisciplinary group of geneticists, clinicians, and the NIH ethics board to 
determine whether the result needs to be divulged to immediate family members and the DPA 
will be notified by telephone or by mail.  Attempts will be made to verify the results in a CLIA 
certified lab prior to notification.  Results may become available for a period of up to two years.  
10.5.3 Genetic Counseling 
Genetic counseling will be provided to the patient by genetic counseling services of the Clinical 
Center upon consent to the protocol and during one of the routine follow up visits to the clinical 
center. In the event a result of urgent importance to immediate family members has to be 
divulged, family members will be offered genetic counseling.  
11 DATA COLLECTION AND EVALUATION 
11.1 Data Collection 
The PI will be responsible for overseeing entry of data into in-house password protected 
electronic systems, C3D and LabMatrix, and ensuring data accuracy, consistency and timeliness. 
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts. All data obtained during the conduct of the 
protocol will be kept in secure network drives or in approved alternative sites that comply with 
NIH security standards. Primary and final analyzed data will have identifiers so that research 
data can be attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention through 30 days after the last study intervention.  
Beyond 30 days after the last intervention, only adverse events which are serious and related to 
the study intervention need to be recorded. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schecule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 8.2.1.  
11.2 Genomic Data Sharing Plan  
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
 
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12 STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. The study calendar does not apply to individuals enrolled 
for EGFR germline mutation testing only; please refer to Section 5.6 for testing and follow-up of 
these individuals. 
 
 
 
 
Screening – Part 1 
Molecular Profiling 
and Correlative 
Studies 
 
Screening – Part 2 
Treatment Arm 
Eligibility (see 
Section 3.3) 
 
 
Treatment Cycles (see Section 5.3; clinic visits 
may be extended to every 6 weeks for the 
Erlotinib, AZD6244, and Lapatinib arms; every 
8 weeks for the MK-2206 arm; and every 12 
weeks for the Sunitinib arm) 
 
Off 
treatment 
Biopsy for 
molecular 
profiling11 
 X 
 
Upon disease progression per section 5 
(optional) 
 
Targeted 
therapies9 
  
 
See section 5 for details regarding agent 
administration and scheduling 
 
Informed 
consent 
 X 
  
N/A 
Demographics 
 X 
 
NOS arm data10 
  
X 
 
 
Medical history9   
X 
Every clinic visit 
X 
Concurrent  
Meds9 
  
X 
Every clinic visit 
X 
NIH Advance 
Directives 
Form14 
 
X 
 
 
 
Physical exam9 
   
X 
Every clinic visit 
X 
Vital signs9 
  
X 
Every clinic visit 
X 
Height9 
  
X 
N/A 
 
Weight9 
  
X 
Every clinic visit 
X 
Performance 
status9 
  
 
X 
Every clinic visit 
 
X 
CBC w/diff, plts9   
X 
Prior to each clinic visit  
X 
Serum 
chemistry1, 9 
  
 
X 
Prior to each clinic visit  
 
X 
PT, aPTT9 
  
X 
As clinically indicated 
X 
Urinalysis9 
  
X 
X 
EKG9 
  
 
 
X 
 
X 
BP3, 9 
  
 
Weekly during cycle 1  
 
ECHO/MUGA4, 5, 9 
  
X  
Every other treatment cycle    
 
Adverse event 
evaluation9 
  
 
 
X-----------------------------------------------------X X 
Tumor 
measurements9 
 
 
X 
Approximately every 6, 8, or 12 weeks, as 
defined for each treatment arm. See Section 
5.8.2 for details. Documentation (radiologic) 
must be provided for patients removed from 
study arm for progressive disease. 
X 
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Screening – Part 1 
Molecular Profiling 
and Correlative 
Studies 
 
Screening – Part 2 
Treatment Arm 
Eligibility (see 
Section 3.3) 
 
 
Treatment Cycles (see Section 5.3; clinic visits 
may be extended to every 6 weeks for the 
Erlotinib, AZD6244, and Lapatinib arms; every 
8 weeks for the MK-2206 arm; and every 12 
weeks for the Sunitinib arm) 
 
Off 
treatment 
Radiologic 
evaluation9 
 
 
X 
Approximately every 6, 8, or 12 weeks, as 
defined for each treatment arm. See Section 
5.8.2 for details. 
X 
B-HCG2, 9 
  
X 
As clinically indicated 
HgbA1c 6, 9 
  
 
X-------------------------------------------------------------X 
Correlative 
studies7, 8, 9, 12 
 X 
 
Upon disease progression if repeat biopsy is performed 
EGFR germline 
mutation 
testing13 
 
X 
 
 
 
 
1:Sodium, potassium, chloride, CO2, BUN, creatinine, glucose, AST, ALT, alkaline phosphatase, bilirubin, albumin, total 
protein, LDH, calcium, phosphorous and magnesium. 
2:Serum pregnancy test (women of childbearing potential). 
3: Required only for patients enrolled on a Sunitinib treatment arm, per section 6.2.1. 
4: Required only for patients enrolled on a Lapatinib treatment arm, per section 6.1.5. 
5: Required for patients enrolled on a Sunitinib treatment arm who have known cardiac dysfunction at study entry and/or 
clinically observed adverse cardiac events. 
6:  For patients enrolled on the MK-2206 arm, who require treatment of hyperglycemia per section 6.1.2, HgbA1c 
monitoring should be performed with each cycle of MK-2206 therapy 
7:  1 5ml EDTA tube (purple top) and 1 urine sample collected in a (yellow top) urine tube. Page Betsy Morrow 10063 for 
pick up. 
8:  1 10ml Sodium Heparin Tube (green top). Call Zied Abdullaev for pick up at 301 451-2711. 
9:  N/A for patients assigned to the NOS arm. 
10:  Required only for the patients assigned to the NOS arm. 
11:  Including any other procedures necessary to do the biopsy, as clinically indicated. 
12:  Correlative Studies:  See Section 9 for details. 
13:  Selected patients only (see Section 5.6). Patient must meet eligibility requirements for EGFR germline mutation 
testing and have signed a separate consent form. 
14: As indicated in section 16.3, all subjects ≥ age 18 will be offered the opportunity to complete an NIH advance 
directives form.  This should be done preferably at baseline but can be done at any time during the study as long as the 
capacity to do so is retained.  The completion of the form is strongly recommended, but is not required. 
 
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13 MEASUREMENT OF EFFECT 
13.1 Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every 6 +/- 1 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained within 4 to 6 weeks 
following initial documentation of objective response. 
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. 
13.1.1 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.  
13.1.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm 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 not be considered 
measurable.   
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 
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effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be 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.  
13.1.3 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 
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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 
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 alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
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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:  
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• 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. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  In 
addition, the FDG-PET may not be used to upgrade a response to a CR if the patient is 
actively being maintained on MK-2206, since the AKT inhibitor blocks intracellular 
glucose transport and may cause a negative FDG-PET result as an artifact, due to its 
pharmacodynamic target effect. 
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. 
13.1.4 Response Criteria 
13.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum of diameters 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
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absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study 
13.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  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). 
13.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
        For Patients with Measurable Disease (i.e., Target Disease) 
 
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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.”  Every effort should be 
made to document the objective progression even after discontinuation of 
treatment. 
 
 
        For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
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13.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
13.1.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
14 DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for adverse event reporting can be found in 
Section 7.2 (Adverse Events: List and Reporting Requirements). 
14.1 Data Reporting 
14.1.1 Method 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31.  Instructions for submitting data using the 
CDUS can be found on the CTEP web site (http://ctep.cancer.gov/reporting/cdus.html). 
14.1.2 Responsibility for Data Submission 
Study participants are responsible for submitting CDUS data and/or data forms to the 
Coordinating Center quarterly at least 2 weeks before CTEP’s due date to allow time for 
Coordinating Center compilation, Principal Investigator review, and timely submission to CTEP 
(see Section 14.1.1).  The Coordinating Center is responsible for compiling and submitting 
CDUS data to CTEP for all participants and for providing the data to the Principal Investigator 
for review. 
14.2 CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix I. 
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The Principal Investigator/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports received from CTEP to all participating institutions for submission to 
their individual IRBs for action as required. 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
14.3 Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, Agent-CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as a “Collaborator(s)”) and the NCI 
Division of Cancer Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in 
addition to the provisions in the “Intellectual Property Option to Collaborator” 
 (http://ctep.cancer.gov/industryCollaborations2/default.htm) contained within the terms of 
award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study.  Collaborator(s) data 
for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such 
by the investigators.  The protocol documents for studies utilizing investigational Agents contain 
confidential information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member participating 
on the study, the individual should sign a confidentiality agreement.  A suitable model agreement 
can be downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as “Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
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3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order.  Additionally, all Clinical 
Data and Results and Raw Data will be collected, used, and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set forth 
in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-Cooperative 
Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior 
to submission for publication.  Collaborator(s) will have 30 days from the date of receipt for 
review.  Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in 
addition to Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must 
be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to presentation at 
the meeting or publication in the proceedings.  Press releases and other media presentations must 
also be forwarded to CTEP prior to release.  Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
Jan M. Casadei, Ph.D.,  
Chief, Regulatory Affairs Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis, NCI 
9609 Medical Center Drive 
Room 5-W532, MSC 9740 
Bethesda, MD 20892-9740 [if US Postal Service] 
Rockville, MD 20850 [if non-USPS/private carrier] 
Tel.    240-276-6125 
E-mail:  casadeij@mail.nih.gov 
E-mail:  ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
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15 STATISTICAL CONSIDERATIONS 
15.1 Study Design/Endpoints 
The primary objectives of this study are to determine the feasibility and efficacy of the use of 
molecular profile directed therapies in the treatment of advanced thoracic malignancies. The 
feasibility rate for the trial will be evaluated by determining the percentage of enrolled patients 
with a successful molecular profile determined.  Efficacy will be determined by assessing if 
patients who have treatment assigned on the basis of their molecular profiling results will exhibit 
reasonable response rates to the drug selected for their particular profile.  
Patients with NSCLC, SCLC, and thymic malignancies will be eligible for enrollment and each 
will be considered a separate cohort. In addition, on the basis of the molecular profiling results, 
one of 5 specific treatments could be assigned to each patient. The particular treatment 
assignments will be made according to a cascading schema as shown. If no profile of one of the 
5 types listed is identified as being appropriate for a given patient, patients will be followed and 
treated in a separate ‘other’ (NOS) category. 
With 3 disease types and 5 possible specific treatments for each, there are 15 possible treatment 
arms which will be under active consideration. For each of these 15, the study will be conducted 
as an optimal two-stage phase II trial (Simon R, Controlled Clinical Trials 10:1-10, 1989). 
In all but the arm for patients who have NSCLC and an EGFR mutation, the trial will be 
conducted in order to rule out an unacceptably low 10% clinical response rate (PR+CR; p0=0.10)  
in favor of a modestly high response rate of 40% (p1=0.40). For those 14 arms, with alpha=0.05 
(probability of accepting a poor treatment=0.05) and beta = 0.10 (probability of rejecting a good 
treatment=0.10), the study will initially enroll 9 evaluable patients in each stratum and if 0 or 1 
of the 9 have a clinical response, then no further patients will be accrued. If 2 or more of the first 
9 have a response, then accrual would continue until a total of 20 patients have enrolled in that 
stratum. If there are 2-4 responses in 20 patients, this would be an uninterestingly low response 
rate in that stratum, while if there were 5 or more responses in 20 patients, then this would be 
sufficiently interesting to warrant further study in later trials. Under the null hypothesis (10% 
response rate), the probability of early termination is 77% for a given stratum. 
In the arm for patients who have NSCLC and an EGFR mutation, the trial will be conducted in 
order to rule out an unacceptably low 30% clinical response rate (PR+CR; p0=0.30) in favor of a 
modestly high response rate of 60% (p1=0.60). The target is higher for these patients since a 
higher response rate is known to be possible for these patients. For that one arm, with alpha=0.05 
(probability of accepting a poor treatment=0.05) and beta = 0.10 (probability of rejecting a good 
treatment=0.10), the study will initially enroll 10 evaluable patients in each stratum and if 0 to 3 
of the 10 have a clinical response, then no further patients will be accrued. If 4 or more of the 
first 10 have a response, then accrual would continue until a total of 28 patients have enrolled in 
that stratum. Under the null hypothesis (30% response rate), the probability of early termination 
is 65% for patients in this stratum. 
As feasibility is an important endpoint as well, the trial will include an early stopping rule for 
accrual to specific arms which are not enrolling adequate numbers of patients. After 18 months 
from the date the first patient enrolls on the trial in any arm, if there are arms with no more than a 
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single patient, then further accrual to that arm will end. This will prevent continued accrual to 
arms which are very unlikely to be able to treat sufficient patients for evaluating the first stage 
(e.g., 9 or 10 patients) within 5 years. 
15.2 Sample Size/Accrual Rate 
With a maximum of 20 patients per stratum, up to 300 evaluable patients may be treated in 
specific arms. All patients in the ‘other’ (NOS) stratum will be evaluated and have their data 
analyzed by disease and type of treatment to the extent possible. As they are considered entirely 
exploratory, no specific targets for accrual will be used for the patients in the ‘other’ (NOS) 
stratum. For the secondary objective of determining the frequency of EGFR germline mutations 
in families with high susceptibility to lung cancer, we plan to enroll 15 families over a period of 
a year; however, specific accrual targets are not provided due to the exploratory nature of this 
endpoint. 
In order to enroll up to 300 patients in the specific arms on the basis of molecular profiling 
results, it is anticipated that based on the rates of mutations that occur in the genes used for 
treatment assignments, approximately 600 patients may need to be enrolled onto the trial.   It is 
anticipated that up to 10 patients per month may be enrolled onto this trial from all participating 
sites and in all diseases combined, and thus approximately five years may be required to enroll 
up to 600 patients. Far fewer patients may be enrolled if the treatments fail to allow accrual to 
the second stage of the trial or if some arms close to accrual due to feasibility issues. 
15.3 Stratification Factors 
N/A  
15.4 Analysis of Secondary Endpoints 
In order to accomplish the secondary objective of identifying molecular profiles in patients with 
NSCLC, SCLC or thymic malignancies and characterize their natural histories, clinical course 
and response to treatment, we will follow all patients that undergo molecular profiling from the 
time that they are enrolled in the trial until the time of death.  Demographic information such as 
age, gender and race will be tabulated.  The frequencies of oncogenic mutations will be assessed. 
The exact binomial two-sided 95% confidence interval for each mutation rate will be reported. 
Kaplan-Meier curves for progression free survival, duration of response, and overall survival will 
be calculated from the patients treated in the different treatment arms of this study (erlotinib, 
lapatinib, sunitinib, AZD6244, MK2206, or NOS). The results of this analysis may be compared 
in an informal manner to any similarly defined curves available from other published studies in 
comparable patients with the same disease. Expression levels of various proteins from pre- and 
post-treatment samples will be compared using an appropriate nonparametric test and pre-post 
differences between responders and non-responders using a Wilcoxon rank sum test. These latter 
evaluations will be considered exploratory and the resulting p-values will be presented as being 
exploratory and without adjustment for multiple comparisons. 
For the secondary objective of determining the frequency of EGFR germline mutations in 
families with high susceptibility to lung cancer, the analyses will be performed in an exploratory 
manner. Hence, statistical power calculations have not been provided. 
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15.5 Reporting and Exclusions 
15.5.1 Evaluation of toxicity 
All patients will be evaluable for toxicity from the time of the biopsy for molecular profiling is 
performed. Patients who are subsequently enrolled in the NOS arm will not be evaluable for 
toxicity.  
15.5.2 Evaluation of response 
All patients included in one of the experimental arms of the study must be assessed for response 
to treatment, even if there are major protocol treatment deviations.  Each patient will be assigned 
one of the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
All of the patients who met the eligibility criteria for a particular treatment arm (with the 
exception of those who received no study medication) should be included in the main analysis of 
the response rate.  Patients in response categories 5-9 should be considered to have a treatment 
failure (disease progression). Thus, an incorrect treatment schedule or drug administration does 
not result in exclusion from the analysis of the response rate.  Precise definitions for categories 
5-9 will be protocol specific.  
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol deviations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided.  
16 HUMAN SUBJECTS PROTECTIONS 
16.1 Rationale for Subject Selection 
This study will be open to all individuals with advanced thoracic malignancies (lung cancer and 
thymic malignancies) regardless of gender, ethnicity, or race provided that the aforementioned 
inclusion and exclusion criteria are met.  For safety reasons, only pregnant women and children 
are excluded from this study.  This study will be recruited through internal referral, our local 
physician referral base, and through various cancer information hotlines (i.e., Clinical Studies 
Support Center, 1-800-4Cancer).  This is a trial designed to evaluate the efficacy of different 
targeted therapies in patients with advanced thoracic malignancies.  Patients should realize that 
we are hopeful that they may gain benefit from this study, but there is no objective evidence to 
support our optimism at this time.  Subjects from both genders and all racial /ethnic groups are 
eligible for this study if they meet the eligibility criteria outlined in Section 3.  To date, there is 
no information that suggests that differences in drug metabolism or disease response would be 
expected in one ethnic group compared to another.  Efforts will be made to extend accrual to 
each representative population, but in this preliminary study, a balance must be struck between 
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patient safety considerations and limitations on the number of individuals exposed to potentially 
toxic and/or ineffective treatments on the one hand and the need to explore racial/ethnic aspects 
of clinical research on the other hand.  If differences in outcome that correlate to ethnic identity 
are noted, accrual may be expanded or a follow-up study may be written to investigate those 
differences more fully. 
16.2 Justification for Exclusions 
Due to lack of knowledge of the effects of most or all of the targeted agents included in this trial 
on the fetus or on infants, as well as the possibility of teratogenic effects, pregnant and nursing 
women will be excluded from this trial.  Patients with unstable or serious medical conditions 
(ongoing or active infection, symptomatic congestive heart failure (AHA Class II or worse), 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements) are excluded due to the possibility that the agents 
used may worsen their condition and the likelihood that the underlying condition may obscure 
the attribution of adverse events with respect to protocol therapy. 
16.2.1 Participation of Children   
Patients under the age of 18 will be excluded from study due to the low occurrence of these 
oncologic histologies in the pediatric population.  In addition, the risk of exposure to an 
investigational agent without proven benefit in the targeted histologies supports excluding 
children until additional safety and efficacy data is available.  Patients under the age of 18 will be 
excluded from germline mutation testing because of the infrequency of lung cancer in this age 
group and because the results would not influence the medical management of individuals under 
the age of 18.   
16.3 Participation of Subjects Unable to Give Consent 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 16.4), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study.  Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate.  For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for 
appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed. 
16.4 Evaluation of Benefits and Risks/Discomforts 
The potential benefit to a patient who enters study is a reduction in the bulk of his/her tumor, 
which may or may not have a favorable impact on symptoms and/or survival.  Potential risks 
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include the possible occurrence of any of a range of side effects that are listed in the 
pharmaceutical section and the consent document.  The procedure for protecting against or 
minimizing risks will be to medically evaluate patients on a regular basis as described earlier. 
As of 3/22/2016, the treatment arms of this study have been closed.  The study remains open 
under NIH Intramural IRB for the molecular profiling arm only.  Participating in the molecular 
profiling arm is associated with risks that may accompany the biopsy required for genetic testing.  
These risks include bleeding or infection at the biopsy site as well as potential radiation exposure 
if the biopsy is done with CT guidance.  Additionally, participation comes with the risk of 
discovering new genetic results that may have implications on the participant and/or family 
members.  The benefits of participation include gaining additional genetic knowledge which may 
provide guidance in cancer treatment options provided outside of this study.  Pre and post testing 
genetic counseling will be provided as these results are disclosed to provide assistance in the 
handling of these results. 
16.5 Risk/Benefit Analysis 
As of 3/22/2016, the treatment arms of this study have been closed, but study remains open 
under NIH Intramural IRB for molecular profiling arm only.  For adults in the molecular 
profiling arm, including those who become unable to consent, there is more than minimial risk in 
participation associated with the biopsy with the possibility of direct benefit by way of return of 
genetic findings that may provide additional treatment options outside of this study. 
16.6 Consent and Assent Process and Documentation 
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
treatment plan, research objectives and follow-up of this trial.  The patient will be provided an 
IRB-approved consent for review and signature and his/her questions will be answered.  After a 
decision is made to enroll into the study, a signature will be obtained from the patient at a 
subsequent visit.  The original of the signed informed consent will be placed in the patient's 
medical record and a copy will be held in the research record. 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 
The proband as well as all family members undergoing germline genetic testing will sign a 
separate informed consent for germline mutation testing. For deceased family members of the 
proband with history of lung cancer, who have available tissue, consent will be obtained from the 
next of kin. 
16.6.1 Telephone Consent (for amendments only): 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent.  
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
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The informed consent process will be documented in the medical record. 
16.7 DATA AND SAFETY MONITORING PLAN 
Any new significant finding that may affect the patient’s willingness to continue in the study will 
be shared with patients.  Data will be monitored regularly by the principal investigator in order to 
identify significant toxicity trends.  Confidentiality will be maintained as much as possible, 
consistent with applicable regulations.  Names of participants or identifying material will not be 
released without patient permission, except when such release is required by law.  No patient’s 
name or identifying information will be released in any publication or presentation.  Records are 
maintained according to current legal requirements and are made available for review according 
to the requirements of the Food and Drug Administration (FDA) or other authorized user, only 
under guidelines established by the Federal Privacy Act. 
This study will also be monitored by the National Cancer Institute Safety Monitoring Committee 
(SMC).   The Coordinating Center Principal Investigator will obtain the required data from all 
participating sites and will report to the SMC annually, or as otherwise directed by the SMC.
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18 Appendices  Appendix A: Study Agent Background Information 
 
This appendix contains background information about the study agents.  This was provided by 
CTEP as a summary of relevant data for each study agent.  More detailed information about each 
agent can be found in their respective investigational brochure. 
18.1.1 CTEP supplied agents 
18.1.1.1 MK-2206 
The PI3K/AKT pathway is downstream of the common growth factor tyrosine kinase receptors 
(RTK), including EGFR, HER2, IGFR, etc., and is a likely driver of tumor progression in most 
carcinomas (127-129). AKT protein kinase is activated in a substantial proportion of human solid 
tumors (breast, endometrial, ovarian, prostate, pancreatic, colon, gastric, and non-small cell lung 
cancer [NSCLC]).  Upregulation of AKT can be caused by direct amplification/mutation of 
AKT, or by overexpression of RTKs, PI3K and RAS, and/or by inactivation of the tumor 
suppressor PTEN.  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.   
The rationale for the use of an AKT inhibitor in treatment of various malignancies is included in 
the following references (3, 127-159).  MK-2206 is the first allosteric inhibitor of AKT to enter 
clinical development (3).  MK-2206 demonstrated AKT inhibition and antiproliferative activity 
as single agent and in combination with other agents in multiple human cancer cell lines, such as 
breast, ovarian, lung, and prostate.  MK-2006 synergized antitumor effects of docetaxel, 
erlotinib, and carboplatin in vivo in various human tumor xenograft models. 
Mechanism of Action 
MK-2206 is a selective allosteric inhibitor of AKT (3). MK-2206 does not bind to the active site 
of AKT, and consequently does not compete with either ATP or peptide substrate for binding to 
AKT.  It is equally potent against the two human AKT isoforms, AKT1 and AKT2, and ~5-fold 
less potent against AKT3.   
Nonclinical Studies 
In Vitro Activity Studies  
In vitro single-agent activity of MK-2206 
In an in vitro kinase assay with GSK3 alpha peptide as substrate, MK-2206 strongly inhibited 
kinase activity of the three human isoforms of AKT, AKT1, 2, and 3, with 50% inhibitory 
concentration (IC50) values of 8, 12, and 65 nM, respectively.  MK-2206 exhibited no inhibition 
(IC50>50 micromol/L (mcM) against the (pleckstrin-homology domain)-deletion mutants of 
AKT, indicating that this domain is essential for binding MK-2206 to AKT.  Apart from AKT, 
MK-2206 was tested at a single concentration of 1 mcM against a panel of ~250 proteins 
including kinases without demonstrating significant (≥50%) inhibition against any kinase. 
The antiproliferative potency of MK-2206 was evaluated against a panel of tumor cell lines using 
in vitro proliferation and viability assays.  Among 52 cell lines, 18 cell lines were highly 
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sensitive (IC50<1 mcM), 7 were moderately sensitive (IC50=1-5 mcM), and 27 cell lines were 
insensitive (IC50>5 mcM) to MK-2206.  Highly sensitive cell lines included breast, ovarian, 
prostate, NSCLC, small cell lung cancer (SCLC), gastric, and endometrial cancer.  At least one 
of the following genetic defects was represented in the majority of sensitive cell lines:  PTEN 
mutation, PI3KCA mutation, AKT amplification, or genomic amplification of HER2 or MET.  
Nine of 27 cell lines that were insensitive to MK-2206 had either PTEN or PI3KCA mutation, or 
were deficient in PTEN protein. Among eight cell lines carrying RAS or BRAF activating 
mutation, six were insensitive to MK-2206.  
MK-2206 activity in combination with other agents 
In a proliferation/viability assay, various degrees of synergism between MK-2206 and lapatinib 
(a dual EGFR/HER2 inhibitor) were observed in eight breast cancer cell lines.   MK-2206 and 
docetaxel demonstrated additive to synergistic antiproliferative activity against nine breast-
cancer cell lines, however, the effects were dependent on agent sequence.  Enhancement of 
antitumor activity occurred only when cells were treated first with docetaxel and then exposed to 
MK-2206.  In contrast, co-administration of the two agents resulted in antagonism.  Combination 
of MK-2206 with erlotinib produced various degrees of synergism in nine NSCLC cell lines, 
including A431 epidermoid cells overexpressing EGFR. 
MK-2206 synergized antitumor activity of carboplatin, gemcitabine, doxorubicin, camptothecin, 
or 5-FU in ovarian, prostate and NSCLC cell lines.  Antitumor activity of MK-2206/carboplatin, 
demonstrated in the ovarian cell line A2780, was accompanied with enhanced apoptosis 
(cleavage of caspases 3 and 7).  However, the effect was dependent on the sequence of agent 
administration, as it occurred only when cells were exposed to carboplatin before or 
simultaneously with MK-2206.  Enhancement of apoptosis did not occur when MK-2206 
preceded carboplatin.  
In Vivo Activity Studies 
MK-2206 monotherapy administered as a single dose (10-240 mg/kg) to mice bearing human 
ovarian tumor (A2780) potently inhibited phosphorylation of AKT1/2 in blood as well as in 
tumor tissue.  After a single dose of 30, 120, or 240 mg/kg of MK-2206, ≥80% inhibition of 
AKT1/2 was achieved in peripheral blood; inhibition persisted at this level for 6 and 24 hours at 
the 120- and 240-mg/kg dose, respectively.  Pronounced inhibition (70-90%) of phosphorylation 
of AKT1/2 (pAKT1/2), lasting for at least 24 hours, was detected also in tumor tissue following 
the single 120- or 240- mg/kg dose.  MK-2206 combinations with docetaxel, carboplatin, or 
erlotinib exhibited significantly more potent antitumor activity than each agent in monotherapy 
settings.  For example, a combination of MK-2206 and docetaxel, administered for 4 weeks as 
one weekly intravenous (IV) dose of docetaxel (30 mg/kg) followed 24 hours later by MK-2206 
(240 or 480 mg/kg) given orally (PO) once a week (QW), produced strong antitumor responses 
in the A2780 ovarian-cancer xenograft mouse model.  MK-2206 monotherapy was ineffective at 
all doses.  Although the combination was significantly more effective than docetaxel 
monotherapy, responses did not endure beyond the treatment period.  Tumor regression was also 
observed in PC-3 prostate xenograft model following sequential treatment with docetaxel and 
MK-2206 (24 hours later).  MK-2206 (120 mg/kg) was given three times per week (days 1, 3, 5) 
and docetaxel (5 mg/kg) once weekly on day 0.  Inhibition of tumor growth was also enhanced 
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when MK-2206 was combined with carboplatin and erlotinib in the NSCLC H460 and H292 
xenograft models, respectively.  Overall, the agents’ combinations were well-tolerated at the 
effective dose levels, although transient 10-20%-weight loss was observed in some animals. 
Pharmacokinetics  
Pharmacokinetic (PK) parameters of MK-2206 in the rat, dog, and monkey are summarized in 
Table 18.  Across the species, MK-2206 showed moderate plasma clearance (Cl) and high 
volume of distribution at steady state (Vdss) and elimination half-life (t1/2) ranging from 4 hours 
in rats to >12 hours in dogs and monkeys.   
Table 18.  Summary of nonclinical pharmacokinetics for MK-2206 
IV Route 
PO Route 
Species 
Dose 
(mpk) 
Cl 
(mL/min/k
g) 
Vdss 
(L/kg
) 
t1/2 
(h) 
Dose 
(mpk) 
AUC 
(mcM∙h
) 
Cmax 
(mcM
) 
tma
x 
(h) 
F 
(%) 
Rat  
2 
27.6 
9 
4.2 
10 
2.1 
0.29 
5 
20 
 
 
 
 
 
100 
35.2 
2.76 
2.7 
35 
Dog  
0.5 
7.7 
8 
12.
5 
2 
8.89 
0.38 
4 
83 
Rhesus  0.5 
10.8 
11 
14 
 
Cl: clearance; Vdss: volume of distribution at steady state;  t1/2: elimination half-life; 
AUC: the area under the time-concentration curve; Cmax:  maximum drug 
concentration in plasma; tmax: time needed to achieve Cmax; F: oral availability; 
mcM: micromol/L; mpk: mg per kg; 
Vehicle: intravenous (IV): DMSO, oral route (PO): 0.5% methylcellulose (10 mpk), 
30% Captisol (100 mpk), or 1% methylcellulose (3 mpk)  
MK-2206 was significantly bound to plasma proteins (ranged from 96% to 88% in 
mice>rats>dogs>monkeys>humans) with moderate Cl in rats, but relatively low Cl in dogs and 
monkeys.   
The oral availability of MK-2206 was acceptable in rats (20%-35%) and better in dogs (83%).  
Plasma Cl in rats occurred primarily by direct glucuronidation with <3% of MK-2206 excreted in 
feces.  In dogs, elimination occurred via multiple metabolic pathways including oxidation 
followed by glucuronidation, direct glucuronidation, and formation of a carbamoyl glucuronide.  
Relative to rats, a higher fraction (30%) of parent compound MK-2206 was excreted (urine, bile, 
and feces) in dogs.  Significant intestinal secretion was observed in dogs.  No metabolites of 
MK-2206 with biologic activity were noted.   
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MK-2206 was also metabolized by oxidation in human liver microsomes, primarily via the 3A4 
isoenzyme of the P450 cytochrome (CYP) enzyme complex.  MK-2206 was neither a potent 
inhibitor nor inducer of human CYPs.  Transport experiments in the P-glycoprotein (P-gp)-
transfected cell lines (L-MDR1) suggested that MK-2206 could be a P-gp substrate.  In addition, 
MK-2206 demonstrated weak inhibition of vectorial transport of digoxin in L-MDR1 cells (IC50 
of 13.4 mcM).  
Toxicology 
In the 10-day tolerability studies, dose-limiting toxicities (DLTs) were observed at the dose of 
≥200 mg/kg/day and ≥15 mg/kg/day in rats and dogs, respectively.  In a 4-week safety study in 
dogs, MK-2206 was administered at 2.5, 5, or 10 mg/kg PO every-other-day (QOD) followed by 
a 2-week recovery period.  The 10-mg/kg dose was poorly tolerated as manifested by severe 
body-weight loss and other physical and histomorphological signs of toxicity, which required 
cessation of dosing by the end of the second week of treatment.  The 5-mg/kg dose was tolerated 
and although treatment-related toxicities occurred, they were transient.  As no significant 
toxicities were observed in dogs at the 2.5-mg/kg dose, this dose was defined as NOAEL (no 
observed adverse effect level).  Exposure at this level characterized by the maximum plasma 
concentration (Cmax) and the area under the time-concentration curve (AUC0-48h) corresponded to 
0.37 mcM and 8.52 mcM*hr, respectively.  A potential safety concern associated with MK-2206 
therapy is prolongation of the QT-corrected (QTc) interval, which seemed to be dose-dependent.  
While QTc-prolongation was persistent in dogs at the 10-mg/kg dose, it declined and returned to 
baseline between 24 to 72 hours post-dosing at 5 and 2.5 mg/kg.  No cardiovascular changes 
were observed at the 1-mg/kg dose of MK-2206 (Cmax of 0.092 mcM and AUC0-24h of 1.6 mcM) 
within 48 hours following dosing in dogs.   
A tissue distribution study demonstrated that [14C]MK-2206 was widely distributed in Sprague 
Dawley (albino) and Long Evans (pigmented) rats except for the central nervous system.  The 
majority of the radioactivity went into the muscle, liver and skin shortly after dosing.  In Sprague 
Dawley and Long Evans rats, the radioactivity in most tissues was comparable.  It declined in 
parallel to that in blood and became negligible 3 days post-dose.  However, the radioactivity was 
more sustained at higher levels in the skin and the uveal tract of the eye in Long Evans than in 
Sprague Dawley rats.  The concentration (ng equivalent [14C]MK-2206/g tissue) in the skin and 
the uveal tract of Long Evans rats was 37- and 84-fold higher than that in the respective tissues 
of Sprague Dawley rats 24 hours post-dose. 
An additional safety concern involves MK-2206-induced hyperglycemia and hyperinsulinemia.  
MK-2206 induced hyperglycemia in all preclinical species tested.  In the most sensitive species, 
the dog, the glucose level was elevated by 24%-35%, when MK-2206 was administered at 5 
mg/kg QOD for 4 weeks (AUC0-48 of 19.6 mcM∙h and Cmax of 0.73 mcM).  Such exposure is 
expected to correspond with human exposures achievable at the upper MK-2206 dosing range. 
Results from genetic toxicology assays demonstrated that MK-2206 was neither genotoxic nor 
mutagenic.   
Clinical Development of MK-2206   
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Preliminary clinical PK/pharmacodynamic and safety experience is derived from a Merck 
(Merck Sharp and Dohme)-sponsored phase 1 study in healthy volunteers (HVs) and company 
phase 1 studies in patients with advanced solid tumors.   
Projections derived from preclinical PK and metabolism studies in dogs suggested that the target 
exposure corresponding to a plasma concentration of ≥100 nM MK-2206 over 8 hours and 
AUC0-48h of ~2 mcM∙h in humans could be attained by MK-2206 dosed at 30-70 mg QOD on a 
28-day cycle schedule.  Clinical PK/pharmacodynamic data confirmed that the MK-2206 dose of 
60 mg QOD conferred substantial and lasting inhibition of AKT as measured in tumor biopsies 
from cancer patients. The 60-mg QOD dose level is being currently investigated as the maximum 
tolerated dose (MTD) in the expanded cohort of patients. 
Preclinical and clinical experience from Merck-sponsored studies suggests potential benefit of a 
less frequent dosing schedule (i.e., QW).  It is potentially feasible to administer MK-2206 at 
higher dose levels on a less frequent dosing schedule to maximize significant or peak target 
inhibition.  This approach may also alleviate DLTs (e.g., skin rash) associated with accumulated 
exposure to MK-2206.  Dose escalation on a QW schedule is currently being evaluated at the 
MK-2206 doses ranging from 90-300 mg. 
Clinical Pharmacokinetics 
The clinical PK for MK-2206 was evaluated in HVs receiving a single dose (0.25-100 mg) and 
in cancer patients given either a 30-, 45-, 60-, 75-, or 90-mg dose on the QOD schedule or 90-, 
135-, 200-, 250-, or 300-mg dose on the QW schedule.   
Although Day 1 AUC0-48h and Cmax values achieved at ≤90 mg in cancer patients overlapped with 
the ranges observed in HVs, overall, MK-2206 exposures in cancer patients trended on average 
somewhat higher than those observed in HVs.  In all cohorts evaluated at ≤200 mg QW, 
exposures after the first and last dose in Cycle 1 were below the dog NOAEL AUC0-48h and Cmax 
values of 8.52 mcM*hr and 365 nM, respectively.  The mean first dose MK-2206 AUC0-48h and 
Cmax were 1.77 mcM*hr and 62.2 nM, respectively, for 60 mg QOD, and 14.8 mcM*hr and 466 
nM, respectively, for 300 mg QW.  The dog NOAEL exposures were exceeded in humans 
following the first dose of 300 mg QW.   
The variability in AUC0-48h and Cmax following the first dose, where it could be assessed, was low 
to moderate across all dose levels, with the coefficient of variation (CV) values ranging from 
approximately 10%–60%.  From a visual inspection of the data 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.Tmax and apparent terminal t1/2 values from 
cancer patients were generally within the ranges observed in HVs.  Median Tmax values ranged 
from 4–10 hours across all dose 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 assessable in one patient and was approximately 50 
hours.   
Clinical Efficacy/Pharmacodynamics 
Preliminary pharmacodynamic results in cancer patients indicate that phosphorylation of AKT in 
whole blood is substantially inhibited at all dose levels evaluated on the QOD and QW schedule.  
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Additionally, preliminary results indicate that substantial pAKT inhibition was demonstrated in 
tumor tissue at 60 mg QOD.  As there is a causal relationship between the development of 
hyperglycemia/hyperinsulinemia and mechanism of AKT inhibition, such events could 
potentially implicate pharmacodynamic activity of MK-2206.  In cancer patients, reversible 
grade 1/2 hyperglycemia was observed across all dose levels in a total of 59 patients.  
Hyperinsulinemia occurred in 26 patients who received MK-2206 60 mg QOD.  From a 
preliminary analysis, these adverse events (AEs) do not appear to be dose-dependent.  Neither 
hyperglycemia nor hyperinsulinemia was observed at any single dose in HVs.   
Thus far, no formal efficacy studies have been performed with MK-2206; however, in patients 
with advanced solid tumors, early indications of antitumor activity included substantial decreases 
in CA125 in some patients with ovarian cancer and PSA stabilization in some prostate cancer 
patients.  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. 
Clinical Toxicology  
Preclinical efficacy and safety studies and preliminary safety data from the clinical studies 
support the use of MK-2206 via the oral route, both as monotherapy and in combination with 
other anticancer agents.   
Overall, MK-2206 has been generally well-tolerated when administered as a single PO dose 
(0.25-100 mg) to HVs, or to cancer patients as the 30-60 mg PO dose on the QOD schedule and 
the 90-200 mg PO dose on the QW schedule.  Mild to moderate skin rash was observed in 21 of 
42 patients (50.0%) and severe skin rash was observed in 5 of 42 patients (11.9%) at the dose of 
60 mg QOD.   Skin rash resolved following the 1- to 2- week therapy break.  The higher doses 
evaluated in oncology patients (i.e., 75 and 90 mg QOD and 300 mg QW) were not tolerated and 
resulted in DLT of grade 3/grade 4 skin rash.   
Mild to moderate mucositis and conjunctivitis were associated with rash.  The supportive-care 
measures included hydration, topical steroid preparations, oral corticosteroids, oral 
antihistamines, and oral antibiotics.  Other common AEs included nausea, fatigue, vomiting, and 
diarrhea.  These AEs were mild to moderate and in most cases were resolved by the standard 
supportive care and did not require therapy modifications. Hyperglycemia and hyperinsulinemia, 
both expected mechanism-based AEs, were observed in approximately 76% and 57% of patients, 
respectively, receiving MK-2206 on the QOD schedule.  Episodes were generally mild, transient, 
and did not require therapeutic intervention. Importantly, administration of insulin may not 
counteract MK-2206-induced hyperglycemia due to mechanism-based insulin resistance.  In this 
case, hydration and oral antihyperglycemic agents can be used as the supportive-care measures.  
Grade 3 hyperglycemia occurred in one patient who received 60 mg QOD and required treatment 
with PO antihyperglycemic medication.  Grade 4 hyperglycemia was reported in one patient who 
received MK-2206 45 mg QOD in combination with erlotinib.  In addition to supportive care 
measures, blood glucose management included administration of insulin and PO 
antihyperglycemic medication.     
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Grade 1/grade 2 prolongation of QTc-interval was observed in 14 out of 64 patients (21.9%) with 
available 12-lead ECG data.  Prolongations ≥30 msec but <60 msec occurred in 4 of these 
patients.  Grade 3 QTc prolongation was reported in one patient who received 135 mg QW.  
Episodes of QTc interval prolongation were in general isolated with no apparent dependency on 
dose or exposure levels, and were not considered clinically significant by investigators and were 
not reported as adverse experiences.  Eleven patients experienced sinus bradycardia (<50 bpm) 
during Holter or ECG monitoring.  These events were asymptomatic and were not clinically 
significant.  While a causal relationship between these events and administration of MK-2206 is 
uncertain, similar side effects were seen preclinically in conscious dogs.  Consequently, patients 
with a history or current evidence of heart disease should be excluded from enrollment on MK-
2206 trials.  Standard 12-lead ECG measurements should be performed at the protocol-specified 
time-points.   
Developmental/Reproductive Toxicity 
Developmental and reproductive toxicity studies of MK-2206 have not been performed thus far.  
MK-2206 was not tested in pregnant or breast-feeding women.  Women of child-bearing 
potential and men participating in clinical studies of MK-2206 must use appropriate 
contraception, including abstinence and double-barrier methods, throughout MK-2206 therapy.  
In preclinical mutagenicity studies, MK-2206 was neither genotoxic or mutagenic. 
Drug Interactions 
No clinical drug interaction studies have been performed with MK-2206.  Oxidative metabolism 
of MK-2206 in human liver microsomes was catalyzed primarily by CYP3A4.  MK-2206 was 
not an inhibitor of the major CYPs.  MK-2206 was shown to be a P-gp substrate. 
Weekly dosing 
Preclinical studies in animal models have shown evidence of improved efficacy of the once 
weekly (QW) dosing in mono-therapy using the A2780 xenograft (PTEN mutant) model in two 
independent studies. Additionally, QW dosing of MK-2206 results in similar or enhanced single 
agent and combination efficacy in NCI-H-292 Xenografts. In the phase I clinical trial PN002,  
MK-2206 showed a Cmax = 170 nM (after 1st dose) and Cmax = 225 nM (SS), which could 
potentially lead to better tumor penetration, more tumor cytotoxicity and better  efficacy in 
comparison to the every other day (QOD) mode of administration. Mean Coverage above target 
PK was 133 hours (out of 168 hours), which may potentially alleviate skin toxicity. Furthermore, 
this dosing schedule is significantly more convenient for the patient.  More detailed information 
and updates about the rationale for the use of QW dosing can be found in the investigational 
brochure. 
 
16.1.1.2 AZD6244 
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 
(Investigator's Brochure, 2009; Friday and Adjei, 2008).  AZD6244 inhibited the activity of 
purified MEK enzyme with an IC50 of 10-14 nM, and was found to be inactive or only 
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A b brevi ate d Title: M olec ul ar Pr ofili n g N S C L C  
Versi o n D ate : 0 1/ 0 7/ 2 0 2 0  
 
 
 
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a n d ot her si g nal tra ns d u cti o n pat h wa ys will n ot be bl oc ke d.  A Z D 6 2 4 4 is m eta b olize d t o 
bi ol o gicall y acti ve N - des met h yl A Z D 6 2 4 4 w hic h is m ore p ote nt t ha n t he p are nt c o m p o u n d.  I n 
vitr o, i n vi v o a n d preli mi nar y res ults fr o m cli nical st u dies s u g gest t hat A Z D 6 2 4 4 e x hi bits a 
fa v ora bl e p har mac ol o gic a n d t o xic ol o gic pr ofile. 
T he  R A S/ R A F/ M E K/ E R K si g nali n g pat h w a y pla ys a ce ntral r ole i n t he re g ulati o n of man y 
cell ular pr o cesses i ncl u di n g pr olif erati o n, s ur vi val, differe ntiati o n, a p o pt osis, m otilit y, a n d 
meta b olis m ( O' N eill a n d K olc h, 2 0 0 4; Well br oc k et al., 2 0 0 4).  T his pat h w a y is o ne of t he m ost 
i m p orta nt a n d best u n derst o o d M A P ki nase si g nal tra ns d ucti o n pat h wa ys, acti vate d b y a di vers e 
gr o u p of e xtracell ular si g nals i ncl u di n g i nte gri ns, gr o wt h fact or rece pt ors (i.e., E G F R, platel et-
deri ve d gr o wt h fact or rece pt or [ P D G F R], a n d i ns uli n-li ke gr o wt h fact or- 1 rece pt or), a n d 
c yt o ki nes (J a nsse n et al., 2 0 0 5).  Acti vate d R A S tri g gers t h e p h os p h or ylati o n a n d acti vati o n of 
R A F ki nase w hic h t h e n p h os p h or ylat es M E K 1 a n d M E K 2 o n 2 seri ne resi d ues ( A h n et al., 
2 0 0 1). Acti vate d M E K p h os p h or ylat es its o nl y k n o w n s u bstrates, E R K 1 a n d E R K 2.  
P h os p h or ylate d E R K di merizes a n d tra nsl ocat es t o t he n ucle us ( K h o k hlat c he v et al., 1 9 9 8) w here 
it is i n v ol ve d i n se veral i m p orta nt cell ular f u n cti o ns, i ncl u di n g cell pr oliferati o n.   
O vere x pressi o n of gr o wt h fact ors or gr o wt h fact or rece pt ors i n v ol ve d i n t he 
R A S/ R A F/ M E K/ E R K pat h wa y a n d act i vati n g ge n etic m utati o ns of t he si g n ali n g pr otei ns ma y 
lea d t o u nc o ntr olle d pr oliferati o n a n d t u m or f or mati o n.  F or e x a m ple, R A S ge n es are t he m ost 
fre q ue ntl y m utate d o n c o ge n es detecte d i n h u ma n t u m ors (J a nsse n et al., 2 0 0 5).  R A S pr otei ns are 
g ua ni n e n ucle oti de bi n di n g pr otei ns t hat acti vate R A F pr otei ns w he n b o u n d t o G T P.  Ca ncer-
ass ociate d m utati o ns i n R A S pr otei ns sta bilize t he G T P - b o u n d f or m of R A S, t here b y pr o vi di n g a 
c o nstit uti ve si g nal d o w nstrea m i n t he cas ca de.  I n a d diti o n t o bei n g f o u n d i n al m os t all 
pa ncreatic a d e n ocarci n o mas, R A S m utati o ns are f o u n d i n ~ 5 0 % of c ol orectal carci n o mas, 2 5-
5 0 % of l u n g a de n o car ci n o mas, a n d als o i n s o me breast or o varia n ca ncers.  B R A F m utati o ns 
ha ve als o bee n o bser v e d i n ma n y h u ma n ca ncers, partic ularl y mela n o ma ( 3 0- 6 0 %), t h yr oi d ( 3 0-
5 0 %), c ol orectal ( 5- 2 0 %), a n d o varia n ( ~ 3 0 %) ca n cers ( Well br oc k et al., 2 0 0 4; Fri da y et al., 
2 0 0 8).  T hese m utati o ns i n B R A F us u all y i n v ol ve gai n- of -f u n cti o n s u bstit uti o ns t hat re n der t he 
ki nases c o nstit uti vel y acti ve.  Als o, st u dies of pri mar y t u m or s a m ples a n d cell li nes ha ve s h o w n 
c o nstit uti ve acti vati o n or o veracti vati o n of t h e M A P ki nase pat h wa ys i n ca n cers of t he p a ncreas, 
c ol o n, l u n g, o var y, a n d ki d ne y ( H os hi n o et al., 1 9 9 9).  T heref ore, a ge nts tar geti n g t he 
R A S/ R A F/ M E K/ E R K pat h wa y  m a y i n hi bit o nc o ge nic si g n ali n g i n t u m or cells.  
N o ncli nic al St u dies 
Effic acy  
I n vitr o st u dies ha v e s h o w n t hat A Z D 6 2 4 4 is p ote nt a n d selecti ve i n hi bit ors of M E K 
(I n vesti gat or's Br oc h ure, 2 0 0 9).  H o we v er, si g nifica nt bi oc he mical acti vit y was n ot detecte d 
w he n teste d at 1 0 µ M a gai nst a di verse pa n el of 3 0 5 ot her m olec ules, i ncl u di n g e nz y m es, 
rece pt ors, ki nases, tra ns p orters, a n d i o n c h a n nels.  T he effects of A Z D 6 2 4 4 o n E R K 
p h os p h or ylati o n a n d cell via bilit y wer e deter mi ne d i n a pa nel of cell li nes i n w hic h t he 
m utati o nal stat us of R A F a n d R A S are k n o w n.  A Z D 6 2 4 4 i n hi bite d E R K 1 a n d E R K 2 
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p h os p h or ylati o n wit h I C 5 0 ra n gi n g fr o m 0. 0 0 1 8 t o 0. 0 4 1 M.  A Z D 6 2 4 4 was partic ularl y p ot e nt 
i n i n hi biti n g t he via bilit y of cell li nes wit h V 6 0 0 E B R A F ge ne m utati o n a n d s o me cell li nes wit h 
K R A S m utati o ns.  Se nsiti ve cell li nes i ncl u de d t h ose deri ve d fr o m c ol orectal, n o n- s mall cell 
l u n g ca ncer ( N S C L C), pa ncreatic, a n d mela n o ma t u m ors.  T w o meta b olites of A Z D 6 2 4 4 ( N-
des met h yl A Z D 6 2 4 4 a n d a n a mi de A Z D 6 2 4 4) ha v e bee n i de ntifie d.  T h e N -des met h yl 
meta b olite was f o u n d t o be 3-t o 5-f ol d m ore acti v e t ha n t he pare nt c o m p o u n d i n cell ular E R K 
p h os p h or ylati o n i n hi biti o n assa ys, w hereas t he a mi de meta b olite was u p t o 5 0- f ol d less acti ve 
t ha n A Z D 6 2 4 4.  I n t u m or cell via bilit y i n hi biti o n assa ys, N-des m et h yl met a b olite was ≥5 -f ol d 
m ore p ote nt i n i n hi biti n g cell via bilit y.   
Si g nifica nt s u p pressi o n of t u m or gr o wt h i n res p o nse t o A Z D 6 2 4 4 treat me nt was o bser v e d i n 
se veral x e n o graft m o use m o dels deri ve d fr o m a ra n ge of t u m or t y p es i ncl u di n g mela n o ma, 
breast, pa n creatic, l u n g, c ol o n, a n d he pat ocell ular carci n o mas. ( Tra n et al., 2 0 0 6; Brei kre utz et 
al., 2 0 0 7; Da vies et al., 2 0 0 7; Tai et al., 2 0 0 7).  I n pa pillar y t h yr oi d ca n cer m o dels, A Z D 6 2 4 4 
effecti vel y i n hi bite d t u m or gr o wt h, b ot h i n vitr o a n d i n vi v o , partic ularl y i n t u m or cells carr yi n g 
acti vati n g B R A F ge ne m utati o ns ( Ball et al., 2 0 0 7).  I n t he Cal u- 6 l u n g ca n cer x e n o graft m o del, 
A Z D 6 2 4 4 s u p presse d t u m or gr o wt h at d oses of 1 0, 2 5, or 1 0 0 m g/ k g gi ve n t wice dail y ( BI D), 
a n d t he mi ni mal effecti ve d ose was i de ntifie d as 0. 7 5 m g/ k g a d mi nistere d BI D ( Da vies et al., 
2 0 0 7).  I n t his m o del, M E K acti vit y w as i n hi bite d as assesse d b y d eter mi nati o n of 
p h os p h or ylat e d E R K ( p E R K) le vels i n t u m or.  St u dies usi n g h u ma n c ol orectal x e n o graft m o dels 
de m o nstrate d t hat A Z D 6 2 4 4 i n hi bite d t u m or gr o wt h b y i n hi biti o n of cell pr oliferati o n i n S W 6 2 0 
m o del a n d b y i n d u cti o n of a p o pt osis i n C ol o 2 0 5 m o del.  I n vi v o st u dies of t he K R A S m utati o n-
p ositi ve ( K R A S +) h u ma n ca ncer x e n o grafts ha v e de m o nstrate d p ote ntial f or a d diti ve /s y n er gi stic 
effects of A Z D 6 2 4 4  i n c o m bi nati o n wit h a n u m ber of c yt ot o xic a n d tar get e d a ge nts, i ncl u di n g 
d oceta x el, iri n oteca n, ge mcita bi ne, Iress a ( gefiti ni b), A Z D 2 1 7 1 (ce dira ni b), ra pa m yci n, cis plati n, 
a n d te m oz ol o mi de (I n v esti gat or’s Br o c h ure, 2 0 0 9). 
P h ar m ac oki netic/ P h ar m ac o dy n a mic St u dies 
T w o oral f or m ulati o ns of A Z D 6 2 4 4 ha ve b ee n test e d i n precli nical p h ar mac ol o g y st u dies:  t he 
ori gi nal mi x -a n d- dri n k f or m ulati o n ( A Z D 6 2 4 4 free- base), a n d t he A Z D 6 2 4 4 h y dr o ge n s ulfate 
salt (ca ps ule) f or m ulati o n ( A Z D 6 2 4 4 H y d- S ulfat e) (I n v esti gat or’s Br oc h ure, 2 0 0 9).  T h e f or mer 
re q uires r ec o nstit uti o n of t he A Z D 6 2 4 4 free- b ase cr ystalli ne p o w der i n t he 2 5 % ( w/ v) A q u e o us 
Ca ptis ol ®(s ulf o b ut yl et her β -c ycl o d e xtri n) ( S B E - C D) s ol uti o n.  A bs or pti o n of A Z D 6 2 4 4 fr ee-
base was m o derate t o hi g h at l o w d oses i n rat, d o g a n d m o n ke y, b ut s h o we d decreasi n g 
bi oa vaila bilit y wit h i ncreasi n g d ose.  T he decli ni n g bi oa v aila bilit y at hi g her d oses ma y be d u e t o 
t he l o w a q ue o us s ol u bilit y of A Z D 6 2 4 4.  W he n a d mi nisteri n g A Z D 6 2 4 4 h y dr o ge n s ulfate, 
A Z D 6 2 4 4 e x p os ure, e x presse d as a n area u n der t h e plas ma c o nce ntrati o n -ti me c ur ve fr o m 0 t o 
1 2 h o urs ( A U C 0- 1 2), i ncrease d r o u g hl y i n pr o p orti o n wit h d ose i n t he m o use a n d m o n ke y.  I n 1-
m o nt h st u dies, 3 t o 6-f ol d gr eater e x p os ures were ac hie ve d wit h A Z D 6 2 4 4 h y dr o ge n s ulfate at 
7. 5 m g/ k g BI D t ha n wit h t he A Z D 6 2 4 4 free- b ase at 3 0 m g/ k g BI D.  T here was n o/ mi ni mal 
acc u m ulati o n of A Z D 6 2 4 4, w het her d ose d wit h A Z D 6 2 4 4 free- b ase or A Z D 6 2 4 4 h y dr o ge n 
s ulfate, o n m ulti ple d osi n g i n t he m o use, rat, or m o n ke y.  Oral bi oa v aila bilit y of A Z D 6 2 4 4 i n 
m o n ke y, f oll o wi n g d osi n g wit h 5 m g/ k g of eit her free- base or ca ps ul e, was 2 9 % a n d 5 6 %, 
res pecti vel y.  N-des met h yl meta b olite w as n ot detecta ble i n rat a n d at o nl y trace le v els i n t he 
m o n ke y, b ut w as pr o d uce d i n m o use at circ ul ati n g le v els ar o u n d 2- 1 2 % of pare nt c o m p o u n d.  
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St u dies i n rats i n dicate t hat A Z D 6 2 4 4 is wi del y distri b ute d, alt h o u g h tiss ue c o nce ntrati o ns were 
l o wer t ha n bl o o d c o nce ntrati o ns.  Hi g h le v els of pr otei n bi n di n g ( 9 3. 7- 9 9. 7 %) were o bser ve d i n 
all precli nical s pecies teste d a n d i n h u ma ns ( 9 8. 4 %).  T here was n o e vi de n ce of A Z D 6 2 4 4-
relate d material bi n di n g t o mela ni n a n d mi ni mal pe netrati o n i nt o t he ce ntral ner v o us s yste m 
( C N S).  A ZD 6 2 4 4 was meta b olize d b y c yt oc hr o me P 4 5 0 ( C Y P e nz y m es) 1 A 2, 2 C 1 9 a n d 3 A 4, 
wit h C Y P 1 A 2 bei n g t he e nz y me pri maril y res p o nsi ble f or t he f or mati o n of t he N- des met h yl 
meta b olite.  Gl uc ur o ni dati o n a p pears t o be a si g nifica nt cleara n ce mec ha nis m f or A Z D 6 2 4 4 a n d 
N- des met h yl meta b olite.  A Z D 6 2 4 4 di d n ot i n hi bit C Y P 1 A 2, 2 C 8, 2 C 1 9, 2 D 6, a n d 3 A 4.  It w as 
a wea k i n hi bit or of C Y P 2 C 9 (I C 5 0 4 4. 7 µ M).  N- des met h yl A Z D 6 2 4 4 di d n ot i n hi bit C Y P 2 A 6, 
2 C 8, 2 C 9, 2 C 1 9, 2 D 6, 2 E 1, or 3 A 4, b ut was a wea k i n hi bit or of 1 A 2 (I C 5 0 of 1 8. 9 µ M).  I n rat, 
m o use a n d m o n ke y, fecal e x creti o n was t he pre d o mi na nt r o ute after oral a n d i ntra ve n o us d osi n g. 
T oxi c ol o gic St u dies 
T he t o xic ol o gic eff ects of A Z D 6 2 4 4 were e val uat e d i n ac ute d ose (si n gl e or t w o d oses o n a 
si n gle da y) a n d 1- m o nt h, re peat- d ose st u dies i n S pra g ue- Da wle y rats a n d c y n o m ol g us m o n ke ys 
(I n vesti gat or's Br oc h ure, 2 0 0 9).  T he repeat -d os e st u d y i n rats i n dicat e d t hat t he a ge nt was well 
t olerate d b ut pr o d uce d s oft st o ols a n d gastr oi ntesti nal m uc osal mi neralizati o n ass ociate d wit h 
i ncreas e d ser u m p h os p h or us a n d decreas e d al b u mi n.  Diarr hea, de h y drati o n, electr ol yte 
i m bala nce, a n d s ec o n dar y r e nal c h a n ges w ere o bs er ve d i n m o n ke ys.  T he v e hicle, Ca ptis ol ®, 
use d t o rec o nstit ute A Z D 6 2 4 4 free- base p o w der, is k n o w n t o ca use gastr oi ntesti nal dist ur ba nces 
i n precli nical st u dies.  A re d ucti o n i n t he v ol u me of Ca ptis ol ® a d mi nistrati o n t o m o n ke ys w as 
ass ociate d wit h a r e d uce d i nci de nce of di arr h ea; h o we ver, it is li kel y t h at A Z D 6 2 4 4 e x acer b ate d 
t he ve hicle effects.  T he n o o bser va ble a d vers e effect le vels ( N O A E Ls) i n rats (fe m ale) a n d 
m o n ke ys i n 1- m o nt h st u dies were i d e ntifie d at 1 0 m g/ k g/ da y BI D ; a N O A E L w as n ot ac hie v e d 
i n male rats.  D osi n g wit h A Z D 6 2 4 4 h y dr o ge n s ulfate ( 0. 5, 1. 5, a n d 4 m g/ k g BI D) f or u p t o 6 
m o nt hs t o m o n ke ys was als o ass ociate d wit h fl ui d a n d/ or re d-c ol ore d feces, b ut wit h n o n ota ble 
gastr oi ntesti nal tr act or r e nal pat h ol o g y.   Tiss ue mi neralizati o n was n ot a p pare nt i n c y n o m ol g us 
m o n ke ys d ose d f or u p t o 6 m o nt hs wit h A Z D 6 2 4 4 h y dr o ge n s ulfate.  H o we ver, mi neralizati o n 
was see n i n m ulti ple tiss ues (c or n ea, ki d ne y, li ver, m y ocar di u m, s keletal m uscle, gl a n d ular 
st o mac h) i n mice d ose d wit h A Z D 6 2 4 4 h y dr o ge n s ulfate f or u p t o 1 m o nt h, a n d i n t he li vers of a 
s mall n u m ber of mice d ose d u p t o 6 m o nt hs.   
A Z D 6 2 4 4 a n d its N- des met h yl meta b olite s h o we d n o e vi de nce of m uta ge nic p ote ntial, b ut 
A Z D 6 2 4 4 pr o d uce d a n i ncreas e i n micr o n ucleate d i m m at ure er yt hr oc yt es i n mice, 
pre d o mi na ntl y via a n a n e u ge ni c m o de of acti o n.  A Z D 6 2 4 4 s h o we d e n h a n ce d c yt ot o xicit y i n t he 
prese nce of ultra vi olet ( U V) li g ht.  Wit h t he e x ce pti o n of tiss ue mi neralizati o n i n rats a n d mice, 
t here was e vi de nce of r e v ersi bilit y of m ost c ha n ges i n t he 1- or 6 - m o nt h st u dies wit h A Z D 6 2 4 4 
(free base or h y dr o ge n s ulfate).  Re pr o d u cti ve t o xic ol o g y d ata i n mice i n dicate t hat A Z D 6 2 4 4 
ca n ha v e a d verse effects o n e m br y ofetal d e vel o p me nt a n d s ur vi val at d ose le vels t hat were n ot 
t o xic t o m others.  
I n s u m mar y, precli nical st u dies de m o nstrate d t hat A Z D 6 2 4 4 e x p os ures ca n be si g nifica ntl y 
e n ha nce d b y usi n g A Z D 6 2 4 4 h y dr o ge n s ulfate, c o m pare d t o A Z D 6 2 4 4 free- base.  I n 6- m o nt h 
t o xic ol o g y st u dies, A Z D 6 2 4 4 e x p os ures ( A U C 0- 1 2) ac hie v e d wit h A Z D 6 2 4 4 h y dr o ge n s ulfate 
at hi g h d ose le v els ( 4 m g/ k g BI D i n m o n ke ys a n d 2 0 m g/ k g BI D i n mice) were a p pr o xi matel y 3-
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fold and 15-fold higher in primates and mice, respectively, when compared with those achieved 
in man at 75 mg BID AZD6244 hydrogen sulfate.  At the NOAEL of 1.5 mg/kg BID from 1-
month and 6-month studies in primates, exposures were generally similar to those seen in man 
after dosing at 75 mg BID AZD6244 hydrogen sulfate.  Exposure achieved in the 6-month 
mouse study at the low dose level of 1 mg/kg BID was slightly below that seen to date in man 
after dosing with AZD6244 hydrogen sulfate (75 mg BID).  Preclinical pharmacology studies 
suggest an acceptable safety profile for the administration of AZD6244 free base or AZD6244 
hydrogen sulfate to human cancer patients.  
Clinical Experience 
AstraZeneca sponsored a phase 1 open-label study designed to assess the safety, tolerability and 
pharmacokinetics (PK) of AZD6244 hydrogen sulfatein patients with advanced solid 
malignancies.  In addition, this study planned to assess the relative bioavailability of the capsule 
vs. free-base formulation.  This is the first clinical study that employed the AZD6244 capsule 
formulation.  The further development of AZD6244 is to be continued with the hydrogen sulfate 
salt (capsule formulation) (Investigator’s Brochure, 2009).   
This study was conducted in two parts. Part A (31 patients enrolled) of the study was a dose 
escalation study, was designed to provide adequate tolerability, safety, PK, and 
pharmacodynamic data.  In Part A, the first cohort received a single 25 mg dose of the AZD6244 
hydrogen sulfate on day 1, followed by BID dosing from day 2 onwards.  Other doses 
investigated were 50 mg, 75 mg, and 100 mg. The aim of Part B (29 patients randomized) was to 
determine the relative oral bioavailability of the AZD6244 hydrogen sulfate, and secondly to 
expand the safety, tolerability and preliminary efficacy data for the maximum tolerated dose 
(MTD) of 75 mg BID.  In Part B, patients received either a single dose of capsule formulation or 
free-base suspension formulation on day 1 and 8, followed by continuous BID dosing of capsule 
formulation from day 9 onwards.    
An AstraZeneca-sponsored multi-arm combination study of the AZD6244 capsule formulation 
that evaluates PK interactions of AZD6244 with selected chemotherapy agents (docetaxel, 
dacarbazine, erlotinib, temsirolimus) is ongoing. 
Pharmacokinetics 
AZD6244 plasma PK parameters of AZD6244 hydrogen sulfate were similar after single and 
multiple dosing, suggesting the minimal accumulation over time after BID dosing.  The 
AZD6244 exposure parameters, i.e., the maximum plasma concentration (Cmax) and the area 
under time-concentration curve (AUC) were approximately dose proportional across the 25- to 
100-mg BID dose range after single (day 1) or multiple dosing studied on days 1, 8, 15, and 22:  
the geometric mean values of exposure parameters were:  Cmax=369-1489 ng/mL and 
AUC=1361-7055 ng∙h/mL on day 1, and Cmax=458-1365 ng/mL and AUC0-12=1515-4758 
ng∙h/mL on day 8.  AZD6244 was absorbed relatively quickly across all dose levels, with a 
median time-to-reach Cmax (tmax) of 1.5 hours.  Following the peak, AZD6244 concentration 
declined multi-exponentially with a mean terminal elimination half-life (t1/2) ranging from 5 to 
7 hours, which was consistent across dose levels.  The steady state volume of distribution (Vss) 
and clearance (Cl) also remained largely consistent across the dose range, with mean values 
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ranging from 87 to 126 L and 12 to 19 L/h, respectively.  Plasma concentrations of N-desmethyl 
AZD6244 followed a similar PK profile as that of AZD6244, although exposure was much 
lower, achieving Cmax and AUC values generally <15% of the parent compound, in each 
patient.  The median tmax was approximately 1.5 hours and t1/2 ranged from 9-13 hours.  The 
AZD6244 amide metabolite showed increased exposure on multiple dosing indicating some 
accumulation.  Concentrations of the AZD6244 amide varied greatly among patients and t1/2 
could not be assessed.  Given the 3-to 5-fold greater potency of the N-desmethyl metabolite 
compared to AZD6244 shown by the in vitro cell-based ERK phosphorylation assay, the former 
is likely to contribute to pharmacodynamic effects.  In contrast, AZD6244 amide, which was 
approximately 40- to 50-fold less active than AZD6244 in this assay, is unlikely to contribute 
significantly to AZD6244 biological activity.  Nevertheless, both metabolites will be measured in 
all future AstraZeneca-sponsored clinical studies of AZD6244 hydrogen sulfate. 
The capsule formulation was demonstrated to significantly improve the oral bioavailability, 
although large inter-patient variability was noted.  The estimated oral bioavailability of capsule 
relative to the free-base suspension based on a dose-normalized AUC0-24 was 263% (90% CI = 
214 to 322%).  The geometric mean values of the exposure parameters obtained for AZD6244 
hydrogen sulfate at 75 mg BID (MTD) were:  AUC0-24 = 6335 and 5448 ng∙h/mL on day 1 and 
8, respectively, and Cmax = 1207 and 1439 ng/mL on day 1 and 8, respectively).  In comparison, 
the exposure achieved by hydrogen sulfate at the MTD was significantly higher than that 
achieved by the free base suspension at 100 mg BID (MTD); the estimated exposures by 
hydrogen sulfate relative to those by free-base, achieved at their respective MTDs, were 197% 
(90% CI = 161 to 242%) and 252% (90% CI = 182 to 348%) based on AUC0–24 and Cmax, 
respectively. 
A food effect study involving administration of AZD6244 hydrogen sulfate 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 mean Cmax and 
AUC values 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 as either twice daily dosing of AZD6244 50 mg or 75 mg with 
docetaxel 75 mg/m2 on day 1 of a 21 day cycle, or as twice daily dosing of AZD6244 50 mg or 
75 mg with dacarbazine 1000 mg/m2 on day 1 of a 21 day cycle. 
Pharmacodynamics 
Inhibition of phosphorylation of ERK as an indirect measure of MEK inhibition by AZD6244 
hydrogen sulfate was assessed in PBMCs from each patient at 4 time-points post-single-dose 
administration, across the dose levels (25-100 mg).  Inhibition of ERK phosphorylation was 
observed at all doses, with the greatest inhibition generally occurring at the first time point (1-
hour post dose); 73% inhibition was seen at 1-hour at the 75-mg BID dose, which declined to 
~23% at 8-hour time-point.  
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Clinical Activity 
In the AZD6244 hydrogen sulfate single-agent study, 55 patients had RECIST evaluable tumors.  
There was one complete response in the 75-mg dose cohort in Part A after 16 weeks.  This 
patient had a BRAF+ melanoma.  At the 75-mg dose, 16/35 (45.7%) patients had stable disease 
for ≥6 weeks.  Nine patients in Part A and 13 patients in Part B had a best response of stable 
disease.  Ten out of 55 (18.2%) patients (not including the patient who had a complete response) 
had stable disease of ≥16 weeks.   
Safety 
Twenty-eight patients were dosed in Part A of the study:  25 mg BID (n=6), 50 mg BID (n=7), 
75 mg BID (n=7) and 100 mg BID (n=8).  One dose-limiting toxicity (DLT) (grade 3 fatigue that 
resolved on discontinuation of AZD6244 hydrogen sulfate) was reported in the first 22 days of 
dosing in the 75 mg BID cohort.  Two DLTs were reported in the first 22 days of dosing in the 
100 mg BID cohort: grade 3 pleural effusion and grade 3 rash.   
Based on the data from this study, the emerging safety and tolerability profiles for the AZD6244 
capsule formulation are broadly consistent with both the patient population, and the adverse 
event profile seen with the AZD6244 free-base suspension formulation.  The most frequently 
reported adverse events (AEs), regardless of dose cohort, severity, causality, or seriousness, were 
fatigue, acneiform dermatitis, nausea, diarrhea, and peripheral edema.  All AEs of acneiform 
dermatitis were considered treatment related in all dose cohorts.  In patients receiving 75 mg 
BID, all fatigue events were considered treatment related.  Twenty-one patients reported at least 
one serious AE.  Seven patients had at least one serious, treatment-related AE, with only 
hypertension being reported on more than one occasion.  Thirty-three of 56 patients (58.9%) 
reported at least one grade 3 AEs during the study, of whom 18/56 (32.1%) experienced at least 
one treatment-related AE of ≥grade 3.  Eighteen patients had permanent discontinuation of study 
treatment due to at least one AE (fatigue, anorexia, vomiting, nausea, left ventricular (LV) 
dysfunction, visual disturbance, fungal urinary tract infection, and acute renal failure).  None of 
the 13 deaths occurred in this study was attributed to the therapy agent.  Comparison of the AE 
frequencies from the AZD6244 hydrogen sulfate study and phase 2 monotherapy studies of 
AZD6244 free-base shows higher proportion of patients reporting the most frequent AEs, such as 
fatigue, dermatitis acneiform, diarrhea, nausea, and peripheral edema, with the capsule 
formulation.  This may be due to the higher plasma exposures achieved with the capsule 
formulation, but may also be in part a consequence of more heavily pretreated patient population 
in the single-agent AZD6244 hydrogen sulfate (capsule) study.  A higher proportion of patients 
withdrew due to AE at the MTD level (75 mg BID in the AZD6244 hydrogen sulfate study than 
at the AZD6244 free-base MTD (100 mg BID), although the different patient populations may 
be a contributing factor.   
Vital signs 
Small increases in mean systolic and diastolic blood pressure (SBP and DBP) were observed 
across most dose cohorts in Part A within the first week of treatment, although no significant 
dose-response relationship could be identified.  In Part B a small mean increase in DBP was 
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observed after 1 week of BID dosing, reaching a maximum increase after 3 weeks BID dosing 
and being resolved by Week 12. 
There were no clinically significant trends observed for pulse rate or percentage of oxygen 
saturation in blood (SpO2) at any dose in study.  Mandatory assessment of LV dysfunction and 
ejection fraction (LVEF) was performed at baseline, after 8 weeks on study, and ad hoc on the 
occurrence of cardiorespiratory AEs.  Data indicate a trend towards a mean decrease in LVEF at 
Week 8 across all dose cohorts, with no obvious dose-response relationship.   
Review of the electrocardiogram (ECG) parameters demonstrated no consistent trend of 
significant prolongation of the corrected QT interval (QTc) across the dose cohorts in Part A, the 
maximum increase in mean QTc was noted in the 75-mg BID cohort with a 12.9 msec increase 
(standard deviation 13.2 msec, range –1 to +27 msec) 2 hours post-dose on day 8, n=5.  
Laboratory parameters 
There were a few minor differences in the clinical laboratory profile (primarily in renal and 
hematological parameters) between the AZD6244 free-base and hydrogen sulfate formulations; 
however, the information for hydrogen sulfate is based on a limited data set. 
The AZD6244 capsule formulation contains vitamin E as an excipient.  High doses of vitamin E 
have been reported to potentiate the anticoagulant activity of coumarins, such as warfarin.  
Therefore, patients who take such anticoagulants and receive the capsule formulation of 
AZD6244 will be advised to have an increased frequency of anticoagulation assessments, such as 
international normalized ratio (INR) measurements, upon starting AZD6244 therapy.  In 
addition, the concomitant intake of excessive doses of vitamin E should be avoided in patients 
receiving the capsule formulation. 
Based on preclinical reproductive toxicology studies, AZD6244 hydrogen sulfate (capsule 
formulation) should not be administered to pregnant or breast-feeding women, and conception 
while on treatment must be avoided. 
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 (Investigator's Brochure, 2009).  
CYP1A2 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 were 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 uM).  Thus, at the 
systemic AZD6244 concentrations observed following 100 mg AZD6244 free-base 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. 
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18.1.1.3 Erlotinib 
OSI-774 (erlotinib, Tarceva®) is an orally active, potent, selective inhibitor of the epidermal 
growth factor receptor (EGFR) tyrosine kinase (160). OSI-774 inhibits the human EGFR 
tyrosine kinase with a 50% inhibitory concentration (IC50) of 2 nM (0.786 ng/mL) in an in vitro 
enzyme assay and reduces EGFR autophosphorylation in intact tumor cells with an IC50 of 20 
nM (7.86 ng/mL).  OSI-774 inhibits EGF-dependent proliferation of cells at submicromolar 
concentrations and blocks cell-cycle progression in the G1 phase.  
OSI-774 appears to bind specifically to EGFR.  In a study of OSI-774 binding specificity, 
affinity of OSI-774 for 67 cellular receptors was examined (160).  OSI-774 was shown to bind 
with low affinity to peripheral benzodiazepine (IC50=2.5 µM [980 ng/ml]), adenosine A1 
(IC50=6.8 µM [2700 ng/ml]), and µ-opiate (IC50=7.0 µM [2800 ng/ml]) receptors.  Binding 
affinities were 1250-fold higher than the IC50 concentration needed to inhibit purified EGFR 
tyrosine kinase (2 nM [0.79 ng/ml]).  When tested at concentrations up to 1 µM (390 ng/ml), no 
significant inhibition of ligand binding to 64 other neurotransmitter receptors, regulatory binding 
sites, calcium channels, opioid receptors, or neurotransmitter uptake sites were observed. 
Nonclinical Studies 
In mice, daily oral administration of OSI-774 for 20 days inhibited subcutaneous (SC) growth of 
the HN5 human head and neck carcinoma in a dose-dependent manner as compared to vehicle-
treated mice, with an estimated effective dose for 50% inhibition (ED50) of 9.2 mg/kg/day (160).  
Treatment with 11 mg/kg/day of OSI-774 immediately halted growth or slightly decreased the 
size of HN5 tumors >1 cm in diameter.  The tumor stasis profile appeared to extend beyond the 
treatment period such that the tumor size for OSI-774-treated animals did not exceed 
pretreatment levels until at least 33 days post-treatment. Similar results were observed in A431 
squamous cell carcinoma xenografts at a dose of 11 mg/kg/day OSI-774 over 20 days.   
OSI-774 (10 mg/kg/day) has been studied in combination with cisplatin, doxorubicin, 5-
fluorouracil, paclitaxel, vinorelbine tartrate, and gemcitabine (160).  No antagonism of 
therapeutic efficacy was observed, and additive effects were observed with cisplatin (10 mg/kg 
intravenous [IV] daily × 1), doxorubicin (15 mg/kg IV daily × 1), paclitaxel (10 mg/kg 
intraperitoneal [IP] daily × 5), and gemcitabine (100 mg/kg IP three times daily × 4).    
Nonclinical toxicology studies in rats and dogs have included acute and long-term general 
toxicology, genetic toxicology, reproductive toxicology, and local tissue tolerance of erlotinib.  
Clinical signs of toxicity in rats and/or dogs following a single dose of OSI-774 were dose 
dependent and included transient emesis, ataxia, papillary dilation, increased heart rate, 
decreased blood pressure, decreased activity, irregular respiration, convulsions, rapid chewing, 
salivation, and death.  Following chronic administration in rats and dogs, the following toxicities 
were observed in at least one species:  effects on the cornea (atrophy and ulceration); effects on 
the skin (follicular degeneration and inflammation, redness, and alopecia); atrophy of the ovary, 
lacrimal glands, and salivary glands; necrosis of the liver; papillary necrosis and tubular 
dilatation of the kidney; inflammation in the mandibular lymph nodes; hematopoiesis; delayed 
gastric emptying; and diarrhea.  Increases in alanine aminotransferase, aspartate 
aminotransferase, and bilirubin were observed. 
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OSI-774 causes maternal toxicity with associated embryo-fetal lethality and abortion in rabbits at 
doses 3 times those in humans (AUC at 150 mg daily dose).  However, when administered 
during organogenesis at plasma concentrations approximately equal to humans, no increase in 
embryo-fetal lethality or abortion in rats or rabbits was observed.  Female rats treated with doses 
0.3 to 0.7 times the human dose prior to mating and during the first week of gestation had an 
increase in early resorptions.  No teratogenic effects were observed in rats or rabbits. 
Pharmacokinetics 
The total clearance of OSI-774 decreased with increasing dose, resulting in supraproportional 
increases in exposure (AUC) over the dose range of 1-2 mg/kg IV in rats and 0.5-7 mg/kg IV in 
dogs (160).  In vitro, OSI-774 is slowly oxidized by liver microsomes.  The majority of the 
absorbed dose is extensively metabolized in rats and dogs, and only a small amount is excreted 
as unchanged drug in urine, bile, and feces.  The oral bioavailability of an aqueous suspension is 
77% in rats and ~88% in dogs.  Plasma protein binding of OSI-774 ranges from 92% to 95% in 
man, monkey, rat, and mouse, and is 85% in the dog.  Corrected for protein binding of 95%, at 
the average plasma concentration responsible for 50% inhibition of tumor growth (oral dose of 
9.2 mg/kg/day in the murine/human tumor xenograft model), the unbound concentration of drug 
in the plasma is estimated to be 86 nM (34 ng/mL).  The estimated unbound concentration of 
OSI-774 in plasma is consistent (4-fold higher) with the IC50 for the in vitro cellular 
phosphotyrosine reduction assay and is 43-fold higher than the IC50 for the in vitro (isolated 
enzyme) tyrosine kinase assay.  Finally, OSI-774 plasma protein binding depends on the levels 
of α-1-acid glycoprotein (AAG).  Thus, AAG might be a significant determinant of 
pharmacokinetic and possibly pharmacokinetic–pharmacodynamic relationships in patients. 
Pharmacokinetic Data 
OSI-774 pharmacokinetics were examined in patients with advanced solid tumors who were 
treated daily for 21 days. Plasma samples were collected on Days 1, 3, and 21 for analysis.  The 
following table lists the pharmacokinetic data for these patients:  
Mean (%CV) OSI-774 Pharmacokinetic Parameters following Daily Dosing 
Dose 
(mg) 
N 
AUC0-24 
(ng•h/ml) 
R* 
Cavg 
(ng/ml) 
Cmax 
(ng/ml) 
Day 1 Day 3 Day 
21 
Day 3 Day 
21 
Day 1 Day 3 Day 
21 
Day 1 Day 3 Day 21 
25 
3 
1580 
(40) 
2180 
(49) 
 
1.38 
(11) 
 
66 
91 
 
208 
(38) 
310 
(40) 
 
50 
6a 
5650 
(54) 
5790 
(57) 
14900 
(69) 
1.59 
(31) 
1.83 
(30) 
235 
241 
621 
508 
(34) 
716 
(55) 
682 
(59) 
100 
8b 9210 
9080 
32200 
1.75 
3.21 
384 
378 
1340 
765 
1140 
1740 
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(92) 
(49) 
(148) 
(35) 
(56) 
(69) 
(49) 
(85) 
150 
7c 
1420
0 (71) 
2060
0 (22) 
45800 
(99) 
1.74 
(6.7 
2.57 
(47) 
670 
859 
1910 
1040 
(70) 
2040 
(21) 
1730 
(82) 
200 
7 
3600
0 (34) 
 
74200 
(29) 
 
2.01 
(42) 
1360 
 
3200 
1420 
(47) 
 
2910 
(29) 
Abbreviations:  AUC0-24, Area under the time-concentration curve from 0 to 24 hours; Cavg, 
daily average plasma concentration; Cmax, maximum serum/plasma concentration; CV, 
coefficient of variance; R, accumulation ratio 
*Accumulation ratio = AUCDay 3 or 21/AUCDay 1 
aOnly 3 patients day 3, 3 subjects day 21 
bOnly 2 patients day 3, 3 subjects day 21 
cOnly 6 patients day 21 
After oral ingestion, the OSI-774 Cmax values (Tmax) were achieved at a median of 3 hours 
(range, 2 to 12 hours). Both Cmax and AUC0-24 values were roughly proportional to the OSI-
774 dose in the range of 25 to 200 mg/d (R2 = 0.33 and 0.46, respectively, on Day 1).  Inter-
subject variability was moderate at the 150-mg/d dose level, as indicated by coefficient of 
variation values of 64% for Day 1 AUC0-24 and Cmax. 
Drug interactions 
In in vitro human liver microsomes studies OSI-774 was slowly oxidized.  OSI-774 appeared to 
be a substrate for CYP3A4, suggesting that OSI-774 could reduce the clearance of co-
administered drugs whose metabolism is dependent on these P450 cytochrome isoenzymes.  
• Erlotinib is both protein bound (92% to 95%) and metabolized by CYP3A4. Therefore, a 
potential for drug-drug interactions exists when erlotinib is co-administered with drugs 
that are highly protein-bound or CYP3A4 inhibitors or inducers.  
• There is a potential interaction between erlotinib and warfarin. Patients have experienced 
elevated international normalized ratios (INRs) and bleeding with this combination of 
drugs. Patients on warfarin and erlotinib should have more frequent INR/prothrombin 
time (PT) determinations (e.g., weekly for the first month and weekly for a minimum of 2 
weeks following Discontinuation of erlotinib). 
• Proton pump inhibitor: Erlotinib's solubility decreases as the pH increases. 
Coadministration of omeprazole with erlotinib will decrease the AUC and Cmax by 46% 
and 61%, respectively. 
• H2-antagonist: Avoid concomitant use of erlotinib with gastric acid-reducing agents if 
possible. When ranitidine 300 mg is given with erlotinib, erlotinib AUC and Cmax 
decrease by 33% and 54%, respectively. Increasing the dose of erlotinib will not 
compensate the loss of exposure. However, if an H2-antagonist receptor is needed, take 
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erlotinib at least 2 hours before or 10 hours following the H2-antagonist administration. 
Dosing such, erlotinib loss of exposure is minimized to AUC of 15% and Cmax of 17%. 
• Smoking:  Advise smokers to stop smoking while taking OSI-774.  Smoking induces 
CYP1A2 enzymes and alters OSI-774 exposure by 64%. 
• Food-drug interaction:  Avoid grapefruit /grapefruit juice (potent CYP3A4) while taking 
OSI-774. 
Safety profile 
Adverse Events Associated with OSI-774 
A comprehensive list of AEs possibly related to OSI-779 is provided in the CAEPR.  Additional 
information can also be found in the Investigator’s Brochure and the Package Insert.  A few 
common or serious AEs are described below. 
Rash or dermatosis: (Grades 1-3) has been reported in many subjects (~50%) during the first 
several days of treatment, although severity diminishes after 4 weeks of therapy.  The use of 
topical agents (i.e., diphenhydramine, corticosteroids) and oral antibiotics (tetracycline) has been 
instituted in some patients with variable results.  In patients with severe rash, treatment has been 
discontinued or the study drug dose reduced.  The etiology of the rash is still unknown, but may 
be related to the mechanism of action of OSI-774.  
Nausea and diarrhea: (Grades 1-2) have been observed in approximate half of all subjects treated 
with OSI-774.  Both adverse events are transient and usually do not require a reduction in 
dosage.  Diarrhea is well controlled in most patients by either the use of loperamide or dose 
reduction.  All ongoing clinical trials recommend the institution of therapy with loperamide.  As 
of June 2001, no significant drug interactions have been observed between OSI-774 and 
loperamide. 
Hepatic toxicities: Cases of hepatic failure and hepatorenal syndrome (including fatalities) have 
been reported during use of OSI-779, particularly in patients with baseline hepatic impairment. 
Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is 
recommended. In the setting of worsening liver function tests, dose interruption and/or dose 
reduction with frequent liver function test monitoring should be considered. OSI-779 dosing 
should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 
x ULN in the setting of normal pretreatment values. 
Renal insufficiencies: Cases of hepatorenal syndrome, acute renal failure (including fatalities), 
and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment 
while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia, 
or concurrent chemotherapy use. In the event of dehydration, particularly in patients with 
contributing risk factors for renal failure (e.g., pre-existing renal disease, medical conditions or 
medications that may lead to renal disease, or other predisposing conditions including advanced 
age), OSI-779 therapy should be interrupted and appropriate measures should be taken to 
intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is 
recommended in patients at risk of dehydration. 
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Gastrointestinal perforation: Patients receiving OSI-779 are at increased risk of developing 
gastrointestinal perforation, which was observed uncommonly. Some cases had a fatal outcome. 
Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane-
based chemotherapy, or who have prior history of peptic ulceration or diverticular disease, are at 
increased risk. OSI-779 should be permanently discontinued in patients who develop 
gastrointestinal perforation. 
Bullous and exfoliative skin disorders: Bullous, blistering, and exfoliative skin conditions have 
been reported, including very rare cases suggestive of Stevens-Johnson syndrome/toxic 
epidermal necrolysis (which in some cases were fatal). OSI-779 treatment should be interrupted 
or discontinued if the patient develops severe bullous, blistering, or exfoliating conditions. 
Ocular disorders: Very rare cases of corneal perforation or ulceration have been reported during 
use of OSI-779. Other ocular disorders, including abnormal eyelash growth, keratoconjunctivitis 
sicca or keratitis have been observed with OSI-779 treatment and are known risk factors for 
corneal perforation/ulceration. 
OSI-779 therapy should be interrupted or discontinued if patients present with acute/worsening 
ocular disorders such as eye pain. 
Fertility and teratology: These studies have not been conducted with OSI-774, and safety for 
women of childbearing capacity cannot be implied from the existing data.  OSI-774 has not been 
tested for carcinogenic activity in a lifetime rodent bioassay. 
16.1.1.4 
Lapatinib 
Lapatinib is a small molecule member of the quinazoline class of kinase inhibitors and is a dual 
reversible inhibitor of both EGFR and HER2 receptors. Lapatinib has a median inhibitory 
concentration for the EGFR receptor at a dose of 12 nmol/l and HER2 receptor at a dose of 9 
nmol/l. Lapatinib prevents phosphorylation and subsequent signal transduction of both the 
Ras/Raf mitogen activated protein kinase and the phosphoinositol-3-kinase/Akt pathways, 
leading to an increase in apoptosis and decreased cellular proliferation. Lapatinib at nanomolar 
concentration blocks cell-cycle proliferation at the G1 phase. It has a high specificity for both the 
EGFR TKD and HER2 TKD and has no other inhibition of other cell receptors and nonreceptor 
tyrosine kinases. Results from pharmacokinetic studies showed that lapatinib is highly protein 
bound in humans (> 99%). Oxidation is the primary route of metabolism via the hepatic 
cytochromes CYP3A4, CYP3A5 and CYP2C19. 
Lapatinib has been approved by the FDA to be used in combination with capecitabine for 
treatment of patients with metastatic breast cancer whose tumors overexpress HER2. A Phase III 
trial in women whose tumors overexpressed HER2 and who had failed trastuzumab randomized 
patients to receive either lapatinib at 1250 mg once daily (continuously) plus capecitabine 2000 
mg/m2/day on days 1 – 14 every 21 days, or to receive capecitabine alone at a dose of 2500 
mg/m2/day on days 1 – 14 every 21 days. The primary end point of this study was time to 
progression (TTP). Based on the results of a prespecified interim analysis, further enrollment 
was discontinued after 399 patients demonstrated an increase in TTP from 19.7 weeks to 36.9 
weeks. The combination increased toxicity with notable side effects of diarrhea (65%), hand-foot 
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syndrome (53%), nausea (44%), rash (29%) and fatigue (24%). QT prolongation is another 
potential toxicity of lapatinib. 
Lapatinib has been evaluated as a single agent in several Phase II studies. It has been studied in 
inflammatory breast cancer overexpressing HER2. This trial demonstrated a 35% objective 
response rate (ORR). It has been further investigated as a monotherapy in a Phase II trial 
involving heavily pretreated metastatic breast cancer patients. In this study no objective 
responses were seen in patients with HER2 negative tumors. A 4.3% response rate in HER2-
positive patients was demonstrated. A third Phase II study involved single-agent lapatinib in 
HER2-positive breast cancer patients with brain metastases. In the 39 subjects enrolled in this 
trial, only one had a CNS response. 
HER2 overexpression has been reported in 4 – 20% of NSCLC and is associated with a poor 
prognosis. A Phase II trial tested lapatinib as monotherapy in the first- or second-line setting in 
metastatic NSCLC. This trial was discontinued after enrollment of 131 patients, after only one 
PR was seen. The use of lapatinib is now being tested in other solid tumors, including gastric, 
ovarian and colorectal carcinomas. 
Predictors of HER2-TKI sensitivity and resistance  
Clinical data have so far demonstrated that tumors must overexpress HER2 to be sensitive to 
either lapatinib or trastuzumab. Lapatinib sensitivity increases with increased expression of both 
HER2 and EGFR. In hormone-positive breast cancer, increased HER2 expression has been 
shown to downregulate estrogen receptor (ER) expression. Signaling through HER2 seems to 
bypass the estrogen requirement for breast cancer cell growth and may drive initially ER-positive 
cells into an ER-negative, or endocrine therapy-resistant state. Overexpression of both EGFR and 
HER2 has been associated with tamoxifen resistance. Estrogen and tamoxifen have been shown 
to increase phosphorylation of HER2. ER and HER2 have a bidirectional crosstalk; therefore 
lapatinib may have the ability to restore tamoxifen sensitivity. A Phase I study combining 
letrozole and lapatinib determined the optimal Phase II dosage of letrozole at 2.5 mg/day and 
lapatinib at 1500 mg/day, which is being tested at present. 
Trastuzumab resistance has been seen in tumors with upregulated insulin-like growth factor 
receptor-1 (IGF-1R), in tumors that lack phosphatase and tensin homolog (PTEN) expression, 
and in tumors with activating mutations in PI3K. An overexpression of IGF-1R leads to 
increased phosphorylation of HER2, resulting in increased signaling. Both PTEN-deficient 
tumors as well as tumors with activating PI3K mutations have an increase in the PI3K signaling 
pathway. Additional resistant mechanisms to trastuzumab include increased membrane-
associated glycoprotein mucin-4 (MUC4), which interacts directly with HER2. MUC4 provides 
steric hindrance to trastuzumab binding. 
There are limited data defining the exact cause of lapatinib resistance. HER2 receptor tyrosine 
kinase mutations have rarely been reported in breast cancer. Proposed mechanisms of resistance 
have included an upregulation of estrogen receptor pathways and overexpression of both HER3 
and HER4. Other proposed mechanisms of resistance have included upregulation of IGF-1R and 
lack of inhibition of surviving. 
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A b brevi ate d Title: M olec ul ar Pr ofili n g N S C L C  
Versi o n D ate : 0 1/ 0 7/ 2 0 2 0  
 
 
 
1 5 7  
1 8. 1. 2  Ot her a ge nts  
1 8. 1. 2. 1   S u niti ni b Malate  
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m olec ule i n hi bit or of t he rece pt or t yr osi ne ki nases ( R T Ks) i n v ol ve d i n t u m or pr oliferati o n a n d 
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tra nsfecti o n), f ms-li ke t yr osi ne ki nase 3 ( Flt 3), basic fi br o blast gr o wt h fact or ( b F G F) a n d c ol o n y-
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Br oc h ure, 2 0 0 9).  I n p has e 2 st u dies i n c yt o ki ne-refract or y m etastatic R C C, s u niti ni b pr o d uce d 
o bjecti ve res p o nses i n 4 0 % of patie nts wit h a me dia n ti me -t o-t u m or- pr o gressi o n ( T T P) of 8. 7 
m o nt hs ( M otzer et al., 2 0 0 6).  I n p hase 3 st u dies of patie nts wit h i mati ni b- resista nt GI S T, 
s u niti ni b was hi g hl y s u p eri or t o place b o ( p < 0. 0 0 0 1) wit h res pect t o me dia n T T P ( 2 7. 3 wee ks vs. 
6. 4 wee ks), pr o gressi o n- free s ur vi val ( P F S), a n d o verall s ur vi val ( O S) ( De metri et al., 2 0 0 6). 
S u niti ni b was gra nte d r e g ular a p pr o v al o n J a n uar y 2 6, 2 0 0 6 b y F o o d a n d Dr u g A d mi nistrati o n 
( F D A) f or t he treat me nt of gastr oi ntesti nal str o mal t u m or ( GI S T) after disease pr o gressi o n o n or 
i nt olera nt t o i mati ni b mes ylate a n d accelerate d a p pr o val f or a d v a nce d re n al cell carci n o ma 
( R C C) ( G o o d ma n et al., 2 0 0 7; Izze di ne et al., 2 0 0 7; R oc k et al., 2 0 0 7), w hi c h was c h a n ge d t o 
re g ular a p pr o val o n Fe br uar y 2, 2 0 0 7.   
Mec h a nis m of Acti o n 
T u m or V E G F e x pressi o n h as bee n ass o ciate d cli ni call y wit h disease pr o g n osis i n ma n y differe nt 
t y pes of m ali g n a ncies.  V E G F e x pressi o n is i ncrease d b y di v erse sti m uli i ncl u di n g pr ot o-
o nc o ge ne acti vati o n a n d h y p o xia, wit h t he h y p o xic state fre q ue ntl y arisi n g i n s oli d t u m ors 
beca us e of i na de q u ate perf usi o n.  I n a d diti o n t o its a n gi o ge nic r ole, V E G F als o pr of o u n dl y 
i ncreas es t he per m ea bilit y of t he v asc ulat ure t here b y, p ote ntiall y c o ntri b uti n g t o t u m or 
pr o gressi o n.  A lea k y t u m or e n d ot heli u m e n ha nces n utrie nt a n d cata b olite e x c ha n ge a n d 
re pres e nts less of a b arrier t o t u m or cell mi grati o n a n d i ntra vasati o n d uri n g metastasis.  T w o 
hi g h -affi nit y rece pt ors f or V E G F wit h ass ociate d T K acti vit y h a ve bee n i d e ntifie d o n h u ma n 
vasc ular e n d ot heli u m; V E G F R- 1/ Flt - 1 a n d V E G F R- 2/ ki nase i nsert d o mai n-c o ntai ni n g rece pt or 
( K D R).  Alt h o u g h t he rel ati ve c o ntri b uti o ns of K D R a n d Flt-1 si g nali n g i n me diati n g t u m or 
pr o gressi o n ha ve n ot b ee n el uci date d, a n u m b er of st u dies s u g gest t hat K D R perf or ms a 
pre d o mi na nt r ole. 
I n a d diti o n t o V E G F r ece pt or si g nali n g, i ncreasi n g e vi de nce i m plicates P D G F R si g n ali n g i n 
t u m or a n gi o ge n esis.  Rece nt n o ncli nical e vi de nce s u g gests t hat i n hi biti o n of P D G F R si g n ali n g 
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augments the antitumor and anti-angiogenic effects of VEGFR inhibitors.  In addition, PDGF 
signaling is implicated in the autocrine growth of tumor cells and in the recruitment and 
regulation of tumor fibroblasts. 
Upon chronic oral dosing, sunitinib is expected to inhibit PDGF- and VEGF-driven angiogenesis 
and as a consequence, limit solid tumor growth.  Because angiogenesis is necessary for the 
growth and metastasis of solid tumors, and VEGF is believed to have a pivotal role in this 
process, sunitinib treatment may have broad-spectrum clinical utility (Chow and Eckhardt, 2007; 
Gan et al., 2009).  Sunitinib also exerts direct antitumor activity on cells that express target 
RTKs associated with tumor cell proliferation, such as KIT, PDGFR, and RET.  The clinical 
activity of sunitinib in patients with advanced GIST is an example of this antitumor effect. 
Nonclinical Specificity and Efficacy Studies 
In vitro studies have demonstrated the specificity of sunitinib for inhibition of the Class 3 and 
Class 5 RTKs, including receptors for VEGF (VEGFR), KIT, Flt-3, and PDGFR (Investigator’s 
Brochure, 2009).  Specifically, receptor phosphorylation inhibition studies have shown that 
sunitinib inhibits KIT-ligand-induced phosphotyrosine levels in a dose-dependent manner with 
IC50 values of 0.001-0.01 mcM in vitro and reduced PDGFR-β phosphotyrosine levels in vivo 
(Abrams et al., 2003a).  Sunitinib also selectively inhibited proliferation of human umbilical vein 
endothelial cells (HUVEC) stimulated with VEGF (IC50=0.04 mcM) compared to FGF-
stimulated proliferation (IC50=0.7 mcM) (Mendel et al., 2003). 
In animal efficacy studies, sunitinib showed broad antitumor activity in mouse xenograft models 
against a variety of human tumor cell lines including colorectal cancer (HT-29, Colo205), non-
small cell lung cancer (H460), breast cancer (MDA-MB-435), melanoma (A375), epidermoid 
cancer (A431), and glioma (SF763T) (Mendel et al., 2003).  Sunitinib has also demonstrated 
antitumor activity against other breast cancer models (MMTV-v-Ha-ras transgenic mouse 
mammary carcinoma and dimethylbenzanthracene [DMBA]-induced rat mammary carcinomas) 
(Abrams et al., 2003b).  In an animal model of KIT-expressing small cell lung cancer (SCLC; 
NCI-H526), sunitinib administration resulted in greater tumor growth inhibition than did 
imatinib (Abrams et al., 2003a). 
Combination studies of sunitinib with docetaxel, 5-fluorouracil (5-FU), or doxorubicin resulted 
in significantly enhanced growth inhibition of human MX-1 breast cancer xenografts compared 
to levels of inhibition with either sunitinib or the cytotoxic agent alone (Abrams et al., 2003b).  
Moreover, the combination therapies each led to a significantly increased survival compared to 
either single agent alone (Abrams et al., 2003b).  Significantly delayed tumor growth has also 
been demonstrated in combination studies of sunitinib and cisplatin in NCI-H526 SCLC 
xenografts (Abrams et al., 2003a). 
Additional nonclinical in vitro and in vivo studies are summarized in Chow and Eckhardt, 2007. 
Nonclinical Toxicology Studies 
Single- and multiple-dose toxicology studies were conducted in mice, rats, rabbits, dogs, and 
monkeys (Investigator’s Brochure, 2009).  The acute oral maximally-tolerated dose (MTD) for 
mice, rats, and dogs was greater than the maximum dose of 500 mg/kg.  The MTD in monkeys 
was greater than the 1200 mg/kg maximum dose tested, but emesis occurred at doses ≥50 mg/kg.  
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A b brevi ate d Title: M olec ul ar Pr ofili n g N S C L C  
Versi o n D ate : 0 1/ 0 7/ 2 0 2 0  
 
 
 
1 5 9  
Treat me nt -relate d eff ects i n t he l y m p h oi d tiss ue, b o ne marr o w, a dre nal gla n ds, a n d b o ne gr o wt h 
plate wer e see n i n r at re p eate d - d os e st u dies wit h gastr oi ntesti nal tract, re pr o d ucti ve or ga n, 
ki d ne y, p a ncr eas, a n d pit uitar y eff ects re p ort e d at t he hi g hest d ose.  Deat h was o bser v e d at t he 
hi g hest d ose le v el of 2 4 0 m g/ k g/ da y.  Gastr oi ntesti nal dist ur ba nces ( diarr hea, l oss of a p petite, 
e mesis) as well as h e mat ol o gic dist ur ba n ces als o occ urre d i n a n 8 -wee k st u d y i n fe m ale 
m o n ke ys.  Ot h er t o xicities see n i n m o n ke ys i ncl u de d mil d ele vati o ns i n A S T, A L T, a n d 
creati ni ne ki nas e ( C K), a dre nal gla n d c orte x he m orr ha ge, aci nar de gra n ulati o n of t he sali var y 
gla n ds, d ecr ease d er yt hr o p oiesis i n t he b o ne marr o w, a n d l y m p h oi d atr o p h y.  P ossi ble 
i m pair me nt of i m m u ne f u ncti o n i n t he hi g hest d ose gr o u p was ma nifeste d as c yt o m e gal o vir us 
a n d bacterial i nfecti o ns.  T here is a n i n dicati o n t hat re peate d hi g h d os es of s u niti ni b ma y l ea d t o 
car diac f u ncti o n/c o ntr actilit y c ha n ges as c o nfir m e d b y altere d E C G a n d M U G A or 
ec h ocar di o gra p hi c par a meters a n d i ncreas e d c T nI a n d/ or T i n si n gle a ni mals t hat die d or were 
e ut ha nize d earl y d ue t o a m ori b u n d c o n diti o n.  T hese c ha n ges a p p ear t o be pri maril y f u n cti o nal 
a n d re versi ble.  D ue t o t h e p o or cli nical c o n diti o n of t hese a ni mals , it a p pears t hat t he car di ac 
c ha n ges w ere n ot a direct res ult of s u niti ni b treat me nt, b ut rat her res ulte d fr o m a n i m p orta nt, 
n o nc o m pe nsate d v ol u me l oss a n d a d diti o nal s u p pressi o n of heart f u ncti o n d ue t o c hr o n otr o pic 
i nc o m pete nce a n d p ossi ble m y ocar dial i n v ol ve me nt of u ncertai n eti ol o g y.  Data fr o m t his st u d y 
i n dicate t hat f u ncti o nal car diac c ha n ges were i n d uce d pri maril y at t he hi g h est d ose of s u niti ni b. 
S u niti ni b was f o u n d t o be ne gati ve f or ge n ot o xicit y i n vi v o a n d i n vitr o. W o u n d- heali n g st u dies 
s h o we d a s u btle tra nsie nt dela y i n s ki n w o u n d heali n g i n mice treate d c o nti n u o usl y f or u p t o 5 
wee ks wit h s u prat h era p e utic d oses of s u niti ni b at 8 0 m g/ k g/ da y.  H o w e ver, it was deter mi ne d 
t hat t his alterati o n i n w o u n d heali n g h as mi ni mal bi ol o gic si g nifica n ce. 
N o ncli nic al P h ar m ac oki netics 
Si n g le- d ose p h ar mac o ki n etics ( P K) was e val uate d i n mice, rats, ra b bits, d o gs, a n d m o n ke ys at 
oral d oses of 2 0, 4 0, 8 0, a n d 1 6 0 m g/ k g, res pecti v el y (I n vesti gat or’s Br o c h ure, 2 0 0 9).  At t hes e 
d oses, t he res pecti ve T m a x val ues i n mice were 3, 3, 0. 5, a n d 6 h o urs, w hile C ma x val ues were 
4 2 0, 7 0 8, 8 7 7, a n d 2 6 7 0 m g/ m L, res pecti vel y.  I n m o n ke ys, t 1/ 2 , t 1/ 2, a n d t 1/2  wer e 4, 
1 4. 9, a n d 2 5 2 h o urs, res p ecti vel y.  Re peat- d ose P K st u dies i n dicate d t hat i ncreas es i n e x p os ure 
were n ot c o nsiste ntl y pr o p orti o nal t o d ose.  Stea d y state plas ma c o nce ntrati o ns were reac he d 
after 2 8 d a ys of d osi n g wit h little c ha n ge i n le vels t hereafter.  S u niti ni b a p peare d t o rea dil y 
distri b ute i nt o t he C N S i n mice a n d t o a lesser e xte nt i n rats a n d m o n ke ys. 
S u nit i ni b meta b olis m is pre d o mi na ntl y me di ate d b y C Y P 3 A 4 a n d pr o d uces a n acti ve meta b olite, 
S U 0 1 2 6 6 2.  T his meta b olite a n d s u niti ni b were t he o nl y maj or dr u g-relate d c o m p o u n ds f o u n d i n 
t he s yste mic circ ulati o n i n mice, rats, m o n ke ys a n d h u ma ns.  S u niti ni b a n d its maj or meta b olite 
are hi g hl y ( 9 0- 9 8 %) pr ot ei n b o u n d i n m o use, rat, m o n ke y, a n d h u ma n plas ma.  I C 5 0 v al ues 
meas ure d i n vitr o are e x pecte d t o be r eac he d wit h t he c urre ntl y rec o m me n d e d 5 0 m g d os e.  
S u niti ni b a n d S U 0 1 2 6 6 2 are n ot p ote nt i n d ucers or i n hi bit ors of maj or C Y P 4 5 0 e nz y mes.  
T heref ore, t he y are b ot h pre dicte d t o ha v e a l o w p ote ntial t o ca use cli nicall y rele va nt dr u g -dr u g 
i nteracti o ns me diate d b y C Y P 4 5 0 e nz y m es a n d effl u x tra ns p orters.  H o we v er, c o nc urre nt 
treat me nt wit h C Y P 3 A 4 i n d ucers a n d i n hi bit ors ma y affect s u niti ni b meta b olis m. 
Cli nic al Ex perie nce  
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As of June 2008, 9204 subjects had received at least one dose of sunitinib in 77 completed or 
ongoing clinical studies, with 8986 subjects having received multiple doses of the agent 
(Investigator’s Brochure, 2009).  In phase 1 studies, sunitinib demonstrated single-agent activity 
in patients with RCC, GIST, non-GIST sarcomas, non-small cell lung cancer (NSCLC), 
colorectal cancer, neuroendocrine tumors (NET), melanoma, prostate cancer, and thyroid cancer.  
Sunitinib has also been studied in the phase 1 setting in patients with acute myeloid leukemia 
(AML).  Pivotal trials of sunitinib in imatinib-resistant GIST (a placebo-controlled phase 3 trial), 
and metastatic RCC (MRCC) (single-arm, non-randomized, multicenter, open-label trial) and 
supporting trials in each disease were completed and submitted in support of the New Drug 
Application (NDA).  In addition, there are several ongoing company-sponsored single agent and 
combination clinical trials for a variety of other indications. 
Phase 1 Experience 
In an early phase 1 study designed to investigate dosing regimen and scheduling (in human 
subjects, the results of clinical pharmacology studies demonstrate that Cmax and AUC increased 
in a proportional manner after single doses of 50 to 350 mg as well as after multiple doses of 25-
100 mg), 41 patients with a variety of advanced solid tumors received sunitinib administered on 
a schedule of 2 weeks of treatment followed by 2 weeks off (2/2 schedule) or 4 weeks on with 2 
weeks off (4/2 schedule) (Rosen et al., 2003).  Doses evaluated on the 2/2 schedule (n=23) 
included 50 mg every other day (n=3), 50 mg daily (n=15), or 75 mg daily (n=5); the 18 patients 
enrolled in the 4/2 schedule received 25 mg daily (n=3) or 50 mg daily (n=15).  The most 
frequent adverse events (AEs) were constitutional (fatigue/asthenia), gastrointestinal (nausea, 
vomiting, diarrhea) and hematologic (neutropenia, thrombocytopenia).  Most of the AEs were 
grade 1 or 2, although at 75 mg daily, grade 3 and 4 fatigue/asthenia were dose limiting but 
readily reversible on discontinuation of treatment.  There were 4 partial responses (PRs) assessed 
by RECIST and 22 patients with stable disease (SD) among the 41 patients. 
A phase 1 dose-escalation study in 28 patients with advanced tumors evaluated sunitinib doses of 
30 mg/m2 every other day, and doses of 30, 42, or 59 mg/m2 daily on the 4/2 schedule (Faivre et 
al., 2006).  Grade 3 fatigue and hypertension were dose limiting at 59 mg/m2 as well as grade 2 
bullous skin toxicity, and the MTD was defined as 42 mg/m2 daily.  Based on these and other 
reversible AEs in the 12 patients treated at the MTD, the recommended phase 2 dose on the 4/2 
schedule was determined to be 50 mg/day.  Responses determined by RECIST were seen in 6 of 
23 evaluable patients: 3 in RCC, 1 in NET, 1 in GIST, and 1 in adenocarcinoma of unknown 
primary.  Tumor responses in patients treated at higher doses were often associated with reduced 
intratumoral vascularization and central tumor necrosis, leading to organ perforation in one 
patient and fistula in another.  These observations suggest the possible necessity for careful 
tumor density monitoring to detect early evidence of necrosis. 
Two phase 1 studies have been conducted in AML, the first with the primary endpoint of 
evaluation of the inhibition of FLT3 phosphorylation (O’Farrell et al., 2003b) and the second 
designed as a conventional dose-escalation study (Fiedler et al., 2005).  O’Farrell and colleagues 
studied FLT3 phosphorylation in 29 AML patients who received a single dose of sunitinib at 
doses ranging from 50-350 mg.  Over 50% of patients showed strong inhibition of Flt3 
phosphorylation at doses of 200 mg and higher.  As anticipated from nonclinical data, patients 
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with FLT3 internal tandem duplication (ITD) mutations were more sensitive than those with 
wild-type Flt3 (FLT3-WT) as shown by 100% inhibition in FLT3-ITD compared to 50% in 
FLT3-WT.  This study also gave evidence of downstream signal inhibition (STAT5 and ERK 
pathways), with STAT5 levels reduced primarily in FLT3-ITD patients while ERK inhibition 
occurred in the majority of patients independently of FLT3 inhibition.  The dose-escalation study 
enrolled 15 patients with refractory or resistant AML who were treated with sunitinib on either 
the 4/2 or 4/1 schedule at a starting dose of 50 mg/day (Fiedler et al., 2005).  Dose-limiting AEs 
(grade 4 fatigue and hypertension) occurred in both patients treated at 75 mg/day, and one of 
these patients (who had received prior mitoxantrone) developed cardiac failure.  The 75 mg dose 
level was therefore terminated and 50 mg/day was considered to be the MTD.  All four patients 
with FLT3 mutations had morphologic or partial responses compared to 2 of 10 evaluable 
patients with wild-type FLT3.  Responses, although longer in patients with mutated FLT3, were 
of short duration. 
Preliminary results from phase 1 studies exploring the combination of sunitinib with 
chemotherapeutic agents like capecitabine (Sweeney et al., 2007; Chiorean et al., 2008; Royce et 
al., 2008), pemetrexed (Chow et al., 2008), docetaxel (Traynor et al., 2008), gemcitabine (Brell 
et al., 2008; Michaelson et al., 2008), FOLFOX (Leong et al., 2007), FOLFIRI (Starling et al., 
2008), carboplatin/paclitaxel (Heath et al., 2008), and metronomic 
cyclophosphamide/methotrexate (Rugo et al., 2008) in patients with various solid tumors have 
been presented.  The MTD of sunitinib on the 4/2 schedule with docetaxel (60 mg/m2) was 25 
mg daily; with capecitabine (1000 mg/m2), it was 37.5 mg daily.  The MTD of sunitinib on the 
2/1 schedule with docetaxel (75 mg/m2) was 37.5 mg daily and with capecitabine (1000 mg/m2) 
was 50 mg daily. The MTD for sunitinib as continuous daily dosing (CDD) with capecitabine 
(1000 mg/m2) was 37.5 mg daily and for pemetrexed (500 mg/m2) was 37.5 mg daily.  Reported 
DLTs included febrile neutropenia, fatigue, hand-foot syndrome, gastrointestinal hemorrhage, 
cerebral hemorrhage, and ischemic optic neuropathy.  Phase 1 trials evaluating the combination 
of sunitinib with other targeted agents like temsirolimus (Patel et al., 2009; Fischer et al., 2008), 
bevacizumab (Feldman et al., 2008; Cooney et al., 2008) and IFN- α (Motzer et al., 2009a) have 
shown problems with increased toxicity in patients with RCC (Feldman et al., 2008, Fischer et 
al., 2008; Motzer et al., 2009a).  However, the combination of bevacizumab with sunitinib in 
patients with miscellaneous solid tumors was well tolerated (Cooney et al., 2008). 
Phase 2 and 3 Experience 
Updated results have recently been published on 750 patients with MRCC treated on a phase 3 
study of sunitinib at a daily dose of 50 mg on the 4/2 schedule compared to interferon (IFN)-α 9 
MU subcutaneously thrice weekly (Motzer et al., 2009b).  Median overall survival (OS) was 
greater in the sunitinib group than in the IFN-α group (26.4 vs. 21.8 months, respectively).  
Sunitinib treatment was associated with a higher objective response rate (RR) than IFN-α (47% 
vs. 12%, respectively).  Eleven patients in the sunitinib group and four patients in the IFN-α 
group achieved a complete response per investigator assessment.  Median progression-free 
survival (PFS) was 11 months for sunitinib compared with 5 months for IFN-α.  The most 
commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), 
fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%).  An exploratory analysis, which 
censored 25 patients from the IFN-α group who had crossed over to receive sunitinib on study, 
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showed a median OS time of 26.4 months for sunitinib compared with 20 months for the IFN-α 
group.  Results from a phase 1/2 dose-finding trial of sunitinib plus gefitinib, enrolling 42 
patients, have been published (Motzer et al., 2010).  In phase 1, patients received sunitinib 37.5 
or 50 mg on the 4/2 schedule plus gefitinib 250 mg, both once daily. The MTD was determined 
to be 37.5 mg.  Two DLTs were observed with the 50 mg dose: grade 2 left ventricular ejection 
fraction decline and grade 3 fatigue.  In phase 2, patients received sunitinib at the MTD plus 
gefitinib.  Thirteen patients treated at the MTD achieved a partial response and 12 had stable 
disease.  Median PFS was 11 months.  The most commonly reported grade 3/4 adverse event was 
diarrhea.   
The promising results in phase 1 trials and the involvement of KIT and PDGFR-α, two of the 
sunitinib target RTKs in GIST led investigators to undertake a phase 1/2 trial in patients with 
GIST refractory or intolerant to imatinib to determine an appropriate dose and regimen for phase 
2 development of sunitinib in this disease.  Patients received up to 75 mg sunitinib daily on the 
2/2, 4/2, or 2/1 schedule, with 50 mg daily on the 4/2 schedule being selected for continued 
study.  In all, 75 patients were treated on the trial.  Among 41 patients treated for at least 6 
months, 6 had an objective response (OR; RECIST criteria) and an additional 16 had cessation of 
disease progression and minor responses for >6 months.  Overall, 54% of the 41 patients had 
evidence of clinical benefit (OR or PFS) (Desai et al., 2004).  Determination of the GIST 
genotype in these 41 patients showed that clinical benefit had been achieved in several secondary 
mutational variants that conferred imatinib resistance (Demetri et al., 2004).  Fifty-three of the 
GIST patients treated on this trial subsequently underwent serial 18FDG-PET imaging where 
qualitative responses were graded as good in 33/53 patients, mixed in 15/53, and poor in 5/53 
(Dileo et al., 2005).  Correlation with clinical response (Fisher’s exact p=0.03) showed that 22 of 
33 patients graded as good by 18FDG-PET imaging had clinical benefit (OR or SD ≥ 6 months) 
after 6 months of therapy while 4 of 15 patients graded as mixed had benefit as did 2 of 5 
patients graded as poor.  
Data from a pivotal multinational, randomized (2:1), double-blind, placebo-controlled phase 3 
trial in over 300 patients with imatinib-resistant GIST has shown significant clinical effect with 
sunitinib compared with placebo (Demetri et al., 2006).  Patients on the active treatment arm 
received sunitinib at a dose of 50 mg daily on the 4/2 schedule.  The median TTP for the 
treatment arm (n=207) was 27.3 weeks compared to a median of 6.4 weeks for placebo (n=105) 
(p<0.0001).  Therapy was reasonably well tolerated; the most common adverse events were 
fatigue, diarrhea, skin discoloration and nausea. 
In addition to patients with RCC and GIST, sunitinib has been evaluated in breast cancer 
(Burstein et al., 2008), NSCLC (Socinski et al., 2008), transitional cell carcinoma (TCC) 
(Gallagher et al., 2008), NET (Kulke et al., 2008), thyroid carcinoma (Cohen et al., 2008), 
certain subtypes of sarcoma (Keohan et al., 2008; Vigil et al., 2008), gastro-eosophageal cancer 
(Moehler et al., 2009), high-grade glioma (Chaskis et al., 2008), squamous cell carcinoma of the 
head and neck (SCCHN) (Choong et al., 2008), hepatocellular carcinoma (HCC) (Zhu et al., 
2008), colorectal carcinoma (CRC) (Saltz et al. 2007; Starling et al., 2008; Pfeiffer et al., 2009) 
and uveal melanoma (Chan et al., 2008).  Results from these trials have been summarized in Gan 
et al., 2009. 
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Safety Profile 
Sunitinib is reasonably well tolerated, with asthenia, hypertension, dermatitis, and mild 
myelosuppression as the most common AEs (Stadler, 2006).  Additionally, the inhibition of TK 
receptors by agents such as sunitinib can result in cutaneous AEs such as acral erythema, 
subungal splinter hemorrhages, modification of hair and skin pigmentation, mucositis, and 
(occasionally) periocular edema (Robert et al., 2005; Suwattee, 2008).  Hand-foot skin reaction, 
a group of signs and symptoms that can affect, usually bilaterally, the hands and/or feet of 
patients, has occurred in patients receiving sunitinib (Porta et al., 2007; Suwattee, 2008).  A 
recent analysis of dermatological AEs in patients receiving sunitinib therapy has reported that 
all-grade hand-foot skin reactions occurred in 19% of patients (5% grades 3-4), skin 
discoloration in 28% (no grades 3-4), dry skin in 16% (1% grades 3-4), skin rash in 13% (1% 
grades 3-4), dermatitis in 8% (2% grades 3-4), hair color changes in 10% (no grades 3-4), 
alopecia in 6% (no grades 3-4), and phototoxicity in <0.1% (no grades 3-4) (Rosenbaum et al., 
2008). 
Cardiotoxicity, including congestive heart failure (3%-8%) and left ventricular dysfunction 
(12%-14%), has been reported in patients undergoing treatment with sunitinib (Chu et al., 2007; 
Khakoo et al., 2008; Schmidinger et al., 2008; Telli et al., 2008).  More subjects treated with 
sunitinib experienced decline in left ventricular ejection fraction (LVEF) than subjects receiving 
either placebo or IFN-α (Investigator’s Brochure, 2009).  In a phase 3 GIST study in subjects 
with imatinib-resistant or -intolerant GIST, 22 of 209 (11%) subjects on sunitinib and 3 of 102 
(3%) subjects on placebo had treatment-emergent LVEF values below the lower limit of normal 
(LLN).  In a phase 3 study treatment-naive RCC patients, 27% and 15% of subjects on sunitinib 
and IFN-α, respectively, had an LVEF value below the LLN.  Among 461 patients enrolled in 
CDUS-monitored trials with sunitinib alone, 2% of patients experienced left ventricular systolic 
dysfunction (CDUS data).  It is unknown whether patients with concurrent cardiac conditions 
may be at a higher risk for developing drug-related LVEF.  Baseline and periodic evaluations of 
LVEF should be considered while these patients are on sunitinib treatment.  In patients without 
cardiac risk factors, a baseline evaluation of LVEF should be considered. 
Sunitinib has been shown to prolong the QT interval in a dose-dependent manner, which may 
lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes.  This 
condition has been reported in <0.1% of sunitinib-exposed patients.  The DCTD, NCI, issued an 
IND AE Action Letter to all investigators using sunitinib describing the occurrence of QTc 
prolongation and Torsade de pointes (ventricular tachycardia) in patients on clinical trials 
utilizing sunitinib.  As a result of this Action Letter, DCTD, NCI-sponsored sunitinib protocols 
were amended to include the requirement for a baseline EKG prior to study treatment, exclude 
patients with histories of serious ventricular arrhythmias or prolonged QTc, and exclude patients 
with certain cardiac conditions. 
Among 8054 solid tumor subjects treated with single-agent sunitinib, Grade 3 hypertension was 
reported in 6.1% of patients and was one of the most commonly reported Grade 3 AEs.  Of 
subjects receiving sunitinib for treatment-naive MRCC, 34% receiving sunitinib experienced 
hypertension, compared with 4% on IFN-α.  Grade 3 hypertension was reported in 13% of 
treatment-naive metastatic RCC subjects on sunitinib compared to <1% on IFN-α.  Severe 
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hypertension occurred in 4% GIST subjects on sunitinib, 1% GIST subjects on placebo, 9% RCC 
subjects on sunitinib and 1% RCC subjects on IFN-α (Investigator’s Brochure, 2009).  Among 
461 patients enrolled in CDUS-monitored trials with sunitinib alone, 28% experienced 
hypertension (CDUS data). 
In subjects receiving sunitinib for treatment-naive MRCC, 37% had bleeding events compared 
with 8% receiving IFN-α (Investigator’s Brochure, 2009).  Bleeding events occurred in 18% of 
patients receiving sunitinib in the double-blind treatment phase of the GIST phase 3 study, 
compared with 17% receiving placebo.  Among 461 patients enrolled in CDUS-monitored trials 
with sunitinib alone or in combination with other agents, there were 103 reported bleeding events 
(CDUS data).  Epistaxis was the most common hemorrhagic AE reported.  Tumor-related 
hemorrhage can occur with sunitinib and in the case of pulmonary tumors, may present as severe 
and life-threatening hemoptysis or pulmonary hemorrhage. 
Hypothyroidism has been reported in 71% patients with RCC (Rini et al., 2007) and in 36% of 
those with GIST (Desai et al, 2006) treated with sunitinib.  Among subjects treated with single-
agent sunitinib, hyperthyroidism was reported in 0.6% and thyroiditis in 0.1% (Investigator’s 
Brochure, 2009).  Baseline measurement of thyroid function is recommended, and patients with 
thyroid dysfunction should be treated appropriately prior to starting sunitinib therapy. 
Nonclinical evidence of adrenal toxicity following sunitinib exposure led the company to 
perform specialized safety assessments in clinical studies, including computed tomography or 
MRI in 336 subjects to specifically identify any change in adrenal gland structure or the presence 
of adrenal gland hemorrhage (Investigator’s Brochure, 2009).  Neither event was observed.  
Adrenocorticotropic hormone (ACTH) stimulation testing was done in 400 patients across 
multiple sunitinib trials.  One subject developed consistently abnormal test results during 
treatment that were unexplained and may be related to sunitinib treatment.  Eleven additional 
subjects had abnormailities in the final test, with low peak cortisol levels.  None of these patients 
had clinical evidence of adrenal insufficiency.  However, based on the nonclinical findings, 
patients receiving sunitinib should be clinically followed for signs and symptoms of adrenal 
insufficiency, especially in (1) patients with comorbidities associated with adrenal dysfunction, 
(2) patients with preexisting adrenal insufficiency (primary or secondary), and (3) patients with 
concomitant stress (e.g., fever, infection, bleeding, serious accident, surgery) that may precipitate 
overt adrenal insufficiency in the presence of subclinical sunitinib-induced adrenal toxicity. 
Diarrhea, nausea, abdominal pain, vomiting, constipation and dyspepsia are some of the most 
frequent AEs reported with sunitinib (Investigator’s Brochure, 2009).  Serum chemistries 
including phosphate should be performed at the beginning of each treatment cycle.  Supportive 
care may include anti-emetic premedication, supportive oral care products, and analgesics.  
Serious complications due to degeneration or shrinkage of tumors, including gastrointestinal 
perforation and tracheoesophageal fistula, have occurred rarely in patients with abdominal, head 
and neck, thyroid, and other malignancies treated with sunitinib, believed to be the result of the 
antitumor effect of sunitinib.  Other serious effects include thromboembolic events, rare 
reversible posterior leukoencephalopathy syndrome (RPLS), proteinuria with rare nephrotic 
syndrome, and rare microangiopathic hemolytic anemia.  
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Orally-administered sunitinib is well absorbed in humans, with linear pharmacokinetics (PK) at 
doses of 50-150 mg/day (Sakamoto, 2004).  Sunitinib is highly protein-bound and metabolized 
through N-de-ethylation by cytochrome P450 (CYP) 3A4 to SU12662 (Investigator’s Brochure, 
2009).  SU12662 has a similar inhibitory profile to sunitinib in vitro and similar protein binding 
properties.  SU12662 is further metabolized by CYP3A4 to a minor inactive metabolite 
(Investigator’s Brochure, 2009). 
The PK of sunitinib was studied in a variety of company-sponsored studies in both healthy 
volunteers (n=135) and in patients with solid tumors (n=266), including GIST and metastatic 
RCC; the PK was similar in the volunteers and in those with solid tumors.  Terminal half-lives 
(t1/2) of sunitinib and SU12662 are 40-60 hours and 80-110 hours, respectively, with a time to 
maximum concentration (Tmax) of 6-12 hours for sunitinib and its primary active metabolite, 
followed by a biexponential decline in concentrations.  The PK of sunitinib and SU12662 were 
measured in a phase 1 dose-escalation study in patients with advanced solid malignancies (Faivre 
et al., 2006).  Twenty-eight patients received doses ranging from 15 mg/m2 to 59 mg/m2 
(ranging from 50 mg every other day to 150 mg/day), on a 4 weeks on, 2 weeks off (4/2) 
schedule.  Concentration-versus-time data were analyzed using a noncompartmental analytic 
technique.  Overall, sunitinib displayed a long half-life and a large volume of distribution with 
moderate interpatient variability.  Trough plasma concentrations of sunitinib and SU12662 
increased with increasing doses.  However, area under the concentration-time curve (AUC) 
values increased less than proportionally with dose.  Accumulation ratios of sunitinib were >1, 
with detectable trough drug levels, suggesting drug accumulation over time.  At the 
recommended dose, maximum plasma concentration (Cmax) occurred approximately 5 hours 
after administration and t1/2 ranged from 41-86 hours.  Doses of 50 mg daily led to plasma 
concentrations ranging from 50-100 ng/mL.  Most patients with DLTs had combined (sunitinib 
plus SU12662) trough plasma concentrations ≥100 ng/mL (Faivre et al., 2006). 
PK values determined from body surface area (BSA)-based doses were adjusted to reflect fixed 
doses of 50, 75-100, and 100-150 mg doses to determine if there was a need for BSA-based 
dosing to be employed.  AUC sum values obtained using BSA-normalized and fixed dosing were 
found to be comparable, suggesting that normalizing the dose based on BSA would not improve 
variability.  Therefore, fixed dosing on a milligram basis was considered appropriate for phase 2 
studies (Faivre et al., 2006). 
To determine the effect of food on the PK of sunitinib and its active metabolite SU12662, 16 
healthy subjects received a single dose of sunitinib 50 mg under fasting conditions and 14 
subjects received a single dose of sunitinib 50 mg under fed conditions (Bello et al., 2006).  
Subjects were randomized to one of two treatment sequences each comprising two treatment 
periods (fasted and fed).  In Sequence 1, the fasted treatment period was followed by the fed 
treatment period, and for Sequence 2, the fasted period followed the fed period.  For the fasted 
period, a single oral (PO) dose of sunitinib 50 mg was administered after a 10-hour fast.  For the 
fed period, a single PO dose of sunitinib 50 mg was administered within 30 minutes of a high-
fat, high-calorie meal.  A washout period of at least 4 weeks separated sunitinib dosing between 
the two treatment periods.  Two subjects in Sequence 1 discontinued prematurely due to grade 1 
and 2 rash, but PK information was collected and included in the analysis.  Only a negligible 
difference in Tmax of sunitinib was observed between fed and fasted treatment periods; 
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SU12662 Tmax was prolonged by 2 hours (median difference) in the fed compared with the 
fasted state.  The 90% confidence intervals (CIs) for Cmax and AUC were within the 80-125% 
bioequivalence range, indicating the absence of food effect.  Sunitinib exposure increased 
slightly in the fed compared with the fasted state (ratios of fed/fasted geometric least square 
means: Cmax 104%, AUC0-last and AUC0-∞ both 112%).  There was a delay in the 
formation/absorption of the active metabolite SU12662 in the fed state (mean Cmax decreased 
23%), but exposure remained unaffected (90% CIs for AUC 0-last and AUC0-∞ were within 80-
125%).  Sunitinib and SU12662 half-lives, and oral clearance of sunitinib, were not affected by 
food (Bello et al., 2006). 
A study of sunitinib PK in patients with AML indicated that a plasma concentration of 50-100 
ng/mL of combined sunitinib and SU12662 could be achieved on the first cycle of a 50 mg/day 
4/2 regimen, similar to that achieved in studies with patients having other tumor types (Fiedler et 
al., 2005). 
In a phase 1 trial of sunitinib given on the 4/2 schedule in pediatric patients with relapsed or 
refractory solid tumors, the median day 21 steady-state trough sunitinib plasma concentration 
was 24.6 ng/mL (range, 6.0-37.7 ng/mL) at the 15 mg/m2 dose and 37.4 (range, 24.2-62.9 
ng/mL) at the 20 mg/m2 dose (DuBois et al., 2008). 
Population PK methods indicated that the covariates of weight, gender, race, ethnicity, ECOG 
score, and tumor type had no clinically significant effects on drug exposure, and that adjustments 
of starting doses based on these covariates were not required (Investigator’s Brochure, 2009). 
Concurrent administration of a single dose of sunitinib with ketoconazole (a CYP3A4 inhibitor) 
in healthy volunteers resulted in 49% and 51% increases in the combined (sunitinib + SU12662) 
Cmax and AUC0-∞ values, respectively, compared with sunitinib alone (Washington et al., 
2003).  Concurrent administration of sunitinib and rifampin (a potent CYP3A4 inducer) in 
healthy subjects resulted in 23% and 46% reduction in combined Cmax and AUC0-∞, 
respectively, compared with sunitinib alone (Bello et al., 2005).  Thus, dose adjustments for 
sunitinib should be considered when coadministered with CYP3A4 inhibitors and inducers. 
Proposed Dose and Schedule for Phase 2 Clinical Trials 
Starting doses in multiple-dose studies were 25, 50, 75, and 100 mg administered orally once 
daily with the majority of patients receiving the 50-mg dose.  Patients in sunitinib studies have 
been treated on four different schedules: schedules 4/1 and 4/2 comprised 4 consecutive weeks of 
daily dosing followed by a 1- or 2-week rest period, respectively, while schedules 2/1 and 2/2 
comprised 2 consecutive weeks of daily dosing followed by a 1- or 2-week rest period, 
respectively.  The majority of subjects were treated on schedules 4/2 or 2/2 in phase 1 studies.  
Schedule 4/2 has been well tolerated with generally mild to moderate adverse effects at a 50 mg 
daily dose.   Alternate regimens of sunitinib are being explored; 50 mg of sunitinib daily for 2 
weeks followed by a 1-week off-treatment period (sunitinib 2/1) (Britten et al., 2008), while 
another schedule is sunitinib 37.5 mg as a CDD (George et al., 2008).  Both schedules were well-
tolerated, achieved therapeutic plasma concentrations and showed no significant accumulation of 
the drug.  
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18.2 Appendix B: Medication Diaries 
 
 
18.2.1  AZD6244 hydrogen sulfate  
PATIENT’S MEDICATION DIARY 
 Today’s date _________________________ 
Agent______AZD6244_____________ 
 Patient Name_____________________(initials acceptable)  Patient Study 
ID____________________ 
1. 
Complete one form for each cycle of treatment. 
2. 
AZD6244 should be stored at room temperature. 
3. 
You will take AZD6244 by mouth twice each day about 12 hours apart.  Take the medicine on an empty 
stomach (no food or drink other than water for 1 hour before or 2 hours after dosing).    
 
Morning dose:  take _____ mg  (____capsules) AZD6244. *********** Evening dose:   take _____ mg 
(____capsules)  AZD6244. 
4. 
Record the date, the number of AZD6244 capsules you swallowed in the morning and again in the 
evening, and when you swallowed the medicine.   
5.        Record the daily dose onto the diary, including missed, skipped, or vomited doses.  If you vomit after 
taking the tablets, the dose is replaced only if the tablets can actually be seen and counted.  If you miss a 
dose, you should resume with the next scheduled dose.  
6. 
If you have any comments or notice any side effects, please record them in the Comments column.   
7. 
Please bring this form and your bottles of AZD6244 when you return for each appointment.   
 
Day 
 
Date 
Time of 
morning 
dose 
Dose taken 
Time of 
evening 
dose 
Dose taken 
Comments 
# of capsule 
taken 
 
# of capsule 
taken 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
CTEP-assigned Protocol #___________ 
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5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
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11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
Patient’s signature  __________________________________________________________ 
Physician’s Office will complete this section: 
1. 
Date patient started protocol _____________________________________________________ 
2. 
Date patient was removed from __________________________________________________________ 
3. 
Patient’s planned total daily dose________________________________________________________ 
4. 
Total number of capsules taken this month _____________________________________________ 
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5. 
Physician/Nurse/Data Manager’s Signature ______________________________________________ 
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18.2.2 MK-2206 
PATIENT’S MEDICATION DIARY 
Today’s date _____________________ 
 
 
Agent:  MK-2206 
Patient Name_____________________(initials acceptable)  
 Patient Study 
ID_________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle of treatment. 
2. You will take MK-2206 tablets by mouth once every week.  You should take the tablets 2 hours 
before or after a meal. 
3. Dose:  take _______5 mg tablet(s), _______25 mg tablet(s), and/or ________ 200 mg tablet(s) 
once every week. 
4. Record the date, the number of tablets of each size of tablet that you took, and when you took 
them.   
5. Record the daily dose onto the diary, including missed, skipped, or vomited doses.  If you vomit 
after taking the tablets, the dose is replaced only if the tablets can actually be seen and counted.  If 
you miss a dose, you should resume with the next scheduled dose.  
6. If you have any comments or notice any side effects, please record them in the Comments column.  
7. Please bring this form and your bottles of MK-2206 tablets when you return for each appointment. 
 
Day 
 
Date 
 
Time of 
dose 
# of tablets taken 
Comments 
5 mg 
25 mg 
200 
mg 
 
1 
 
 
 
 
 
 
2-7 
 
 
 
 
 
Days 2-7 drug holiday 
8 
 
 
 
 
 
 
9-14 
 
 
 
 
 
Days 9-14 drug holiday 
15 
 
 
 
 
 
 
16-21  
 
 
 
 
Days 16-21 drug holiday 
22 
 
 
 
 
 
 
23-28  
 
 
 
 
Days 23-28 drug holiday 
 
CTEP-assigned Protocol #___________ 
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               Patient’s signature  
_________________________________________________________________________ 
      Physician’s Office will complete this section: 
         1. 
Date patient started protocol treatment  __________________________________________ 
         2. 
Date patient was removed from study  ________________________________________ 
         3. 
Patient’s planned total daily dose  ____________________________________________ 
         4. 
Total number of tablets taken this month  _____________________________________ 
         5. 
Physician/Nurse/Data Manager’s Signature  ______________________________________ 
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18.2.3 Sunitinib 
PATIENT’S MEDICATION DIARY 
Today’s date _______________________________  
Agent:  Sunitinib 
Patient Name___________________ (initials acceptable) Patient Study ID _______________ 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each 4 week-period while you take sunitinib. 
2. You will take your dose of sunitinib by mouth each day in the morning.  You will take ____12.5 mg 
capsule(s), and/or ____ 25 mg capsule(s); or ___ 50 mg capsule.  You may take the capsules with or 
without food as you wish. 
3. Record the date, the number of capsules of each size you took, and when you took them.  
4.  Record the daily dose onto the diary, including missed, skipped, or vomited doses.  If you vomit after 
taking the tablets, the dose is replaced only if the tablets can actually be seen and counted.  If you miss 
a dose, you should resume with the next scheduled dose.  
5. If you have any comments or notice any side effects, please record them in the Comments column.   
6. Wash your hands with soap and water after touching the capsule(s).  Do not share this medication with 
anyone. 
7. Please return unused sunitinib capsules (or empty bottles) and this form to your physician when you 
go for your next appointment. 
 
Day 
 
Date 
Time of 
daily dose 
 
# of capsules 
taken 
Comments 
12.5 mg 25 mg 
50 mg 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
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13 
 
 
 
 
 
 
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17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29-42  
 
 
 
 
Days 29-42 drug holiday 
               Patient’s signature  ______________________________________________________ 
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      Physician’s Office will complete this section: 
         1. 
Date patient started protocol treatment  __________________________________________ 
         2. 
Date patient was removed from study  ________________________________________  
         3. 
Patient’s planned total daily dose  ____________________________________________ 
         4. 
Total number of tablets taken this month    ___________________________________ 
         5. 
Physician/Nurse/Data Manager’s Signature  ______________________________________ 
 
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18.2.4 Erlotinib 
PATIENT’S MEDICATION DIARY 
Today’s date _____________________ 
 
 
Agent:  Erlotinib 
Patient Name_____________________(initials acceptable)  Patient Study ID 
________________ 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle of treatment. 
2. You will take theErlotinib tablets by mouth once every day.  You will take ____ 25mg tablets, 
____100mg tablet, ____150mg tablet.  You should take the tablets either 1 hour before or two hours 
after a meal. Take the tablets with 8 ounces of water. 
3. Record the date, the number of tablets of each size of tablet that you took, and when you took them.  
4.  Record the daily dose onto the diary, including missed, skipped, or vomited doses.  If you vomit 
after taking the tablets, the dose is replaced only if the tablets can actually be seen and counted.  If 
you miss a dose, you should resume with the next scheduled dose.  
5. If you have any comments or notice any side effects, please record them in the Comments column.   
6. Please bring this form and your bottles of Erlotinib tablets when you return for each appointment. 
 
Day 
 
Date 
 
Time of 
dose 
# of tablets taken 
Comments 
mg 
mg 
mg 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
CTEP-assigned Protocol #___________ 
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11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
               Patient’s signature  
_________________________________________________________________________ 
      Physician’s Office will complete this section: 
         1. 
Date patient started protocol treatment  ______________________________________ 
         2. 
Date patient was removed from study  _______________________________________  
         3. 
Patient’s planned total daily dose  __________________________________________ 
         4. 
Total number of tablets taken this month  ________________________________________ 
         5. 
Physician/Nurse/Data Manager’s Signature  ______________________________________ 
 
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18.2.5 Lapatinib 
PATIENT’S MEDICATION DIARY 
Today’s date _____________________ 
 
 
Agent:  Lapatinib 
Patient Name_____________________(initials acceptable)  Patient Study ID _______________ 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle of treatment. 
2. You will take Lapatinib tablets by mouth once every day.  You should take the tablets 1 hours before 
or after a  meal 
Dose:  take ___ mg tablets. 
3. Record the date, the number of tablets of each size of tablet that you took, and when you took them. 
4.   Record the daily dose onto the diary, including missed, skipped, or vomited doses.  If you vomit 
after taking the tablets, the dose is replaced only if the tablets can actually be seen and counted.  If 
you miss a dose, you should resume with the next scheduled dose.  
5. If you have any comments or notice any side effects, please record them in the Comments column.   
6. Please bring this form and your bottles of Lapatinib tablets when you return for each appointment. 
 
Day 
 
Date 
 
Time of 
dose 
# of tablets taken 
Comments 
mg 
N/A 
N/A 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
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12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
               Patient’s signature  
_________________________________________________________________________ 
      Physician’s Office will complete this section: 
         1. 
Date patient started protocol treatment  __________________________________________ 
         2. 
Date patient was removed from study  ________________________________________  
         3. 
Patient’s planned total daily dose  ____________________________________________ 
         4. 
Total number of tablets taken this month  ______________________________________ 
         5. 
Physician/Nurse/Data Manager’s Signature  _______________________________ 
 
 
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18.3 Appendix C: Performance Status Criteria 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
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18.4 Appendix D: New York Heart Association Classifications 
Clinical Evaluation of Functional Capacity of Patients with Heart Disease in Relation to Ordinary 
Physical Activity 
 
 
 
Class 
 
 
Cardiac Symptoms 
 
 
Limitations 
 
Need for 
Additional 
Rest* 
 
Physical Ability  
      to work**__ 
 
 
 
 
 
I 
None 
None 
None 
Full time 
 
 
 
 
 
II 
Only moderate 
Slight 
Usually only 
slight or 
occasional 
Usually full  
time 
 
 
 
 
 
III 
Defined, with  
less than  
ordinary activity 
Marked 
Usually 
moderate 
Usually part  
time 
 
 
 
 
 
IV 
May be present  
even at rest,  
and any activity 
increases discomfort 
Extreme 
Marked 
Unable to work 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
** 
At accustomed occupation or usual tasks. 
 
Reference: 
Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956.  
 
 (Modified from New York Heart Association, 1953). 
 
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18.5 Appendix E:  MEDICATIONS THAT MAY CAUSE QTc PROLONGATION 
The following table presents a list of drugs that prolong, may prolong or are unlikely to prolong the 
QTc. These drugs are prohibited during the treatment with some study agents. Please note that this list is 
frequently updated.  For the most current list of medications, users should be directed to the following 
website: http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.  
 
Compound 
 
Compound Half Life 
Possible 
Washout 
Period - 
Hours 
Possible 
Washout 
Period - 
Days 
Alfuzocin 
~10 hours 
 
7 
Amantadine 
17 +/- 4 hours (10-25) 
 
4 
Amiodarone (cordarone) 
58 days (15-142) 
36 days (active metabolite) 
 
180 
Amitriptyline* 
> 24 hours, wide interpatient 
variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hr (26-64) 
 
10 
Chloral hydrate 
Readily converted to 
Trichloroethanol (active metabolite 
T1/2=7-10 hour) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30 +/- 7 hours 
 
7 
Cisapride 
6 – 12 hour, up to 20 hour 
60 
 
Clarithromycin 
Non linear PK3-4 hr (250mg Q12) 
5-7 hr (500mg Q12) 
36 
 
Cloroquine 
6 to 60 days; mean 20 days 
 
 
Desipramine* 
> 24 hours, wide interpatient 
variability 
 
 
Disopyramide 
6.7 hr (4-10) 
36 
 
Dofetilide 
10 hr 
48 
 
Dolesetron 
8.1 hr 
 
 
Domperidone 
7-8 hr 
48 
 
Doxepin* 
> 24 hours, wide interpatient 
variability 
 
 
Droperidol 
2.2 hours 
10 
 
Erythromycin 
* Each salt form has different Half 
life* 
 
 
Felbamate 
20-23 hr 
 
5 
Flecainide 
20 hr (12-27) 
 
5 
Foscarnet  
87.5+/-41.8 hours 
*distribution and release from bone* 
 
20 
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Fosphenytoin 
12-29 hr 
 
6 
Gatifloxacin 
7-14 hr 
48 
 
Gemifloxacin 
7 hours 
48 
 
Grepafloxacin 
16 hr 
 
3 
Halofantrine 
6-10 days ( variable among 
individual) 
 
45 
Haloperidol 
18 +/-5 hr 
 
5 
Ibutilide 
6 hours (2-12) * variable among 
subject* 
36 
 
Imipramine* 
> 24 hours, wide interpatient 
variability 
 
 
Indapamide 
14 hours (biphasic elimination) 
 
3 
Isradipine 
8 hours ( multiple metabolites) 
48 
 
Levofloxacin 
6-8 hours 
48 
 
Levomethadyl 
Multiple compartment PK with 
active metabolite 
2.6 day for LAAM, 2 day for nor-
LAAM, 4 day for dinor-LAAM 
 
20 
Lithium 
24 hour (10-50) 
 
7 
 
Compound 
 
Compound Half Life 
Possible 
Washout 
Period - 
Hours 
Possible 
Washout 
Period - 
Days 
Mesoridazine 
24-48 hours ( animal study) 
 
10 
Methadone 
15-30 hours 
 
7 
Moexipril/HCTZ 
2-9 hour (include active metabolite) 
for moexipril; 5.6-14.8 hours for 
HCTZ  
48 
 
Moxifloxacin 
12 +/-1.3 hours 
72 
 
Naratriptan 
6 hours 
36 
 
Nicardipine 
~ 2 hour post IV infusion 
12 
 
Nortriptyline* 
> 24 hours, wide interpatient 
variability 
 
 
Octreotide 
1.7 hours 
12 
 
Ofloxacin 
5 to 7.5 hours 
 
2 
Ondansetron 
4 hours (IV/IM); 3 hours (PO) 
 
1 to 3 
Pentamidine 
6.4+/-1.3 hours 
36 
 
Pimozide 
55 hours 
 
10 
Procainamide 
3-4 hour for PA and NAPA (active 
metabolite) 
24 
 
Protiptyline* 
> 24 hours, wide interpatient 
variability 
 
 
Quetiapine 
6 hours 
36 
 
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Quinidine 
6-8 hours in adult; 3-4 hours in 
children 
36 
 
Quinine 
4-5 hours 
 
 
Risperidone 
3-20 hours (extensive to poor 
metabolizer) 
9-hydroxyrisperidone (active 
metabolite) T ½ =21-30 hours 
(extensive to poor metabolizer) 
 
4 
Salmeterol 
5.5 hours ( only one datum) 
36 
 
Sotalol 
12 hours 
72 
 
Sparfloxacin 
20 hours (16-30) 
 
4 
Sumatriptan 
2.5 hours 
12 
 
Tacrolimus 
~34 hours in healthy; ~19 hours in 
Kidney transplant 
 
7 
Tamoxifen 
5-7 days (biphasic) 
 
30 
Telithromycin 
2-3 hr 
24 
 
Thioridazine 
20-40 hours (Phenothiazines) 
 
7 
Tizanidine 
2.5 hours 
12 
 
Vardenifil 
4 to 5 hours 
 
 
Venlaflaxine 
5 +/-2 hours for parent comp. 
11+-2 hours for OVD (active 
metabolite) 
60 
 
Voriconizole 
6 hours; dose dependent 
 
 
Ziprasidone 
7 hr 
36 
 
Zolmitriptan 
2.8-3.7 hours (higher in female) 
18 
 
* Weakly associated with Torsades de Pointes and/or QT prolongation but that are unlikely to be a risk 
for Torsades de Pointes when used in usual recommended dosages and in patients without other risk 
factors (e.g., concomitant QT prolonging drugs, bradycardia, electrolyte disturbances, congenital long 
QT syndrome, concomitant drugs that inhibit metabolism). 
   
 
 References: 
1. Physician’s Desk Reference 2002 
2. Facts and Comparisons ( update to June 2005) 
3. The Pharmacological Basis of Therapeutics 9th Edition, 1996 
 
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18.6 Appendix F:  LIST OF CYP3A4 INHIBITORS AND INDUCERS 
 
CYP3A4 Inhibitors 
HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
 
clarithromycin 
itraconazole1 
ketoconazole1 
nefazodone 
saquinavir 
telithromycin 
aprepitant 
erythromycin 
fluconazole 
grapefruit juice 
verapamil2 
diltiazem 
cimetidine 
amiodarone 
NOT azithromycin 
chloramphenicol 
ciprofloxacin 
delaviridine 
diethyl-dithiocarbamate 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin 
norfluoxetine 
starfruit 
voriconazole 
 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital  
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort (3) 
When Study Agent is co-administered with drugs classified as “substrates,” the plasma concentration of 
the substrate is high. When Study Agent is co-administered with drugs classified as ‘inhibitors,’ plasma 
concentrations of the Study Agent will be high.  When Study Agent is co-administered with drugs 
classified as “inducers,” the plasma concentration of the Study Agent will be low.   
In general, drug interactions occur significantly between substrates and either inhibitors or inducers of 
the same enzymes usually classified as “strong” substrates, inhibitors, or inducers. 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, 
Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; 
LexiComp Inc. 2007: 1899-1912.   
Only major substrates and effective inducers are listed.   
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 
(1)   Investigator’s Brochure, MK-2206. Merck.. January 2009. 
(2)  Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23. 
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(3)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249. 
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329. 
Updated on May 1, 2007 
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18.7 Appendix G: INFORMATION ON POSSIBLE INTERACTIONS WITH OTHER 
AGENTS FOR PATIENTS AND THEIR CAREGIVERS AND NON-STUDY 
HEALTH CARE TEAM 
The patient _________________ is enrolled on a clinical trial using the experimental agent 
________. This clinical trial is sponsored by the National Cancer Institute. This form is 
addressed to the patient, but includes important information for others who care for this patient.  
_________ interacts with many drugs that are processed by your liver. Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study. It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study. When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the counter 
remedy), or anything that you buy from the health food store or grocery store (herbal 
supplement).  
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you. These are the things that you and they need to know:  
• ________ is metabolized (converted in the body) by a liver enzyme called CYP3A4. 
________ must be used very carefully with other medicines that need this liver enzyme to 
be effective or to be cleared from your system.  
• You and healthcare providers who prescribe drugs for you must be careful about adding 
or removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4.” 
• Your regular prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.asp to see if any medicine they want to 
prescribe is on a list of drugs to avoid.   
• Please be very careful! Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye. They also have a generic name—it’s usually small and 
printed on the ingredient list. Find the generic name (your pharmacist can help) and look 
at the table on the back of this page. Be careful. 
• You should not take St. John’s wort or grapefruit juice with _________.  
• You should not receive steroids unless they are absolutely necessary; tell your study 
doctor if you are taking, have a prescription for, or have been given steroids. 
• You should not take drugs that affect your heart rhythm.  Tell your study doctor if you 
are taking, have a prescription for, or have been given such heart medications. 
• Other medicines can be a problem with your study drugs.  
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• You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.  
• Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you. Your study doctor’s name is _______________ 
and he or she can be contacted at _______________________.  
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18.8 Appendix H: Hypertension management tools for patients in sunitinib 
Oral Antihypertensive Medications 
Agents in bold characters are suggested as optimal choices to avoid or minimize potential drug-
interactions with sunitinib through CYP450. 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 
substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
and inhibitor 
Selective 
β Blockers 
(BB) 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x daily 
50 mg 3x daily 
CYP 2D6 substrate 
enalapril 
5 mg daily 
10-20 mg daily 
40 mg daily 
CYP 3A4 substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used: 
perindopril 
 
4 mg daily 
 
none 
 
8 mg daily 
 
Yes, but not 
CYP450 
Rarely used: 
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin II 
Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
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valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not 
CYP450 
α and β 
Blocker 
labetolol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice 
daily 
CYP 2D6 substrate 
and inhibitor 
 
Collection/Recording of Blood Pressure Information 
1.0 
General Guidelines 
1.1          Frequency of monitoring.  Blood pressure (BP) should be monitored weekly during the 
first cycle of sunitinib therapy, then at least every 2 weeks for the duration of treatment.  More 
frequent monitoring may be considered on a study by study basis, particularly during the first 
two cycles of sunitinib therapy. 
1.2          Data recording.  All required data should be recorded in the appropriate CRF or on the 
patient’s blood pressure monitoring diary, as appropriate.  The following data are required at 
baseline and at each subsequent assessment: 
• Assessment date and time 
• Pulse 
• Systolic and diastolic BP (2 readings/assessment taken 5 minutes apart while patient 
sitting) 
1.3         Risk factors for hypertension (assess and record data in baseline history/physical CRF) 
• Diabetes (type 1 or type 2) 
• Renal disease (specify on CRF) 
• Endocrine condition associated with HTN (specify on CRF) 
• Use of steroids or NSAIDs (specify all concomitant meds) 
• Underlying cardiovascular condition – specify (i.e., ischemic heart disease) 
 
2.0         Baseline data collection  (at study arm entry) 
       2.1 
All patients 
• Current BP 
• Proteinuria, if present 
      2.2 Patients with preexisting hypertension (i.e., those for whom “hypertension” is entered as 
a concomitant condition at study entry, or those who are currently receiving therapy with 
antihypertensive medication) – also record: 
• Date of HTN diagnosis (original) 
• Type HTN (essential or secondary) 
• CTCAE grade of HTN (at time of study entry) 
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• Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the following: 
- 
Antihypertensive agents taken at study entry 
- 
Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack of 
efficacy) 
 
3.0       Follow up BP data collection (during study) 
      3.1 All patients (at each clinic visit) 
• 
Current BP 
• 
Proteinuria, if present 
     3.2 Patients with treatment-emergent hypertension [defined as BP increase of >20 mmHg 
(diastolic) OR systolic BP  >139 OR diastolic BP > 90  (if previously normal or grade 1 per 
CTCAE v4) – record at time of hypertension diagnosis and at all subsequent clinic visits: 
• 
BP changes from baseline (or from previous assessment) (specify CTCAE grade 
changes) 
• 
Hypertension-related symptoms as reported by patient (e.g., headache) 
• 
Other relevant changes associated with development of hypertension (e.g., ECG 
abnormalities) 
• 
Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of currently 
prescribed antihypertensive agents 
     3.3 Patients with pre-existing hypertension at study entry – record at each clinic visit 
• 
BP changes from previous clinic visit (specify CTCAE grade changes) 
• 
Hypertension-related symptoms reported by patient (e.g., headache) 
• 
Other relevant changes associated with development of hypertension (e.g., ECG 
abnormalities) 
• 
Changes in antihypertensive medications since last assessment (e.g., dose change, 
add/discontinue drug) 
Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha 
blockers, beta blockers, diuretics, angiotension II receptor antagonists. 
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18.9 Appendix I:  CTEP MULTICENTER GUIDELINES 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
Responsibility of the Protocol Chair  
• 
The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• 
The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• 
The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• 
The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
Responsibilities of the Coordinating Center 
• 
Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
• 
 Prior to the activation of the protocol at each participating institution, an OHRP form 
310 (documentation of IRB approval) must be submitted to the CTEP PIO. 
• 
The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• 
The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
The Coordinating Center will maintain documentation of AE reports.  There are two options for 
AE reporting: (1) participating institutions may report directly to CTEP with a copy to the 
Coordinating Center, or (2) participating institutions report to the Coordinating Center who in 
turn report to CTEP.  The Coordinating Center will submit AE reports to the Protocol Chair for 
timely review.
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Audits may be accomplished in one of two ways:  (1) source documents and research records for 
selected patients are brought from participating sites to the Coordinating Center for audit, or (2) 
selected patient records may be audited on-site at participating sites.  If the NCI chooses to have 
an audit at the Coordinating Center, then the Coordinating Center is responsible for having all 
source documents, research records, all IRB approval documents, NCI Drug Accountability 
Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the 
audit. 
Inclusion of Multicenter Guidelines in the Protocol 
• 
The protocol must include the following minimum information:  
• 
The title page must include the name and address of each participating institution and the 
name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
• 
The Coordinating Center must be designated on the title page. 
• 
Central registration of patients is required.  The procedures for registration must be stated 
in the protocol. 
• 
Data collection forms should be of a common format.  Sample forms should be submitted 
with the protocol.  The frequency and timing of data submission forms to the 
Coordinating Center should be stated. 
• 
Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center. 
• 
Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
• 
Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO.  
 
 
 
 
 
 
 
 
 
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18.10 Appendix J:  Molecular Profiling Follow-Up Worksheet 
Patient Name:______________________________________________________________________
Circle: Living or Deceased
If deceased, DOD:____________________
Further Chemotherapy/Biotherapy Treatment(s)
Date of follow up:__________________________ Completed By:____________________________
Drug Name:_____________________________________________________ 
Dates of administration:
Start:___________ Stop:_____________
Reason Treatment ended: Progression / Other
Entered into database by:__________________________Date:____________________________
Date of follow up:__________________________ Completed By:____________________________
Drug Name:_____________________________________________________ 
Dates of administration:
Start:___________ Stop:_____________
Reason Treatment ended: Progression / Other
Entered into database by:__________________________Date:____________________________
Date of follow up:__________________________ Completed By:____________________________
Drug Name:_____________________________________________________ 
Dates of administration:
Start:___________ Stop:_____________
Reason Treatment ended: Progression / Other
Entered into database by:__________________________Date:____________________________
Date of follow up:__________________________ Completed By:____________________________
Drug Name:_____________________________________________________ 
Dates of administration:
Start:___________ Stop:_____________
Reason Treatment ended: Progression / Other
Entered into database by:__________________________Date:____________________________
 
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18.11 Appendix K: Tobbacco Use History Questionnaire 
 
 
 
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18.12 Appendix L: Acquisition, Storage, Interpretation and Reporting of Low-Dose CT 
Scans for Enrolled First-Degree Relatives 
 
Low-dose computed tomography acquisition parameters (adapted from NCCN Guidelines 
for Lung Cancer Screening, version 1.2012)  
Acquisition  
Small patient (BMI ≤30) 
Large patient (BMI >30) 
Total radiation exposure 
≤ 3 mSv 
≤ 5 mSv 
kVp 
100-120 
120 
mAs 
≤ 40 
≤ 60 
All patients 
Gantry rotation speed 
≤ 0.5 
Detector collimation  
≤ 1.5 mm 
Slice width  
≤ slice width; 50% overlap preferred for 3D and CAD 
applications 
Scan acquisition time  
≤ 10 seconds (single breath hold)  
Breathing  
Maximum inspiration  
Contrast  
No oral or intravenous contrast 
Ct scanner detectors  
≥ 16 
Abbreviations: CAD: computed aided diagnostics; BMI: body mass index  
 
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